Usher Syndrome Blog

The Bella Chronicles, Part II: The Search for the Source

2012-01-13T11:05:00.000-05:00

By Mark and Bella Dunning

My daughter, Bella, is thirteen years old and a good student. She has always loved going to school and was one of those kids that teachers described as a joy to have in class. She is even tempered and rarely gets upset.

So why was she crying every day before school?

In the first part of this series I wrote about Bella’s history in detail and why it was such a surprise that she was suddenly having problems in school. In this post, I will write about our search for the source of her problems.

One more quick point: I worked on this post with Bella. I wanted to make sure she was comfortable with the content, and, in truth, it gave me a chance to check in with her. I wanted to make sure we hadn’t missed anything, but also Bella’s answers and her reaction were telling. She liked the idea of having input on the article, so you’ll see her name in the byline. I wrote it but she read it and contributed, too.

So what was the problem?

Our first thought was bullying.

This is Bella’s first year in middle school. Girls are tall and gangly. Boys are getting their first whiff of testosterone. Everyone is self-conscious and some try to point out the faults of others to distract from their own.

Bella would seem an easy target. She is different. Though she is blond and beautiful, she has Usher syndrome. She wears cochlear implants and glasses. She can be clumsy and has problems seeing in low light. The school has made accommodations for her, which is good but which sometimes make her stand out. She doesn’t have to attend gym. She has an FM system in class. There is a hand mike that the kids pass around when they ask questions.

Bella’s middle school is a regional school. Six elementary schools come together there. The grade school kids in Bella’s old school have grown up with Bella. They have been passing the hand mike since before they can remember. There was always a kid in class with cochlear implants. To them it was normal. But to the kids from other schools it had to be different. Were they picking on Bella?

When I asked Bella, she made a face that said the very idea was foreign to her. “The kids treat me like all the other kids,” she said, as if that were expected.

But were they embracing her?

That was the next idea. Was Bella simply lonely? The other kids were not picking on her, but perhaps they were isolating her. She is thirteen and thirteen-year-olds swirl with hormones. All the kids want to be the same and Bella is different. What if she was feeling left out?

Having Usher syndrome can be very hard socially. The hearing loss is the hardest part. Kids miss out on pieces of conversations. They hear the other kids laugh but they missed the joke and it’s awkward to ask to have it repeated. Often they tire of straining to hear the conversation, so they don’t bother any longer. They just laugh when others laugh and agree when others agree all the while slowly glazing over. Everyone gets up to go somewhere they all agreed to go, but the kids with hearing loss stays, not sure of the destination or the invite.

Some kids with hearing loss take the opposite approach. They hijack the conversation. If they are always the one talking then they always know what is being said. But that, too, can be socially isolating. Kids tire of the one man show and make plans that don’t include the kid that talks too much.

In middle school there is no recess. Socializing occurs in the cafeteria. The cafeteria is constructed like a hangar, with high ceilings, tiled floors, metal appliances and folding tables. It’s built for cleaning up after four hundred sloppy students, not for acoustics. Bella couldn’t hear a thing. So the school allowed Bella to have lunch in a conference room next the nurse’s office. They thought Bella could invite a friend or two to lunch so she could be involved in the conversations.

Bella brought nine kids with her the first day. Social isolation was not her problem.

“The nurse’s office is good,” she says, “I can hear everybody. I can see everybody better because in the cafeteria it’s darker. And my friends don’t mind going to the nurse’s office for me. They think it is fun.”

In the background of all of this, the Penn State and Syracuse abuse scandals were playing out. So another possibility was more sinister.

Was Bella being abused?

Let me take a moment to say Bella is NOT being abused and we have no reason to suspect she is. But when Bella was behaving in a way that is completely out of character, we had to consider all sources, no matter how unlikely, especially knowing what we know now about places like the Catholic Church (we’re Catholic) and Penn State. Being deafblind, beautiful, and innocent might make Bella an inviting target.

So we tried to think of places where Bella was alone with adults or older kids. There weren’t many. The only place where she was alone for any significant time was the farm where she rides horses and that didn’t fit the profile at all. Bella wanted to go the farm. It had been Bella’s oasis during her tough time at school. It was the one place she wanted to go more than anywhere else. This was not a kid afraid of abuse. On the contrary, this was her sanctuary.

When we hinted at the farm as a source of concern to Bella, she again thought we were crazy. “Everybody over there knows me and they are all good people,” she said, “They take care of me. They would never hurt me.” The farm remained above reproach in her mind and remains there in ours as well. We’re lucky to have it.

When we further examined her schedule, we couldn’t find any other time or place where even the most opportunistic abuser could have been alone with her.

No, Bella was not being abused.

Maybe it was the opposite. Maybe Bella was in love.

Was Bella having trouble with a boyfriend?

“Daddy!”

Uh, no. She was not. Bella does not have a boyfriend. She is open and honest, if a little shy, about her crushes.

“You’re embarrassing me!” she said.

We asked if maybe there was a boy she liked who didn’t like her back. Or maybe a boy who she thought liked her who later gave her the cold shoulder. We probed every angle of puppy love to see if we could find evidence of a broken heart. But Bella still likes horses more than boys, for the moment. (“Horses or boys?” I asked. “Horses. Not even close.”) That will change at some point. It just hasn’t yet.

A lot will change for Bella in the next few years. She is full on into puberty now. Her body is changing and the hormonal shifts are startling at times. I have been writing for years about my phobia of having a thirteen-year-old daughter. Well, the time has arrived and it is everything I dreaded and nothing like I imagined at the same time.

There was a point this summer where I feared for the life of my ten-year-old son. His mere scent was enough to ignite the normally placid Bella. And, of course, being a younger brother, he took every opportunity to set her off. She was his own personal firecracker and he lit the fuse every chance he got.

On the flip side, Bella has moments of maturity that are just as startling as the moments of fury. You can hold a thoughtful, adult conversation with her now as this post can attest. At a party on New Year’s Eve, she didn’t go downstairs with the kids right away. She sat at the table with the adults until the topics became too boring (which was pretty quick).

So maybe it was just the hormones and puberty themselves that were the cause of Bella’s problems.

Bella has had her highs and lows with her entry into adolescence, but that’s why we ultimately dismissed it as the cause. Puberty is peaks and valleys, yet her problems with school were a constant. She got upset every morning. Hormones may have been contributing, but they were not the cause. The problem was too consistent.

There was one other possibility that we examined and quickly dismissed. Maybe Bella was just faking it. Maybe she had decided that she preferred to be home and had learned that if she made enough of a scene, she could eventually get sent home.

Was Bella purposely crying her way out of school?

As I wrote in the last post, she was clearly feigning illness to get out of class, but that’s not what I mean by purposely crying her way out of school. I don’t mean she was so scared or upset that she didn’t want to go. I mean what if she was NOT really scared or upset but instead had decided she preferred being home and was pretending to be scared and upset so she could stay home and play video games or watch TV or do something else. What if she just wanted to play hooky?

This feels almost crazy to write if you know Bella. It’s completely out of character for her. Indeed, nothing brought a more vigorous denial from Bella than the suggestion she was faking it. She got upset to a degree rarely seen.

“You always make me feel like I’m faking it and I’m NOT,” Bella said, “I like school. I want to learn stuff. I’m not like Jack.”

Jack is her little brother and he agreed with a twinkle in his eye as he played his video game that he would fake it. All kids are different. Bella is a kid with a real problem at school and the suggestion that she didn’t have one sent her to an extreme level of frustration. No, Bella was not faking it just to get out of school.

So what was the problem?

Well, it’s complex but it comes down to two things. Bella does not have a relationship with her teachers this year. It’s not a bad relationship or a good relationship. It’s no relationship. Because she has no connection with her teachers, Bella is uncomfortable advocating for herself. As a result, she has gotten increasingly frustrated at school. Finally it reached the boiling point and spilled over in tears.

Having Usher doesn’t help. She assumes she is missing information. She assumes she is having a harder time than the other kids. These points are probably fair. She does miss information and have a harder time. But she also assumes that means she is doing worse in class than the other kids. She is not. In fact, she’s a solid ‘B’ student which in this school really is above average. Given her situation, that’s quite remarkable. I’ll go in to the advocacy problem more in a future post.

But here’s the second issue. Bella puts a lot of pressure on herself. That is in part because she is very empathetic and wants to please others. It also has its roots back in San Diego at the Classy Awards and right here in the blog. Not many kids have numerous blog posts dedicated to them or are recognized as they walk the streets of a city on the other side of the country. Bella knows that a lot of people look up to her and she doesn’t want to let them down.

“I feel like everyone is disappointed in me,” Bella said, her eyes glistening.

That’s my fault and it will be the subject of the next post.

The Bella Chronicles, Part I: The Symptoms

2012-01-05T13:31:00.003-05:00

by Mark Dunning

I haven’t been very active in writing for this blog recently. There are a lot of reasons involved, but the biggest has been my daughter, Bella. She’s been having a tough time. I have spent a good amount of time trying to help her, which is part of the reason I have not written lately. But her problems have also shaken my confidence considerably. It’s hard to feel worthy of sharing your knowledge about Usher syndrome and parenting when you feel like you are doing a lousy job.

Bella’s life is a frequent topic in this blog, in large part because without her, there is not blog. But she also provides very relevant subject matter. She is, in a lot of ways, a success story. Her vision hasn’t changed noticeably in several years. Her grades are on par with her hearing peers. She has lots of friends. She is a model Usher kid. It seems that everything is going great.

Except, it isn’t.

Until recently, Bella cried every day before she went to school this year. Every day. When she was in school, she had trouble staying in class. She has been to the nurse’s office 50+ times this year. This is completely out of character for her and extremely puzzling to all that know her. Clearly, something has gone wrong.

Over the next several posts I want to take you through the whole story because I think it will be valuable for other parents to hear it. You can learn from what we did right and what we did wrong. But let me set your mind at ease up front. The source of Bella’s problems at school are nothing sinister. There is no abuse or bullying or anything untoward. She’s just a 13 year old girl going in to middle school who happens to have Usher syndrome. That’s enough of a reason for her to have a hard time in school and that’s the point.

Bella attends a mainstream public middle school. She is profoundly deaf, but she has two cochlear implants. She understands sign language, but has chosen to use spoken English primarily for communication. She speaks nearly flawlessly, with no deaf accent, though she does still struggle with some words (which her little brother takes great joy in pointing out).

Bella has always loved school. She has been popular with the other kids, active socially, and a solid ‘B’ student. She rarely complains about homework and has always been quick to advocate for herself. Her situation has required some accommodations, of course. She still attends speech therapy sessions in school, though it is mostly for vocabulary preview at this point. Given her vision and balance issues, she does not attend gym. She rides horses regularly so we are not worried about her fitness. She uses the period when she would have had gym for either speech therapy or as a study. Often she gets help in the study with material she may not have understood in class.

Socially, Usher syndrome can be isolating at times, but Bella has never had a problem making friends. She has always been comfortable explaining to people that she is deaf and asking them to repeat something she missed. She has friends who are happy to guide her in situations where she has difficulty seeing. The cafeteria can be loud and difficult for a kid with hearing loss, so the school has made an effort to accommodate her socially by offering up a conference room in the nurse’s office for lunch. They expected Bella to invite a friend or two to join her there. Nine kids showed up. Bella is not short of friends.

She has some of the best professionals in the world involved in her education. Honore Weiner and Tracy Evans Luiselli have (sorry ladies) several decades of experience educating kids. Honore is currently the Education Director of the Decibels Foundation and spends her days consulting with multiple school systems on how best to accommodate kids with hearing loss. There’s no one better at what she does. Tracy is the Director of the New England Center Deafblind Project. She has spent her career helping families deal with Usher syndrome, particularly kids in school. Again, there is no one better at what she does.

Honore and Tracy have followed Bella for years and have spent hours working with her teachers to address Bella’s needs. For the most part, the teachers have been very receptive of the advice. Her school seems to be genuinely interested in accommodating her needs. Occasionally the bureaucracy is slow in delivering, but there has been little pushback about giving her what she needs to do well, both in terms of scheduling and technology.

At home, my wife, Julia, and I are actively involved in Bella’s life. Julia works at the Minuteman Arc Early Intervention Program for Children with Hearing Loss so she spends her day working with kids with hearing loss. I’m the Executive Director of the Coalition for Usher Syndrome Research. We have access to most of the world’s experts on the disease. We have many friends with Usher and we work closely with professionals who help kids with Usher in school. So we as parents are well versed in the issues facing a kid with Usher and hearing loss.

Bella herself is well versed in her condition. She has worked with mobility specialists and has been trained on how to advocate for herself, which historically she has done quite well. (Too well at times. She’s a big advocate for herself around the house when it suits her.) Finally, she has attended several Usher Syndrome Family Conferences where she has made many friends and has learned a lot about the condition.

Bella has been actively involved with the Decibels Foundation for many years. Julia and I founded the organization so her involvement was not voluntary, but she seems to have enjoyed it. She is always asking about upcoming events and genuinely likes working with the young kids in the program. As I have written before, her sixth grade class ran an event for the Decibels Foundation last winter for which they received national recognition. Bella was very proud of her class and her friends, but looking back, it was also the first sign of trouble.

The Classy Awards were held in San Diego in early September. We live outside of Boston so we had a long flight. We left on a Thursday so Bella missed two days of school. It was early enough in the year that there was not much content being discussed. It was mostly orientation. She got the homework and was able to finish it on the plane. The missed time seemed unlikely to put her far behind.

The event in San Diego was attended by several hundred people and they all stayed in the same few hotels. So when we walked through the lobby or along the streets in the area, Bella was often recognized by people she had never met. This isn’t all that new to her. As I said, she is actively involved with events for Decibels and is well known in the Usher community. She is used to being greeted by people she has never met before. Still, she was a minor celebrity and I needled her about being famous.

Her reaction was not what I expected. Bella has always been buoyant and even tempered. She doesn’t get rattled and always maintains her sense of humor (well, unless her little brother is involved). But that wasn’t Bella in San Diego. She was not excited about her celebrity or embarrassed by it, the two most logical reactions. She wasn’t overwhelmed, either, though that would be understandable, too. Instead, she just seemed weary, as if she were carrying a great burden.

“I don’t want to be famous,” she said one evening with such sad conviction that I promised her she would never have to attend another event unless she chose to. She’s thirteen, I told her, and old enough to make those decisions.

When we got home, Bella came down with a heavy cold. She missed another couple of days of school. She was probably fighting it in San Diego, so that seemed to explain her weariness. When she was healthy enough to go to school, things figured to go back to normal.

But they didn’t. The school nurse called. Bella was complaining of stomach pains. She was sent home. This is worth noting because Bella gets stepped on by horses and doesn’t cry. Bella didn’t blink (literally didn’t blink) when she got her ears pierced earlier this year. She once spent the day gallivanting at her grandmother’s house then collapsed in the car when we took her home. We went straight to the doctor and found out she had pneumonia. In other words, when Bella says she’s sick, it’s usually serious. So the next day when she didn’t want to go to school, we kept her home.

But the following day brought more of the same. We forced her to go to school, but that brought another call from the nurse. You see the pattern. Headaches, stomach aches, earaches, sneezes, sniffles. Anything and everything was a reason to go to the nurse. Or, rather, to leave class.

And every morning she had a reason she couldn’t go to school. Tears flowed. We coaxed her encouraged her, yelled at her, and ordered her. She dropped Spanish because it was too hard (which it probably was). She wanted my wife to drive her to school instead of taking the bus. She wanted to change her schedule. Math was too hard. Social studies was too hard. She said the teachers didn’t like her. She spent hours with the guidance counsellor, missing class time.

Bella, this little girl who had always been a success story, a model for what a child with Usher syndrome could accomplish, was falling apart. Worse still, we couldn’t figure out why. In the next post, I’ll take you through our search for a reason.

The Anxiety of Deliverance

2011-12-20T13:51:00.000-05:00

A Poem by Mani G. Iyer

Editor's Note: Jennifer and Mark will be back after the holidays. Mani G. Iyer was born and raised in Bombay, India and has lived in the United States since 1985. He is deaf-blind due to Usher Syndrome. He became deaf by the age of 4, night-blind by the age of 12, and now has very little usable vision

A whole fifteen minutes left
what if he shows up early
has the time wrong
left already, after waiting
the classical music wafting
through the waiting room is sombre
let’s get out.
Begin the descent
Be careful
the stairs are not blind-friendly
use the right mobility techniques
remember the instructor’s admonitions
damn it, overstepped the last one,
pause.
A sweet-scented voice’s offer for help
humorously refused
blaming it on the instructor’s ghost
these stairs have treacherous depths
easy, easy, you can’t afford to fall
Ah, some light down below
wait, wait, the rails start one step late
stoop down to touch it
which bloody blind man designed these stairs?
The cane slips
rattles down in flight
panic
hold your lifeline
one sure step at a time
is that sweet-scented lady anywhere near
ah, the bottom at last.

Get down on the knees
not in prayer of gratitude
grope for the cane
finally,the doors to freedom
wait inside
no, go outside
advertise your blindness
close to the door, though,
in case it rains.
The air is invigorating
where is he
he surely can’t miss the cane and the dark glasses
what if he is expecting a wheelchair-bound pickup
make a decision, quick
The watch talks
five more minutes
sounds and voices everywhere
a car door slams
no one is approaching
smell more scents of women
snatches of conversations
boyfriends and vacations,
can’t grab their attentions.
Finally, a man’s attention
ask if he can see a white taxicab around
sorry, none in the vicinity
panic
call the wife or friend,
warn them to get ready
wait for a few more minutes.

Check the time again
one minute late
action required
call the dispatcher
bypass the automaton
speak to a human
frustrating apologies and music
finally the dispatcher
a pronouncement
the driver is on time and is on his way
furtively scan with neck
A minute later,
a voice
“Sir, are you looking for the ride”
“Yes, yes”
a handle of an elbow magically appears
grab it
walk to the gaping car door
plonk into the passenger seat
He ignites the engine
"Was the wait too long?”
“Yes, but I enjoyed some fresh air”
“I am sorry you can’t see, but
it is a beautiful day”.

The Cane

2011-10-19T09:30:00.002-04:00

by Mark Dunning

“The only thing we have to fear is fear itself.” – Franklin Delano Roosevelt

It’s hard to believe that I am afraid of a white folding piece of aluminum, especially when there’s a little rubber ball on the end of it or maybe a tennis ball. Yet the cane scares me and it should scare you, but not for the reasons you think.

I was walking with a friend of mine one warm summer day along the crowded streets of Boston. She held my elbow as we were bumped and jostled by the business people racing to lunch and back. After a minute of excuse me’s and dirty looks, she stopped and unfolded her cane.

“I don’t really need it right now,” she said, “but it clears the streets.”

So it did. The stream of people parted and we walked hassle free. The cane, it turns out, has an unmatched power to divide.

And that’s the problem.

Walk with me for a moment and I’ll explain. See, we want treatments for Usher syndrome. To develop treatments we need lots of researchers doing lots of work. That costs lots of money. The best large funding source out there is the National Institute of Health. The NIH is a governmental agency that, while it is independent of Congress, certainly heads the wishes of the Congress. If enough members of Congress tell NIH to fund a certain project, NIH will fund that project. So for us to get substantial funding for Usher syndrome research from NIH to pay for lots of researchers to do lots of research, we need members of Congress to tell NIH to fund Usher syndrome research.

Members of Congress work for you. You elect them and they act on your behalf. The reason they have not asked NIH for more funding for Usher syndrome research is because we have not done a good enough job of letting them know that we want them to do that. We need everyone with Usher syndrome to work together to encourage Congress to push NIH for Usher syndrome research funding.

Recognizing that fact, we have been working to build an Usher syndrome community. We want to identify everyone with Usher syndrome, educate them on what it will take to find treatments, then enlist their help lobbying Congress for increased NIH funding (among other things). As part of that effort we have developed a Family Network to connect families and have been running annual Family Conferences to further build that Usher syndrome community we so desperately need.

Enter the cane.

Parents of young children fear the cane. Adults who’s vision is still good fear the cane. It’s not the painted aluminum they fear, obviously, but what it represents. To them it is a frightening future of limitations and loneliness. They don’t want to see anyone using a cane because they might glimpse the difficulties ahead. They don’t want to meet anyone using a cane because they might learn how this person was once happy and free and then, when the cane arrived, they turned miserable and downtrodden. The cane, to families not using the cane, is the very symbol of the fear they try so hard to control so they avoid it. They don’t want to know the truth about it because the truth might be even worse than they fear.

People who use a cane know that. They feared the cane themselves. They fought against it and dreaded the time when they would need it. They know that people look at them with their cane and make assumptions about them. They also know that the cane rather than closing doors, often opens them. The cane is a source of mobility and comfort. The cane parts crowds and allays fears. Oh sure, everyone using a cane would rather not have to use one, but given the alternative, it’s a big help. But they understand why people might fear the cane. So they avoid people who don’t use the cane because they either don’t want to upset them or they don’t want to try to explain its benefits to someone near panic.

As I said, the cane has an unmatched power to divide.

We see this all the time with the family network. Families of young children don’t want to be contacted by adults with Usher, adults who might use a cane. Adults who don’t use the cane don’t want to be contacted by adults who do. Adults who do use the cane don’t want to get involved, don’t want to invite tough questions, and don’t want to be treated with gentle fear just because they carry a piece of folding aluminum. Now none of these folks openly say that they don’t want to be contacted. They just don’t join the network or they do join but don’t contact people on the other side of that thin white line.

We see this all the time at family conferences, too. In the morning you’ll find groups of people who use a cane and groups of people who don’t.

“I shouldn’t be here,” a friend who uses a cane said to me at the last family conference, “I’m scaring people.”

“I shouldn’t be here,” a friend who has Usher but does not use a cane said to me at the last family conference, “I keep staring at the people with canes and I think I’m embarrassing them. I can't help wondering if that will be me.”

Of course, you know where this story goes. My two friends eventually met each other. Cane and No Cane. No Cane had just recently had to give up driving. Cane understood. He remembered how hard it was for him at first. No Cane met Cane’s wife, learned he had two happy, successful grown children. She felt better about her future. Cane offered advice to No Cane. He felt better about attending. For once, having Usher was a good thing. He wasn’t scaring people. He was helping people. Cane and No Cane frequently trade e-mails and advice now. They are part of the same community. That’s exactly what we need.

Look, I understand the emotions involved. I fear the cane, too. I don’t want my daughter to ever have to rely on one. I want to find treatments that make the cane unnecessary. But more than that, I fear the cane’s power to divide. Usher syndrome research is woefully underfunded because we are not a strong community and therefore not a strong lobby. And it’s our fears that are the biggest obstacle to changing that.

Usher syndrome, part III: The Plot Thickens

2011-10-06T11:45:00.001-04:00

by Jennifer Phillips, Ph.D.

The time has come to delve into the retinal component of Usher syndrome. In Part II, I briefly described the results of protein localization studies, in which most members of the Usher cohort were found at the connecting cilium of the photoreceptor and at the photoreceptor synapse. The following diagram summarizes these findings:

Adapted from Reiners et al, 2006. Colored blocks show subcellular localiazation of the various Usher proteins in photoreceptor cells. Colocalization is densest in the region of the connecting cilium (CC) and the synapse (S). Other abbreviations: BM: basement membrane; RPE: retinal pigmented epithelium; OS: outer segment; IS: inner segment; N: nucleus.

So, as we saw in the ear, the proteins with the equipment for physically interacting with one another are gathering in specific places, and thus multi-protein complexes are most likely to be formed at these locations. The cluster of Usher proteins around the connecting cilium has been the focus of most of the current retinal studies, and to understand the potential importance of an Usher complex at that subcellular location we must address the importance of the connecting cilium itself.

Recall the structure of the photoreceptor cell described in Part I. The inner segment, just above the nucleus, contains all the standard-issue cell operating equipment: specialized molecules required for producing protein, degrading cellular waste products and performing various other metabolic functions. The outer segment contains the intricately folded membrane discs with which light sensitive molecules are associated. Between these two cellular compartments lies the connecting cilium, which grows out of the inner segment, extends up into the outer segment, and is surrounded by a structure known as the periciliary ridge, which encircles the connecting cilium like a little cuff. The cilium serves as a functional connection between the inner and outer segments, as well as a structural one. Proteins and other cellular materials synthesized in the inner segment need to get to the outer segment in order to perform their particular jobs up there, and materials that are no longer needed in the outer segment need to be carried away and dealt with in the inner segment. The connecting cilium acts as a transport system to which motor proteins can anchor and pull their molecular cargo up or down as needed.

The localization studies of the Usher proteins reveal that many of them are in the vicinity of the connecting cilium, but a closer look at this region of the cell shows that they are specifically either in the periciliary ridge (the ‘cuff’) or the space between the periciliary ridge and the connecting cilium:

Adapted from Märker et al, 2008. Panel B shows a cutaway side view of the connecting cilium (CC) and surrounding terrain. The ‘peninsula’ (marked with a * near the top) shape to the right of the CC and beneath the outer segment (OS) is the structure known as the periciliary ridge. Panel C shows a top-down view of this same region, in which the periciliary ridge is depicted as a crescent shape that wraps around most of the circumference of the CC. In both panels, colored shapes depict the various usher proteins that are hypothesized to provide structural and functional links between the CC and the periciliary ridge. Other Abbreviations: MT: microtubules.

Thus, the model for Usher protein function in the retina is that these complexes somehow assist in the cilium-based transport system. Here’s where things get a bit sticky, though. As most of our readership knows all too well, unlike the congenital nature of the hearing defects in most forms of Usher, the retinal symptoms don’t manifest all at once. Rather than being diagnosed at birth, vision loss usually isn’t noticed until a few years later—sometimes not until adolescence. Furthermore, they progress quite slowly, well into the third decade of life in most cases. How can the same defective proteins that cause such significant developmental problems in the hair cells not cause early problems in the retina as well?

The congenital deafness in human patients and mouse models of the disease, and the defects in stereocilia formation seen in the Usher mice are nicely explained by the model of protein interaction and function in the developing hair cells, discussed in Part II. The retinal cells, however, appear to develop normally and apparently function normally until they begin to degenerate. I say ‘apparently’ because the ‘pre-death’ state of the photoreceptors has been difficult to observe thus far. Historically, the first sign of a problem in human Usher patients occurs when the hearing-impaired child or teenager begins to experience night blindness due to a loss of rod photoreceptors in the periphery of the eye. By the time of this first clinical exam in such cases, the degeneration is already well underway. Fortunately (from an investigative point of view, at least) this is changing with genetic screening and early identification of Usher patients, but even with earlier eye exams it’s still not at all clear what is going wrong in the retina at the molecular level.

At this point you might well ask what clues the Usher mutant mice, which proved so valuable in adding to our understanding of the disease progression in the ear, can tell us about the events leading up to retinal degeneration. To our great consternation, most of the originally identified Usher mice do not undergo retinal degeneration at all! A number of these mutant mice have been examined expectantly until the end of their natural lives (around 2 years) and most do not exhibit any abnormality in their retinas. The exceptions to this are older mice with mutations in the Cadherin 23 (ush1d) gene, which show a slight reduction in visual function older ages, and Myo7a (ush1b) mutant mice, which exhibit a fairly distinct defect in moving proteins around in the retinal pigmented epithelium. Neither type of mouse shows any retinal degeneration.

Several theories have been put forth to explain this discrepancy between the mouse and human forms of the retinal disease. One possibility is that mice, being nocturnal animals and usually raised in low-light laboratory conditions, may not endure the bright light exposure that human retinas must withstand. Another explanation may lie in the slow, progressive nature of the human disease and the relatively short life cycle of the mouse—perhaps two years just isn’t long enough for the retinal defects to manifest in the mouse retina. A third theory centers on the fact that all of the known Usher proteins actually exist in multiple variations—the genetic code that specifies each of these proteins can be cut and spliced in a few different ways, giving rise to similar, but not identical protein products. The exact roles of the different isoforms of every gene aren’t yet clear, but some of them do appear to be more important in the ear than in the eye. It’s possible that the mutations in mouse Usher genes that give rise to such a strong ear phenotypes don’t affect the part of the protein that’s important for retinal cell function, and thus the mouse is spared the vision loss that characterizes the human disease. In further support of this latter theory is that fact that many of the Usher syndrome genes are also linked to non-syndromic deafness in humans—hearing loss without associated blindness.

None of the above theories are mutually exclusive, and it may turn out to be a combination of genetics, environment and life span that has limited the retinal phenotype of these Usher mutant mice. Encouragingly, excellent progress has been made through the use of genetically engineered mice, in which an Usher protein is removed completely (see knockout mice for more on this technique) or, alternatively, a targeted mutation is introduced into a particular Usher gene that renders the encoded protein non-functional. Thus far, these genetically modified mice show late-onset retinal degeneration (I’ve blogged about two such strains previously, here and here) and are providing important new avenues for therapeutic research. In these mice, therefore, we have a more complete model of Usher syndrome, although the retinal degeneration still appears to initiate later in mouse development than in the corresponding human lifespan. Moreover, as useful as these new strains have been, the Knockout technique isn’t foolproof. Knockout mice for at least two Usher genes (Ush1c and Clrn1) have not displayed significant retinal degeneration in any studies published to date.

In short, there are still a great many unanswered questions surrounding the pathophysiology of Usher syndrome, particularly with respect to the retinal phenotype. To complement the data being collected from the mouse models, myself and other scientists have investigated various Usher proteins in the zebrafish. There are some differences in the retinal anatomy of zebrafish and humans, but basic cell structure and function is conserved between the two species. Additionally, there are some similarities that make zebrafish an especially appealing organism for this type of study, including the fact that fish are diurnal animals with rich color vision--even better than humans, in fact, as they can see light in the ultraviolet range of the spectrum. Other advantages to using zebrafish are related to their development. Zebrafish embryos undergo fertilization and development outside the mother’s body, and usually several hundred embryos are produced from a single mating. They develop rapidly and are able to swim, see and hear just a few days after fertilization. Thus, we can conduct vision, hearing and balance tests within the first week of development and obtain results quite rapidly to learn more about the consequences of losing Usher gene function.

Understanding the cellular events that precede the death of these cells will be crucial in identifying ways to improve diagnosis and treatment of Usher syndrome. In the conclusion of the Usher story, I’ll discuss current clinical practices for managing Usher syndrome, and the direction of the research efforts designed to enhance these treatments.

Where Have I Been?

2011-09-29T08:55:00.001-04:00

by Mark Dunning

My apologies for not posting recently, but I have excuses (yes, not a single excuse, but multiple excuses).

Excuse #1: The Usher Syndrome Registry
Back in January, I wrote about the need for an Usher syndrome registry and what it might look like. The gauntlet was picked up by a gentleman with Usher syndrome who was also a programmer. He and a few others (including me) have been working to design and build the registry and bring it online. We’re getting close and in the last six weeks or so began the first rounds of testing the site. We’ve gotten feedback on the bugs and have gratefully accepted the pro bono assistance of a law firm to pull together the legal language and disclaimers for the site. We hope to launch in the next six to eight weeks, which is exciting but time consuming. Hence Excuse #1. Watch this space for the launch date and then be sure to register. We will definitely need your help spreading the word, as well.

Excuse #2: The Monthly Usher Syndrome Conference Calls
We run a monthly Usher syndrome conference call for families, care givers, and researchers. The calls are the second Monday of every month (unless that falls on a holiday) at 1:00 PM Eastern Time. Everyone is welcome to participate. If you’d like to join in, feel free to contact me for the call details. The topics change from month to month but we’ve lined up the next several speakers. It’s amazing how generous people are with their time, but coordinating the speakers takes some work. So that’s Excuse # 2.

Here’s a list of upcoming speakers and the dates in case you are interested in joining the call.

October 17, 2011
Accommodations in School for Kids with Usher - Honore Weiner, Educational Director for the Decibels Foundation and Tracy Luiselli, Project Director for the New England Consortium of Deafblind Projects

November 14, 2011
How Does Genetic Testing Work and What Does the Future Hold – Dr. Heidi Rehm, Harvard Medical School Center for Hereditary Deafness

December 12, 2011
The Impact of Genetic Testing on Families – Dr. Margaret Kenna, Children’s Hospital Boston

*Excuse #2a is that I spoke about the Coalition for Usher Syndrome Research on the September call.

Excuse #3: My Daughter, The Classy Awards, and the Decibels Foundation
Let’s see, I don’t think I’ve bragged about Bella since, um, well, since the last post. But since that was such a long time ago, it seems about the right time to do it again. My wife and I run the Decibels Foundation, which helps support the educational needs of kids with hearing loss (and, therefore, Usher syndrome as well). Last winter Bella’s sixth grade class held an inspirational fund raiser to support the Decibels Foundation. They raised $20,000 doing a roll-a-thon and the stories of their efforts, like the kids that shovelled every driveway in their neighbourhood to give money to the cause, still bring a tear to my eye.
It was frustrating when we couldn't get any of the local media to report the story.
Well, they finally got the recognition they deserved. The Classy Awards, which is a national awards ceremony for philanthropic achievement, recognized the Blanchard School’s Sixth Grade Class and the Decibels Foundation with the award for Most Successful Fundraiser by and Individual or Group. There were hundreds of entrants from around the country, so it was an incredible honor. As a result, we took an unexpected vacation to San Diego for the awards ceremony. So that’s Excuse #3.

Bella giving the acceptance speech on behalf of her class at the Classy Awards in San Diego

By the way, my son already plans on winning the award next year. We were fortunate to meet Adam Garone, one of the co-founders of Movember. If you don’t know them, they are the charity that encourages people to grow moustaches to raise awareness of men’s health issues, particularly prostate cancer. Adam told the story of how the charity started. It seems he and his buddies decided to grow moustaches each November for fun. After a couple of years, they finally tired of explaining to their wives, girlfriends, and bosses why they had that hideous facial hair so they decided to legitimize their efforts and Movember the charity was born (a ‘mo’ is a moustaches in Australia where Adam lives). Last year they had 450,000 moustaches grown worldwide and raised $81 million dollars. Yikes! Oh what we could do with $81 million dollars for Usher syndrome research.

Adam Garone, CEO and Co-Founder of Movember (and his 'stache)

The light bulb went on with my ten year old son. It’s not that he wanted to raise money so much as he has lots of socially frowned upon habits he wants to legitimize. Probably the worst is his reluctance to change his underwear.

I wrote about this once before for another blog: “We noticed a nasty smell in the house recently. We assumed it was my son. He’s taken to wearing the same pair of underwear every day. We’re going to have to scrape them off of him like paint from a window. Needless to say, Julia and I are not on board with the whole ‘wear the same pair of underwear until it decomposes on you’ stunt. In response, we’ve been ordering him to show us his skivvies every morning to ensure that he’s actually changed.

This led him to change tactics. He still didn’t change. He just kept layering each new pair of underwear on top of the old. My wife figured it out when he could no longer buckle his pants. She peeled off five pairs of fruit of the looms, like he was a tighty whitey onion.

Anyway, turns out the smell last night wasn’t Jack. It was sewage. We hope that being mistaken for a sewage backup will be enough to discourage future perma-undie adventures from Jack.”

Well, Adam and Movember took that hope. We hadn't made it back to the hotel after the ceremony before Jack had planned a “Stink Week” to raise money for kids with hearing loss by “making a stink for hearing loss.” He plans to wear the same shirt for an entire week or until he reaches his fund raising goal, whichever comes first (we convinced him to go with not changing his shirt instead of not changing his underwear). The idea, I suppose, is that some desperate teacher, tired of him stinking up the classroom, will write him a check if he promises to change.

This all seemed sort of an insincere ploy to me until I attended the open house at his school last night (Excuse #3a!). All the kids in class had written lists about what they would do if they were in charge of the world. Number two on Jack’s list was “I would take Usher syndrome away from my sister.” I now fully support his “stink week”.

In case you are wondering, number one on his list was “I would make Pokemon real” so he still has his ten year old priorities straight.

Excuse #4: Don’t Worry, the Wings of the Airplane are NOT on Fire
That comes from an old Monty Python skit where pilots of an airplane are bored and decide to mess with the passengers. Understandably, saying the wings are NOT on fire over the intercom leads to the passengers freaking out. We had a similar but far less humorous situation here on the comments section of this blog. A reader said he was told by a doctor that there was a link between Usher syndrome and cancer, which understandably caused a stir among our other readers. I spent quite a bit of time (there’s Excuse #4) asking as many experts as I could about this rumor. They all said the same thing. There is no known link between Usher syndrome and any form of cancer. So the wings are NOT on fire. You can now return to your seats.

OK, I’m now officially out of excuses. Time to go work on that next post!

Seeing Things

2011-08-22T14:00:00.003-04:00

by Mark Dunning

“I like having Usher syndrome because I have gotten to see a lot of things.” – Bella Dunning

The first place I thought of was Monterrey. The wildlife is so close there and Bella loves animals. Harbor seals sleep on the beaches, the dark pupils of their eyes visible when they blink out of the sea and flop, flop, flop ashore. Sea lions argue and wrestle like siblings on the breakwaters or bark unpleasantries at the fishermen that chase them from boat decks with hoses. The mats of kelp sit heavy on the swells just off the pier and are home to families of comical otters waving and rolling, scratching and napping.

The sky is gray in August, the mist cold and fresh. The canneries are gone replaced by colorful shops all tossed on top of one another, the usual tourist fare; chocolates and ice cream, “I’m with Stupid” t-shirts, Bubba Gump Shrimp restaurant and gift shop. Brown signs praise Steinbeck and eulogize the way things were; black cars with bald tires, tired men with cigarettes in their mouths, piles of fish still silver even in black and white photos. The aquarium sits unassuming at the end of cannery row. Inside it’s an ode to what is outside with otters and thin legged birds and blue fine tuna and sardines and sardines and sardines.

Take the Pacific Coast highway from the south. The vistas are beyond words. Thousand foot drops to the steel gray Pacific below, a rickety fence all that stands between fender and oblivion. The road crumbles in hairpins and drops and climbs up, up, up, until the ocean mist melts in to the clouds. Knuckles turn white on the steering wheel. Kids unconsciously slide toward the middle of the seat, away from the windows and the door that might accidentally flip open. Everyone giggles and gasps in awe. It has to be seen to be understood.

That’s why I thought of Monterrey when we first got Bella’s diagnosis. I thought she’d never see it. It’s a long way from the east coast where we live. It’s too far. It costs too much. I hadn’t been there in fourteen years and Bella probably never would be. She’d never see it and it had to be seen to be understood.

At the Usher Syndrome Family Conference in July, Bella sat on a panel and answered questions for the audience about what it was like to have Usher syndrome. At 12, she was the youngest of the panelists. When she was asked her thoughts about having Usher syndrome, she answered, to my amazement, that she liked having Usher syndrome ‘because I have gotten to see a lot of things.’

Now it was true that we had gone to Iowa via Chicago to visit Drs. Stone and Kimberling. We had also driven to Philadelphia to see Dr. Jacobson. And the Usher Syndrome Family Conference was in Seattle last year, so we took it as a vacation and went to Vancouver, too (long before my Bruins won the Stanley Cup there and set off riots). But I think Bella meant more than that. She meant she’d seen the leaves change in the fall and the snow piled three feet high and the hummingbird that likes to visit our daylilies. She’d seen me trying to coax another circuit around the lawn out of our lawnmower (it didn’t make it) and seen her two year old nephew bright pink with popsicle drippings. It’s something she’s learned from having me nudge her to watch life closely, to pay attention to things she might never see again. I’m no sage. I’m just a dad terrified his daughter might lose her sight. But Usher syndrome has taught her well.

See things while you can and enjoy them. You never know when you’ll see them again.

A couple of weeks ago I had to travel for business. San Francisco one week, Los Angeles the next. I took the family with me. Over the weekend we drove down the Pacific Coast Highway to Monterrey. Bella saw the aquarium, the wildlife, the vistas. She spent hours glued to the window of the car or the rail of a pier. I stayed on her shoulder, gently reminding her that she may never be back and she should be sure to take it all in.

She reminded me to do the same.

Usher syndrome, Part II: a complex molecular picture

2011-08-12T11:44:00.001-04:00

by Jennifer Phillips, Ph.D.

In Part I I gave a rough overview of Usher syndrome and went over a bit of cell physiology of auditory and visual sensory cells. In this post, I’ll introduce the molecules known to be affected in Usher patients, and begin to describe what is known about their function.

As mentioned previously, variations in the clinical presentation of Usher syndrome have resulted in the creation of three clinical subtypes. Type 1 is characterized by severe to profound congenital hearing loss, balance problems, and early onset vision loss, usually beginning before the patient’s 10th birthday. The type 2 hearing loss is also congenital, but tends to be less severe. Although the vision loss in type 2 can become as severe over time as that seen in Type 1 patients, the first symptoms usually begin to occur a bit later, in the early teen years. Finally, these patients do not present with balance problems. In Type 3 patients, all three categories of symptoms—vision, hearing, and balance, are progressive, with even the hearing loss commencing in childhood or adolescence rather than at birth.

Despite these differences, the specific combination of deaf-blindness, plus or minus balance defects, led researchers to predict that multiple mutations in a single gene, or perhaps in two or three genes at the most, would turn out to be responsible for the symptoms observed in all Usher patients. This is the case, for example, with Cystic Fibrosis. Just like Usher syndrome, CF is a recessive disease, meaning that you need two defective copies of the gene to show the disease symptoms. Importantly, even though there is a remarkable degree of variation in symptom severity, the vast majority of CF cases are due to mutations in only one (albeit extremely large) gene.

With respect to Usher syndrome, the advent of genetic mapping led to surprising results in pinpointing the genetic underpinnings of the disease. To date, at least 11 different genes have been implicated in USH, nine of which have been molecularly identified thus far. More surprising still is the wide variety of proteins encoded by the identified genes. In contrast to standard signaling or metabolic pathways, in which a genetic defect at any point in a linear chain of events will result in the same basic problem downstream, the Usher proteins do not appear to act in stepwise fashion to regulate a cellular process. What they actually do, in fact is not entirely clear, but the various proteins contain functional domains known to be important for:

scaffolding: providing a structure on which multiple proteins can convene to assemble into a complex.
cell adhesion: spanning the minute distances between a cell and its neighbor.
signaling: molecular chitchat between cells in the same neighborhood.
extracellular matrix components: proteins that confer structural support to the regions around cells.
motor activity: the job of transferring molecules from where they’re made to where they’re going to work in the cell.
membrane integration: a protein that inserts itself into the membrane of a cell, sometimes weaving in and out multiple times. Transmembrane proteins perform a wide variety of functions, so this characteristic alone tell us only where to find it, not what it’s doing.

Table of the known Usher genes and protein identities.

Structural information about the Usher proteins provide a starting point from which researchers can begin to investigate their localization within the various working parts of the sensory cells affected in Usher syndrome, their potential physical interactions with one another and, ultimately, the role of these proteins in sensory cell function and survival.

Antibodies to these proteins enable us to visualize their exact position within the cell, and such experiments show that most of the Usher proteins colocalize to the very structures that are involved in specific sensory cell function—the photoreceptor connecting cilium , the stereocilia of the mechanosensory hair cells, and the specialized, neurotransmitter-laden synapses of both cell types. Laboratory experiments with the various functional domains of these proteins have further shown that they have the ability to physically interact and bind to one another to form a protein complex.

So, what might this motley crew of proteins be doing hanging out together at these very specific subcellular locations? The function of the Usher complex at the stereocilia has been fairly well studied using mouse or rat models of the disease to examine the effects of depleting the function of any one Usher gene. In the first panel of the figure below, hair cells from the cochlea of a young mouse with no defective Usher genes are shown to have rows of stereocilia that are nicely arranged in a crescent shape, as well as consistent length, width, and orientation of the individual stereocilia. In contrast, the stereocilia of mice with mutated forms of Usher genes (all Type 1 genes in this case) are dramatically misshapen and disorganized.

from Brown et al, 2008. The top left panel shows an electron micrograph of a normal, healthy mouse cochlea. Above each additional panel, showing cochleae from Usher mice, is the name of the mutant line, chosen based on the observed behavior. Because of the balance problems, these mice tend to run in circles and toss their heads. The affected gene in each case is listed below the name.

The subcellular localization of Usher proteins in hair cells, illustrated in the schematic drawing below, provide insights to how such disorganization might come about. Usher protein localization in the stereocilia are shown at three timepoints ranging from late embryonic to several weeks postnatal.

From Brown et al, 2008. This is a cartoon of highly magnified stereocilia, just showing the relationship between two neighboring stereocilia projecting from the same hair cell. Each little colored shape represents an Usher protein or a known interacting protein. Three different developmental time points are shown, from left to right. The stereocilia on the far left represents a time spanning from late gestation to newborn, followed by representations of two additional postnatal time periods. Note that the location of and relationships between the little colored shapes changes quite a bit over the course of this two week period.

It’s important to note here that baby mice are born deaf and do not begin to hear until about the 6th postnatal day. The dynamic localization of the Usher proteins in the schematic above, in which many of them appear to move from one part of the stereocilia to another over time, serves to illustrate that even after birth there is still quite a bit of fine-tuning going on both structurally and functionally with respect to the stereocilia in the mouse. Human auditory development occurs on a different time scale (not surprising considering that mouse gestation only takes 21 days versus 40 weeks in humans); fetuses can hear sounds in utero for several months prior to birth, but it’s likely that a similar process occurs in the growth and maturation of stereocilia in human hair cells prior to the 30th week of gestation.
Thus, noting that the presence of Usher proteins is required for normal growth and patterning of the stereocilia prior to the acquisition of hearing, it is easy to understand why the hearing loss in patients with mutated copies of these Usher genes is congenital. These data also indicate that although Usher proteins may also play a role at the hair cell synapses, based on their expression there, the primary cause of deafness, at least in Usher type 1 patients, is probably due to the perturbations of the stereocilia. These changes in stereocilia structure and function can also explain the balance defects associated with the type 1 and type 3 forms of the disease, but it still isn’t clear why patients with mutations in any of the three Usher type 2 genes dodge this particular symptom.

Compared to the situation in the ear, the functional importance of Usher proteins in the retina is relatively poorly understood, but I’ll summarize the findings thus far in Part III, and then wrap up with some information about clinical diagnosis and treatment options in part IV.

The Only Certainty

2011-08-01T09:31:00.000-04:00

by Mark Dunning

Forever is composed of nows. ~Emily Dickinson

I have a friend with Usher syndrome. She worries about it. I know she does. I can see it in the way her eyes brighten when we talk about potential treatments. I can feel it in her enthusiasm for knowledge about the disease. Yet she does not live like someone who worries about Usher syndrome. She stubbornly refuses to let the future decide her present. She lives for today.

She has long been my hope for my daughter’s future. When she was young she drove thousands of miles with a vanload of friends to exotic locales, scraping by, sleeping on floors and in hostels. She lived crazy, carefree. She got her nose pierced. When she was older she fell in love, got married, had children. She travelled for her career then, dressed stylishly, pulled a rollerboard and used a smartphone. But she still has that same young smile, she still has her nose pierced. She has always been alive. That’s the best description of her. Alive. I want my daughter to be that way. I want Bella to be alive.
______________
I am training to run a half marathon. I ran ten miles this past weekend and when I finished, I felt more like a corpse than an athlete. I have never been a runner before. Just read this if you don’t believe me. The irony is that I have taken up running to escape death, rather than court it.

When Bella was diagnosed with Usher syndrome, I found myself laying on the floor in the dark, my mind racing uncontrollably into the future. In a blur she was giving up horse riding, struggling in school. Then she was out of work, living in a sterile apartment. Then she was grey haired with a cane sitting at a family outing oblivious as her brother’s kids scurried around her. Then, just like that, she was dead.

Wait a minute. She was dead? That’s it? Four sentences then dead? The diagnosis had turned out to be far more dire than I ever imagined. It was even worse when I put myself in the story. If Bella was grey haired at her brother’s party, where was I? Gulp.

I put down the Ring Dings and took up running. I did it so I could be alive to help Bella. I wanted to be there to help her find a way to keep riding horses. I wanted to kick her out of the house to go to parties and socialize and make friends. I wanted to embarrass her when she felt sorry for herself and make her go to college even if she didn’t want to. And I wanted to be at that party to see grey haired Bella smiling as her children played with her nieces and nephews.

More than anything I swore to do my best to live in the present. That is where I am content. In the present Bella can see and in the present I am alive.

People with Usher syndrome are not miserable. They are not unhappy. Oh sure, they might get frustrated with their condition from time to time, but I don’t think they curse their fortune any more than, say, the average middle-manager cubicle jockey. The distinction lies in the future. The cubicle jockey envisions a brighter future in the corner office while people with Usher tend to fear the future. They dread a darker tomorrow.

The truth is, though, that we all face a darker tomorrow. If we look too far in to the future, we’ll find that we’re all dead. Sorry, but it’s true. A thousand years from now we’ll all be dirt. But none of us look THAT far in to the future. To think a thousand years ahead would cripple all of us. We couldn’t function. We are much better served living today, trying to improve tomorrow, and not thinking about the distant future.

I often wonder why we families with Usher struggle so hard to take that same approach to the disease. It’s not like we are unfamiliar with the process. We all ignore the future to some degree. Today, we are happy and functioning. Do we really need to concern ourselves with more than that? As Albert Einstein once said “Never think of the future. It comes soon enough.”
_____________________

My friend inspired me to write this post. She always inspires me. She was recently diagnosed with cancer. I don’t write this as a eulogy for her, but I am very worried about her. I know it is constantly on her mind. I know she sees it in the mirror in the morning, in the eyes of her husband, in the faces of her children.

This is a painful irony. She has spent her life refusing to believe she would lose her vision. Now that might be true, but for the all the wrong reasons. I want Usher syndrome to be prominent in her life once more. I wish more than anything that it could be the reason she enjoys today. She has always been alive, thriving in the present. I wish she could stay that way forever. She is my hero. I want my daughter to be just like her.

I want her to be alive.
______________________

EDITOR'S NOTE. My friend passed away a few weeks ago. She never lost her vision to Usher syndrome. Somehow that doesn't seem to matter at all.
-Mark

Usher syndrome Part I, 2011 edition: An introduction to sensory perception.

2011-07-25T10:33:00.000-04:00

by Jennifer Phillips, Ph.D.

Note: this is the first of a four-part installment on the science of Usher syndrome. This series was posted on the Usher Syndrome Coalition Website and the ScienceBlogs network a few years ago, but given the amount of specific Usher science we discuss here on our blog, it may be helpful to readers to have these resources ‘in house’. Part I gives an overview of hearing and vision at the cellular level, parts II and II discuss the known Usher genes and proteins, and their proposed roles in the eye and ear, respectively. Finally, Part IV brings all this cellular and molecular information back to the clinical level, and includes a survey of current and future research directions. Understanding how the human body works, and what goes wrong in any given disease, has value in and of itself. But for those of us hoping and striving for a treatment, a better understanding of the biology of Usher syndrome will be necessary for understanding how potential therapies might work.

Usher syndrome is a genetically recessive condition characterized by hearing impairment--usually from birth--due to defects in the sensory neurons of the inner ear, and vision loss due to retinal degeneration, which begins to occur in childhood or adolescence and progresses through several decades. Additionally, some Usher patients have balance problems associated with the sensory cell defects in the ear. There is a great deal of variation in the clinical presentation of the disease, and three clinical subtypes can be classified by the severity and age of onset of the symptoms. The latest estimates project that Usher syndrome affects about 1 in 6,000 people.

To begin to understand the pathology of this disease, one needs to focus on the affected cell types: Mechanosensory hair cells and photoreceptors. Both are highly specialized types of sensory cells, but they’re performing essentially the same function, namely receiving an environmental stimulus and converting it into an electrical signal that is transmitted to the brain for interpretation. Although the nature of the stimuli—sound and light—are quite different, they are processed in much the same way, and thus it is not surprising to find a number of structural and functional similarities between photoreceptors and hair cells.

Figure 1: comparative anatomy of a photoreceptor cell (A) and a mechanosensory hair cell (B). The Outer Segment (OS) membranes of the photoreceptor are similar in form and function to the stereocilia (SC) of the hair cell. Both cell types contain cilia (labeled CC [connecting cilium] in A; KC [kinocilium] in B) and have specialized synapses (S) through which signals are sent to second-order neurons (‘2nd’, labeled in A; supporting cell projections can be seen at the bottom of the cell in B).

Sensory neurons are constantly stimulated with a complex array of information. Photoreceptors respond to all wavelengths of light within the visible spectrum as well as transmitting information about total light levels and movement. Mechanosensory hair cells can not only respond to physical contact by sound waves, they transmit information detailed enough to determine whether the sound waves in question were generated by a lover’s whisper, breaking glass, or a bow being drawn across the strings of a cello. In order to intercept and convey information at this level of specificity, sensory cells have evolved specialized structures to meet the high demands of both input and output. On the receiving end are intricately organized membranes built to respond to the environmental signals. In photoreceptors, the outer segment contains stacked discs filled with opsin proteins, (remember those?) that trigger a cellular response when activated by light. In the hair cell, the sterocilia (not actually “cilia” at all, but finger- like projections made of the protein actin) move when they encounter sound waves, opening channels through which ions can enter the cell and initiate a response.

On the outbound side of things, these sensory neurons have a mechanism by which they can adequately relay the complexities of the environmental input they receive. In physiology 101, we learn about the classic type of neuronal response, in which the nerve cell needs to reach an action potentials to fire. Basically, these nerves are in a state of rest until they are sufficiently stimulated to elicit a response. Even though these responses to stimuli, such as a command from the brain in the case of motor neurons, or stepping on a sharp rock in the case of pain receptors, are fast, they are usually a simple binary, on/off type of response, and tend to be short lived.

The constant bombardment of information that our sensory cells endure is something along the lines of the chaos of the trading floor of the New York Stock Exchange, 24/7. A conventional neuron relying on action potentials to convey this information would be woefully overmatched in such a situation because it just wouldn’t have time to ‘reload’ under such constant stimulation, nor would it be able to convey the specificity of information in the light or the sound stimulus receiving. Instead, photoreceptors and hair cells keep stockpiles of neurotransmitters tethered to the cell membrane. When the cell is stimulated by the environmental signal, no action potential needs to be achieved. Multiple neurotransmitters are right there, ready to be released, and, unlike a typical neuron, these sensory cells can be active in the long term—for as long as there is a stimulus to report. When these cells release neurotransmitters, they activate neurons waiting nearby to,pass the message through additional channels leading to the sensory processing centers of the brain. The downstream message processing is far too complex to describe here, but the important thing to remember is that the message originates from these specialized sensory cells. They’re responsible for collecting the information in the first place in a way that conveys a great deal of detail and specificity about the environment.

Finally, the presence of a true cilium is yet another commonality between these cells, although its function in each is quite distinct. So, in sum, we have two cell types that use similar cellular equipment to fulfill their roles as reporters of complex environmental information. We know that in cases of Usher syndrome, a genetic disorder, these two cell types are affected. This is strong evidence that the similarity between photoreceptors and hair cells goes deeper than the cellular similarities. In fact, the molecules regulating the specific sensory functions performed by these cells are yet another commonality, and this makes a lot of sense if you’re trying to understand why both hearing AND vision are affected in Usher syndrome. It’s all down to the molecular toolkits these cells use to develop and do their jobs properly.

In Part II, I’ll introduce the proteins affected in Usher syndrome and describe what they tell us about the disease itself.

The Cure?

2011-07-18T10:55:00.004-04:00

by Mark Dunning

What if Usher syndrome no longer existed? What if it went the way of Polio and Small Pox? But as with the Polio and Small Pox vaccines, this treatment would not change the fate of those of us who already have Usher syndrome. In short, we’d be the last, a people destined to be a footnote in the history books. How would you feel if no one was ever born with Usher syndrome again?
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I don’t know much about preimplantation genetic screening which is not surprising. I don’t know much about a lot of things. Actually, I’m sort of fascinated to even be writing the words preimplantation genetic screening. Five years ago I had never heard of those words and would have never, ever considered writing them in a blog that I co-write with a molecular biologist from Oregon. A lot has changed for me since my daughter was diagnosed with Usher.

One of the things that has changed is that I now sit on the board of directors for a genetics group. I was invited to join because my daughter has Usher syndrome. I’m the consumer representative which means, basically, that I ask dumb questions that everyone else in the room already understands. That’s because 95% of the topics we discuss go over my head like balloons released at a carnival. Every once in a while a string passes close enough that I can reach up and grab it. That happened recently with preimplantation genetic screening and it is where I learned the little I know about the topic.

So here’s the Idiot’s Guide (and I do mean idiot) to preimplantation genetic testing. Using in vitro fertilization an egg (or eggs) is fertilized in a petri dish. The genetic material resulting from this fertilization is then genetically tested for certain known genetic conditions. Based on this testing embryos are chosen that do not have the genetic condition with the intention of ensuring that the coming baby does not have said genetic condition. The chosen embryo(s) is/are then implanted into the mother to continue development.

Preimplantation testing is not done prior to every pregnancy right now nor is there any indication that it will be any time soon. But it is not farfetched to think that someday it might be. When my parents had kids, caesarian sections were almost never done. Now according to Wikipedia (and Wikipedia is always right) almost 20% of births in the US and nearly half the births in China are c-sections. So it is not crazy to think that in vitro fertilization and preimplantation testing might one day become the norm.

So for the sake of this post, let’s imagine a world where preimplantation genetic testing is in fact the norm.

One obvious benefit would be the potential elimination of some terrible disorders, such as Tay-Sachs, a neurological disorder that usually results in children dying before the age of four. The world would undoubtedly be better off without that disease, right? And it would be gone forever. Such testing would allow us to not only identify eggs that had Tay-Sachs but also eggs that were carriers. Since no one would still carry the gene, within a generation Tay-Sachs could be gone.

That would hold true for any genetic condition, including Usher syndrome. And the world would be better off without Usher syndrome, right?
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My son spent a recent Saturday playing a soccer game with an exaggerated limp. He claimed to have hurt himself kicking a ball against a wall the day before. I would have held him out of the game but for two reasons. First, the limp changed sides frequently and often disappeared altogether. Second, a hangnail can put him the verge of tears. In short, I love him dearly, but he’s a wimp. That’s OK, so am I.

My daughter on the other hand is tougher than a three dollar steak. She takes knocks on a daily basis that would make a boxer wince and does so without so much as a change of expression. Bella has Usher syndrome. She has spent her life tripping over things and bumping in to things. She falls down a lot. She expects it. She knows how to deal with it. She is an expert at picking herself up. So when she goes down, she pops right back up. Jack, on the other hand, rarely hit the canvass. When he does, he stays down for an extended period more from surprise and inexperience than from any real injury.

So why are my kids so different? Is it genetics? Is Bella genetically designed to be tougher than Jack? Or is it more environmental? Or is it a combination of both? The answer might be simply that Bella has a genetic condition called Usher syndrome that causes her to come in to conflict frequently with her environment and that makes her tougher.
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One of the big ethical questions facing preimplantation genetic testing is what genetic traits should a parent be able to eliminate? Diseases like Tay-Sachs are easy decisions. Bringing a child in to the world to suffer and die is not anything anyone would support. But where is the line on suffering? If a gene meant someone was destined to get cancer in their forties, should that be eliminated? How about if the cancer is treatable with a nearly 100% survival rate? According to ABC news, “social research suggests that shorter people…make less money, hold fewer leadership roles and are less sexually active than their taller peers.” That same article states that 10% of the genes that control height have been identified. Someday it will be 100%. When it is, is short stature suffering worth avoiding?

There are treatments for hearing loss. Many in the Deaf community don’t even consider hearing loss to be a handicap. But a large percentage of the causes of hearing loss are genetic. Is hearing loss a trait that should be eliminated?

And what about Usher syndrome? The hearing loss is treatable. There will someday be treatments for the vision loss. So does Usher syndrome bring so much suffering upon families that it should be genetically eliminated?
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We recently ran a charity horse show to benefit the Decibels Foundation. My whole family was there. My daughter rode in the show. My father came over to the farm at the crack of dawn to help my sister, my wife, me, and a host of friends set up. My son helped with the raffle and worked the concession stand.

My wife and I started the Decibels Foundation ten years ago because our daughter was born deaf. Decibels does a lot for families with Usher syndrome these days, too, because Usher is turning out to be a much more common cause of hearing loss than first thought.

My parents are the reason I am a carrier of Usher syndrome. My wife is a carrier, too. Because of us, Bella has Usher syndrome. So you could say that our parents are the reason that there was a horse show. Without them, there is no Bella and without Bella, there is no charity horse show, and no benefit to hundreds of other deaf families.

I know a man. He had a son who had Tay-Sachs. His son lived longer than most. He died when he was seven. The boy never left his bed, never said a word. The man started a national Tay-Sachs foundation and has raised millions for research. He has two other children and is the kindest, gentlest, most loving father I have ever met. When I told him I admired his patience and the love he clearly displayed for his children, he said he wasn’t always that way. Tay-Sachs had changed him.
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“Character cannot be developed in ease and quiet. Only through experience of trial and suffering can the soul be strengthened, ambition inspired, and success achieved.”- Helen Keller

Here’s a question for you: Has mankind thrived in spite of its challenges or because of them? And what does it mean for society if we eliminate those challenges?

My daughter always stands tall in the face of adversity because she has Usher syndrome. My family is closer and more giving because of Usher syndrome. My friend is a better father because of Tay-Sachs and I dare say I am a better man because of Usher syndrome.

Would we have become who we are without those challenges? And would the human race have achieved what it has without its innumerable challenges?
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We watched X-Men: Last Stand the other night. The premise of X-Men is that mutations in the human genome lead to a group of people, mutants, with super powers. In this particular movie, a ‘cure’ is found that can eliminate the mutation, essentially turning the mutants back in to people. This is a source of contention among the mutants. Many are happy just the way they are. Some are worried about what it would mean if everyone else takes the ‘cure’ and they do not. What happens to them?

We sometimes joke with my daughter that she is a mutant like the X-Men. This has always been a source of pride for her, given that they are super heroes and all. During the movie, in one of my frequent bad parenting moments, I casually mentioned to Bella about preimplantation testing. I told her that we might someday have a ‘cure’ like in the movie, a way to ensure that no one would be born with Usher syndrome again. She started to cry. She didn’t want people like her to no longer exist, in part because of the implication that she was something horrible that needed to be eliminated, but also because she didn’t want to be alone. She didn’t want to be the last mutant.
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What does it mean to ‘cure’ Usher syndrome? Does it mean viable treatments like cochlear implants? Does it mean identification at birth like PKU where a simple blood test in the first days of life (remember the heel-stick in the maternity ward?) allows a disease that can cause severe mental retardation to be avoided by simple dietary modifications? Or does it mean that the disease, like Polio, is simply eradicated and gone forever? And what would that mean for us, the last families with Usher syndrome?

Preimplantation screening is gaining popularity. A host of genetic disorders, including Usher syndrome, could eventually be eliminated from the human race. At some point in the not too distant future it’s entirely possible that no family will have to suffer the agony of Tay-Sachs or fear for the deaf-blindness of Usher syndrome. And the world would be a better place because of it.

Right?

Science, Truth, and Choices

2011-06-14T19:13:00.002-04:00

by Jennifer Phillips, Ph.D.

Here’s my somewhat belated follow up to Mark’s last post regarding the unanswered questions about Vitamin A as a potential treatment for Usher syndrome. I regret that in doing so, I may be igniting another Summer Debate conflagration, but I would be remiss if I didn’t attempt some response to Mark’s complaints that the ‘scientific community’ (that’s right, Large Hadron Collider people, you’re on the hook for this too) has ‘dropped the ball’ by failing to produce research that would definitively support or reject the use of Vitamin A in Usher patients.

Mark’s main specific query is on the subject of why there have been no additional studies to clarify the original research by Berson et al. I think the answer is multifaceted, but boils down to the fact that our resources for addressing these kinds of research questions are not limitless. Studies of this magnitude (the 1993 Berson study had over 600 participants who were followed clinically for over 4 years) are expensive. Is it worth spending money to address such questions? Generally speaking, yes. However, recall that this particular study was lauded--even by its critics--for its excellent methodology. It was the strength of the conclusions that were questioned, not the study design. This raises the question, at least in my mind, that if a study of this admirable magnitude and quality could not arrive at a more convincing conclusion, how could further studies be expected to add much more?

I think it would be a hard sell to get institutional support for such a study. “Resources” doesn’t just mean money. One is also committing laboratory and clinical space, equipment and personnel to work on this research, thereby limiting the extent to which they can be used for other projects. Moreover, one is committing subjects—patients with Usher, or at least a mixed cohort of RP patients—to participate in this study rather than another. Should we be willing to expend all of these extremely valuable resources—years of people’s lives, millions of dollars—to readdress the question of vitamin A rather at the expense of studying another potentially more promising compound (like, for example, Valproic Acid, or TUDCA)? I don’t think that’s an easy choice to make, by any means.

The more general complaint that Mark shared in his previous post, though, is one of frustration with the fact that science is failing to find solutions fast enough. More than once on this blog, Mark has lamented that there aren’t more concrete answers about so many aspects of Usher syndrome. I am truly sympathetic to the frustration that such uncertainty engenders, and I fully understand that the clock is ticking here. While ‘science’ takes its sweet time pondering these pressing matters, more Usher patients and their families are coping with vision loss and other life-changing aspects of the disease. That said, and at the risk of sounding callous, if you’re looking to science to provide ‘proof’ and illuminate the ‘truth’ of any given situation, you’re thinking about science all wrong.

Science is the best way humans have ever devised to ask questions about the natural world. However, both the complexity of the questions and the completeness of the answers we obtain from this method are heavily dependent on how much we already understand. There is always more to learn; we are never finished. When you ask for proof, the best we can offer in return is evidence. What some might describe as ‘truth’, a committed scientist would qualify as ‘our most informed opinion based on the current data’.
The amount of data we have about Usher syndrome has grown exponentially in the past few decades. We are now engaged in targeted research of interventions to improve all aspects of the pathology. Thousands of people are working very hard on these questions right this minute, and in doing so we have to remain focused and specific about our goals. There are more questions to answer than we have hours in the day, and more potential lines of inquiry than we can possibly pursue in a lifetime.

Choices about what particular research to engage in, whether basic or clinical in nature, are made based on a huge array of variables. Is there enough time, space, money, and need for another study on Vitamin A? I don’t know—but I do know that if the clinical researchers actively studying Usher at the present time choose not to follow up on the original findings with another study to address the efficacy of Vitamin A on forestalling vision loss, it will NOT be due to a lack of enthusiasm for helping RP patients, or incompetence, or callous disregard for the need to provide families with satisfying answers. Rather, it will simply be due to the decision to put valuable resources, both material and human, toward what are judged to be more promising lines of inquiry.

Third Annual Usher Syndrome Family Conference

2011-06-08T17:55:00.000-04:00

by Mark Dunning

The Coalition for Usher Syndrome Research in conjunction with the Usher Syndrome Foundation and the Decibels Foundation will be holding a third annual Usher Syndrome Family Conference this July 8th in at the Host Hotel in Sturbridge Massachusetts. The conference is an excellent opportunity to meet other Usher families and to network with some of the leading Usher syndrome researchers. I strongly encourage you attend if you can. I will be there and look forward to meeting some of you then.

You can register for the conference here.

Here’s some more about the speakers:

William J. Kimberling, Ph.D., is a senior scientist at the Boys Town National Research Hospital in Omaha, Nebraska and a professor of Ophthalmology at the University of Iowa, Carver School of Medicine. Dr. Kimberling has published more than 250 scholarly papers on a variety of topics from population cytogenetics to kidney disease. He has recently focused his studies on the genetics of sensory loss, specifically on combined vision and hearing loss, including Usher syndrome. His laboratory has been responsible for the identification and characterization of several genes that cause Usher syndrome.

Margaret Kenna, MD, focuses her research on pediatric otology; currently, she is studying the underlying causes of sensorineural hearing loss (SNHL), the most common congenital sensory impairment. Her research includes the genetics of hearing loss, especially GJB2 (Connexin 26) and Usher syndrome; anatomic inner ear anomalies and vestibular function testing; and congenital cytomegalovirus infection. Dr. Kenna received her MD degree from Boston University School of Medicine. She completed an internship and residency in Otolaryngology-Head and Neck Surgery at the University Hospital of Arkansas and a fellowship at in Pediatric Otolaryngology at the Children's Hospital of Pittsburgh. She received a MPH in Clinical Effectiveness from the Harvard School of Public Health in 2005.

Heidi Rehm, Ph.D., is a board-certified clinical molecular geneticist, Director of the Laboratory for Molecular Medicine at the Partners Center for Personalized Genetic Medicine and Assistant Professor of Pathology at Harvard Medical School. She studies genetic hearing loss and Usher syndrome and has developed novel approaches to molecular diagnostic testing including a recent test called the OtoChip for identifying a genetic cause of hearing loss or Usher syndrome (http://pcpgm.partners.org/lmm/tests/hearing-loss/OtoChip). Dr. Rehm has also created many resources to help educate physicians and families about the genetic causes of hearing loss.

Mark Dunning is the father of a daughter with Usher syndrome type 1b. He is also a founding member of the Coalition for Usher Syndrome Research, the President and co-founder of the Decibels Foundation, a member of the Board of Directors for both the Hear See Hope Foundation and the New England Regional Genetic Group, and the IT Director for L.E.K. Consulting, a global strategic consulting firm.

The Snake Oil Salesman’s Guide to Vitamin A

2011-05-16T16:47:00.000-04:00

by Mark Dunning

You should take vitamin A. You should give it to your children. You should take it, of course, in a dose that is safe and prescribed by a physician, but you should take it. My daughter takes vitamin A and her vision has not changed perceptibly in the last four years. I have a friend who has two daughters that take vitamin A. Their vision has not changed in nearly a decade. You should take vitamin A.

STOP!!!

Don’t act on that!

The above is true about my daughter and my friend’s children. They all take vitamin A and their vision has not changed for a number of years. That does not mean, however, that vitamin A is the reason. It might be, it might not be. We don’t know.

In spite of that first paragraph, I’m really not going to get in to the problems with the vitamin A study or argue that it should be prescribed to everyone with Usher. No, today I’m going to vent my frustration at the scientific community. Sorry, but you guys have dropped the ball.

There is little more controversial in the Usher community than vitamin A and I have to say it drives me bananas (which are not high in vitamin A, by the way). I am not a scientist or a physician. I read all I can on Usher syndrome and have learned a lot. I regularly blog about Usher syndrome, but the truth is I’m still just a dad trying to do the right thing for his child. But I don’t know what the right thing is when it comes to vitamin A.

Many doctors and researchers I trust offer a tepid endorsement of vitamin A. Many others, including a certain person that shares this space, don’t believe the current research justifies vitamin A as a treatment for Usher syndrome. And there are a couple of doctors on both sides who are fervent in either their support or their opposition to vitamin A. In the middle are families, like mine, left to make a decision with a paucity of information and, quite frankly, a ton of conjecture.

Let me take a moment to praise my friend Jennifer. Her posting on vitamin A does a good job of reviewing the studies done to date and laying out the facts. I’m paraphrasing here, but in her opinion, based on the currently available studies, she would not give her child vitamin A as a treatment for RP. I have read the same studies and have a different opinion. Hence, my daughter does take vitamin A.

But here’s where I agree with Jennifer. We need more studies on vitamin A! The study done by Dr. Berson and his colleagues is an excellent study that has followed hundreds of families for decades. The study suggests that vitamin A has the potential to be a successful treatment for retinitis pigmentosa. But it leaves more questions unanswered than it answers.

So why have there been no other studies on vitamin A? Why haven’t other scientists and researchers and physicians sought to answer the questions that have arisen from the original study? Would a potential treatment for cancer sit unconfirmed for this long? For as good as it is, there are problems with the original study. Dr. Berson and his colleagues would be the first to admit it. Heck, they spend a lot of time trying to answer the questions that remain open. But that’s part of the problem. Dr. Berson and his colleagues should not be the only ones answering the questions.

The best science is that which is proven over and over again by different studies performed by different researchers. Imagine if we had three different studies that drew the same conclusions as Dr. Berson’s original study. What would be the advice given to families then? Or imagine the flip side, where three other independent studies found that vitamin A has no effect, or worse, an adverse effect on RP. What would we do then?

Instead families are left to guess and to draw conclusions from an impossibly small sample size. We have essentially one study and the word of mouth of other families, both pro and con. Families should not be listening to me on this subject! (Seriously) Jennifer has written about sham science and I am the embodiment of that. Bella is one kid out of thousands with Usher. Maybe her experience is just the normal progression of the disease. Maybe (and I pray this isn’t true) her vision would be better if she didn’t take vitamin A.

The point is we don’t know. If I were truly a Snake oil salesman, I would present the experience of my family and of my friend’s family as proof positive that Vitamin A is THE CURE for Retinitis Pigmentosa. But I can’t sell that in good faith. Just because I write a blog on Usher and sound like I know what I’m talking about doesn’t mean my opinion on Vitamin A should matter.

The good news is that there is a way through this uncertainty. It’s called science! Do more studies on vitamin A. Answer all the questions. Take the guess work out of it and find the truth. I’ll even help write the grant proposals (writing is about all I’m qualified to contribute). Families will do the right thing once the proof is there. We just need to know what it is.

We need a consensus on vitamin A. My daughter’s vision, and my sanity, depend on it.

Dispatches from ARVO: Day 5

2011-05-06T09:58:00.002-04:00

By Jennifer Phillips, Ph.D.

The last day of the ARVO meeting was short and sweet, and the very last presentation I saw before heading to the Ft. Lauderdale airport was the one I’m choosing to recap here. The talk was by Hari Jayaram of the University College London’s Institute of Ophthalmology , who described a collaborative research project in which cultured human retinal cells were implanted into a rat model of retinal degeneration. At first glance it might sound like the premise of a Mad Scientist thriller, but it was actually quite a well-designed and relevant study. Here’s an overview of the experimental rationale, set-up, and outcome:

Main goals of the research: The primary task was to optimize methods of culturing a type o f human retinal cells that had the ability to develop into photoreceptor cells. The subsequent goal was to actually implant these cells into a rat model of retinal degeneration and observe the cellular activity and the effects, if any, on the visual function of the rat.

Methods of achieving the first experiment: Müller Glial Cells (MGCs) were isolated from donor human retinas and cultured with the addition of various growth factors and other molecules. The researchers were seeking to find the best ‘cocktail’ of ingredients that would stimulate the MGCs to do what they are known to do in intact, living retinas under certain conditions, specifically to de-differentiate and divide to create a population of cells with the potential to become other retinal cells. In this case the goal was to influence these new “cells with potential” to begin developing into rod photoreceptor cells.

The challenge in such an experiment is not only to find the right ingredients to add, but also the right stage of cell specification to achieve. Highly differentiated cells, e.g. fully formed photoreceptors, tend not to be very happy in cell culture, and usually die off pretty quickly. Minimally differentiated cells can live quite happily in cell culture for an amazingly long time, but for the purposes of transplantation, these cells may not have sufficient guidance (by way of internal and external molecular cues) to become the cell type of the researcher’s choosing.

Results of the first experiment: In addition to being able to culture MGCs in a relatively undifferentiated (read: having the potential to become a number of different cell types) state, the investigators also hit upon a successful combination of growth factors and molecules known to stimulate rod photoreceptor development. They confirmed their success by analyzing the molecules being produced within the differentiated cultured cells and found that they were churning out molecular markers of rod precursor cells (RPCs)—specialized enough to know to develop into rods, but not so specialized that they would become unhealthy before transplantation time.

Methods of achieving the second experiment: The investigators selected a rat model of retinal degeneration, known as the P23H rat, bearing a mutation in rhodopsin, the light-sensitive protein found in rod outer segments. In both rats and humans this mutation causes RP due to rod photoreceptors death. Unlike the Mertk mouse model described in yesterday’s post , in which photoreceptors die because of a protein dysfunction in the neighboring RPE cells, the retinal degeneration in the P23H rat is due to a defect in photoreceptors themselves. This is important because the researchers needed to be sure they were targeting the right population of cells, replacing the particular cell types that were defective, namely rod photoreceptors.

P23H rat retinas received transplants of either the MGC cultures or the RPC cultures. Each rat in the experiment received cells in only one eye, with the other eye remaining untreated for use as an experimental control. The researchers waited 3 weeks, during which time the rats received drugs to suppress their immune response so that they wouldn’t reject the donor tissue. After this waiting period, visual function was analyzed by ERG, and retinal tissue was examined to evaluate the growth and development of the implanted cells.

Results of the second experiment: When the researchers observed the retinal tissues of the rats that received the “undifferentiated” MGCs, The researchers observed that these cells had incorporated into the retinal layer usually inhabited by MGCs and had developed an MGC-like morphology. These cells send processes throughout all the other cells layers of the retina, and have a very distinctive shape.

In the retinas of rats receiving “differentiated” RPCs, the investigators reported that these cells incorporated into the photoreceptor cell layer of the retina. No outer segments appeared to form in these cells, suggesting that they did not complete the process of becoming mature rod cells. However, they did form connections with other retinal neurons, which demonstrates the extent to which they were incorporated into the existing retinal structure. The researchers also determined that these cells were producing proteins exclusive to rod cells. So, although the transformation from RPC to fully specialized rod cell was incomplete, the cells did display a “rod-like” molecular profile and cellular behavior.

Visual function was tested by measuring the ERG response to various light intensities. In the eyes treated with RPCs, the investigators detected a greater photoreceptor response to bright light compared to controls. Even without evidence of forming outer segments—the part of the rod cells where rhodopsin functions, the inclusion of RPC-derived cells resulted in a boost in visual function. Interestingly, researchers saw a less dramatic, but still significant increase in photoreceptor response to bright light in the eyes containing undifferentiated MGC transplants. No evidence of additional rod or rod-like cells originating from the transplanted human cells was detected in these eyes by histology, yet the presence of the new Müller-like cells seemed to improve function nonetheless.

Conclusions: These experiments have clear implications for future work toward cell-replacement therapy for photoreceptor degeneration. The experimental design might seem unusual, particularly the idea of putting human cells into a rat retina, but it was important to ascertain how human retinal cells might behave in a complex, living system. Clearly, there were some limitations to this experiment—the cell differentiation was incomplete, in that neither the MGC nor the RPC transplants appeared to mature to 100% fully functional cell types. This may indicate that the cell culture conditions need to be optimized further, but it may also be due to the limitations of cross-species transplants. As you might imagine, human retinal cells are somewhat larger than their rat counterparts, so there may have been some physical limitations to cell growth and differentiation.

Although further optimization and additional testing in animal models will be required before this treatment is ready for clinical trials, this work will likely make a significant contribution to the field of retinal cell replacement.

So, as I wrap up my final report from ARVO, 20,000 feet above Middle America, I can say unreservedly that this is one of the best, most diverse, career enriching meetings around. I’m full of ideas for my own experiments, and I’m already looking forward to the 2012 Annual Meeting.

Jen’s final ARVO stats, by the numbers:

5 science-filled days
38 talks
75 posters
4 walks on the beach
2 swims
7 airplanes
1 missed flight
3 delays
18 hours in flight
100 new ideas

Dispatches from ARVO: Day 4—Valproic Acid revisited

2011-05-05T10:17:00.001-04:00

by Jennifer Phillips, Ph.D.

Last month, I blogged on some peer reviewed research describing a clinical observation of the effects of Valproic Acid in patients with a particular form of retinitis pigmentosa (not Usher). Today at the ARVO meeting I saw a nice poster presentation that may add a bit more data to that story. The authors, from the same research group at U Mass that produced the original patient study published in the British Journal of Ophthalmology, now report the results of dosing mice with a severe form of RP with Valproic Acid.

This particular mouse model has a mutation that affects the Retinal Pigmented Epithelium (RPE), the cell layer that lies adjacent to the photoreceptor outer segments. The RPE is important for keeping the outer segments—and, by extension, the entire photoreceptor—healthy, and defects in the molecular pathway responsible for the RPE-Photoreceptor relationship often lead to retinal degeneration (the RPE65 gene, which causes Leber’s Congenital Amaurosis when mutated, is another example of an RPE gene crucial for retinal cell health).

This mouse strain, with a mutation in a gene called Mertk, has an RPE defect that causes RD very early on in life, with the standard flattening of the ERG and thinning of the neural retina as cells die in large numbers. Unlike the human patients reported in the study by Clemson et al., this form of RP is autosomal recessive in both mice and humans. These researchers gave daily doses of Valproic Acid to Mertk mice over a period of four weeks, beginning when the mice were about 1 month old. ERG amplitudes and retinal thickness were recorded from a group of about 20 control and experimental Mertk mice at the beginning of the period, and again after the four week treatment ceased.

At the end of the trial, the retinal thickness in the Valproic Acid treated mice was significantly greater than that of the control group, indicating that fewer cells had died during the four week treatment period. There also appeared to be some benefit to the ERG response, although not as dramatic as the retinal thickness differences.

So, although there are one or two more controls I would like to see in this particular data set, I can’t find too much fault with it, and it does seem to lend more credence to the clinical trial of Valproic Acid treatmemt for Autosomal Dominant RP that is currently recruiting participants, in that it provides another situation in which Valproic Acid appeared to slow the rate of photoreceptor death in a progressive retinal degenerative disease. I’ll pass on further developments in this story as they are reported.

Tomorrow is the final day of the ARVO meeing—a shorter day to accommodate everyone’s travel plans, but a number of interesting presentations on the program nonetheless. Tune in Friday for one last dispatch from this wonderful meeting.

Dispatches from ARVO: Day 3

2011-05-03T22:55:00.002-04:00

By Jennifer Phillips, Ph.D.

Today’s cool Usher science story comes from Kate McCaffrey and colleagues at Rosalind Franklin University, who are making some interesting discoveries about a new potential therapy for Usher type 1C.

In the past when we’ve talked about gene replacement therapy, the focus has been to find ways of replacing a gene product that is absent or faulty in some way. The exact nature of the mutation causing the absence or faultiness doesn’t usually matter—as long as you know which gene is affected, substituting a good copy should solve the problem.

Be that as it may, Usher gene replacement has barely gotten going in animal models yet, let alone human patients. And, as we’ve discussed, some Usher molecules will likely be very difficult to work with, due to their large size or other constraints.

Another approach to this that has met with some preliminary success in the hands of McCaffrey et al. is to target a particular mutation for correction, rather to replace the whole gene. The mutation in question is the USH1C G216A mutation, which is prevalent in Acadian populations ~~as well as in people with Ashkenazi Jewish ancestry~~[this is only common in Acardian populations as far as we can tell]. This is a mutation that alters the normal splicing of the USH1C gene.

So what is ‘normal splicing’ exactly? Briefly, splicing occurs in the transitional molecule between the DNA code housed in the nucleus and the protein product that goes out into the cell and does stuff. The transitional molecule is called messenger RNA, and its job is to faithfully copy the genetic code from a particular address on the chromosome and then serve as the blueprint for assembling the protein. But before it can provide a coherent recipe, the content has to be condensed.

The information on the chromosome that codes for the protein, called exon sequences, is interspersed with other DNA sequence that isn’t part of the instructions, called intron sequences. When the messenger RNA is first synthesized, it contains both exonic and intronic bits, which need to be excised before the message will make any sense as protein building instructions. Think about an article on how to build a gazebo in a Home Improvement magazine. If the instructions were spread out on consecutive pages, it would be straightforward to build. But if after every page or two there were instructions for a different project, or page after page of advertising, you would probably either include extra, incorrect steps in your building project or perhaps abandon it altogether, leaving it unfinished and non-functional.

Fortunately, the cellular machinery that processes messenger RNA is pretty clever about locating the parts that need to be deleted (or, if you will, the pages that need to be torn out) and then splicing together the ends of the exons so that the instructions are arranged in one continuous string of code. How does this machinery know how to tell exons from introns, you might ask? It’s all in the code! DNA base sequences indicate where the junctions are between the parts to keep and the parts to delete.

So, sorry for the protracted explanation (I’m not doing to well at ‘short and pithy’, am I? ) but if you followed it, it now shouldn’t come as much of a surprise that while mutations in the protein coding, exonic sequence of Usher genes can and do lead to Usher syndrome, so can mutations affecting the splice sites of these genes. The G216A mutation is an example of this. It creates an extra splice site in the middle of the code, which leads to some of the exon sequence being lost and the protein being incomplete, which in turn leads to a severe form of Usher syndrome.

As it happens, we molecular biologists have several tools for inhibiting splicing at a particular site on a messenger RNA molecule. We can generate small molecules that physically interfere with the splicing machinery, blocking a particular part of the code that indicates ‘splice here’ such that it will skipped over while the splicing machinery moves on to the next splice site. Sometimes we do this when we want to interfere with normal splicing and create a poorly constructed protein, but in this case, McCaffrey and colleagues used it to block that mutated extra splice site, G216A. They tested their interfering molecule in cell cultures containing the human USH1C G216A mutation and in a mouse model containing the same mutation. When they did this, they found that splicing at the wrong site caused by the mutation was effectively blocked, and both the human cells in the dish and the tissues they examined from the mouse were able to revert back to making the normal USH1C protein again.

The research presented was mostly a test of whether or not this technique would work at the molecular level, and it did, rather impressively. More work is needed to decide how and when to deliver a dose of this molecule to the affected tissues in the mouse model, and then to examine the effects on the observed hearing and vision defects, but it’s a great start.

Dispatches from ARVO: Day 2

2011-05-03T10:43:00.003-04:00

by Jennifer Phillips, Ph.D.

Today was a 12-hour juggernaut of talks, poster presentations (mine included) and really good scientific and social conversations. While many of these situations would make great blog fodder, one series of talks really had the wow factor. This session was entitled “Optogenetics, Visual Function and Restoration”. I’ll skip over the highly technical side of this field and cut to the chase as quickly as possible here:

I know I’ve mentioned opsins before on the blog, but to recap briefly, opsins are light-sensitive molecules in photoreceptors that change shape in response to light of a particular wavelength, which causes the cell membrane to change polarity, which in turn causes in an electrochemical signal to be transmitted to nearby ‘receiver’ neurons. As it happens, light sensitive opsin-type molecules are present in a lot of different multicellular organisms, some of which completely lack eyes, and even in various species of bacteria. The principal function of the molecule is the same, all throughout the evolutionary tree: Light activation creates an electrochemical response that allows a polarity change in the cell membrane—negative to positive, or the other way around. Changing polarity is useful component of cell biology, and cells of all sorts use polarized membranes, and channels or gates within those membranes, to regulate the flow of charged particles in and out.

So here’s wow factor part A: scientists have figured out how to isolate these molecules from bacteria. When introduced into neurons, these molecules can be stimulated to either activate or silence a neuronal signal. There were numerous patents mentioned in these talks, as these molecules are impressively multipurpose for manipulating electrochemical cellular responses of all imaginable types.

Now here’s wow factor part B: The last talk discussed the application of this technology as a possible treatment for RP patients. In most forms of RP, including that seen in Usher syndrome, rod photoreceptors die off, causing night blindness and tunnel vision. Changes occur to the remaining cone cells throughout the eye, most particularly in the outer segment of the photoreceptor where these light-sensitive opsins are housed. For some time, it’s been assumed that at advanced stages of RP, severe loss of vision correlates with severe loss of photoreceptor cells of all types. Recently, though, clinicians and researchers have discovered that a respectable number of cone cells in these eyes remain viable, although not functional. So, to recap: cone photoreceptors in an RP patients eye still exist—they are not dead—but they do not function because the portion of the cell containing the opsins that kick off the whole signaling cascade throughout the retina has degenerated.

This technology could potentially enable us to replace the degenerated native opsins with a light sensitive ‘alternative’ opsin that would serve basically the same purpose: open a channel in the cell membrane, allow charged particles to flow through and signal to the neighboring neurons. One research group has already done this replacement experiment in a mouse model of retinal degeneration, and by observing the behavior of mice navigating a maze, they were able to record an increase in visual function following the treatment. Wow!

Cooler still, as some of these bacterial opsins have been found to respond to specific wavelengths, we may be able to target them to particular subtypes of cones to give RP patients some degree of color vision!

Based on what I heard today, it seems like more preclinical testing will be required before this technology approaches readiness for Phase I Clinical trials, but the power of the system is undeniable. I predict we will be hearing a lot more about this in the coming years.

In the meantime, please take a moment to appreciate the contribution of basic research to this potentially groundbreaking advance in human health. Bacteriologists are the ones who first discovered these species, living happily in extreme environments of high salt or high methane levels that would be instantly lethal for most other critters on the planet. These basic scientists were not out to find a cure for blindness, but only to better understand the diversity of life. In doing so, they identified these molecules and introduced them to the larger scientific community which is now only just beginning to understand how to harness their potential. As I’ve said before, you never know where the next great discovery might come from.

Dispatches from the ARVO Annual Meeting: Day 1

2011-05-02T02:02:00.001-04:00

By Jennifer Phillips, Ph.D.

Hello readers! I’m here in sunny Ft. Lauderdale attending the Association for Vision Research and Ophthalmology meeting—that’s right the teeming nerd hordes are at it again. But rather than waiting until the end for a long, post-hoc recap as we’ve done with past scientific meetings, this time I thought I’d try to mix it up with some short, pithy daily notes from the event. I realize I’m not exactly known for ‘short and pithy’ around here, but I’ll do my best.

Topic of the day: Ethics of Genetic Applications in Ophthalmology

This was a talk session with presentations by four speakers, a mix of genetic counselors, clinicians, medical ethics specialists, and researchers. One common theme was the psychological and emotional impact of a diagnosis via genetic testing. There was a bit of friendly debate about the benefits vs. the harm of testing and informing children of later-onset genetic diseases and some general recommendations of having qualified genetic counselors—or clinicians with sufficient training in such counseling, be involved in delivering this news to families and following up with them to make sure they had adequate support. We’ve talked quite a bit on this blog about ways to make this clinician-patient-family interface more successful, so this isn’t anything new, but hopefully it will reassure some of you to hear that the problem is being recognized and discussed in this kind of professional setting.

The most interesting point of discussion, though, by which I mean, the one that made me perk up and say “hey, I should totally blog about that!” was put forth in a very nice talk by Bernard Lo, a professor of medicine and director of the medical ethics program at UCSF. He talked generally about the ethics of clinical trials, and specifically used the RPE65 gene therapy story as an example. I’ve described a few clinical trials here, so the basics—random assignment of participants into a control group or an experimental group, reasonable efforts to prevent the patients from knowing which group they’re in until the end of the study, etc.--should be familiar to most readers. However, the ethical conundrum this speaker put forth that attracted my attention was something neither Mark nor I have discussed in our various posts about clinical trials: any participant in a clinical trial, particularly a Phase I trial, is taking a personal risk so that researchers might benefit from new knowledge and so that future patients might benefit from the studied treatment. There is absolutely no guarantee of any personal gain—it’s altruism, pure and simple. Moreover, conducting such studies runs quite counter to the primary goals of most medical professionals, in that treatment is not being personalized and is not designed to improve the condition of the participants.

The RPE65 story was used as an interesting illustration of this ethical morass. As you may recall, the ‘control group’ did not consist of a separate group of people, but instead patients received treatment in one eye, and had ‘sham surgery’ on the other. Is sham surgery, in this case sticking a needle deep into someone’s eye without delivering any potential treatment, ethically justifiable? Thinking about it from a pure research point of view, it is an important control. The placebo effect is a powerful factor in any clinical trial and must be accounted for in order for any results to be meaningful. Even seemingly objective things like eye chart tests can be influenced by patient effort or the belief that he or she should be seeing better after treatment. And interestingly, the more invasive the intervention, the more powerful the placebo effect. Injecting a completely inactive substance elicits a stronger placebo response from patients than orally consuming the same substance. And the placebo response to surgery has been shown to be more powerful still. Thus, it’s pretty important to control for this with any new treatment being tested. That said, sham surgery is a heckuva lot riskier than taking a sugar pill. Is it ethically permissible? And, if so, under what circumstances?
This is an intriguing question, and one that should prompt a bit of reflection about the risks and benefits of participating in a clinical trial. The potential benefits are great, but not necessarily for the participants. The risks are not inconsiderable, and are very personal. Yet people routinely consent to participate in these trials. Just as the clinicians conducting the trials must subvert some basic tenets of their training regarding individualized care for any given condition, the participants are also willing to forego personal gain so that others might benefit from whatever the study shows. That fills me with awe.

So, for those of you who have already participated in trials, and those who are planning or considering participation in upcoming trials, THANK YOU. You are all truly my heroes.

My Fault

2011-04-13T13:43:00.001-04:00

by Mark Dunning

“Those who dare fail miserably can achieve greatly.” – John F. Kennedy

My daughter has Usher syndrome because of me. She has my genes. I gave them to her. I gave her the mutation that causes a certain protein to be produced incorrectly. I am the reason she was born deaf. I am the reason she can’t walk a balance beam. I am the reason her vision is getting worse.

When she trips over the dog, it’s my fault. When she bumps in to the door frame, it’s my fault. When she can’t see at night or can’t hear the teacher or knocks over the glass that she couldn’t see, it’s all my fault. I’m guilty.

Guilt is one of the many traits of Usher syndrome. Deafness, vestibular issues, vision loss, and guilt. Parents are not alone. People with Usher feel it, too. My daughter dumps a glass of chocolate milk during dinner at Grandma’s house and apologizes a thousand times. It’s her fault. Her little brother never spills the milk. He’s younger than she is and yet Grandma has to clean up after her all the time. Not him. Grandma says it’s OK. She tells Bella it’s not her fault that she has Usher. Bella doesn’t agree. She spilled the milk. It IS her fault and she feels guilty about it.

Adults with Usher feel it, too. A husband needs to go to the doctor so his wife has to take a vacation day to drive him. He feels guilty. A girlfriend feels lost at loud, dark parties so the boyfriend not only doesn’t go, he doesn’t even mention the invites. She feels guilty. A father can’t teach his youngest child to drive. A grandmother trips over her grandson and knocks him down. A mother has to ask her parents for help driving the kids to school while her husband is away on business. They all feel guilty.

I hate that life is often tough for my daughter. I hate that little things are a struggle some times. I hate that I can’t make her problems go away. I’m her father. I’m supposed to take care of her, to protect her, and I can’t. It tears at my heart. It’s all my fault.

____

In February my daughter’s sixth grade class held a fundraiser for the Decibels Foundation to help children with hearing loss. Bella is passionate about helping little kids like her and the kids in her school were inspired to raise $20,000 to help. It was a lot of work, $20,000 in $10 and $50 and $100 increments from aunts and uncles and neighbors and friends. Two kids shoveled every driveway in their neighborhood after one storm and gave all the money to Decibels. It was an effort that stirred the soul. Our future is in good hands with kids like that running the show. And at the heart of it was my daughter.

Because of her efforts Bella’s school superintendent nominated her for a Make A Difference Award given by the John F. Kennedy Library in Boston. The library gives the award to 100 kids each year that show leadership in charitable endeavors. Bella’s school had submitted kids in the past but none from the school had ever been honored before Bella was chosen.

The award ceremony was held at the prestigious JFK Library overlooking Boston harbor. It’s a place where world leaders have spoken. The superintendent and all her teachers left school early to attend. The words of John F. Kennedy were read. “Ask not what your country can do for you…” Bella shook the hand of the State Treasurer when she picked up her award. The thousand people in attendance gave the kids a standing ovation.

It tore at my heart. I have never been more proud. That was my little girl. She had my genes.

____

There is good and bad with Usher syndrome. For every spilled milk there is an astonishing accomplishment. John F. Kennedy is one of my heroes, but most of my heroes have Usher syndrome. As families with Usher, we can’t take the blame for the bad and not take credit for the good. My daughter is an inspiration who manages daily to exceed my highest expectations for her. I am lucky. My daughter and my son make me proud every day.

And it’s all my fault.

Valproic Acid and Retinitis Pigmentosa: Testing a new use for an old drug.

2011-04-04T09:38:00.001-04:00

by Jennifer Phillips, Ph.D.
In the summer of 2010, a small observational study of the effects of Valproic Acid was published online in the British Journal of Ophthalmology1. This study reported on seven patients with autosomal dominant retinitis pigmentosa (ADRP) who were given daily doses of a drug called (in its generic form) Valproic Acid, or VPA. According to the authors, these patients showed some improvements to their visual field and to their visual acuity after a few months on the drug. The authors used this result, coupled with other, in vitro studies by the same research group, to justify approval for a larger clinical trial to come that will test the effects of Valproic Acid on visual function in ADRP patients. There has been a great deal of interest, and more than a smidge of controversy, about this story in the vision research community, so I’ve put together a ‘FAQ’ about the work that I hope will be of interest to our readers.

1. What is Valproic Acid?

It is a fatty acid, chemically similar—but not identical—to the active ingredient found in the herb valerian. It has been FDA approved since 1976 for the treatment of epilepsy, and is also approved for use in treating schizophrenia, bipolar disorder and migraine. More information can be found here.

2. Why did anyone think such a drug would be useful for treating Retinitis Pigmentosa?

Valproic acid is an effective treatment for the above neurological conditions because of its known effects on neurobiology. It is known to impact brain function by inhibiting certain neurotransmitters and also has a role in modifying gene expression by inhibiting an enzyme that regulates the conformation of DNA molecules. More recent work with this compound has shown that it and other similar molecules also have an effect on reducing the inflammation that results when nerve cells are damaged or ailing. Finally, the authors of this study report that they conducted experiments in cell culture to test the ability of VPA to associate with rhodopsin, a light sensitive pigment found in the outer segment of rod photoreceptors. Some forms of RP are caused by mutations in opsin genes, resulting in poorly formed or shaped proteins that can’t get to the right places in the cell because they are unable to bind to the chaperone proteins responsible for delivering the opsins to their proper position within the photoreceptor. These researchers previously published a report testing whether various small molecules could act as substitute chaperones for these poorly folded proteins2. In the current clinical report, the authors refer to their unpublished result that VPA was similarly tested and found to be an effective chaperone.

3. How was this study conducted?

The authors report that seven patients at the University of Florida Ophthalmology department clinic were treated “off-label” (meaning that the condition—RP—for which they were receiving the drug is not an FDA approved use for this drug) with VPA and subjected to ‘before and after’ visual function tests during a brief period of between 2 and 6 months. All patients in the study were being seen for an unspecified autosomal dominant form of retinitis pigmentosa (ADRP), so there were no Usher patients included. Mutations in any one of 17 known genes can lead to ADRP, and it wasn’t clear how many different types of ADRP were represented in this study. The authors define this as a ‘retrospective study’.

4. What is a retrospective study?

This type of study involves reviewing previously recorded patient histories and looking for correlations between patient disease profiles and some other factor—some difference in the diet, or behavior, or genetic background that may change the outcome or progression of a particular disease. This is in contrast to a ‘prospective study’, where a research question is posed and patients with a particular condition are given treatment, monitored for changes, and, usually, compared to another group of patients with the same condition who did not receive that treatment.

In general, prospective studies are considered to be more rigorous, because they can be carefully thought out and designed to include all the appropriate controls and statistical bells and whistles that make the findings more believable. However, prospective studies aren’t always possible, and retrospective studies can often yield useful health data. At a minimum, a retrospective study can give one a jumping off point for new investigations. If, for instance, a correlation is noted between consuming Factor X and having a milder manifestation of disease Q, more formal studies of the effects of X on Q could be justified.
That said, I question whether this was truly a retrospective study in the usual sense of the term. If a chart review of ADRP patients had shown that those who had been prescribed VPA for some other reason (unrelated to the RP) had a slower decline in vision, than ADRP patients of a similar age and disease profile who were not taking VPA, that would be a retrospective study. In this case, however, someone decided, ahead of time, to give these particular ADRP patients a dose of VPA for something other than the conditions it is normally used to treat. Indeed, the “off-label” dosage prescribed to all seven patients is reduced by 25-50% from the dose usually prescribed to treat the neurological conditions for which VPA is approved. The authors spend some time justifying how they chose the starting dose, and explain that in two of the seven cases they decided to increase the dose by 25% at some point during the testing period. Baseline visual measurements were taken, and additional measurements were collected from each patient at a follow-up visit. Then someone perused the patient charts, extracted the relevant data, and wrote up the paper. So, either there is some dramatically different definition of ‘retrospective’ in play here, or there is some information missing.

Another odd thing about the origins of these data is revealed when the authors state: “The data reviewed from these patient records were not collected originally with the intent to study.” Why were ADRP patients given off-label doses of VPA, if not to study the effects? The authors never explain this, and although in and of itself it doesn’t affect the outcome or impact of the results to any great extent, I find it unusual, to say the least.

5. What were the results of the study?

Briefly, data were collected from 13 eyes from 7 individuals with ADRP. The authors explain that data from the 14th eye were not included in the analysis due to ‘poor quality’. When the results were averaged together, there was a small improvement in visual acuity, comparable to going from about 20/50 vision to about 20/30 vision. There was also an increase of about 10% reported in the average visual field areas of these patients. Considering the 13 eyes of these 7 patients individually, 9 eyes were judged to have increased visual field areas, 2 had no change in visual field, and 2 got worse, with diminished visual field areas between the initial exam and follow-up. The results per individual eye on the ‘eyechart’ test that measures visual acuity were a mixture of improved (7 eyes) and no change (6 eyes). These changes were judged to be statistically significant, but because there was no control group, the ‘controls’ used to compare the treatment group to were calculated as ‘no change’ in visual field area or visual acuity.

6. What is the significance of these results?

Taken at face value, the data are interesting but inconclusive. There are a number of factors that limit what can be interpreted from this study. The small size of the study is a big consideration—seven subjects is a miniscule sample size, and given the variation in the genetic basis of their disease, the difference in their ages (between 16 and 56 years), the short duration of the study, and the differences in the degree of RP they were experiencing during the time of the study (some quite a bit more advanced than others), it is challenging to extract a clean signal from all that noise. These differences tend to average out with more individual data points, but in a study of this size, there are ambiguities all over the place. In fairness, the authors do acknowledge the sample size and study duration as limitations in the paper.

7. Will further studies be carried out to confirm these results?

The authors state that further pre-clinical studies have already been carried out, and/or are underway; however, all remain unpublished at this writing. Several studies with rodent models of RP and cell culture were presented at the ARVO meeting last year, but are not yet published in peer-reviewed journals. Approval was granted for a larger Phase II Clinical trial on the basis of these collective results, however. ADRP patients are currently being recruited for this prospective study in which about 100 ADRP patients will receive either VPA or a placebo for one year while their vision is monitored.

8. Can VPA be used to treat RP due to Usher syndrome?

At this point, there is not enough information to justify such treatment. We know very little about how VPA might be working in the ADRP patients, and it will be impossible to extrapolate that potential benefit to other forms of RP until we know more.

9. Should Usher patients start taking VPA, just in case?

Short answer: No. Most importantly, no one should ever take any medication for anything without consulting a qualified physician. No Usher patient should ever take, or be given, a drug or supplement without consulting a doctor who specializes in Usher syndrome.

10. But what’s the harm? VPA is an FDA-approved drug—so isn’t it safe?

One of the strong ‘selling points’ of this particular study was that it explored a new use for an already FDA-vetted pharmaceutical. That saves both money and time that would have been spent on developing a novel drug AND safety testing it in pre-clinical and Phase I clinical trials. We have over 30 years of data on the safety profile of VPA in humans, so any future trials using this drug, including the one now being organized for ADRP patients, can start at Phase II. But does that mean that VPA is ‘safe’? In the sense that it is generally well tolerated, not toxic when taken at prescribed doses, and improves the specific conditions for which it is currently approved, yes. BUT—and this is a really big BUT—safety is relative. VPA has well documented and potentially serious side effects, which must be weighed against any potential benefit. Furthermore, this is a drug with known neurological effects. A choice to take VPA for RP is way, WAY different than just choosing to eat more paella or supplement with DHA.

11. What is the “take-home” message from this study?

That a very small and limited case study has generated some interesting results that bear following up. The authors have been subjected to some criticism by other clinician scientists, who wrote letters to the journal 3,4opposing the strength of the conclusions, based on the available evidence. The authors wrote nearly as much in response to these letters as they did in the original article5,6, and, much like the Vitamin supplementation for RP story, the controversy will likely roil for some time, at least until more robust data are available.

Personally, I am interpreting these results with even more caution than I applied to the supplementation story, given the limitations of the study described above, the lack of peer-reviewed supporting data, and some level of unease about how the study was conducted. I am also, as always, mightily chastened by the findings of John Ioannidis, who, in addition to his work on the impact of translational research on the discoveries of new treatments, has also used impeccable statistical analysis to show that ”for most study designs and settings, it is more likely for a research claim to be false than true”.

It is unquestionably beneficial to research potential new uses for existing drugs. I regard this study and the proposed trial with interest, and I will hope that all due rigor will be applied to the collection and interpretation of the data. It is a reasonable expectation that a bigger study with the proper controls, in addition to some results from animal RP models, can tell us what we need to know about if—and how—VPA works in RP patients, and what kinds of RP it might benefit.

The bottom line is that there is reason to hope—not necessarily for this particular drug to be THE ONE for Usher syndrome, but because lots of similar research is happening every day, and every one of these studies brings us closer to finding a treatment that will work, even if part of the progress results from the process of elimination. Watch this space for further updates.

References:

1Clemson, M. et al., 2011. Therapeutic potential of valproic acid for retinitis pigmentosa. British Journal of Ophthalmology 95 (1): 89-93. (published online July 20, 2010)

2Noorwez, SM et al., 2008. A high-throughput screening method for small molecule pharmacologic chaperones of misfolded rhodopsin. Investigative Ophthalmology and Vision Science 49: 3224-30.

3vanSchooneveld, MJ et al., 2011. The conclusions of Clemson et al. concerning valproic acid are premature. British Journal of Ophthalmology 95 (1): 153-154. (published online October 22, 2010).

4Sandberg, MA et al., 2011. Lack of scientific rationale for use of valproic acid for retinitis pigmentosa. British Journal of Ophthalmology (published online December 3, 2010).

5Clemson, M et al., 2011. Author’s response [to vanSchooneveld, et al.]. British Journal of Opthalmology 95(1): 153-154. (published online October 22, 2010).

6Tzekov et al., 2011. Author’s response [to Sandberg, et al.]. British Journal of Ophthalmology (published online January 9, 2011).

What You Should Tell Your Child About Usher Syndrome

2011-03-15T09:13:00.000-04:00

by Mark Dunning

In the last post we discussed when to tell your child that he or she has Usher syndrome. The conclusion of that post, in short, was when you are emotionally ready to discuss it, discuss it. I don’t care if your child is 15 months or 15 years. Talk about it as soon as you, the parent, can handle it because your child is already able to handle it. You just learned your child has Usher syndrome but your child has had Usher syndrome their entire life. It's new to you. It's not new to them. They just don't have a name for it yet. I can’t tell you how many Usher adults I have spoken to who either a) wished they had talked with their parents earlier and/or b) felt some level of resentment that their parents kept the diagnosis from them for a period. Remember, the most important thing in a parent-child relationship is trust and honesty.

Of course, when you do speak to your child about Usher syndrome, you don’t want to freak them out. I can give you some guidelines on what to say, but I can’t tell you the specific words or tone to take. That’s because every child and every situation is different. How and what you would say to a teenager is different than what you would say to a young child. Kids have different personalities and families have different ways of speaking to each other. I’ve known perfectly functional emotionally stable families that love each other who were most comfortable when they were yelling at each other. I can’t tell you what works best. It’s your family.

But I can give you advice on the message you should deliver. So here goes:

Be positive and don’t put limits on them.

Usher syndrome will not prevent your child from living a happy life. Don’t give them the impression it will. There is no reason that they can’t accomplish anything they want to do. When my daughter was born deaf I assumed she would never appreciate music. Now she sings in the chorus. She’s probably not going to win American Idol any time soon, but if I had told her she’d never be able to sing she might never have tried and I would have been wrong.

What to say? “You can accomplish anything you want to accomplish. You just might have to work harder than most to achieve it. But if you really want to accomplish something, if you really are committed to it, no matter what it is, you can do it.”

Now somewhere out there a reader is saying, um, my kid is NOT going to be able to be an airline pilot. I strongly disagree. It might not turn out exactly as they expect, but who’s to say the technology doesn’t change enough to allow them to do it. Heck, if your child is committed enough to doing it, they might be the one that invents the technology that allows them to do it. Don’t limit what they can do.

Tell them the truth and don’t try to predict the future.

The truth does NOT include telling them they will go blind. That is the future and the future is not the truth. The future is a possibility. And don’t even get me started on what, exactly, constitutes blindness. The truth is today and only today. Here’s the truth I told my daughter:

“You have Usher syndrome. You were born with it. It’s not catchy so your brother and Mommy and Daddy won’t ever get it. It’s the reason you are deaf. It’s the reason you have trouble with your balance. It’s the reason you have trouble seeing at night. It also means that your eyesight might get worse over time so we need to see the doctor regularly to check your eyes.”

That’s it. That’s the truth of Usher syndrome as it pertains to my daughter. My daughter might have severe vision issues later in life. We might also find a cure and she never loses her vision. I can’t predict the future. When you tell your child they have Usher syndrome is not the time to turn in to Nostradamus.

Talk about it a lot and talk about it a little

I told my daughter she had Usher syndrome when she was 9 years old (because she was diagnosed when she was 8). She didn’t have any questions about it at the time because, as I said, she was 9 years old. She just went back to playing with her model horses. But that wasn’t the end of the conversation.

When she wanted to go trick or treating with her friends, we said “sure, but remember, you have Usher syndrome and you don’t see well at night so be careful.” When her class held a roll-a-thon to benefit the Decibels Foundation (and raised $20K, by the way), we talked about Usher. we said, “It will be noisy and dark and you’ll be on roller skates. You have Usher syndrome so that will be hard. Do you want to do it?” She did and was better than half the other kids.

The point is we talk about Usher syndrome all the time. We make it part of our lives but we don’t dwell on it. It’s easier to discuss in short snippets. Someday, maybe, she’ll want to have a long conversation about it. If she does, fine. We’ll talk about it for as long as she wants, but that will be her call.

It’s OK to say ‘I don’t know’.

We’re all dummies when it comes to Usher syndrome. No one knows everything about the disease. When your child asks a question and you don’t know the answer, don’t make one up. Tell them you don’t know. Then tell them that you know how to find the answer, because you do know how to find the answer. You know how to get in touch with the leading experts in the world and if they don’t know, well, no one knows. Then contact the Coalition for Usher Syndrome Research. They know all the experts.

Use language to which your child can relate

This part is for Jennifer. If you are a molecular biologist and your child is comfortable discussing the Myosin 7a protein at the age of 3, well, have at it. Most kids won’t get it. Use metaphors they understand. My son Jack asked if Bella was going to go blind. He likes sports. I told him that was a possibility, but Bella had a long time before that would happen and a lot could change. I used the analogy that we were only in the second inning when it came to Bella and you can’t tell how a game will end in the second inning. I’d like to think he understood that language, but by the time I finished my sentence, he’d changed the subject to Pokemon. Which brings us to…

Why are you crying?

You are most likely taking this harder than your child will. I fretted over telling my daughter for months. When I told her, it was over in 30 seconds, she shrugged, and that was it. You just learned that your child has Usher syndrome. You think something has changed. They’ve lived with it their whole lives. Nothing is different from their perspective. Keep it that way. By the way….

Don’t limit them!!!!

Did I mention this already? I did. You know why I’m repeating it. BECAUSE IT’S IMPORTANT! A young woman I know said it best. Again, I'm paraphrasing. She said yesterday you didn’t know I had Usher syndrome. I was allowed to ride my bike at night and I was fine. Today you know I have Usher syndrome and suddenly it’s too dangerous. What changed from yesterday to today besides what a doctor told you?

Exactly. Remember the diagnosis of Usher syndrome is just a diagnosis. It’s not a fortune. It’s not a sentence. To your child Usher syndrome is the only thing they have ever known. Just because you’re putting a name to it and calling it a diagnosis doesn’t mean that anything has really changed for your child. Remember that when you talk to them. Their star hasn’t faded. They can still be anything they want to be.

When Should You Tell Your Child That He Or She Has Usher Syndrome?

2011-03-04T14:28:00.001-05:00

by Mark Dunning

Thanks to genetic testing, we are now able to identify children with all types of Usher syndrome at a much younger age. This is a good thing for a lot of reasons (which you can read here, here, and here). It also presents an unexpected challenge for parents. When should you tell your child that he/she has Usher syndrome and what, exactly, should you tell him or her? I’ve thought a lot about this since a recent conference call we had on the subject (you can read the transcript here). I’ve come to the conclusion that, in my opinion, a child is always ready to learn he or she has Usher syndrome. It is the parents that may not be ready to deliver the news. This does not mean that someone other than a parent should deliver the news. I’m looking at you, doctors. Please don’t deliver the news to the parents in front of the kids or to the kid directly. Let the parents handle. But the parents should only do so when they are ready.

The vast majority of people with Usher to whom I have spoken about the subject say they would have preferred to learn they had Usher syndrome sooner than they did. Not everyone, mind you, but most. That sampling includes teenagers, young adults, and older adults.

One young lady explained it best. I’m paraphrasing here, but she said that before she learned she had Usher syndrome, she felt stupid. She would trip over things the other kids didn’t. She would be unable to see things the other kids saw. She would feel anxious in places like movie theatres when the other kids weren’t. She wondered what was wrong with her. Learning she had Usher syndrome was difficult in many ways, but it was also a relief in others. She wasn’t stupid. She had Usher syndrome. These weren’t personal failings. It was genetic. She could make accommodations to deal with Usher syndrome. She could ask for assistance or bring a flashlight and when the other kids asked why, she could tell them. It wasn’t easier, but it was better.

In my opinion, the earlier a child knows they have Usher syndrome, the better. They become more comfortable with their condition if it’s the only condition they have ever known. They are more willing to advocate for themselves if they have always done so. And the vision issues tend to scare them less if they are very young because 1) they don’t fully comprehend the implications of the disease and 2) their vision is usually pretty good at the time.

Of course, all of this assumes that the diagnosis is delivered to the child appropriately by the parent. You don’t want to explain the molecular structure of the myosin 7a protein to your three year old (Sorry Jennifer). They won’t get it. But telling them that they should take your hand when it’s dark because they have Usher syndrome and that means they might have more difficulty seeing is more than appropriate.

None of this means that a parent who has just received the Usher diagnosis for their child should scoot home and tell the child the news. You shouldn’t. Just because the child is prepared to hear the news doesn’t mean you are prepared to deliver it.

It is hard to understate the strain the news puts on parents. They are in a terribly fragile emotional state for months afterward. Most parents of children with Usher syndrome (and all types of hearing loss, for that matter), do not have a history of Usher syndrome in their family. Few have ever heard of it much less met someone with it. They don’t know what to expect. All they know is that they were told their child had hearing loss and would at some point have vision problems. They hear deaf and blind and think of the lonely child being picked on in school or the homeless man with the cup full of pencils. They feel frightened, uneducated, unprepared, and impotent. In short, they are not in a good position to give sound advice.

So when should you tell your child he or she has Usher syndrome? I think there are two milestones to pass before you discuss it.

Discuss Usher syndrome with your child when you are emotionally prepared to do so.

This isn’t the movies. You don’t need to have the sobbing scene where you choke out the news to your child. Kids can sense when you are upset and it makes them upset. I’ve smashed my thumb with a hammer and started cursing only to see my son go screaming and crying out of the room. When you are hurt, they are hurt. If you are scared, they are scared. Make sure you have your emotions in check before you discuss it.

This does not mean you should be cold or flippant about it. You just shouldn’t turn to jelly before you get to the second syllable of Usher. That’s not as easy as it sounds when you’re looking into the searching eyes of your child.

Just remember that they probably already suspect something is up. They may not know the whole story but they overheard you talking to your husband or your mother or your best friend. They saw you searching the web or reading a pamphlet. They caught you crying in the bathroom or grumpily polishing off a second box of Ho-Ho’s.

I had another young lady tell me the following story. Again, I’m paraphrasing. “My Mom told me that she had something important to tell me. She started to cry which made me start crying and that made my mom even more upset. We were sobbing in each other’s arms and she told me I had Usher syndrome. We cried some more and then I asked her what she wanted to tell me. What was upsetting her so much? My Mom was confused. She said ‘I just told you. You have Usher syndrome.’ I was SO relieved. I already knew that. My brother had heard my parents talking about it a long time ago and told me. I thought I had cancer or something.”

In short, if you are still lying awake every night with tears in your eyes you are probably not ready. You child is ready. You are not.

Learn everything you can about Usher syndrome.

Once you are able to pull yourself off the floor, you should spend some time educating yourself before you talk to your child. This is helpful for a number of reasons.

1) You’ll find out that a diagnosis of Usher syndrome is not the hell you first expect it to be. It’s scary, sure, but most Usher adults are happy and successful. Your child did not get a death sentence. This will help to keep you from losing it when you talk to your child about the diagnosis.

2) You’ll learn that there are a lot of things you can do to help your child right now and that there are even more potential treatments in the pipeline. This will help you should your child get scared when you talk about the diagnosis. It’s good to focus on a hopeful future.

3) You’ll learn how a child with Usher can live safely with few restrictions. Nothing upsets a kid more than to hear that a) they have Usher syndrome so b) they can no longer ride the bike they just rode that afternoon. They can do anything. They just need to be smart about it.

4) You will feel confident that you can answer any question that your child might ask. And remember, ‘I don’t know but I can find out’ is always a good answer.

At that point, grasshopper, you are ready. In the next post I’ll give some advice on what you should say and how you should say it.

New Horizons: Modeling Usher gene therapy treatments in animals

2011-02-01T08:09:00.002-05:00

by Jennifer Phillips, Ph.D.

A study published in the journal Investigative Ophthalmology and Visual Science this month reports on a study that could lay the groundwork for a clinical trial at some point in the future. The laboratory of Jun Yang, at the Moran Eye Center in Salt Lake City, uses mouse models of Usher syndrome to study the molecular basis of the disease.

Last year, Yang and colleagues reported on a ‘knock-out’ mouse family in which the Ush2d gene has been deleted. These mice don’t have the genetic information needed to make a functional copy of the Ush2d protein*, and thus have the mouse version of Usher syndrome type 2, with hearing loss from birth and vision loss later in life.

In this recent report, the Yang laboratory conducted a gene replacement experiment using this Ush2d knockout family of mice. They used a viral delivery system similar to what I’ve described here previously. Briefly, modified viruses containing the genetic code for Ush2d were delivered into the retinas of the Ush2d knockout mice. The basic mechanism is that, once the virus and its cargo is inside the retinal cells, the cellular machinery identifies the Ush2d genetic information associated with the virus and uses it as a template to make Ush2d protein.

So, what happens when you supply the blueprint for making Ush2d protein to an eye that can’t make any on its own? The investigators limited this particular study to assessing the molecular changes resulting from the treatment. Using various methods of visualizing proteins within cells, they determined that:

1. Ush2d protein was made after viral injection.

Ush2d knockout mice don’t make any Ush2d protein at all, so the presence of Ush2d protein in the retinas of treated mice show that the viral vector is successfully delivering its cargo so that it can be used to synthesize protein. Better still, the effect seems quite long lasting. The treatment was given in a single dose at about 3 weeks of age (that’s young adulthood in mousie life cycles), and Ush2d protein was still being made at 6 months.

2. Ush2d protein is transported to the correct cellular location.

As discussed previously, photoreceptors have a lot of specialized parts that help them perform their sensory cell functions. Many Usher proteins are known to localize to the region of the connecting cilium and are thought to be important for cellular functions associated with the cilia. Determining that not only is Ush2d protein made in treated retinas, but the protein is also being delivered to the right place after it’s made, is an important way to demonstrate that the replacement protein is behaving normally once it’s produced.

3. Ush2d protein performs predicted molecular functions.

This was determined by looking for two other proteins that Ush2d is known to physically associate with. These happen to be the other two known Usher type 2 proteins, Ush2a and Ush2c. In the Ush2d knockout mice, Ush2a and Ush2c localization near the connecting cilium is lost—without the Ush2d protein to bind them, these other proteins just can’t stay in the area. In Ush2d knockout mice treated with the virus, Ush2a and Ush2c proteins can again localize to the connecting cilium region—further evidence that the replacement protein should be capable of restoring normal Ush2d function.

The other part of this study dealt with the safety of the treatment. Viral delivery systems are pretty routine at this point, but it’s still important to show that this particular virus with this particular cargo doesn’t do any damage to the tissues of the eye or any other part of the body. These are, of course, important prerequisite experiments for any approval of a clinical trial.

Electroretinograms were measured from treated mice and other tests on the retinal tissue were performed to demonstrate that the intervention didn’t lead to retinal damage or other problems with visual function early in life.

So, this is promising, but there’s a fair amount we still don’t know about this treatment that needs to be sorted out before the next step is taken.

Primarily, we still need data on whether or not this treatment actually helps the Ush2d mice see better. We know that the protein itself seems to be doing all the right things in there, but is that going to translate to better vision for the mouse—and, hopefully some day, human USH2D patients?

I hasten to point out that I’m not criticizing the paper in any way for not including this information. In general, if scientists waited until they had all the answers to every possible research question before they published, well, they’d never publish! For this study in particular, there’s an extremely valid reason why the information is missing and that’s because the loss of visual function in Ush2d knockout mice isn’t detectable until after 2 years of age, which is really pretty old in mouse years. They can detect changes in the structure of the retina before then, but the ERGs are normal before then. Clearly any report of functional improvement with this treatment is going to have to include these late-stage analyses.

Once they have a sufficient number of mice raised to older ages, there are several smaller issues to address as well, such as the optimum time of treatment. From this recent IOVS report, we know that protein is still made ~5 months after treatment, but how much longer will it last? Will it have enough staying power to make a difference at that 2-year time point? Will supplying functional Ush2d protein earlier in life forestall the later effects regardless? Mouse and human lifespans are obviously very different, but these sorts of preliminary experiments could provide crucial information for planning any forthcoming clinical trials.

Dr. Yang’s team has done wonderful work on this model thus far, and I look forward to what the next phase of this investigation will tell us about progress toward a potential treatment.

*Note: in the literature this protein is often referred to by the name ‘whirlin’. For simplicity’s sake I have substituted ‘the Ush2d protein’ in this article.

References:

Yang, et al. (2010). Ablation of whirlin long isoform disrupts the USH2 protein complex and causes vision and hearing loss. PLoS Genetics 6 (5): e1000955

Zou, et al. (2011). Whirlin replacement restores the formation of the USH2 protein complex in whirlin knockout photoreceptors. IOVS 10-6141 (published ahead of print January 6, 2011).

Follow-up On The Need for an Usher Registry

2011-01-24T15:10:00.002-05:00

by Mark Dunning

The registry idea is clearly a hit. We’ve gotten more comments on this posting than any other. Rather than respond to each individual comment (and since I clearly forgot some important details), I figured I would do another post with answers to the most common questions.

Who would administer the registry?

The intention right now is to have the Coalition for Usher Syndrome Research build and administer the database, though that could change. The Coalition is a 501(c)3 not for profit organization dedicated to supporting Usher syndrome research by engaging families in the process. The Coalition has a web site [www.usher-syndrome.org] (which is how many of you found this blog) and already maintains a database for the Usher Syndrome Family Network. The intention would be to hire staff and to engage volunteers to administer and promote the registry.

Why not use an existing registry from a larger institution with more resources?

There are a number of reasons. 1) There are few Usher specific institutions out there and none with any real size. That means that we would be lumped in with other conditions where the goals of Usher families might not always be the top priority. 2) Universities, hospitals, and fund raising organizations all compete at some level. While most try to be open in their sharing of critical data, that’s not always the case. 3) Many of these larger institutions have a lot of rules governing the collection and sharing of data that might restrict or delay the availability of that data. We want to be quick and nimble. Remember, the goal here is to quicken the pace of research.

Who would ‘own’ the data and what entities would have access to this data?

The Coalition for Usher Syndrome Research is ultimately a family focused organization (6 of 11 board members either have Usher or have family members with Usher including, for purposes of full disclosure, me). The IRB would have a similar makeup. Usher families would determine the access to the data so Usher families would ultimately ‘own’ the data. As such, any legitimate researcher or support organization with a legitimate need would have access to the data. Of course, data sharing would have to meet HIPAA guidelines for confidentiality, but it’s hard to imagine a scenario where any legitimate organization with a desire to advance research that would help Usher families would be denied access to the data by those same families.

Great idea. How can I help?

Remember the first question about administering the database? Well, follow this logic: We won’t have to hire anyone if we get volunteers to do it. If we don’t have to hire anyone we don’t have to get the funding to hire someone. If we don’t have to fund a position that money can go to the development of the registry rather than to pay someone to manage it. And finally, if we don’t have to raise the money, we can focus on building it rather than paying for it. Make sense? So…

Volunteer to help administer the registry: We need people to help take questions about how to use the site, to schedule IRB meetings and set the agenda for those meetings, to take data requests from researchers and to help fill those requests, and to help those with low vision to enter their data whether it be online or over the phone or via a visit to a home to write it on paper. If you help administer it, the registry will begin paying dividends sooner

Volunteer to help with the design, testing, and quality assurance of the registry: When we begin building the system we’ll need families with Usher to help with the user interface design, to test the ease of use, and to ensure that everything works as intended.

Volunteer to promote the registry: The key to the success of the registry is getting families involved. To capture the information of every family we first need to let every family know about its existence and explain its importance. That’s going to take a lot of people spreading the word to make it happen.

Enter your data: Not just on day one, but going forward as well. We’ll most likely have new questionnaires coming online over time. The more you tell us about yourself, the more it helps us learn about the progression of the disease.

Donate to the cause: I hate to even mention this because it is not the intent of this blog to solicit funds. However, there are a lot of busy people out there who would prefer to help the effort monetarily. If you are one of them, you can contact me directly to discuss how you can help. I can be reached at m.dunning@lek.com

Obviously that same e-mail works for volunteering as well, which, quite frankly is more important than the financial support.

Thanks to all those that submitted comments and keep them coming!

Why We Need an Usher Syndrome Registry

2011-01-21T13:09:00.000-05:00

by Mark Dunning

Let’s start with some good news. There are a number of treatments nearing clinical trial that could potentially help people with Usher syndrome. There are an even greater number of areas of interest that researchers think might be the source of future treatments but which are as of yet fairly unexplored. In other words, there’s a lot of hope for the future for families with Usher syndrome.

But the pace of discovery is slow, much slower than most families would like. I won’t discuss all of the reasons here today, because there are a lot. Instead, I’m going to focus on one of the main reasons:

Researchers have access to too few Usher syndrome patients and have too little information about most of those to whom they do have access.

Now, again, there are reasons why we know such a small percentage of information about a limited number of Usher families and, again, I’m not going to get in to that today. Today is about one step to solving that problem.

The idea is to create an Usher syndrome registry with the grand goal of identifying everyone with Usher syndrome in the world. OK, so we won’t actually find everyone, but that really is the goal. After all, how can we help them if we don’t know who they are?

The registry would be voluntary and secure. A family would only have to submit what they were comfortable submitting. At a minimum we would need a name, type of Usher, and a means of contacting the person. Families would be given the option to supply more demographic information if they chose (address, age, place of birth, doctor’s name, etc.) In keeping with HIPAA guidelines, information that would allow viewers of the data to identify an individual would be accessible only on a need to know basis by the few people that administer the registry.

Once we gather this pool of Usher patients, researchers could begin to ask them questions via questionnaires. The information gathered would help us to learn about the true nature of how the disease works. For instance (and I’m making this up here), a question about how many apples you eat a day and a question about your rate of vision loss might just show that people that eat more apples appear to have a slower rate of vision loss. If we were able to ask that question of everyone with Usher syndrome, we’d have a pretty good idea if apples would be worth investigating as a potential treatment for the vision loss component of Usher syndrome. Again, I making this up. We have no idea if apples help. But that’s the point. We have no idea because we have no means of asking the question. A registry would give us that means.

Questionnaires would be subject to strict review before they were presented to families. An Institutional Review Board (IRB) made up of well respected, experienced Usher researchers as well as Usher families would scrutinize the questions, the purpose, and the value of the questionnaire. Once approved, registered families would be given the option of filling out the questionnaire. They would not be required to do so. And, again, the researchers would have no access to the registry information so they could not coerce anyone to fill out a particular questionnaire.

Data gleaned from these questionnaires would be available to any credible researcher. Again, a request for data would have to be approved by the IRB but the data would be owned by the families, not by any institution or researcher. We want as many researchers to have as much data as possible. Limiting access only limits the pace of treatment development.

As clinical trials begin for treatments, researchers could ask the IRB for the right to contact potential candidates in the registry to gauge their interest in participating in the trial. The researchers would never be given demographic information, however. In keeping with HIPAA requirements, they could request that the administrators of the registry contact individuals that meet certain criteria (age, type of Usher, location, etc.). The researcher would be asked to develop a one page document describing the trial and the participation requirements. This would be given to the registry administrators. The administrators would pull the appropriate list and the administrators, not the researcher, would send the families information about the trial along with the contact information for the researcher. It would then be up to the family to determine if they wanted to contact the researcher or not.

So let’s look at where this registry get us:

1) Families know that they will hear about any treatments going to trial that might be appropriate for them.

2) Families can not only contribute to the search for treatments, they can increase the pace at which they are found simply by sharing information about themselves.

3) Researchers can have access to information about Usher syndrome and have a means for answering questions which does not exist today.

4) Funding for research would be easier to attain because researchers would be able to better demonstrate the potential correlation between a particular activity (eating apples, say) and a positive outcome (better vision longer).

5) Pools of potential candidates for clinical trial would be readily accessible.

But wait, there’s more. This registry could also be used to connect families. The Usher Syndrome Family Network could be incorporated in to the registry. A family that registers could choose to share the contact information automatically with other Usher families. And because the registry is secure, they could choose to share it with only certain Usher families (only families with children under 5 or families in the US, for instance). Better still, since the registry would be accessible online, a family could change its mind at any time and decide to no longer share certain information or to begin sharing certain information.

Beyond research, such a registry could be used to contact families about conferences or support networks or just about anything else deemed appropriate. But, again, any contact with the families would have to be approved by the IRB so people in the registry don’t get spammed and the communication would come from the administrators to protect the identities of the families.

Can you tell that I like this idea? It addresses the fundamental problem of access to information for both families and researchers. If it’s done right, it can not only be secure and safe but it could also accelerate the pace of discovery and help bring treatments to our loved ones more quickly.

How to Be a Bad Parent

2011-01-11T15:05:00.001-05:00

by Mark Dunning

It’s winter here in Boston and that means runny noses, Nor’easters, and home skating rinks. For those of you in warmer climes, the concept of a home rink is probably foreign so I’ll explain how it works.

1) Pick out a spot in your yard which is open and grassy for your home rink. This spot will soon be open and not so grassy.

2) Put up a veritable shanty town of boards and plastic sheeting in the open and soon-to-be-formally grassy area.

3) Run out the hose and pour untold amounts of water into said shanty town until it is roughly 4 inches deep everywhere. Of course, since the open soon-to-be-formally grassy area is most likely less than level, expect bare plastic in one corner and a foot and a half of water in the other.

4) Pray for cold weather so that the ugly swimming pool turns into an ugly skating rink and kills all the grass beneath it.

5) Spend the next eight weeks either shoveling snow off the ugly skating rink or sinking your arm elbow deep into frigid water in an attempt to duct tape the latest leak caused by errant skate blades and vindictive moles.

6) Skate twice.

7) Remove the eye sore, spread grass seed, and repeat when the first snow flake flutters past.

Bella's hockey playing little brother

Last night was the first of those two times that we’ll skate on our home rink. My daughter Bella and my son Jack spent a couple of hours on the ice. I mean that quite literally for Bella. Jack plays hockey. Bella plays Zamboni. She spends most of her time either in a heap on the ice or suspended in the air about to become a heap on the ice. Jack stickhandles around her like she’s a giant highway cone. Of course she doesn’t always stay in the rink when she falls. Often she’s bottom up in a snow bank having gone screaming over the side. We pull her loose by her skate like she’s a cork in a wine bottle, help her clear the snow from her helmet, and send her back on her way.

It doesn’t help that she wears skates that are either three sizes too big or two sizes too small. We try to buy her skates every year, but she’s growing like a kudzu these days and it’s tough to keep ponying up for skates she’ll wear twice before she outgrows them. So she borrows her mother’s skates which look like two white battleships on her feet.

As you might imagine skating and Usher syndrome don’t go well together. The rink is lit by spotlights from the house and by several work lights, but there are lots of shadows out of which the aforementioned hockey playing little brother darts. And those giant skates give her lots of room to wobble. We pad her up well, with hockey pants, shin pads, elbow pads, and a helmet complete with a cage. She looks more like Jason Voorhees than Dorothy Hamill. If her bottom is especially bruised from previous crash landings, we might stuff a couch pillow in which gives her the appearance of a giant baby with a loaded diaper. Twelve year old girls, especially those that attend pedicure birthday parties these days, love looking like Frankenstein’s toddler.

Ah, but here’s the thing. She keeps going out. Every year we build the eye sore and every year we buy more padding and every year she goes out, gets airborne a few dozen times and lands like a Cessna in a gale. In between deposits in the snow bank, she’s learned how to snow plow to a stop, wobble her way backwards, and even to do a crossover. Again for those in warmer climes, a crossover is the act of stepping one skate across the other. It’s used to maintain speed while turning. You need to lean to the inside a little, stand on one skate for an instant, and lift the other over all while moving at a pretty good clip. Like skating, it’s not something a person with Usher, at least Bella’s type 1, is supposed to be able to do. Yet she does it.

The point is this. It is hard for family members to know where to draw the line on safety versus desire when it comes to our loved ones with Usher. I write this from the perspective of a parent, but I hear similar concerns from children with Usher parents, from spouses, and from friends. We don’t want our loved ones to get hurt, physically or emotionally. But there is a great risk to being over protective. Separating people from their dreams and desires is often more harmful than letting them risk failure. What’s the point of being alive if you’re not allowed to live?

We have one rule for the home rink: “No dyin’ and no cryin’”. In other words, you can do anything you want as long as you don’t kill yourself or get hurt/hurt others to the point that you/they cry. Seems to me like that’s a good measure for people with Usher syndrome, too. As long as there’s not a high percentage risk of death or injury, have at it.

So here’s my home rink worthy advice: Pad them up and send them out. Do what you can to make them safe as long as it falls short of discouraging them from trying. They will figure out when or if it’s time to quit, but it will be their decision, not yours. It’s a lot easier to live with a choice when you’re the one making it. Trying something they’ve always wanted to try, tasting life as it were, is often all that is desired. They might find themselves skates up in a snow bank but at least they got on the rink. Failure IS success when the alternative is never getting a chance to try. And you never know, they might just learn to do a crossover.

As for Bella and skating, I suspect she’ll decide sometime soon that she doesn’t want to skate any longer. She’s almost a teenager and falling like the scarecrow from the Wizard of Oz while bundled up beneath a crash helmet just isn’t going to work for her. She’ll want to be more Mariah Carey and less Jim Carrey. One day soon I’ll ask if she wants to skate with Jack and me and she’ll give me the stink eye and go back to texting her friends. That’s fine. That’s what all young girls do to their dads, whether they have Usher or not. It might not be my choice, but it will be hers.

Should Auld Acquaintance Be Forgot?

2011-01-05T11:43:00.002-05:00

by Jennifer Phillips, Ph.D.

It’s New Year’s Eve as I write this. The end of a week of feasting, hilarity, family bonding and general merry-making is nigh, and we have just one final celebration in to get through before we start reinstating regular bedtimes, diets, and schedules again. I haven’t been completely out of touch with the world of science, however, as I’ve been working long hours preparing a manuscript for submission. It’s a labor of love, to be sure, combing through pages and pages of carefully laid out results, multi-panel figures, looking for opportunities to make tiny improvements and (hopefully) spotting glaring omissions before the reviewers find them. It’s the summation of several years’ worth of work, done by many collaborators around the world. In short, my co-authors and I have much time and effort invested in this project, and I’m hopeful that it will be of some significance to the greater Usher community when it finally sees the light of day.

These final labor pains have prompted me to reflect upon an exchange I had a few weeks ago. As I have mentioned previously on this blog, I volunteer for scientific outreach opportunities quite often—school tours, demonstrations, Rotary Club lectures—I’m there, spreading the science-y goodness around. From time to time people in my personal realm express some interest in seeing what I’m up to in the lab, and I’ll cheerfully invite them in for the nickel tour. So, I was not put out in the least when an acquaintance emailed me to ask if he might schedule a time to take a tour of our research facilities. I readily agreed, and we exchanged a few messages about good dates and times. And then…it got sort of weird. The e-mails continued, but a curious tone of reluctance began creeping in. Was I sure it wasn’t too much trouble? I must be very busy…Really, it seemed so selfish to take up my time with such a silly request…I should feel free to cancel…and on and on like this. I responded to each one with a brief and chipper ‘no worries! Come on along!’ sort of message, but I was beginning to wonder what was up. The last communication, though, really left me speechless:

“Before I let another word appear on the screen, I have to admit something about my own philosophical/epistemological make up:

I don't know three things about the world around us. And even though I enjoy tinkering with the methods and conventions devised and developed by human beings, it all seems kind of tinny to me. So I'll understand if you would like to withdraw the open invitation for my visit.”

Um…ok. So, trying to understand the world—to ‘know’ things that might have some impact on reality—is, apparently, considered a fairly ineffectual use of time by people of a certain ‘philosophical/epistemological make up’. In other words, this acquaintance doesn’t really respect what I do, and seems to think efforts to understand anything are futile, but I guess I have to give him credit for being up front about it. Imagine how silly I’d feel dragging him all over the lab facilities, gushing about how many brine shrimp we produce each day to feed the many thousands of zebrafish housed here, or what my latest histological experiments had revealed about the genes I study, not realizing in my blinkered, materialistic stupor how ‘tinny’ it all sounded. Yes, ‘tinny’. Defined (I assume, as this is the only definition that makes sense in the context of the original message) as weak, flimsy, or shoddy. Yeah.

Figure 1: Captain Picard probably gets e-mails like this all the time.

I’m a little piqued about this, can you tell? I’m mad because it’s just so dang passive-aggressive and rude, for one thing. I have great respect for a wide array of different philosophies. However, the whole post-modernist ‘you can’t really know anything’ position really puts my teeth on edge, as it is so utterly antithetical to every scientific discovery—great and small—that has ever sought to understand or improve the human condition. Are there universal wonders and conundrums beyond our comprehension? Heck yeah! Does that mean we, as a species, should just lie back, contemplate the Mystery and quit trying to understand any of it? Heck no!

I’m mad because of the ignorant bliss conveyed by this acquaintance’s admission. He’s spared the tedium of thinking about scientific questions because other people are doing it for him. Other people are supplying his engineers with updated figures on the tensile strength of new materials; his computer designers with the technology for building faster processors; his physicians with the latest research on physiology and molecular biology. To some degree we’re all guilty of this—I freely admit that I don’t know very much about how my car engine works, for example. But lots of people do know how it works at a level of detail sufficient to repair or build a car engine. I could know, if I chose to take the time to study it properly, but the fact that I choose not to do this doesn’t make the mechanism of the combustion engine any less important, in the empirical sense. To believe otherwise would seem shockingly arrogant.

It occurs to me that this acquaintance is a really lucky—if scandalously incurious—fellow. All the science and technology he needs to improve his life can carry on with the business of improving it without recognition or appreciation from him. And, importantly, neither he nor anyone close to him is suffering from any absent or incomplete application of science. He doesn’t have to stop and wonder, “Was there a new discovery today that might help my child keep his vision?” And while I certainly don’t begrudge him the good health and privilege that has allowed him to cultivate this world-view, I’m mad on behalf of all the people who don’t have that luxury.

Usher syndrome is complicated. No one knows everything there is to know about it yet. Most of the people whose lives are affected by it don’t understand the biology and chemistry required to comprehend what is know about it, at a genetic, cellular, or molecular level. But I’d wager that very few of the people who fit into this category would tell those of us who are actively engaged in studying these very subjects that our efforts were rather meaningless; that we couldn’t really come to ‘know’ anything useful from our studies. As our discoveries about Usher syndrome lead to better diagnostics, and, eventually, to treatments, it will certainly not be required that every patient receiving these advanced standards of care have a Ph.D. level understanding of how they work. But I doubt very many of you would want to pursue such a treatment without some assurances that someone had done the work necessary to understand it. I think most of us realize that although there will always be some uncertainty in life, there is value in trying to increase the number of facts we can be reasonably sure of.

So, scientific outreach proclivities aside, I haven’t mustered a reply to that last, facepalm-worthy message. I honestly can’t think of an appropriate response. Should I re-re-re-reiterate my invitation and assure him that there is no philosophical prerequisite for touring the facility? Should I try to convince him that, although I can’t absolutely prove that the universe isn’t a computer simulation, I still think dedicating my life to understanding a little more about the mysteries of Usher syndrome is one of the best choices I could ever have made? Should I just let him off the hook from taking a tour he’s clearly ambivalent about? Should this particular acquaintance be forgot, and never brought to mind?

I haven’t decided what to do yet, but in the meantime I have poured every ounce of effort and clarity of thought into a soon-to-be-submitted manuscript that represents the scientific output of myself and others trying to shed a little more light on Usher syndrome. That means something to me. It is the farthest thing in the world from ‘tinny’.

A New Year is upon us. May it be filled with memorable, meaningful times, great discoveries, greater understanding, and, above all, hope.

The Gift

2010-12-21T12:39:00.001-05:00

by Mark Dunning

I spend a lot of time in this blog writing about the desperation of Usher syndrome. I write about the fear that we all feel, the fear of what the disease might one day take from us. But it’s the holiday season s and for today, I’d like to talk about the flip side of that fear. I want to talk about the gift of Usher syndrome. First a quick story:

I met a fascinating man in London last week or, rather, I was reintroduced to him. I was traveling on business. My company’s home office is in the city. I have been with the company for 12 years now and when I first started, the Chief Financial Officer was a volcanic man, legendarily crass and vicious. Staff of all levels feared approaching him for he was wound so tight that the mere quiver of a voice could cause him to explode. When he was terminated a few years later for telling the Chairman to perform and unnatural act on himself a few too many times, there were streamers in the sky and Eewoks dancing in the trees. Tears were shed, but they were born of joy and relief. A time of great evil had passed.

So imagine my surprise when I was invited out by a large group of those I have worked with for a long time to go have a few pints with the very man described above. Stranger still, they were positively giddy at the prospect. He is a changed man, I was told, you will hardly even recognize him.

Well, I recognized him as soon as we walked in to the pub. He still had the same salt and pepper hair, the same glasses, the same roundish physique. There was only one noticeable difference. He was smiling. A lot. And he greeted everyone warmly, like he’d been anticipating the evening with relish. Before long he and I had a chance to talk alone and he told me his transformational story.

He had never liked his old job. Never liked the pressure. It wore on him every day, cranking him tighter and tighter and tighter until he could not help but explode only to be wound up again. After he was fired, he tried similar positions, always with the same result: pressure, explosion, and termination. Finally he reevaluated his life and thought about what he really enjoyed, what he really wanted to do, what would really make him happy. And the answer was clear.

He wanted to go to the pub, drink beer, and talk with friends.

That’s it. That’s what he enjoyed most. Well, it’s a little more than that. He didn’t want to just slink off and become some drunken sod propped on the corner bar stool. He wanted to experience lots of pubs and lots of beer and make lots of friends. He wanted to talk philosophy and sports, politics and love. He wanted a fulfilling life surrounded by people he enjoyed. He wanted to be happy.

His termination was the catalyst that committed him to action, but it was not for several more years before he found his opportunity. His epiphany came in the form of a contest. It was a beer tasting contest that included an essay and speech on why you liked a particular beer and what, exactly, beer meant to you. The winner was to be named ‘Official Beer Taster for the City of London’.

He entered, spilled his passion before all to see, and won. Now he writes a blog on beer and is paid several thousand pound a year to travel the city, visit the pubs, and have a few pints with friends. He is invited all over the world to beer festivals and brewery openings. And he is undeniably changed for the better. He is now one of my heroes.

But I have lots of heroes these days for his story is not unique, at least not in the world of Usher syndrome. You see we, too, find ourselves reevaluating the rubble of our lives. Yes, the man above chose his stresses while we had ours thrust upon us, but it doesn’t really matter what started the fire. All that matters is that the house burned to the ground.

In blowing away the ashes, I have uncovered the most amazing stories of success. People with Usher syndrome are not supposed to be able to ride horses or to dance or to sing in a chorus, but my daughter does. People with Usher are not supposed to travel Europe or speak multiple languages or be accepted to study at University College London, but I had lunch last week with a young lady with Usher who did. They are not supposed to pack up a van with other young deaf people and drive from the UK to India (yes, India!), but I dined last week with a woman who had. They are not supposed to climb mountains or change the ways of the US Senate or win awards for their charitable efforts when they are still teenagers or be invited to stand beside the President at a bill signing, but I know people with Usher who have done those things, too.

This past year I have traveled to Spain and Denmark. I have dined with friends in London and had a barbeque on a beach in Seattle. I have made new friendships with people in Taiwan, Australia, Greece, France, Israel, the Netherlands, Sweden, and Germany. I’ve watched my daughter speak at MIT and been taught genetics by professors at Harvard. I’ve run a road race and seen my daughter win a blue ribbon in a charity horse show. None of it happens without Usher syndrome.

I hope you don’t take the above paragraph as pretentious or promotional. It is simply to marvel at my family’s good fortune. My life, my daughter’s life, and those of the people described above are deep and fulfilling not in spite of Usher syndrome, but BECAUSE of Usher syndrome. Like my friend the beer taster, we all were forced to reevaluate our lives and to think about what we really wanted to accomplish. We all recognized that time is short and that the time to act on our dreams is now. Because time IS short. It’s short for all of us, regardless of whether we have Usher or not. The clock on our mortality is always ticking. It’s amazing how few people recognize that fact and how many fewer act because of it.

The beer taster and I talked about that over a pint. We talked about the massive river of commuters we saw in Victoria station plowing from somewhere to somewhere else. We wondered how many of them were really going where they wanted to go and what it would take to cull them from the herd.

For him it took a conflagration to cut him loose. For my family and me, and the many, many, many people I have been blessed to meet, it was Usher syndrome that changed their course. We all know the potential dangers that lurk out there, but at least for today we should see the good in Usher syndrome. It builds more families than it tears down, welds together more people than it separates, and enriches more lives than it ruins.

I still would not choose Usher syndrome for our family but I’m thankful we received it as a gift.

Happy Holidays.

Mentor torment

2010-12-07T15:53:00.000-05:00

by Jennifer Phillips, Ph.D.

Time passes in the research lab marked by scientific conferences, submission deadlines, and project completion. There’s not much awareness of the academic calendar for those of us who don’t teach regularly, but from time to time we host a new graduate student for a 12-week stint that corresponds to our academic quarter system, which tends to wake us up to the fact that we actually work at a University (well, ok, that Oregon Duck Football thing is kind of hard to miss, too).

In most of the science disciplines, incoming Ph.D. students spend their first year ‘rotating’ through different labs they think they might be interested in. They usually complete a short, focused research project during this time, but it’s generally less about gathering scientific data than it is about an opportunity for the student to gather general information about the projects and personnel in a given lab and determine whether it would be a good place in which to pursue Ph.D. thesis work. Similarly, the lab personnel use this time to judge the performance and compatibility of the student, and at the end of the first year students select a research group to join.

Our lab had one such student—I’ll call her “RS”-- for the first term of this year’s rotation cycle, which is now in its final week. RS completed a very nice project in line with the Usher focus of the lab, and will give an oral presentation mere hours from now summing up the results obtained in the past 12 weeks. And herein lies the first great hurdle of first year Grad students: the bane of the short-format talk. These oral presentations are 10-12 minutes in length, during which time the speaker is required to give enough background on the topic to give their specific project relevance, present the results of their particular experiments (assuming there are any), draw conclusions from their findings, relate them back to the big picture, and graciously thank the members of the lab who helped them complete the work. This is followed by questions from the audience. Sounds simple, right? Except that for the neophyte researcher, it can be completely overwhelming and terrifying. Scientific presentations are different from nearly every other kind of public speaking, especially in the short format talk. Words must be chosen prudently, for maximum precision and impact. The data presented must be explained clearly and credibly, and the speaker must have sufficient grasp of the material to do this and field questions at the end of the talk, possibly from crotchety skeptics who didn’t buy a word of it. It’s a humbling experience, and it’s hard to do well right out of the gate, which is why everyone in my lab has been working overtime to whip our little RS into good shape for her presentation.

Frankly, it hasn’t been easy going, for any of us. RS did great work on her project, and actually has some pretty cool data to talk about, but she’s had trouble putting her work in context with the larger lab focus, namely our exploration of the molecular basis of Usher syndrome using zebrafish. There’s no denying that this is a daunting topic. Understanding Usher syndrome requires absorbing some amazingly complex cell and molecular biology, and it would be unreasonable to expect a student at the beginning of her scientific training to take so much on board without a struggle. Nevertheless, while one shouldn’t expect a perfectly polished, Nobel-laureate caliber talk from a first year Grad student, it serves as a useful vehicle for facing down the second great hurdle most of these newbies face: changing from informational learning to investigative learning. Think about it: every scholastic experience, from kindergarten through four years of college, is about absorbing canonical information from a variety of sources—books, video, instructors—all filling students’ heads with facts to be memorized and related to other, previously memorized facts. Training to be a professional scientist begins with the realization that, while there are still many facts to be learned, YOU, the researcher, are now required not just to learn them, but to vet them, and eventually, to produce them yourself. It’s a pretty significant paradigm shift, and one that a lot of students struggle with.

That’s where our intrepid RS is now: at the beginning of learning to question…everything. At the beginning of the realization that overstating a result, or putting too much stock into a hypothesis, or any number of other credulous rookie mistakes, can get you into big trouble. So we’ve been listening to her fun through practice talks, spending hours poring over every PowerPoint slide, nitpicking her every word, hammering her on the need to back up or back off her often overstated claims. Would it be simpler to take it easier on her and just let her give the talk she wants to give? After all, she did great work at the lab bench, got along well with everyone else in the research group, and generally had a good rotation experience. Is this 11th hour torment really necessary?

In my view, we’d be doing her no favors in the long term by giving her a pass on a sub-par presentation. We do have to torment her, constructively, just a little, because this is part of the training. Because most scientists will only ever get to work on one very tiny piece of a very big puzzle, and understanding the background and relevance of the work is a huge part of being able to formulate a scientifically and financially tenable project. Moreover, scientists who do good work but can’t effectively talk to other people about it tend to have a much more difficult time getting support for their ideas.

So, while I remain sympathetic to the enormity of her task, I will continue to try to impress upon RS the importance of choosing the best images and the best words to go with them. She may be stressed out, frustrated, and relieved when it’s finally over, but maybe the challenges she’s meeting now will make her next talk a little easier to get through. And maybe, just maybe she’ll decide that a project focusing on a complex disease like Usher syndrome, and coworkers who challenge her to be precise and focused in communicating science might provide the best environment for her scientific training.

I hope so, because we need more talented researchers working on Usher syndrome, now and in the future. We need fresh perspectives and innovative ideas that will be grounded enough in good, rigorous science to withstand criticism and contribute to our growing body of knowledge about what happens in this disease and what tools we can develop to stop it. We academic Usher researchers are not only in the business of discovering new things about the disease, but also of discovering and cultivating new talent. For that reason we need to keep our intellectual standards high, to continue to hammer prospective contributors on getting it right, all the way down to the nitty gritty. This is not just to benefit lab productivity in the short term, but to benefit the entire research field, and, most importantly, the Usher families who are relying on us to come up with something to help them.

Whether RS, in the fullness of time, will become the next great Usher researcher, or indeed whether she will even choose to join our lab remains to be seen. Whatever the case, we have provided her with the first exposure to Usher syndrome research, and the rigor and critical thinking necessary to succeed in this field. Furthermore, we have added one more to the total number of people in the world who know a bit about how Usher syndrome works and what’s at stake for the families affected by this disorder. And, when RS delivers what I’m sure will be a completely awesome talk, she’ll use her 10-12 minutes to enlighten a few other people who, until today knew nothing about Usher syndrome. There’s no way to predict the potential impact of these presentations on anyone in attendance, but this is how new ideas and collaborations are born. These students, these talk formats, provide yet another opportunity to spread the word and raise awareness of what we’re all working so hard to conquer.

Here’s wishing everyone a joyous and peaceful holiday season.

Living With Ushers Syndrome

2010-11-29T09:48:00.001-05:00

by Molly Watt

Editor's Note: Molly has been a guest blogger on this site in the past and wishes to share more of her experiences. Her past posts have been among the best received on the site. It's no wonder. She was recently named 'Young DeafBlind Person of the Year' by SENSE in the United Kingdom. As always, we're thrilled to welcome her involvement.

20th August 1994, a very special date might I say. I’m Molly, I’m 16, I have one younger sister and two older brothers, and I have lived in Maidenhead all my life. No, it doesn’t end there, behind all smiles; there were a few complications! At 18 months old, as cute and cuddly as I was, mum and dad could sense there was something that wasn’t quite right. Mum was getting worried that I wasn’t responding when my name was called. So I was taken for some hearing tests, and it proved I was in fact moderate-severely deaf. This was a tough phase for my parents, they were distraught, I was too young really to understand any of it, would you know what you’re doing at 18months old?

So I was given my first hearing aids, which I detested right from the beginning, I would hide them under the sofa, In the toilets- anywhere but my ears! I attended Wessex nursery, at 3 years old, it included a hearing impaired unit. This is where I met two girls both deaf, and I remained very close to them both, one of which I’ve lost touch within age, and the other I now attend Mary Hare with. I grew up with a hearing family, so I had always been a very oral child, with many hearing friends. After nursery, I then went on to go to Oldfield Primary, no hearing impaired unit, no hearing impaired friends. I had a teacher for the hearing impaired, called Jane Perry, I bonded with her very quick, and we had a great relationship. This is of course, when we had our one to ones, I developed more oral skills. I was always the ‘odd one out’ but I grew up with that, and got used to it. It never occurred to me that I was different to the others at a young age. I always quoted, “I’m not different, I’m unique.” I mixed in very well with all hearing people, and lingered in the hearing world.

Mum always wanted me to grow up in the “real world,” she wanted me to be able to communicate with everybody, not just deaf people. I was happy with that, I was always happy, as far as the eye could see, I was coping well with my impairment and lived life like any other, could it really get any worse?

Well, not for another 6 years! A few more years later, when I got toward the end of my Primary school years, at 11 I started recognising some difficulties in my sight. I started walking up to the white board to read what was written, I felt reasonably clumsier than before, and I was constantly getting headaches. I reported this to my parents throughout year 6. Our instinct was that I might of needed prescriptive reading glasses to release strain of the eyes. At the time, I quite liked the idea of wearing glasses! So we went for a routine eye check, and shockingly it lasted hours. There I was perched on this big chair, with not one, but many eye opticians, gawking intently into my eyes, repeating the same tests with every possible instrument that had in the room! What was I thinking? I wasn’t sure, I didn’t understand it, I’d never had an eye check before- many hearing tests, but never an eye check, maybe eye checks were supposed to be considerably longer? After a long tiring few hours of remaining present in Vision Express, it was time to let my parents know they had found something peculiar, something they had never viewed before. I was too busy choosing frames for my reading glasses with my younger sister, too busy to notice my parents having a very sensitive conversation with the optician. That was all a mystery for a while, I still had no clue, and just finishing year 6 meant I had to make a big decision. So I had other things on my mind then; which secondary school? Decisions are never easy. Before long, I chose to go to Cox Green School, a mainstream school, that was in fact round the corner from where I had attended nursery, so Cox Green had actually seen through a few deaf people and had experience, perfect! ...Not for long, when people in my year were becoming 13, they had big parties, I got invited to lots of them, I thought, “Oh wow, a party, a chance for me to socialise and have a bit of fun!” After going to a few of them and realising my eyes were starting to affect my confidence. One party I remember, I walked in and it was pitch black, I recall thinking, “I’m not going to enjoy this,” I was struggling to walk across the hall without someone’s arm to hang on to, I felt so overbalanced and unsafe that I was going to fall off a step any moment.

This isn’t normal? Why can’t I see people’s faces? Why do I trip up on steps? As a result of this, I’d return home in tears, devastated, and stopped going to parties altogether. After being at Cox Green 2 years, things were getting rather tough. By then, I had an idea that I had some sort of eye condition, that I had restricted sight and poor vision in the dark, so I had extra help for modified papers at school, and I relied more on my friends to hold on to me when I was out and about. After having many meetings with visually impaired teachers as well as hearing impaired teachers, I got a bit curious. I was falling over at school, finding it hard in crowded places, I started to isolate myself at home, I didn’t have much understanding of what was going on.

At home, I began to question my parents about my scenario. It all got out one day, mum and I, have a really close friendship as well as a mother daughter bond, so when It was out, I felt comfortable to turn to her and talk to her about how I felt. I recall being sat in our car, mum started asking me what I could see our of my peripheral side, “Can you see my hands? Can you see the steering wheel? Can you see your window? I told her what I could and couldn’t see. Mum went silent, was she just concentrating on the road? I thought. I thought this was a good time to ask about my eye condition, I wanted to put a name to it. It all got exposed, emotionally. Not only am I deaf, but I’m also a victim of blindness. Deafblindness. “You’re just extra special!” I tend to hear a lot.

Cox Green was starting to illustrate they were beginning to struggle with providing the right support. It wasn’t their fault. Why couldn’t I just be easy like the rest of us? No, I had to be complicated!

After a lot of forward thinking, we looked around two schools. One was Newlands Girls School, didn’t like the idea of an all girls’ school, so that was out of the question. The other was Mary Hare School for the Deaf. I visited the school for a week; it did have its disadvantages, a boarding school? Be serious!

After being there one week, I was stunned. I felt that being there would finally blend myself in and be like everyone else. Year9 I went to Mary Hare, a new start, a new positive chapter and new friends.

I was tearful most nights; I hated being away from home. Where I had been bought up orally, and all the students in my year were BSL signers, I couldn’t make friends as easy as I thought I could. Great, just what I needed! It took me a year to settle in properly, I eventually made friends and picked up sign language, just so I could communicate with everyone at the school. I had, and never will, have any intention, in taking up sign language, I was bought up in an oral world, and that’s where I’ll stay. I learnt sign language to benefit my peers. It took a very long time for everyone to adapt to how things were in my situation, both teachers and students had to get to know me first, before being entirely aware. But now everyone is aware, my life is so much easier with the right support I’m getting. Being at Mary hare, doesn’t make me feel I am one of them, I am oral, I have quite a different outlook on life to the others. I’m not proud of being either deaf or blind, that’s just unfortunate, but I am proud of who I am, as a person. I’ m me, and I’ll always maintain that, life is too short to please others, being myself and being positive is the only way forward- even if I’m going blind. I’m now a day pupil at Mary Hare, I only live 40 minutes away, I get a taxi to and from school, I’m happy with that. Now being in Year 11, it’s definitely a harder year, but one of the highlights would be work experience. Now, where was I going to do that? My first instinct was to go to my old primary school, I knew of the head teacher very well, and had always welcomed me to go in and help out. The school had said that it had to be arranged specially, as it was outside Newbury. I was desperate to go there, so within a couple of weeks, it was all ready to go. My job interview wasn’t at all nerve racking, I felt completely calm, as I said, I knew Mr Jarratt, the head, very well, he had taught my brother, and became head when I was at that school. He mentioned that I was to be placed in year 1 for the whole week. I was a little disappointed, I was hoping I’d be in one of the slightly older classes, where their English was more understandable and they were just a little bit more human!

Surely a week of work experience is far more exciting and easy going than a normal school week in Year 11, I thought to myself. Boy was I wrong!

There’s me walking through the old school gates I used to walk through, all those years ago at primary school, was I excited? I didn’t know, was I nervous? I didn’t think so, I knew the head of Oldfield Primary pretty well, and so I was in good hands.

“Morning Molly, go straight in, sign in, and head to your first lesson.” Cool, I thought, nice and easy. So many memories flew right back at me as I entered the year 1 classroom. My first day was lots of fun, but I was completely and utterly shattered by 3 o clock. The class was filled with tiny dots, -smaller than me! All buzzing with inquisitiveness and giggles. I got told that I was to work on one particular table, and to participate with a small, sweet boy named Samuel, “He’s just a very young five year old” I recall Mrs Brooklyn, the year 1 teacher, saying, “No problem!” I was fine with that, I felt so comfortable in their presence. “Today and tomorrow, we are going to be talking about fireworks! Have any of you lot, ever seen any fireworks?” Within a split second, all the class had their arms up, incredibly excited and desperate for her attention. They got out their writing books, and had to write three sentences, I saw... I heard... I felt... And being 5 years at the least, their spelling and vocabulary were very basic, so I was pleased that I could easily help them out without fail. As I got to know Samuel better throughout the week, I realised I had to do his writing for him, and read out whatever I wrote, I wanted to make sure he was part of the class as much as possible, no one likes being the odd one out, I would know, from my own experience. The children never failed to make me laugh, I forgot how easy life was in those days, I so badly missed those days, with no trouble, where all you had to do was cut and stick, and play in the sand! By the second day, I was so proud; I was taught how to use the photocopier! The whole staff were so friendly, some of which taught me in the past. Every lunch time they asked me, “where’s your lunch!?” It was like having thirty paranoid mothers! The fact was, because key stage 1 finished for lunch fifteen minutes earlier than key stage 2, I had already finished my lunch by the time all the rest of the teachers came in the staff room for their break, besides, I would never forget my food! I helped out both the teachers and the pupils in year 1, it was an interesting experience, and now I have developed more of a plan for after my school years; I’d like to stay on and do Year12 and 13, then do a gap year, and go into different schools to be a teacher assistant, just to see if I want to go down that teaching path. I feel better now having more of an idea of what to do. The week had flown faster than I wanted it to, before I knew it, it was Friday!

I bought in some stickers to hand out to all the pupils, just a personal gift from me to them, for being a great class to work with. They were overjoyed. It was sad to leave, especially because I knew what was ahead of me: Saturday school!

I thoroughly enjoyed my week, and felt physically exhausted, little ones are just simply shattering. But all in all, I loved it there, felt really relaxed not pressured at all; it all came to me naturally. A lot of the teachers I spoke to at break times in the staff room, really boosted my confidence, one of them, had been my TA (Teaching Assistant) all through from Reception to year 4, commented on how my speech had improved. None of the new teachers noticed I was deaf, until I told them.

Mum and I have been working hard to raise a profile of my condition, and due to my achievements, (I won the ‘Young DeafBlind Person of the Year’ award), I was in The Maidenhead Advertiser a few times, my Dad also worked his socks off and raised a huge sum of money for doing the 3 Peaks Challenge, because of all this we had been in our local papers and also ‘Chat’ magazine.

So I had a lot to talk about, some were amazed and gob smacked by my achievements. Mr. Jarratt had also pinned up some of the articles on the walls of the staff room. I felt very proud to be me, and to be able to talk to people about it too. After this experience I’ve felt confident enough to go into schools and help out to the best of my ability, maybe help out the less able, because I grew up being one of them, I felt it came naturally just helping out. I think doing a gap year will help a lot, because then I could experiment with what age groups, and whether I’d like to specialise, like being a ‘teacher for the visually impaired’ or maybe a ‘multi-sensory impaired teacher’. I can see myself doing something along these lines, in the future.

Too Early for That

2010-11-10T09:02:00.003-05:00

by Mark Dunning

My daughter’s vision is getting worse. It shows up in a lot of little ways. She plays street hockey with my son but can’t see the ball as it comes to her (to the screaming frustration of her ever sympathetic little brother). She’s told to pick up all the Legos, which she does in good faith. When told she left some behind, she sweeps her hand across the floor like someone searching for a lost earring under a bed. She needs an elbow to get from the car to the house in the dark. She knocks over more glasses. She trips over the dog more often. She walks in to more door frames than she walks through.

I see all of these things, I expect them, I internalize them, but somehow I don’t believe them. My little girl can’t really be losing her eyesight. I hope that it’s my imagination, delude myself to believe that she has always been this way. I just recognize it now that I am aware of her diagnosis. It’s a bias, not a reality. It can’t be reality.

Then the school calls. They notice that she is holding her books a little bit closer. She is missing lines on quizzes, skipping sentences when she reads. It’s small. It’s subtle. Her grades have not changed, but they will. My daughter needs more help and the school wants to offer it. It would help them make the case to the pencil pushers and green eyeshades if they had her latest vision tests. You know, the ones that will inevitably show that her vision is declining, that will confirm what we all know to be true. The last results we have were from 18 months ago. Has she had any tests recently? No, huh. And none scheduled for another six months? Any chance you could move up them up to, like, now?

No, I’m sorry, I can’t. Whether it’s right or wrong for her to have the tests, whether it’s necessary to get her the services she needs or not, she’s not having it. My argument is that it’s too difficult to reschedule. No, wait, my argument is that the ERG is too taxing for her and besides she really can’t afford to miss another day of school. I cite mouse studies and the effects of light on the retina and all those flashes in her unblinking eyes and it’s just too dangerous. I make most of it up.

No, I’m sorry. She can’t have the test. I don’t want proof that her vision loss is progressing.

I’m too scared.

…..

I recently met a friend for dinner, an adult with Usher syndrome. When I got home later than usual, Bella asked where I had been. I told her about my dinner guest. She asked matter-of-factly “Is he blind yet?” I was staggered by her lack of emotion as much as I was by her comment. I didn’t know that she fully understood the possible end game for her diagnosis. “Do you worry about losing your eyesight?” I asked. She shrugged. “Nah,” she said as she returned to her drawing of a horse, “it’s too early for that.”

Is it too early for that? Is it too early to worry?

I’m the level-headed parent brimming with life experience. I’m in charge of the ‘be carefuls’ and the ‘brush your teeths’ and the ‘don’t stick your finger in the sockets’. I’m responsible for evaluating the risk and protecting her welfare. I’m responsible for her future.

But Bella is twelve and she is living in the now. She’s as tall as her grandmother and she makes her own lunch and tacks up a horse and goes out trick or treating with her friends without a chaperone. In the dark. On a street with no streetlights. She doesn’t have time to worry about the future. It’s too early for that.

……

Families have a tremendous influence over the care a person with Usher receives. They drive to appointments and schedule tests. They talk to school systems and translate doctors. They encourage and discourage, cheer up and calm down. And they worry.

The trick is in identifying when certain emotions are influencing a decision to the point that it may no longer be the right decision. Usher syndrome progresses slowly. A day or two does not make a great difference. Heed Bella’s advice and realize that you don’t have to make any decision immediately. There is time. There is always time. Time to think. Time to sort through the fears. Time to be certain you are acting rationally and not emotionally. “I’ll have to think about it,” is always an acceptable response. Then go for a run. Take a bath. Write a blog post. Cry in the garage when no one’s around. Clear your head, drain the emotion, then decide what is best.

The reality is that while the disease will not change, your attitude about it can, and families and caregivers could do worse than to take their cues from the Usher patients themselves--even if the patient in question is only twelve.

Well, we’ve taken time and thought about it and we are not rescheduling Bella’s vision tests. We’re not rescheduling because missing more school at this point will only put her farther behind. We’re not rescheduling because she has access to professionals who can teach her techniques that will allow her to keep up, at least for now. We’re not rescheduling because the teachers feel they have a strong case to get her more services even without test results to back it up. But mostly we’re not rescheduling because my wife and I had a logical, sane, emotionless discussion about what was best for our daughter and decided this was it.

We’re not acting out of fear for the future because, like Bella said, it’s too early for that.

All you need to know about the Usher Syndrome and Related Diseases Conference Part V: Screening and Diagnostics

2010-10-28T15:31:00.000-04:00

by Mark Dunning

Well, it’s November and we are still summarizing the International Symposium on Usher Syndrome and Related Diseases that took place in May. That should be heartening for our readers. Obviously a lot happened at the conference.

A lot is happening in the real world, too, especially when it comes to diagnosing Usher syndrome and understanding the genetics. Now, if you or your family member have already been genetically tested and an Usher syndrome mutation has been identified, you might wonder why you care about the testing of others. I mean, besides the fact that you are a nice person.

I’ve said this a lot, but it always bears repeating: to find a cure is going to require the efforts of all Usher families. We need their natural histories, their genetic information, their experiences, and yes, their money (or at least the money they might help raise). Eventually we will also need Usher families to participate in clinical trials. In short, we want to find as many Usher syndrome families as possible.

That’s what makes the sessions on genetic screening so important. Like I wrote earlier, the good news is there is a lot going on.

A DNA based screening test for Usher syndrome
William Kimberling
University of Iowa Carver School of Medicine and Boys Town National Hospital

Dr. Kimberling has been working on an inexpensive screening test for Usher syndrome. The test looks for the most common mutations in all known Usher genes. The idea is that this test would be part of a tiered approach. A screen essentially tests one chromosome. But remember, Usher syndrome is autosomal recessive, so both chromosomes need to have a mutation for it to actually be Usher syndrome. The second tier is DNA sequencing to verify the first tier finding.

One interesting result of their testing so far is that more than 10% of children with severe to profound sensorineural hearing loss may have Usher. That’s much higher than was historically believed to be the case.

Why you care

Genetic testing is expensive. I speak all the time with adults who have been diagnosed with Usher but have never had it confirmed genetically because their insurance wouldn’t cover it. A screen like this would make the most basic testing more widely available at a low cost. Remember, finding everyone with Usher is a good thing for everyone with Usher.

In proof reading this post, Jennifer made another good point for why you care. Her words: “To me the big ‘why you care’ point is the impact of adjusting the prevalence upward so dramatically. For years we have been saying that Usher syndrome is rare, citing the prevalence of 1 in 25,000 Americans derived from several older studies. Extrapolating from the new Kimberling data gives us something closer to 1 in 6000, which is more common than a lot of higher profile genetic diseases. This could potentially give us a lot more leverage in funneling research dollars to Usher studies as well as enhance our general efforts to raise awareness about Usher syndrome in the social, educational, and clinical realms."

An excellent point.

Developing more comprehensive genetic screening strategies for congenital sensorineural hearing loss (SNHL)
Richard Smith
University of Iowa

All the states in the US and many other countries do a standard newborn hearing screen. As a result more than 4000 infants are diagnosed with severe to profound SNHL each year in the US. According to Dr. Smith, screening programs have focused on follow-up physiologic tests to determine how well a given child hears. Genetic testing has been used to confirm the diagnosis but Dr. Smith argued that we need to develop a more comprehensive strategy for using DNA testing as part of the screening process.

Why you care

This is a frustrating point for many of us. We already catch most kids with Usher through the newborn hearing screen (though Usher 3 kids may slip through with their progressive hearing loss). However, a lack of a strategy for including genetic screening as part of the newborn hearing protocol means a lot of these kids slip right through our fingers. We find them again later when they are late walkers or begin to have problems seeing at night. We shouldn’t lose them in the first place. Imagine pairing a low cost genetic screen with the newborn screen and you see where Drs. Smith and Kimberling are going with this.

Asper’s diagnostic tool for Usher syndrome
Ilona Lind
RetChip1.0
Bernhard Weber
Institute of Human Genetics, University of Regensburg, Germany
The OtoChip sequencing array for hearing loss and Usher syndrome
Heidi Rehm
Partners Healthcare Center for Personalized Genetic Medicine

I’m putting these three together because they are all genetic tests for Usher syndrome. What is kind of cool about the three is that they each are aimed toward a different diagnostic population. The Asper diagnostic tool is specific for Usher syndrome. So if a patient is suspected of having Usher, this test aims to confirm it. But say a patient has hearing loss or vision loss but it’s not clear if the cause is Usher or something else. That’s where the RetChip 1.0 and the OtoChip come in. RetChip 1.0 tests for a bunch of different genetic causes of RP including Usher syndrome. The OtoChip tests for a bunch of different genetic causes of hearing loss, including Usher.

Why you care

Having multiple paths that lead to an Usher diagnosis is critical. As we just saw in the talk by Dr. Smith, we catch a lot of kids with the newborn hearing screen. They presumably would be candidates for the OtoChip test since they wouldn’t necessarily be demonstrating any vision problems yet. We also know that a lot of kids slip through our fingers at that point and don’t show up again until they start to have vision problems. The OtoChip would still be a viable test but they would also be caught if the RP was the focus and the RetChip 1.0 was used. Again, the more families we identify the better and these give us several ways to do so.

The utility of databases in diagnosis
Anne-Francoise Roux
Laboratoire de Genetique Moleculaire, CHU Montpellier, Montpellier, France

We’ve talked about Dr. Kimberling’s DNA screen that tests for common mutations. Tests like the OtoChip and others like it seek to find a specific mutation no matter how unique. This has led to a number of different variants being identified. Dr. Roux and her colleagues have created a database to store those mutations that is searchable for all researchers. These can then be folded in to the screens and the OtoChip-like tests so that they are more comprehensive and find more patients faster.

Why you care

Read that last line again. A database of all known mutations helps us to more quickly identify more people. That’s a good thing.

Lessons from the UK National Collaborative Usher study
Maria Bitner-Glindzicz
UCL Institute of Child Health, London, UK

One of the things we have long struggled with is connecting genotype (the genetic mutation) to phenotype (the physical changes caused by that mutation) in Usher syndrome. This study is an attempt to do that. They studied 190 families in the UK with Usher syndrome. They were able to identify 80% of them by sequencing known Usher genes. They also identified a number of new mutations in the process.

Why you care

This is exciting stuff. There have been very few comprehensive phenotype/genotype studies done on Usher syndrome. Being able to predict phenotype by genotype would be a great thing for all Usher patients. The question I hear most often is “what does the future hold for me or my family member?” This type of study can help us to be able to find the answers. It will be interesting to see the results. And remember the database talked about by Dr. Roux. This study identified 80% of the patients using known genes. That means 20% were unique. It takes a lot of work to identify those novel mutations. But if all newly discovered Usher mutations were put into a database that researchers around the world could easily reference, the next time a similar study is done those new mutations can be included.

OK, next post on the symposium should be the last. We should be finished just in time for the next symposium!

Usher Syndrome Working Group in Aalborg Denmark

2010-10-20T10:27:00.003-04:00

by Mark Dunning

Thanks to Jennifer for carrying the blog while I procrastinated. I do have a partial excuse. I was in Denmark for a few days at the Usher Syndrome Working Group put on by Sense in conjunction with the Acquired Deaf Blindness Network conference.

This was my first trip to Denmark. In fact, if I were to list the places I never expected to visit Denmark would have been just above Romania on the list. Aalborg is the fourth largest city in Denmark which has about 6 million people in it. That’s about the size of my home state of Massachusetts. The fourth largest city in Massachusetts is Lowell which we in the area not so lovingly call Hole. Let’s say my expectations for Denmark were low.

Well, it was wonderful. Nice people, long history, beautiful architecture, and terrific pedestrian friendly outdoor shopping. It was chilly (as one might expect) and I couldn’t help but think of the holidays as I walked the streets even though it had just turned October. Most commute by bicycle even with the chill so on a Sunday morning with most sleeping in and only a few bikers around, Aalborg might be the quietest place on earth. An absolutely lovely city.

Aalborg Denmark

The conference was excellent, too. I had seen many of the presentations before. Bill Kimberling gave his omprehensive talk on the clinical and genetic aspects of Usher syndrome. Claes Moller gave an interesting talk on hearing loss differences in siblings with Usher II and Moa Wahlqvist presented the same psychosocial findings that were presented in Spain. All were great and Moa in particular was a big hit, but like I said, it wasn’t new to me. What was new to me was the session on social-haptic communication. I know I won’t do it justice, but in short, where tactile sign communicates language, social-haptic communication is the use of touch to convey emotions and space. If you are deaf blind, you may not be able to see a smile or tell where in the room the speaker is standing. Social-haptic communication uses touch to convey that information. Very cool.

Probably most valuable, as is usually the case with these things, was the opportunity to network. I was able to connect with people from all over Europe (Bill and I were the only two people from the US) and from as far away as Australia (and I thought my flight was long). This networking is already paying dividends as we were able to at least start a global dialogue on the need for an Usher syndrome registry (a posting for another day) which I doubt gets started without the study groupUsher Working Group.

Thanks to the good folks at Sense for pulling it together. Marilyn Kilsby (who’s retiring) and Tamsin Wengraf (who is not) did a terrific job. It was well worth the trip and I look forward to doing it again in two years

Because I'm from just outside of Lowell and don't want the
chamber of commerce after me, here's a nice picture of the city.
Kind of like Aalborg, no?

All you need to know about the Usher Syndrome and Related Diseases Conference Part IV: New Genes and Common Denominators

2010-10-07T09:48:00.002-04:00

by Jennifer Phillips, Ph.D.

Here I am again to do some of the heavy scientific lifting required for a subset of the talks presented at the Valencia meeting. Last time I covered the presentations dealing with the molecular and cellular activity of Usher proteins--the factors known to cause clinical Usher syndrome in humans when altered by changes in genetic code. To briefly summarize, there is strong experimental evidence to suggest that at least some of the time these Usher proteins physically link together to form molecular complexes that carry out some cellular functions. There are a lot of different Usher proteins involved, so understanding just the activities of those proteins has been quite challenging.

In the next series of talks, the picture gets even more complex, as we learn about still more proteins, contributing to other disorders of vision and/or hearing. Some of these may be added to the list of known Usher proteins, while others are associated with vision and hearing disorders distinct from Usher syndrome, but also appear to have molecular relationships to Usher syndrome proteins. If this sounds complicated, well, it is. But fear not, dear readers. I’m here to guide you through this confounding thicket of information, and I will do my best go easy on the technobabble whenever possible, link you to backup resources when I just can’t help myself, and ferry you safely to the other side. Here we go:

Identification of a new Usher 3-like locus
Shzeena Dad, Kennedy Center, Glostrup, Denmark

This research described the discovery of a new gene causing Usher-like symptoms in a Dutch family. As the hearing loss is progressive in these family members, who also exhibit balance defects and retinal degeneration, the condition is is classified as most like Usher type 3. Two things convinced the researchers that it isn’t Usher type 3a: The genetic change that the affected family members share is not in or near the Ush3a gene, or indeed, in any of the other eight known Usher genes. Moreover, all affected members of this family were born with cataracts—defects in the lenses of their eyes, which has not been reported in other Usher cases (some Usher patients do develop cataracts later in life, but this is the only family we know of who are born with this problem).

Why you care
One of the endearing realities about biology is that, however complex things might initially appear, they usually turn out to be even more complex than that. Studying Usher syndrome is already a formidable challenge, made more so because we know, with absolute certainty, that we have not yet identified all the molecular players. Obviously this is important, because despite the amazing progress we’ve made in being able to screen for mutations in Usher genes, we can only screen for the things we know to look for. Thus, the more new gene information we can generate, the more complete our picture will be, enhancing screening efforts as well as our ongoing searches for therapies. Adding this new locus to the list gives us another target to aim for.

New strategies/technologies to identify new genes
Hanno Bolz, Institute of Human Genetics, University Hospital of Cologne, Germany
Center for Human Genetics, Bioscientia, Ingleheim, Germany

This speaker described a several new screening strategies that could help cast a wider net for known Usher genes as well as new players. On the species level, there is a huge amount of variability in the human genome, so in the noise of all those normal, background genetic variations, small changes in genes that lead to disease can be hard to pick up. Traditionally, the most successful way to reduce the signal to noise ratio was to conduct genetic testing on large families, thus reducing the background level of genetic variation and making the important, disease-causing changes easier to spot. Happily, new technologies have delivered success in looking for disease genes even in small gene pools. New ways of searching, with better resolution for picking up the small changes, different techniques for finding a broader variety of changes, and better, faster sequencing so that vast amounts of genetic information can be collected in a very short period of time, are all working to our advantage. For example: deleted information in a particular region of a chromosome can be difficult to spot with traditional DNA sequencing methods if you’re not specifically looking for it, but with a new technique called Comparative Genomic Hybridization such changes, and a number of other irregularities, can be detected without prior knowledge. This is useful not only for screening known Usher genes, but as a first step in changes in novel genes that might contribute to Usher syndrome as well.

In part III of the meeting summary, I explained how zebrafish are used as an animal model for Usher syndrome. In his talk, Dr. Bolz discussed a new way that zebrafish can contribute to the discovery of new Usher genes. Techniques that we use to disrupt gene function in zebrafish can be used to test whether a particular gene might be likely to contribute to Usher syndrome in humans. I humbly present one such example of this strategy here.

Why you care
In short, discovering new ways to examine the genes we know are involved in Usher syndrome as well as ways to identify new players is crucial to improving diagnosis and treatment.

Modifiers of ciliary diseases
Nicholas Katsanis, Duke University Medical Center, Durham, NC, USA

We’ve already discussed the putative role of the cilia in contributing to the symptoms of Usher syndrome. Cilia are important components in photoreceptors, hair cells of the inner ear, and many other cells of the body. Thus, it’s not surprising that defects in these structures underlie a number of human diseases. These conditions have an extremely wide range of associated symptoms, which sometimes include, but are by no means limited to, hearing and vision defects. However, as the source of all these problems can be traced to problems with the cilia in some or all cells, they are classified collectively as “Ciliopathies” (diseases of the cilia).

Katsanis and colleagues have taken a systematic approach to studying factors classified as ‘ciliary genes’, using molecular screening techniques and animal models to characterize mutations in these genes and their potential disease causing effects.

Because a definitive link between the pathology of Usher syndrome and defects of the cilia is still being established, there is currently some debate about whether or not to include Usher syndrome on the official list of ciliopathies. The fact that many Usher proteins are known to colocalize in the region of the photoreceptor connecting cilium can be used to make a case for including Usher genes in this group. Another compelling argument for doing so is that we already know there is some level of molecular cross-talk between Usher proteins and other factors known to cause ciliary disease.

Why you care
The interactions between known Usher proteins is already pretty complex, but interactions also occur between Usher proteins and other, non-Usher proteins. Understanding more about how this works could enable us to identify new ciliary genes that may, in some circumstances, cause Usher syndrome, providing new targets for diagnosis through genetic screening and research for therapies.

The USH2A Interaction Partner NINL Associates With BBS6, Plays a Role in Establishing Planar Cell Polarity and Functions in Cilia Assembly
Erwin van Wijk, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

As much as I’d love to wax expansive on the particulars of this really exciting research, I’m starting to have that feeling I get at parties when I geek out over some neat bit of science in the news and chat excitedly about it for too long before it dawns on me that my conversational companion is surreptitiously making the ‘SAVE ME!’ sign to his or her partner across the room. So, let’s do a very rough sketch of the basics based on the informative title of this talk, and call it a day:

The USH2A Interaction partner NINL: USH2A is the gene behind Usher Syndrome Type 2A. It encodes a very large protein called either USH2A or Usherin. It’s a common biochemistry research tactic to use all or part of a known protein and find other proteins that can physically interact with it. These researchers used a portion of the Usherin protein as their ‘bait’ to fish through a solution containing many proteins to see what would stick to it. One of the proteins they discovered was an already characterized factor called NINL.

NINL associates with BBS6: As soon as the researchers determined that NINL interacted with Usher syndrome, they wanted to figure out what the effect of a mutation or other disruption of NINL might be. So, they depleted NINL in a young developing zebrafish (using the same technique of disrupting zebrafish gene function discussed above). These animals had developmental defects that were reminiscent of the defects seem when genes involved in Bardet-Biedl Syndrome (BBS) are disrupted in zebrafish. BBS has a number of genes associated with it, is officially classified as a ciliopathy, and has symptoms that include progressive retinal degeneration. The researchers continued to investigate the consequence of depleting NINL in tandem with members of the BBS gene family, and observed genetic interactions between NINL and many of the BBS genes. They then conducted the same type of protein interaction experiment as was used to identify NINL as an USH2A interaction partner, only this time they used NINL as the bait. Through this experiment, they were able to show a direct physical interaction between NINL and one of the BBS proteins, BBS6.

NINL plays a role in establishing planar cell polarity: In a nutshell, planar cell polarity refers to the organization of cells that make up a given tissue or organ. During development, the cells have to coordinate their growth and movement to form eyes, ears, kidneys, brains, etc. Determining which end of the cell is ‘up’ is an essential part of this organization, and it is known that the cilia of cells contribute to this organization. Thus, it is hardly surprising to note that mutations in genes known to be important for ciliary development or function can lead to disrupted cell polarity. This is true of the BBS genes, and in this study, the researchers noted disrupted cell polarity in zebrafish with reduced NINL gene function.

NINL functions in cilia assembly: The evidence from zebrafish, as well as what was already known about the localization of NINL protein, was suggestive that NINL might have some role in cilia formation or function. To establish this more directly, the researchers conducted an experiment with ciliated cells in culture dishes. They depleted NINL function in these cultured cells and observed a defect in cilia formation. This added data makes it even more likely that the problems seen in the zebrafish model are the result of poorly assembled cilia.

Why you care
Essentially, this is proof of principle for the approach that Hanno Bolz, Nicholas Katsanis and many others are advocating on a wider scale: Look for connections between known and potential contributors to Usher syndrome, or to cilia formation and function. Use genetic and biochemical tools to identify new molecular players, use model organisms to study the effects of disrupting these factors alone or in combination with other known contributors. Fill in the gaps and refine the definitions of these disorders by revealing how they relate to one another.

I see you giving the high sign to your spouse over there, so I’ll let you off the hook for today, and I thank you for indulging me. Next time, Mark will be back to conclude this meeting summary with some information about new genetic screening techniques for Usher syndrome. Until then, be well!

All you need to know about the Usher Syndrome and Related Disorders Conference, Part III: Genes, Proteins, and Networks

2010-09-15T10:44:00.003-04:00

by Jennifer Phillips, Ph.D.

We’re slowly progressing through the wealth of interesting talks at the Conference last May, and even though I didn’t actually attend the Valencia meeting, I have enough familiarity with the dense molecular topics therein to give an adequate summary and their relevance to the Usher community. My plan is to cover the Usher gene overviews along with a few studies of particular players in Part III, and recap the talks that dealt with the topics of new genes and related genetic disorders in Part IV.

Prologue: It should come as no surprise to the readers here that Usher syndrome has multiple genetic causes—that is, mutations in one of twelve (so far) distinct chromosomal regions known as loci result in deafblindness in humans. Even though there are important differences in the onset, and precise symptoms of Usher syndrome, there are obviously enough commonalities to treat all cases of Usher as one general disorder. As such, one of the main research goals for those of us who study these molecules is the two-pronged investigation of

a) what they have in common, i.e. why defects in all these different genes cause a very specific type of sensorineural deafness and retinal degeneration, and
b) what makes each gene different, i.e. why mutations in some genes cause more severe forms of Usher than others.

So with that in mind, let’s get started on the summaries…

The Usher protein network in the inner ear
Hannie Kremer, Radboud University Nijmegen, The Netherlands

Figure 1: A—an electron microscope scan of the actin bundle, made up of organized stereocilia, projecting from a single hair cell. B—a cartoon of these structures showing a passive mode (gray, background) and an active mode (green, foreground), in which the stereocilia bend in unison in response to an incoming sound wave. C. A cartoon showing a magnified view of the tips of two individual stereocilia (green) tethered together by the Usher protein, Cadherin 23.

The above figure shows the organization of a specialized structure found in mechanosensory hair cells. The hair bundle is the structure that give ‘hair cells’ their name, although it’s not really made of hair, but actually comprised of tubes of actin that protrude in the same direction from the tops of these cells and are connected at the tips so that they will move as a unit in response to vibration, causing the hair cell to signal the auditory neurons that a sound has been perceived. Mice with mutated or deleted Usher genes have clear and specific defects in the formation of stereocilia, the actin bundles that project from the tops of the mechanosensory hair cells:

Figure 2: from Lefevre et al, 2008. The far left panel shows several hair cells (outer hair cells (OHC) and inner hair cells (IHC) )from the cochlea of a mouse without an Usher mutation. The rest of the panels are images from this same region of the cochlea from mice with defects in Usher genes. From left to right: wild-type, Myo7a, Ush1c, Cdh23, Pcdh15, Ush1g.

The observed defects in the length, width, orientation and abundance of stereocilia in the Usher mice show a clear requirement for Usher proteins in the proper formation of these structures. As all of this growth and development takes place before birth in humans, it’s no surprise that the hearing loss in most Usher cases is congenital. But what exactly makes the stereocilia so disorganized? We know from biochemical studies that many of the Usher proteins can physically interact with each other, and we know from antibody localization studies that many of the Usher proteins localize to particular regions of the hair bundles, so detailed studies of these in combination with the mouse Usher mutants provides evidence (alluded to in figure 1C) that the Usher proteins work together in a complex to guide the organized growth of the actin bundles by linking the individual stereocilia together. In addition to this proposed function of an Usher complex, individual Usher proteins appear to play a role in the outgrowth of the actin structures. Finally, there is some, less-well understood evidence that some Usher proteins may also be involved in events at the other end of the hair cell—the part that communicates with the auditory neurons.

Why you care

Understanding when and how the Usher proteins are required for normal cellular development and function is critical for the discovery of targeted therapies. The more we can find out about what these molecules are doing in there, the better chance we have of identifying ways to compensate for defective proteins in Usher patients.

The Usher proteins in the retina
Uwe Wolfrum, Johannes Gutenberg University of Mainz, Germany

Figure 3: Usher protein localization in subcellular regions of the photoreceptor cell. Abbreviations from top to bottom: BM: basement membrane; RPE: retinal pigmented epithelial cell; OS: outer segment; CC: connecting cilium; IS: inner segment; N: nucleus; S: synapse; N: neuron.
adapted from Reiners et al, 2006.

One of the confounding things about Usher syndrome is the asynchronous timing of the hearing and vision defects. We have good evidence from the mouse models that the congenital hearing loss is due to developmental defects, but the vision loss is progressive, which would suggest a problem with function rather than with formation. In all the human and animal models we currently have access to, there doesn’t appear to be anything wrong with the structure of the retina, but something is causing photoreceptors to die, slowly, over a course of months or years. Again, researchers can seek answers by looking at the protein localization within the retina, and from knowing that these proteins have the potential to physically interact with each other to form multi-molecular complexes. Because it’s the photoreceptor cells that degenerate, most of the protein localization studies have focused on this cell type. Similar to the colocalization pattern seen in hair cells, many Usher proteins conglomerate in distinct functional regions of the photoreceptor cells. One exciting finding is that many of these proteins (indicated by colored boxes in figure 3) localize in the region of the connecting cilium. The connecting cilium in photoreceptors serves as a conduit for moving proteins and other molecular cargo that are synthesized in the cell body, or inner segment, up to the outer segment where they’re required to perform various functions. The abundance of Usher proteins at this particular location has prompted researchers to examine whether any of them might interact with known factors in molecular trafficking, and indeed, some do. Although the evidence is still being gathered, it’s tantalizing to imagine that defects in cargo loading or transport, or indeed, in the structure of the conduit itself, might be responsible for the reduced function and ultimate degeneration of photoreceptors. This is a very hot area of research and new ways of assessing these functions are being developed in numerous labs worldwide. Additionally, and not unlike the situation in hair cells, there is some evidence that these proteins localize to and function somehow in the synapse, through which the photoreceptor signals to adjacent neurons when stimulated.
Why you care

Again, understanding the where, when, and how of Usher protein activity is essential to finding therapeutic ways to overcome defects in these processes. These are incredibly complex cells, and there is strong evidence that Usher proteins perform multiple functions within them, so there is still a great deal to be learned, but every new bit of data adds to the big picture that will someday reveal new ways to address or prevent this progressive vision loss.

Usher scaffold proteins provide complementary functions in retina and inner ear
Monte Westerfield, University of Oregon, Eugene, Oregon, USA

Most of the Usher gene studies using animal models have been conducted in mice or rats, but a few of us are using the zebrafish to address these questions. Zebrafish have hair cells and retinas very similar those found in humans and these animals provide a great system in which to study the consequences of targeted Usher gene or protein disruption. In the above summaries, I alluded to the fact that Usher proteins display the ability to physically interact in a complex. This is achieved through the presence of particular protein interaction domains, some of which provide a place to stick, and others of which are capable of binding to that sticky place, rather like the hook and loop surfaces found in Velcro. Several Usher proteins contain multiple sticking places, called PDZ domains, along their length, and are thought to be required inside a particular cell (e.g. a photoreceptor or a hair cell) to serve as a scaffold or an organizing structure for localizing other Usher proteins that may function across cell boundaries, or, in the case of the links between stereocilia depicted in Figure 1C, way up the page, between membranes of structures from the same cell. Interestingly, although there are characteristics that make PDZ domains identifiable, there appears to be a great deal of specificity in which PDZ domains certain Usher proteins with PDZ-binding capabilities choose to interact with. In other words, even though there are a couple of different Usher proteins, namely Ush1c and Ush2d, that look very similar with respect to the presence and placement of PDZ domains, they don’t appear to have very much functional overlap. Is this because they’re not in the same place at the same time, or are there other regulatory factors that influence which of these proteins is the more suitable ‘scaffold’ in a given cellular situation? We are pursuing these questions, as well as ones of general function of all the involved PDZ proteins. Zebrafish in which these PDZ proteins have been disrupted appear to have similar functions in hair cells to what has been shown in mice, with respect to the development and organization of stereocilia. We can also detect functional problems at the behavioral and cellular level. In the retina, we see specific defects in synaptic transmission between photoreceptors and retinal neurons when we disable one of the PDZ domain containing proteins (Ush1c) and we’ve also discovered that Ush1c and Ush2d proteins are all present in another retinal cell type called the Müller glia. Müller glial cells have a variety of functions related to maintaining the health, development and function of retinal neurons, including photoreceptors, so the possibility that these cells could somehow be involved in the defects observed in Usher syndrome is intriguing.

Why you care

Investigating Usher gene function in organisms other than Mammals adds a wealth of additional experimental techniques with which to understand the role of Usher proteins at various developmental and functional time points in the ear and the retina. In addition to the general benefit of obtaining more information about the complex workings of these molecules, the zebrafish system also lends itself to high-throughput testing of various genetic and molecular therapies.

A Low Cost Solution to a Difficult Problem

2010-09-02T11:42:00.001-04:00

by Mark Dunning

Jennifer wrote about vitamin A in her last post and gave her opinion on whether or not the studies done to date were enough to warrant prescribing vitamin A in supplement form to patients. My first thought on reading her post was ‘Hmm. I respectfully disagree with her.’ I know the studies and came to a different conclusion. My daughter takes vitamin A supplements under the supervision of a physician. Please note the last part of the sentence. You should not take my advice on this. Nor, I know she would agree, should you take Jennifer’s advice. You should take that of your physician.

That brings me to my second thought. ‘Why the heck didn’t any doctor ever explain their opposition to vitamin A supplementation to me as well as Jennifer did?’ I’ve talked to a lot of physicians that don’t prescribe vitamin A, some who are strident opponents of prescribing it, and none of them explained their reasoning as clearly as Jennifer. On the one hand I’m proud of my blog mate for her thoughtful review but I’m also terribly concerned about it. Like I said, you shouldn’t take the advice of Jennifer or me. But if you’re not getting lucid advice from your physician, what do you do?

Looking back at our decision, the reason we chose to use vitamin A supplementation was because one doctor took the time, much like Jennifer, to go through the studies with us and explain why he thought these studies supported using supplementation. We spoke to other doctors that did not agree with supplementation, but none of them went through the studies that supported their position. In fact, most of them didn’t mention any other studies done at all. They were just worried vitamin A wasn’t safe in large doses.

Now being worried that vitamin A isn’t safe is a justifiable concern, but they came to that conclusion somehow. They didn’t just pull it out of the air. Why couldn’t they, like Jennifer, tell me how they came to that conclusion? This left us with the opinion that they either 1) didn’t know about the studies and were just winging it or 2) didn’t really have anything to support their opinion. But if you read Jennifer’s post, you can see that there certainly is an argument to be made against it. So how come, in my experience, was only one side able to make their case?

All of this brings us back to another of Jennifer’s recent postings. We have to educate physicians on Usher syndrome and the treatments that are currently available, or might soon be, so they can advise patients accurately and appropriately. But we also desperately need to train them on how to appropriately communicate with patients and that is the focus of this post.

I have a little experience in this area. I have been fortunate enough to be asked to speak on a number of occasions to doctors, nurses, professional staff, and medical school students at Harvard Medical School, Children’s Hospital Boston, and M.I.T. These are some of the most prestigious institutions in the country. I’m not pointing that out to brag (OK, maybe a little) but rather to illuminate a fact which I will get to in just a bit. First, here are the things I usually tell them:

We live in a Google world. As soon as you hint that you, Mr. Doctor, suspect Usher syndrome as a diagnosis that family is going to go home and Google it. Even if you don’t breathe the term Usher syndrome, they are going to go home and Google all of the symptoms they saw you scribble down and come up with Usher syndrome on their own. Be prepared before you meet with them and give them ‘safe’ web sites for information on Usher syndrome (like this and this) so you can be confident that they are finding out the information from accurate, credible sources instead of reading it from some crackpot blog. Oh, wait, that didn’t come out right...

Make sure the family understands when they will receive the results of tests. This is a personal bugaboo for me. I didn’t go for the ABR test of my daughter’s hearing because I thought it was like a blood test. I didn’t realize we would get the results right then. So I learned about my daughter’s deafness over the phone from my sobbing wife. On the flip side, there is no need to get a family all worked up over having blood drawn for a genetic test when the results will not be known for weeks. It’s just a blood draw, nothing more.

Schedule a time to meet with the family to discuss the test results when you schedule the test. In other words, don’t wait until you get the test results to call the family and schedule a time to talk. Why? See below.

Never give the test results over the phone. Look, I know a negative test for Usher can be given over the phone, but you really need to talk in person with someone if it is a positive result. Heck, given the sensitivity of some of these genetic tests (50% accuracy) even a negative test result might not eliminate Usher completely. This brings me back to point number 3. If you call up a family and say ‘Hi, I have your test results. I’d like you to come in to discuss them’ the family is going to read in to that. It must be bad. Why wouldn’t they just tell us over the phone? So solve the problem up front and tell them before they have the test that they will have to come in to get the results, good or bad, because you never give results over the phone.

Never tell a family their loved one ‘failed’ a test. This one drives me batty because I know it’s used with the newborn hearing screen all the time. Right when mom and dad are basking in the promise of their newborn child, they are told their baby is a failure. No, it’s not. You don’t fail a hearing screen or an ABR or a blood test. The results are positive or they indicate that we should do more testing. This isn’t calculus. You’re not a failure if you have Usher syndrome or hearing loss.

After you give the diagnosis, schedule a follow-up appointment with the family. When a family gets the diagnosis they go numb. That first appointment is not the time to discuss how the myosin-7a protein chain operates. Even if you are speaking to a family of genetic engineers, they are not going to hear you or be able to absorb all you are telling them. Answer every question they have but encourage them to ask the same question again later if they need clarification because they will. Then schedule a follow-up appointment with them for a week or so later when they’ve had time to digest the diagnosis and clear their heads. That’s when they will have the best questions and it’s a time when they will remember the answers. This follow-up appointment, by the way, could be by phone. Whatever method will most encourage the family to show up.

Tell them what they might do next. Just because there are no more tests to be done and a diagnosis is made isn’t the end of the line. Sure, in the case of Usher syndrome there are no certain treatments, but don’t shrug and tell them to come back next year to see if their vision has deteriorated. Give them options (like vitamin A) along with your opinion on it. Tell them where to find the studies, the supporters and the opponents. Tell them about research under way or where to find out information about it, like the Usher Coalition site or the Foundation Fighting Blindness. It’s alright to give them hope for the future.

Tell the family what that future might hold. This isn’t ‘you’ll meet a tall dark stranger’ stuff. I mean tell them the truth and not just about the diagnosis. In fact, the stuff beyond the diagnosis is more important (I’ll explain why in a bit). You can and should tell them, Ms. Doctor, about the normal prognosis for someone with RP, and with hearing loss, both with an implant or hearing aid and without, and about the vestibular component. But you should also tell them that most people with Usher syndrome who want to go to college, get married, have kids, and have a challenging career do just that. Again, it’s alright to give them hope.

Physicians are responsible for physical well being. They work with the body. But the diagnosis of Usher syndrome is not traumatic for families only because it may portend a life of deaf-blindness in the future. It is traumatic for families because they interpret deaf-blindness to mean a life of isolation and limitation. It’s not just the physical results of Usher syndrome that are frightening, it’s the potential social and psychological results. Physicians need to recognize this and address it as part of delivering the diagnosis.

Now the list above, to me, seems like pretty obvious stuff. The first time I presented it I thought I was going to get a ‘no duh!’ type response. I didn’t. In fact, I’ve heard from a number of people that after attending the talk they fundamentally changed their approach to some of their processes. If these prestigious institutions that I mentioned and those that attend them or work for them find this illuminating enough to change their way of doing things, we’ve got a big problem. If they aren’t teaching doctors this stuff, no one is. These are the most forward thinking institutions who, to their credit, are willing to not only listen to some dumb parent but act on what he says. I shudder to think what is going on in the rest of the world.

So back to Jennifer’s point about educating physicians. One of the problems is how to do it at a reasonable cost. We could, for instance, hire a blimp to drop Usher syndrome flyers on the next AMA convention. I don’t think that’s our most cost effective approach. More to the point who is the ‘we’ that might write up the flyers and hire said blimp?

I think that gets lost in all of these discussions. We all fall in to the ‘someone should do something’ trap sometimes. We see pictures of floods in New Orleans or unemployment statistics or polar bears swimming where there once was ice and say ‘someone should do something.’ But who, exactly, is the ‘someone’ who is going to do something to help educate physicians about Usher syndrome?

Well, I have seen that someone and he (or she) looks a lot like you. You see that list above? Talk to your doctor about it. Make sure he or she is thinking about it. Send them a link to this post. Or the next time you see them tell them that you read this fascinating article by this brilliant author who suggested that you should never give test results over the phone and ask them for their thoughts. Put the bug in their ear. Make them think about it. They might not agree with all of it, but don’t assume they are thinking about it. They weren’t thinking about it in the group I met at the places I’ve spoken, I can tell you that, and they are just about the best in the world.

The point to all of this is that there is a low cost way to educate the physicians that are diagnosing Usher syndrome that can began immediately. It’s you.

Vacation Photos

2010-08-25T14:22:00.003-04:00

by Mark Dunning

I need a vacation.

Somewhere on Cape Cod

We spent last week on Cape Cod. We stay at the same rickety little cabin with the rock hard beds and the 1970 décor. It’s just a half a mile walk from the town beach. It’s a nice beach. It’s not really well maintained and more rocky than sandy, but it’s walking distance and because it’s not a premier location it’s never crowded. There are dunes there, like most of the Cape, and a broad salt marsh with a long boardwalk that crosses the winding channels that drain down with the tide. The kids love the channels because the water is shallow and warm and full of sea critters. We caught hundreds of hermit crabs and chased minnows while the terns plopped into the water around us like stones.

I like to walk down around the sandy point. It’s a good distance from the parking lot so it’s usually pretty deserted. Out there I don’t check e-mails. I don’t listen to voicemails. I don’t see the lawn that needs to be mowed or the office with the stacks of papers or the piles of toys that need to be put away. I leave most of my daily stresses behind.

Sandy Neck Beach

But I never escape Usher syndrome. Not even on vacation. I think this is true of every family that deals with Usher. It’s always there, grinding away, sneaking in to every thing you do everywhere you go. And it’s exhausting.

We walk down to the beach and my daughter keeps bumping into me. She has Usher syndrome and she has poor balance. She can’t really walk a straight line. So we keep drifting toward the center of the road until I’m staring at the grill of an oncoming UPS truck. Or I keep pushing her back in line, step after step, harder and harder, until we are jokingly jostling each other or, if we’re not in the best of moods, shoving each other in to shrubs and parked cars.

Sunset over the salt marsh

Or we have a fire on the beach. We walk down to the beach loaded with firewood and chairs and blankets and marshmallows and chocolate bars and juice boxes. It’s still light when we set up and slowly the sun burns down as the firewood dwindles. When the last of the logs is thrown on it’s dark and the moon has tossed a fistful of stars in its wake. Bella can see well enough by the light of the flames, but when we douse them it becomes a logistical disaster. Bella is a pack mule. She carries most of the chairs down to the beach. But in the dark she can’t see well enough, even by the light of the flashlight, to carry the weight and negotiate the soft sand and loose stones. So we load up my seventy year old mother-in-law with everything. No, I’m kidding. She leads Bella and the rest of us turn in to Sherpas. Of course Bella needs all the flashlights so I stumble through the dunes bristling with furniture and sticky with s’more residue.

Or we walk through the shallows in waist deep water, trailing a bucket, and dipping for snails and crabs and minnows and other sea critters. Our eyes are focused on the sand. All the action is at our feet. Bella doesn’t wear her cochlear implant because she occasionally has to dip her head in the water. She drifts beyond arm’s length and watches the rocks and sand. So when a flounder settles in the sand or a blue crab skitters past, I can’t yell to get her attention. I can’t splash her to get her to turn and see me sign because it spooks whatever would be of interest. My son Jack hears me call so he sees what I see. But Bella misses a lot, sometimes gets frustrated, and I feel guilty.

The photographer's little brother

Bella brings her camera on vacation. She likes to take pictures which is good, because none of the rest of us do. It’s nice to finally have some vacation photos with which to bore our friends. Better still, she’s becoming a good photographer. Her little brother says her pictures look like National Geographic. She has a great eye. In fact, all these photos are hers. But I find it hard to celebrate her growing skill. I’m wary of encouraging her to pursue it. I’m worried she’ll lose it in time.

Stoopid Usher syndrome.

I go for a walk around the point to try to forget about my vacation. It’s night and the moon is bright. The beach is silver and the tide is coming in. I pass one fisherman, but otherwise I’m alone. On the tips of the lapping waves, I notice fluorescent dots. They wind and loop along the sand as the sea inhales and exhales. It’s phosphorescent plankton and it blinks bright green on the sand and fades before the next wave arrives to replace the glowing dots. It looks like the stars are washing ashore. The kids would love it. But it’s dark on the beach and Bella would have a hard time walking. For all the effort it would take to get her down there, she might not even be able to see them. I might be rousting her to remind her of all she misses. So I walk back home, give them each a kiss, and keep the wonders I’ve seen to myself.

I don’t know if any of this is right or wrong or just is. The trip was a lot of fun and the kids, particularly Bella, look forward to it every year. I do too. Family vacations are rarely relaxing. There’s always bickering and ‘tell him to stop touching me’ and uncomfortable beds and odd schedules. But in the past, they were also an escape. They were a new set of simpler problems instead of the raw, rubbing, every day problems. That’s not the case with Usher syndrome. It’s always there, like beach sand in your hair.

A self portrait of the photographer in a typically serious mood.

Examining the Science Behind Dietary Supplements for Retinitis Pigmentosa

2010-08-10T09:57:00.001-04:00

by Jennifer Phillips, Ph.D.

We’ve filled a lot of blog space over the past year discussing ongoing and eminently promising research efforts to find a cure for Usher syndrome. This is a target-rich topic, as you may have observed, with hundreds of researchers all over the globe working toward future treatments. This wealth of potential stands in stark contrast to the paucity of treatments available today, particularly with respect to the progressive loss of visual function inherent to Usher syndrome. Currently, the only recommendations in the neighborhood of being therapeutic with respect to preserving the vision of USH patients are the dietary supplements.

Mark has previously discussed the particular compounds on this list a bit, emphasizing them as components of a healthy diet, as opposed to prescribed as supplementation. As some vision care specialists do recommend bona fide supplementation for their Usher patients, though, I thought it would be a worthwhile endeavor to examine the evidence for this particular recommendation. Before I begin, though, I must vehemently nod toward that long, tedious ‘Terms and Conditions’ disclaimer found on the lower right margin of this page. As it clearly states, this site does not provide medical advice. In general, it’s a terrible idea to take medical advice from anyone on the internet, regardless of his or her credentials. So, even though I’ll spend the rest of this post talking about clinical studies and the basis for their application to real patients, I am merely a scientist with an opinion, which should not be construed as medical advice.

The data:

Over the last 20 years or so, several studies have been conducted examining the effects of various dietary supplements on patients with progressive Retinitis Pigmentosa (RP) from a variety of causes. As a minor but important side note, these studies excluded patients with clinically diagnosed Usher type I, but did include some patients with diagnoses of Usher type 2.

It is generally agreed upon that the studies were soundly designed and executed. That is, the questions that these studies were addressing were clear, specific, and answerable by the data obtained; the proper experimental controls were used, and the methods of collecting data were acceptable. The first study, published in 1993, investigated the effects of high doses of vitamin A on preserving visual function in patients with RP from various diseases. The authors reported that patients who consumed these large doses of vitamin A over a 4 to 6 year period had a slowed rate of vision loss compared to control groups, and concluded with a recommendation for vitamin A supplements at this dose for typical RP patients. There was also some indication from this study that consuming larger doses of vitamin E led to an accelerated loss of vision.

The second study, published in 2004, examined the rates of vision loss over the course of several years in RP patients treated with the same high dose of vitamin A combined with DHA, compared with patients receiving the high dose of vitamin A alone. The researchers reported no differences between the ‘A + DHA’ group and the ‘A only’ group. However, when they examined a subgroup of patients who hadn’t taken vitamin A supplements before the study began, they observed that DHA in combination with A seemed to have a protective effect on vision loss in the first two years of the regimen.

The third study, which came out earlier this year, examined the effects of lutein in combination with Vitamin A supplementation on vision loss, compared to a control group taking Vitamin A alone. Again, the primary result was that there was no difference between the ‘A + lutein’ and the ‘A only’ groups, but again, a secondary examination of a subset of the data showed that for selected, specific measures of vision loss, the ‘A + lutein’ group scored better. Based on this secondary outcome, the authors made further recommendations for dietary supplementation with lutein added to high-dose vitamin A for RP patients.

The controversy

As you may have surmised from our previous vitamin discussions here, the findings described above are not universally accepted by the medical community. In particular contention are the recommendations regarding vitamin A: since the first publication of these findings, a clash of opinions has ensued, with a flurry of letters to the journal in which this and all subsequent studies were published. Researchers and clinicians questioned the strength and interpretation of the data and in particular reacted unfavorably to the unambiguous recommendation by the authors that RP patients should commence high dose vitamin A therapy—a recommendation that was widely reported in the media and which many felt was premature considering the strength of the study upon which it was based. The controversy fumed on for months, deepening when members of the Data and Safety Monitoring Committee—those charged with oversight of ethics and procedures of trials involving human subjects—wrote in contending that the raw numbers of the study did not support the conclusions. Both DSM committee members praised the study for the quality of its methodology, but expressed specific concerns about how the numbers were crunched after all the data were collected, concluding (with my bold emphasis):

“This excellent study provides useful information for future investigators, but it fails to scientifically establish a significant beneficial effect for vitamin A in the treatment of RP"

and

"This study was meticulously designed and extraordinarily well performed…however, I would argue that its message should be one of caution more than enthusiasm. Patients should be informed that vitamin A may be only marginally beneficial if it helps at all, and this fact must be weighed against a somewhat uncertain risk of liver or other toxic side effects…”

Although the outcry was greatest with respect to the original 1993 report on vitamin A supplementation, minor controversy has continued to dog these studies, particularly with respect to the question of how much the conclusions of these studies, which relied heavily on spotting differences between groups that were only revealed when the statistical analysis was conducted in a certain way, should inform the standard of care for RP patients.

The outcome

To the best of my understanding, this issue is nowhere close to being resolved. The authors of these three studies have stood by their original recommendations, as evidenced by the subsequent studies focusing on the effects of extra dietary supplements in addition to the baseline high dose of vitamin A. Meanwhile, clinicians appear split on whether or not to recommend these supplements to their RP patients.

Based solely on the evidence in these publications, my opinion is that there is insufficient data to recommend supplementation. I know that some other scientists and physicians have reached the same conclusion, but still others, viewing the very same body of evidence, have determined that supplementation is the way to go and have incorporated it into their limited arsenal of therapies for retinitis pigmentosa. The only way through this apparent impasse will be through additional research to provide more evidence for—or against—these clinical recommendations. In the absence of new data, however, I can only proceed from my interpretation of the existing evidence as I consider the implications of these recommendations:

As Mark has previously written, we should all try to include more DHA and lutein in our dietary intake. Even knocking down a few extra carrots and other vitamin A rich foods is a good thing, as Martha Stewart would say. As a part of a healthy diet they appear to have no side effects (beyond the yucky faces pulled by unwilling recipients of mackerel, kale et al., on their dinner plates), so making an extra effort to consume them for overall health would seem not to have a downside. Daily doses of supplements, on the other hand, can be expensive and difficult to comply with. An additional concern stems from the fact that, unlike pharmaceuticals, dietary supplements are not regulated by the Food and Drug Administration, which opens the way for disturbing variations in ingredient content and quality. As such, informed consent for this type of treatment should include a discussion of the cost to benefit ratio, based on the available data. Moreover, unlike supplementation with benign compounds like DHA or lutein, high-dose vitamin A supplementation does carry with it some non-trivial health concerns, including liver problems and developmental defects. Thus, the ‘cost’ element of the cost to benefit ratio of vitamin A supplementation must include some risk factors that should be clearly spelled out when such treatments are being discussed.

For the clinicians who recommend this therapy for their eligible Usher and other RP patients, it’s not clear to what extent this advice is based on a more favorable interpretation of the study data discussed herein, or a more general embrace of something, anything, to suggest to patients in the way of treatment. To me this latter view is an issue of medical ethics and informed consent: If the physician prescribing long-term vitamin supplementation to his or her patient is doing so based on a belief that it will help, or a desire to offer something more than a sympathetic pat on the shoulder as they watch a young person’s vision deteriorate, then he or she has left the realm of science-based medicine, and may be even edging into the gray area between hope and false hope.

The pursuit of scientific ‘truth’ is always a work in progress: What we think we know today could be dramatically altered by what we learn tomorrow. Today, I know further dietary supplement studies are ongoing. Some of them are specifically looking at Usher patients, and even particular clinical subtypes of Usher. Good, targeted information about the potential benefits of supplementation for Usher patients will be forthcoming, and there is hope—real hope—that convincingly evidence-based recommendations can be made based on the findings.

References
Archives of Ophthalmology vol. 111, pp 751-772; 1456-1461
Archives of Ophthalmology vol. 122, pp 1297-1314
Archives of Ophthalmology vol. 128, pp 403-411; 493-495

All You Need to Know About the Usher Syndrome and Related Disorders Conference, Part II: Psychosocial Aspects

2010-07-16T13:44:00.001-04:00

by Mark Dunning

Yikes. I’m way behind on posts. I will respond to Jennifer’s last post soon. First, a quick update on the Usher Syndrome Family Conference held last weekend in Seattle Washington. In a word: Awesome. Some of the leading experts in the world spoke and they all did so at a level that was possible to follow even for the recently diagnosed. They were great. It was also terrific to see so many Usher adults in attendance. We quite literally emptied Seattle of interpreters for the day and it was mesmerizing to watch so many communicating using sign language and tactile sign. Bella has pretty much dropped sign at this point, so I had to knock off a lot of rust but I held my own (mostly I signed ‘Wait. I don't understand. Where’s an interpreter?’)

In the evening we held a cookout at a waterfront park. The weather could not have cooperated more. It was 90 degrees and dry. We had a nicely shaded reserved section with a dozen picnic tables and a large percentage of the conference participants came. Families got to mingle with each other and with many of the speakers, who also came for burgers and hot dogs. There were a dozen kids around the age of my kids there. Miraculously they all seemed to get along well. So well, in fact, that I had to drag my kids out of there.

All in all it was a terrific day and the organizers, particular Hear See Hope, Seattle Children’s Hospital, The Decibels Foundation, and the Coalition for Usher Syndrome Research, are to be commended. I’m already getting inquiries about next year. We’ll be working out those details soon so watch this space.

OK, now back to one of many unfinished topics. I have already given a summary of the first session of the Usher Syndrome and Related Disorders Conference held in Spain back in May. Here is a summary of the second session. Keep in mind this is still just the afternoon of day one, so more will follow (assuming I ever get my act together).

State of the art clinical and genetic diagnosis and early intervention in Usher syndrome
Claes Moller
Orebro University Hospital, Orebro, Sweden

Thanks to newborn hearing screening and vestibular testing, the folks in Sweden are getting pretty good at diagnosing Usher 1. However, Usher 2 and 3 patients are still very difficult to identify at a young age without genetic testing because of the absence of early balance issues. Now that it’s been several weeks, I can’t remember if Sweden is doing regular genetic testing of kids that fail the newborn hearing screen or not, but I do know that Dr. Moller feels it is the best way to find Usher 2 and 3 kids at a young age.

Why you care

There may not be a person in the world that knows Usher syndrome better than Dr. Moller and even he is finding it hard to diagnose Usher 2 and 3 at a young age without a genetic test. Early diagnosis remains critical because there is so much that can be done, from hearing aids and cochlear implants to sunglasses and dietary changes, all of which are more beneficial when done early. If you have a child with hearing loss and don’t know the cause, early genetic testing is a good idea.

Psychosocial impact of Usher syndrome: Adults and the family
Ilene Miner
Licensed Social Worker, Venice, California

More than 100 people with Usher were interviewed over many years and then an additional 10 in Denmark and 12 in the United States. The study found a number of similarities between countries but in all cases Usher syndrome has a significant psychosocial impact throughout life. In particular both groups, Danes and Americans, suffered consequences from having Usher that included job loss, depression, and problems with family relationships. There was a difference in that Danes had significantly more access to services than people with Usher in America and that had an impact on their ability to have contact with others and socialize.

Why you care

Well, if you want to have a social life or you want your child to have a social life, you care. The study showed that more services meant more opportunities for social interaction. It seems pretty clear that we in the United States need to fight for more services for people with Usher.

Usher syndrome and psychosocial health
Berth Danermark
Orebro University Hospital, Orebro, Sweden

This was a study of 96 persons with Usher type II and 16 persons with Usher type III in Sweden. The participants filled in a questionnaire through a national public health survey, so the results could be compared to those from the general population. The goal was to study psychosocial factors that promote health. It was not good news. People with Usher were more likely to have depression, anxiety, sleeping disorders, low self esteem, and thoughts of suicide than the general Swedish population.

Why you care

This is the stuff that scares people. It’s not the blindness or the deafness or the balance problems. It’s the social isolation and the psychological problems that go with it. I talk a lot about treatments for the physical ailments but we need to treat the social and emotional impact of Usher as well. Expect more discussion about this in future posts.

How do people with Usher syndrome live their lives?
Ole Mortensen and Bettina Moller
Information Center for Acquired Deafblindness, Denmark

Over a five year period, “The Nordic Project” interviewed 20 people with Usher in Scandinavian countries. The interviews were conducted once a year and focused on how the participants lived day to day, not just on their problems. The hope is that some knowledge can be gained that can be helpful in developing social supports for people with Usher.

Why you care

Seems sort of silly to have to discuss this, huh? I mean, many readers of this blog have Usher or a family member with Usher and live a life every day. But for researchers who don’t live the life, this is an important topic. They need to know about how Usher actually impacts the daily lives of their patients and research subjects if they want to know if treatments are improving those lives. And, quite frankly, for families this matters too. Just see my post on my first deafblind party to get an idea of how foreign living with Usher can be even for someone who, like me, lives with Usher every day.

So that gets us through most of day one of the symposium. From here on, it gets pretty technical which means two things: 1) I’ll be soliciting Jennifer’s help and 2) my descriptions will be much shorter.

If You’re Not Part of the Solution…

2010-07-07T08:30:00.001-04:00

by Jennifer Phillips, Ph.D.

Editor’s note: This is a planned public debate between Mark Dunning and Jennifer Phillips, the two primary contributors to this blog. The ideas expressed in the posts during this debate will be purposely provocative and unfinished to invite a response from the other party. We hope you find the discussion valuable.

...you are, as they say, part of the problem (science geek variant: “you’re part of the precipitate."). The funny thing about this debate is that Mark and I are not arguing from very polarized positions. We have a common goal (improving communication between patients, physicians and scientists), we recognize many of the same problems (communication between these groups can be challenging), and we more or less agree on the broad strokes of the solutions (everyone needs to work harder at transparency and full disclosure). Where we differ is in the details of this last category, mostly because while I agree with the basic ambition of facilitating communication on global efforts to find a cure for Usher syndrome, there are some undeniable hindrances to fully achieving that goal. I dealt with some of these issues in my first debate post, so I won’t rehash them except to say that it will be difficult to completely solve this particular problem without addressing several larger, overarching challenges, such as the inherently unpredictable pace of biomedical research, the competitive nature of research funding, and society-level problems with science communication. That said, even a foregone conclusion of limited success is no reason not to forge ahead and do what we can to improve the situation. “Difficult” does not equal “Impossible”.

So, if we agree that change needs to happen, and that we have the power to influence this happening, let’s start talking about HOW it should happen. I’ll begin by addressing improved Doctor-Patient communication, which, to me, can be broken down into quantitative and qualitative components.

I have heard only a few stories recounting the Usher diagnosis experience, so my sample size is small. However, all that I have heard, including all that Mark and our readers have shared on this blog, have been infuriating and frustrating, and if they are (and I have no reason to doubt that they are) indeed representative of the average Doctor-Patient encounter, then this is an area that screams out for improvement.

The quantitative problems that have been described center on a paucity of information or resources, while the qualitative shortcomings have to do with the tone or demeanor of the doctor-patient encounters. Families are broadly and cursorily informed of an incurable condition and left, it seems, to work out the details on their own. In my opinion, any visit to a health care provider that ends with the patient’s family frantically ‘Google-ing’ for answers is an abject failure. We can do better.

We want to improve on both the volume and the worth of information that Usher patients get from their health care providers, from the first diagnosis onward. Furthermore, we want to improve the way in which it is delivered. Current, comprehensive, evidence-based information about Usher itself and locally available resources for coping with it, presented compassionately and optimistically, would certainly go a long way toward delivering the message of hope we are seeking.

Working within the parameters of the current American health care system, a top-down approach to solving this problem would include:

1. Compiling information and resources on Usher syndrome that would encompass both national and regional information. This would probably need to happen through the NEI or the FFB or some large-ish, well-connected entity at the national level, and would be modified with input from regional specialists and providers. Such information should be in the form of both printed and web-based material, and should be updated regularly.

2. Training a broader segment of physicians to become familiar with these resources and to standardize the dissemination of this information to families with an Usher diagnosis. Continuing Medical Education is a requirement for everyone holding a medical license. Ophthalmologists, Otologists, and all other providers who see Usher patients, especially if such patients are outside of their primary specialty, need to have regular access to current information on Usher research, specialists in their area, and so forth.

3. Prompt delivery of this information to patients and families. It seems to me that it would be a huge assist for the doctor if he or she had a concrete and comprehensive repository of information to offer and refer families to at any point in the process, but particularly at the initial diagnosis. This would take at least some of the pressure off of the provider to deliver all relevant information off the cuff, and off of the families to hear and process this information during a highly emotional encounter. Instead of navigating unguided through the vast, confusing, and often inaccurate morass that is the Internet, families would be given virtual destinations, in addition to helpful local or regional contacts.

Overall, current, comprehensive, evidence-based information about Usher itself and locally available resources for coping with it, presented compassionately and optimistically, would certainly go a long way toward delivering the message of hope we are seeking. Such an endeavor would require input from a broad array of professionals and family advocates, and it would likely be a fairly complex and protracted process…but it is inherently possible.

The above proposal is deliberately presented in very broad strokes. I have specific ideas for each component, but I hope that leaving the details out for now will allow you, readers, to formulate some specifics of your own. Think about it. Discuss the pros and cons of such an endeavor with the families and professionals you are in contact with. Figure out what you can do to contribute to creating this resource, if you think it’s a worthwhile cause. And if you don’t, think of a better alternative. In short, be a part of the solution. I look forward to hearing your ideas.

My First Deafblind Party

2010-06-30T13:41:00.001-04:00

by Mark Dunning

We're heading in to summer so the posts will be more spaced out. Here’s a quick one for you. Julia and I recently attended our first deafblind party and I thought I’d tell you about it.

Let me stop there and put this in a larger context. First, I’m a little embarrassed that this is a big deal. I don’t want it to sound like I went to the zoo. These were real people, after all, and I have a great respect for them. But I don’t know them all that well and the usual apprehension that goes with a social event with unfamiliar people was compounded by the fact this was also an unfamiliar setting for me.

Second, prior to Bella’s diagnosis almost four years ago and I had no experience with blindness. Heck, prior to her birth I had not experience with deafness, either. Like most parents of children with Usher syndrome, I am terrified of what the future might hold for my daughter. And, like a lot of families, I didn’t want to know if it’s going to be bad.

So I avoided adults with Usher syndrome for a long time. I was afraid they would lead a difficult life, a lonely life, a life without joy. I had done the same thing with deaf adults when Bella was first born. I just didn’t want to know.

I find this with lots of families of children with Usher. They avoid conferences and deafblind functions. They don’t want to connect with adults with Usher. Part of it is that many adults with Usher were born long before cochlear implants and digital hearing aids, so most of them sign. This furthers the divide between newly diagnosed Usher families, the majority of whom do not sign. Add in that the sign language is often tactile sign and newly diagnosed families find the communication all the more difficult. This feeds their anxiety. They picture their son or daughter using tactile sign, speaking to them through an interpreter, and it scares them to imagine that distance between them and their own child. I know it scares me.

But those that read this blog know that I am a vocal advocate for building an Usher syndrome community for both practical reasons and personal reasons. Practically speaking, to find a cure is going to require the efforts of all Usher families. We need your natural histories, your genetic information, your experiences, and yes, your money (or at least the money you might help raise). Eventually we will also need Usher families to participate in clinical trials and the best candidates for those initial trials are Usher adults.

On a more personal note, I want a cure for my daughter. I don’t want her to go blind. The only way that is going to happen is if Usher adults and other Usher families are engaged in the process. And, as I regularly advocate, the only way to keep families engaged, whether they be newly diagnosed or older adults, is to connect with them and build an Usher community.

So that’s what I do these days. I connect with Usher families and with Usher researchers. I have made a ton of great friends through it and many of them are Usher adults. Still, most of my communication is through e-mail and I do not often meet deafblind adults outside of conferences where accommodations are made and professionals are around. So my experiences in the ‘real’ world are few.

My first real experience with blindness came at a dinner several years ago with a well known blind author. We were both traveling in Seattle and staying at the same hotel. I was terribly nervous meeting him, more because he was blind than because he was relatively famous. But he was gregarious and funny and dinner turned out to be memorably fun. Especially when we left the restaurant a number of drinks later and I realized I didn’t know how to get us back to the hotel. This led to several wandering blocks of ‘the blind leading the blind’ jokes from my companion and at least one trip into a hedge when I forgot that I was leading him. Thankfully he had a good sense of humor.

But this was my first deafblind party. This was the first time that I would be immersed in the daily life of adults with Usher syndrome. I was very nervous. It helped that my wife Julia was with me. At least one of us could fake an injury if we couldn’t handle it.

There were 15-20 people at this party. About a half dozen of them had Usher syndrome. All were adults. All had pretty severe vision problems. But their communication varied. Some only used sign language. Some used a combination of spoken English and sign language, depending on the audience. And some used spoken English exclusively. Most of the sighted party members knew sign language, too, and there were several interpreters about, so communication was surprisingly easy.

I sign a little, but mostly I needed assistance communicating. I did not follow etiquette very often. You have to wait to reply when someone is using an interpreter and, well, I have a big mouth and I’m from Boston so I tend to talk over people and talk very fast. By the end of the night I had it down, though.

And the conversation was wonderful! These were fascinating people. There were college professors and state representatives. People had travelled the world, written books, and been on the radio. The party was to celebrate the success of a recent deafblind day at the state house and there was a declaration signed by the governor that was passed around. Forget faking injuries. Julia and I didn’t want to leave. I went in expecting a bunch of silent, moping people sitting in the dark bemoaning their fate. I found one of the most upbeat, positive, energetic, and capable group of people that I have ever had the pleasure of meeting.

Now, this is not to say that the night went entirely smoothly. The guide dogs were let off their leads and they partied like sailors, tearing around the house and knocking over anything in their path. Since their owners (is that the right word?) couldn’t see them, the dogs were usually one step ahead of retribution. A lamp would break and by the time everyone turned to the sound, the dog was long gone and the owner was yelling at the vacant rug. Julia and I have two dogs, one of whom is a conniving son of a gun, so we could relate.

Even more humorous was the making of dinner. Our hostess, who has Usher and can not see or hear very well, insisted on command of the kitchen. She was making pasta in a giant cauldron and was completely oblivious to the boiling water spilling everywhere. It was an open floor plan and those of us without Usher could all see what was happening so, one by one, we stepped in and offered to help. And one by one, we were shooed away. At one point I was standing with her husband as she knocked over a bottle of wine and grabbed a knife by the blade as the pot boiled over and I said, “Uh, should we offer to help?” He just waved a hand as only a husband can and said “Nah. She’s fine. She wouldn’t accept help anyway.” Boy, did he know his wife.

The good news is that our hostess survived the making of dinner and the house did not burn down. I’m pretty sure her husband would have stepped in if fire broke out, though knowing our hostess, I’m also pretty sure he would have been swiftly shooed away. And dinner was excellent. I’m not just saying that. It was really excellent. Better than I could have made (though I struggle with grilled cheese, so that’s not saying much).

So we had a great time at our first deafblind dinner. But that’s not the point. It could just as easily have been packed with dullards and been the most boring three hours of my life (next to that time I watched Waterworld). The point is that we have to find ways to bridge the divide between Usher adults and families with Usher children. We need each other. We can learn from each other. And there is no one that understands us better. This is not to suggest that every Usher family will like every other Usher family. We’re a cross section of the population at large. You’ll click with some and not with others. But you have to try for your own good or for the good of your children. And you never know, you might just wind up having a great time. Who would have thought that would come from an Usher diagnosis?

Solutions, Part I

2010-06-14T16:47:00.001-04:00

by Mark Dunning

Editor’s note: This is a planned public debate between Mark Dunning and Jennifer Phillips, the two primary contributors to this blog. The ideas expressed in the posts during this debate will be purposely provocative and unfinished to invite a response from the other party. We hope you find the discussion valuable.

It seems like this is a good time to start discussing solutions rather than problems. First, a truth, since I know you can handle it: I don’t really have much resentment toward researchers. The truth is a lot of them have become good friends of mine. I am amazed by the hours they work and the amount of dedication they have. In fact, it was the willingness and downright eagerness of three researchers to include me in the process that gave me the confidence to stick my nose in all of this in the first place.

I now know many (if not all) of the top Usher syndrome researchers in the world. They treat me like a peer even though I’m not. They never withhold information and actually appear to take great joy in educating a neophyte like me (most of them are professors, after all).

But my frustrations with the communication between families, researchers, and physicians is very real. I have burrowed in to the research community, but how I got here was all trial and error. I feel very fortunate to have gotten access to the information I have. I didn’t leave a trail of breadcrumbs for other families, however, and quite frankly it took a LOT of time, effort, and luck. Most families don’t have the resources available to them that I did.

One of the comments on Jennifer’s last post struck a chord with me. It was anonymous, but it was clearly posted by a family member well versed in research (the writer mentioned glial cells, for goodness sake). As I read it, I could hear the pleading of the writer for information. The writer mentions hearing about a potential treatment in 2008 but not hearing anything about it since.

The post rings with questions: Has nothing happened since then? Did it get dropped? Did they find out it’s not going to help? Did they just hit a roadblock? Do they need money to pursue it further? Who’s working on it? If I give money, will it get to them? How can I help?

No one answers these questions for families and that makes them, as this particular commenter put it, ‘frantic’. Jennifer’s 911 call would be a good metaphor except that for families with Usher syndrome, there is no number to call, no dispatcher to talk them down, and no siren in the distance to let them know help is coming.

So that’s where we stand in the debate. How do we get researchers the tools and information they need while keeping families involved in the process? How do we overcome the fear of false hope while ensuring that frantic families are informed?

Once More, From The Top, With Feeling

It all starts with the communication process of the initial diagnosis. Hope in the diagnosis is not a luxury. It’s a necessity. Every time a family with Usher syndrome is so devastated by the diagnosis that they never get genetically tested, never go back to the doctor, and/or never share their natural history information, it limits our overall knowledge about the disease and lengthens the timeline to a cure. It also limits the available pool of candidates for clinical trials which may delay them or even keep them from happening.

We need to keep families engaged, and that makes hope as important as fact to finding a cure. Families that believe we can help them, whether it be today or in the future, will stay in touch with us and remain involved in the process. So, going back to my opening salvo, facts need to do what I want them to and that’s support the case for a hopeful future. Remember, as I wrote previously, we can handle the truth. (And, yes, I did actually write that, Jennifer. I must say that using my actual quote against me in your last post was dirty pool.)

So here are some truths that families should know as soon as Usher syndrome is suspected:

1. The truth is that while there are no proven treatments for Usher syndrome, vitamin A is often prescribed. It might help with Usher syndrome, it might not, but it is generally considered safe in proper doses, especially when combined with regular tests of liver function . Most importantly, it offers hope to families that take it because they are doing something to help themselves or their loved one.

The same can be said for other dietary changes like DHA (Please note that I say dietary changes, not supplements. That’s different.). The truth is that most kids (and many adults) hate to eat fish but it’s good for them and not just for their eyes. Whether or not you have Usher syndrome you should probably work fish that’s high in DHA in to your diet (unless, of course, you’re allergic in some way). Lutein is the same. It’s found in spinach and broccoli and other stuff kids hate, but it’s good for them and they should eat it whether they have Usher syndrome or not.

It is also the truth that sunglasses make you look cool, so if there is a chance they might slow the vision loss, you should probably wear them. They offer hope and the chance to look like a rock star.

2. The truth is that there are a number of treatments in development, many of which hold a lot of promise. Gene therapies have worked in clinical trials for other related disorders and there are a number of groups that intend clinical trials on Usher syndrome treatments.

3. The truth is that before any treatment can be used in humans, it needs to be tested in animals. The good news is that there are animal models for Usher syndrome. True, they have not consistently demonstrated the vision phenotype, but there are a lot of good people working on it that believe we will have one that does very soon (I’ll write more about this in a later post). It will be about thirteen nanoseconds before all those treatments under development are tried on an animal model that has the vision phenotype once it’s developed (OK, that’s probably not the truth, but it will happen quickly)

4. The truth is that these treatments under development are, depending on the treatment, 5-10 years away from helping you or your loved one, but we don’t know for sure when, or if, they will ever arrive. Sorry. It’s a hard truth, but you can handle it. However, keep in mind that…

5. The truth is that we don’t know enough about the vision loss associated with Usher syndrome to know for certain the rate of deterioration that any individual faces. In short, we don’t know when, or even if, you or your loved one will lose their vision. What we do know is that the vision loss is progressive and that, except in rare cases, most people with Usher, regardless of type, retain some useable vision until later in life.

6. The truth is that, when you consider the number of treatments under development, the time frame for delivering those treatments, and the rate of vision loss (which may or may not be slowed by sunglasses, DHA, vitamin A therapy, lutein, anti-oxidants, or other potential dietary changes), a child born today with Usher syndrome has a chance of NEVER LOSING HIS OR HER VISION.

See? Families can handle those truths, right? Now, a lot of what I proclaim above as truth might not be so quickly supported by others (I won’t get in to the vitamin A debate again, for instance). However, even if a physician disagrees with any of the above and does not want to share it with families, I believe he or she, at a minimum, has a duty to tell families the following facts (note I said facts, not truths):

1. The majority of people with Usher syndrome that want to go to college go to college.

2. The majority of people with Usher syndrome who want to get married, get married.

3. The majority of people with Usher syndrome who want to have children, have children.

4. The majority of people with Usher syndrome who want to pursue a challenging career, pursue a challenging career.

In short, the majority of people with Usher syndrome live happy, fulfilling lives. That, above all else, is the fact that families seek and all too often it is never mentioned to them by anyone.

The Debate Goes Thermonuclear

2010-06-10T09:31:00.002-04:00

Figure 1: “Dear Dr. Phillips” preparing to rush into the blazing thicket of WRONG!

Stop, Drop & Flip-flop

In the intro to his last debate post, Mark concedes the point that research scientists do, in fact, talk to each other—or does he? After opening with comments that seem contra his original position, he claims to never have held that position in the first place, stating “I merely said that researchers give the impression that they don’t talk to each other”. Well thanks to the marvels of the internet , we have a handy record of what Mark actually did say, back on April 29th. To wit:

“Researchers are loathe to discuss any research that is currently underway because until the results are not only in but have been peer reviewed, they can not be trusted to be fact…Many researchers take this secrecy to the point that they won’t even discuss what they or others are working on.”

Hmmmmm…Well, perhaps he meant to say that “Researchers merely give the impression that they are paranoid control freaks”. Either way, I think we can consider this “impression” falsified, at least in the generalized manner in which it was originally applied, and move forward.

Shouting “Fire!” in a crowded Symposium

In mulling over how to reply to Mark’s June 3rd post, relating his experiences at the Usher Syndrome Symposium, I reconceived our dialogue in in the form of a 911 transcript. The ‘Caller’ script recapitulates portions of Mark’s last contribution to this debate:

Dispatcher: “911, what is your emergency?”

Caller: Help, Operator! “Few families actually saw what was going on or heard any of the presentations” and “The information was also brutally technical and scientific”!!

Dispatcher: Stay calm, sir; given that this was a professional conference targeting clinicians and scientists rather than families, unrelenting technobabble was completely appropriate—necessary, even!—to convey the important details of these cutting edge scientific studies.

Caller: But…but, “The Researchers Are Too Distant From Their Real Purpose!” “I got the sense that a child with Usher was a rarity in their lives when, in truth, they probably should all have a picture of a patient with Usher taped above their door.”

Dispatcher: Sir, please, you seem to be having difficulty separating your personal investment in identifying a cure for Usher syndrome from other more professional motivations for pursuing research in this area. Let’s say you can persuade every researcher currently working on Usher studies to prominently display a picture of an Usher patient. It probably wouldn’t be difficult, as you concede that at least some of the researchers you have interacted have acknowledged the important perspective that patient interactions can offer. Then what? Will the presence of these pictures inspire formerly indolent or indifferent researchers to greater works? The insinuation here is that researchers who don’t have regular, personal contact with Usher patients (or, indeed, this could easily expand to any basic research field with potential clinical impact) aren’t sufficiently motivated to fully apply themselves to their professional endeavors. That’s deeply insulting, and, more importantly, spectacularly wrong. To suggest that we’re just not that into it because we don’t have a personal stake in the outcome is an absurd mischaracterization. It is undeniable that a personal connection to Usher syndrome would be motivating to someone contemplating a career in research and/or medicine. However, it is far from the only motivator, and absent any further evidence, I reject the assertion that this personal stake is a prerequisite for professional commitment.

Caller: Well, yeah, but “In the end, the families are all that matter. Even if you were an empty hearted researcher you would have to recognize that without Usher families, you don’t have a job. No one cares about developing an Usher syndrome animal model if no one has Usher syndrome!”

Dispatcher: Sir, human biology is incredibly complex. And within that broad category, Usher syndrome is just one of many phenomenally complex diseases. As thinking feeling human beings, we hope fervently that our research will to contribute to future treatment options. As professional scientists we are required to focus on the really nitty-gritty complexities of the system—and we like it! Most of us didn’t become Usher researchers because we know someone with Usher and wanted to help them. Most of us got here because of a deep and abiding interest in understanding complex molecular/cellular sensory processes. Usher syndrome research provides us with abundant complexities to which we can apply our collective decades of scientific training and problem-solving skill sets. Furthermore, just like content of the meeting that you found so dense and unpalatable, it is necessary for scientists to consider the fine and intricate details of Usher pathology at the cellular and molecular level. That we may not also consider the existence of patients and families awaiting a cure from the fruits of our labors during every phase of the experimental process is NOT a liability. In fact, I should think you’d prefer us to have our full attention on the nitty-gritty. Let us attend to the task of figuring out how things work with obsessive, laser-like intensity. Once we gather those data, we can proceed to the logistic steps of incorporating them into a treatment option, but we cannot skip or hasten the first step without running the risk of laying a shaky foundation for all that is to come.

Banking the embers

Ok, I think the smoke and fumes have dissipated enough—for now—to get to the more substantive issues. For me, those issues involve identifying ways in which we ALL--Patient families, Clinicians, and Researchers--can improve and expand our communication with each other

The concerns Mark and I have voiced about withholding or selectively disseminating information, about media coverage, and overall about patient access to the research findings that could benefit them are complex, but addressable. The tricky part of this, of course, will be agreeing on the best ways to address these problems. Discussion of the pros and cons of different solutions will, I think, be the principal topic of the remainder of our open debate. I have some specific ideas about how to proceed; I know Mark does too, and it’s probably not too much of a stretch to predict that our respective opinions on what constitutes the best choices will not perfectly align. But it’s a conversation worth having, and I’m looking forward to the process. As we flesh out some of these ideas for public consumption, I hope that our readers will get involved in the discussion as well, so don’t be shy about commenting!

Usher syndrome Family Conference, July 10, 2010

2010-06-09T13:19:00.001-04:00

by Mark Dunning (biographical sketches by Karmen Trzupek)

Jennifer and I have been debating the difficulty in establishing and maintaining relationships and open communication between researchers, professionals, and families. The family conference in Seattle on July 10th is a great opportunity for families not only to connect with other families, but also to meet and talk with some of the leading researchers and Usher syndrome professionals. I strongly encourage you to attend if you can. Both Jennifer and I plan to be there and would love for the chance to meet our readers.

Here’s the link to register and some information on the presenters:

Dr. William Kimberling, PhD
University of Iowa and Boystown National Research Hospital
Dr. Kimberling is internationally known as an expert in Usher syndrome, with over 30 years of experience in the clinic and in the laboratory. Over that time, he has received many federal and private grants to study Usher syndrome and related disorders. Through these studies he and his collaborators have been responsible for the identification of four of the nine Usher genes. He currently holds a dual-professorship at Boystown National Research Hospital and the University of Iowa, where he is working with Dr. Edwin Stone to develop an inexpensive but accurate means of screening young children for Usher syndrome.

Linda Ramsdell, MS, CGC
Seattle Children's Hospital

Linda Ramsdell is a certified Genetic Counselor working in Medical Genetics at Seattle Children’s Hospital. Since becoming certified in 1993, Linda has been involved with a variety of specialty genetics clinics at the University of Washington. She now works closely with Dr. Kathy Sie, director of the Childhood Communication Center, and co-director of the Pediatric Cochlear Implant Program at Seattle Children’s, to provide genetic counseling, testing, and support to families with inherited forms of hearing loss. Linda also serves on the Genetic Services committee of the National Society of Genetic Counselors (NSGC.)

Peter Francis, MD, PhD
Oregon Health & Science University

Dr. Francis specializes in research and medical care of the retina and has a particular interest in ophthalmic genetics, practicing at Oregon Health & Science University. He is intimately involved in the design and execution of current and upcoming clinical treatment trials for inherited retinal and macular dystrophies, working closely with the Foundation Fighting Blindness. Dr. Francis directs a stem cell research lab at the new Biomedical Research campus at OHSU. Prior to joining OHSU, he practiced at St. Thomas' Hospital in London, and was director of undergraduate teaching at the medical school for Guy's, King's College, and St. Thomas' hospitals in London. He is also is the editor of the ophthalmology review journal “Ophthalmology International.”

Jim Phillips, PhD
University of Washington

Dr. Phillips is the director of the Dizziness and Balance Center with the department of Otolaryngology at the University of Washington Medical Center, and the director of the Clinical Oculomotor Laboratory within the Division of Ophthalmology at Seattle Children’s Hospital. His work bridges the gap between the research laboratory and the clinic, translating scientific theory into practical tools for assessment of patients. Dr. Phillips studies the genetics of vestibular function in mice, basic physiological mechanisms in non-human primates, the development of behavior in infants and children, and the behavioral consequences of disease and developmental disorders in patients.

Dorothy Walt
Helen Keller National Center

Dorothy Walt is a regional representative for the Helen Keller National Center, northwest region. She earned her M.A. in Rehabilitation Counseling from Gallaudet University and has worked in the field of deaf-blindness for over 15 years. After starting and managing a statewide deaf-blind program in Anchorage, Alaska, Dorothy accepted a position as a HKNC regional representative and became involved with advocating for deaf-blind people nationally and worldwide. She now lives in Seattle.

Nancy Hatfield, MS, PhD
Washington Sensory Disabilities Services

Nancy Hatfield has worked with Washington Sensory Disabilities Services since 1992 to enhance statewide capacity to meet the needs of children and young adults with sensory disabilities. She co-directs the deaf-blind project and coordinates early childhood activities, as well as functioning as administrative director of WSDS staff and grants based at Puget Sound ESD. Nancy holds a B.A. in Speech Pathology/ Audiology and a M.S. and Ph.D. in Education and Human Development. Nancy's prior work experience includes early intervention services for families with infants and toddlers who are deaf, hard of hearing, and deaf-blind. She wrote grants for and directed Project SIT-UPS (Sensory Impairment Training to Upgrade Professionals' Skills) and the Shared Reading Video Outreach Project.

Amelia Westerfield

Amelia Westerfield is a recent master’s degree graduate of the University of Washington’s School of Social Work. Together with her husband, she lives and works independently as a social worker, and is an ardent supporter of local outreach programs and fundraisers serving the deafblind community. She recently wrote an article for the Oregon DeafBlind Project entitled, “Thoughts on Transitioning: One DeafBlind Woman’s Approach to Life.”

Katie Humes

Katie Humes has an extensive background with young children with hearing loss, including children with multiple disabilities. She has a Masters in Education, with a specialty in infants & toddlers with hearing loss. In addition to her 15 years as a parent-infant specialist with families of young children in the Seattle area, Katie was executive director of Whatcom Center for Early Learning, a birth-to-three program for children with special needs, from 2001-2004. She is currently a state-wide coach with Washington Sensory Disabilities Services (WSDS), providing support for families and service providers using the SKI HI Curriculum for a range of issues relating to hearing loss.

Richard Weleber, MD, PhD
Oregon Health & Science University

Dr. Weleber is double-boarded in ophthalmology and medical genetics, and heads the division of Ophthalmic Genetics at Oregon Health & Science University. He specializes in inherited retinal and macular dystrophies. His research interests include retinitis pigmentosa and allied disorders, electrophysiology of the eye and visual system, congenital anomalies, dysmorphology, and genetic and metabolic disease of the eye and visual system. He has pioneered the development of novel measures for testing retinal disease using the electroretinogram (ERG) and visual field analyzers, and works closely with the National Eye Institute, the Foundation Fighting Blindness, and pharmaceutical companies to validation testing strategies as endpoints for clinical trials for retinal degenerations.

All You Need to Know About the Usher Syndrome and Related Disorders Conference, Part I: Potential Therapies

2010-06-07T10:18:00.004-04:00

by Mark Dunning

Valencia, Spain is beautiful. I have to confess with my America centric view of the world I knew nothing about Valencia, outside of their football club. Incredible architecture, parks, beaches, and food. Wonderful place. The conference was held in La Ciudad de las Artes y las Ciencias (The city of arts and sciences) in the auditorium of the Science building. It was a great facility for a conference.

The hosts, too, were wonderful. Dr. Jose Millan and his staff deserve a lot of credit for putting on such an event. It’s nice to know that Usher families have folks like them looking out for them.

The conference was enlightening and, at times, exciting. I’ll give you as brief a summary of the two and half days as I can, highlighting what you really need to know.

The conference was broken in to multiple sessions. I’ll go through the first session on the first day in this post then discuss the other sessions in later posts. This session was on potential therapies, which is probably of the most interest to this audience.

Clinical Trials for CNTF for Retinitis Pigmentosa
Paul Sieving, M.D., Ph.D.
National Eye Institute

We’ve known about neurotrophic factors (of which CNTF is one) for a while. These compounds seem to keep the cells in the eye from degenerating. However, targeting therapeutic compounds to the eye is a tricky business, as there is a barrier between the blood and the retina that prevents most molecules from entering retinal cells.. You can’t just take a shot in the arm, like with a vaccine, and necessarily have the treatment reach the retinal cells. So CNTF has been put in to this kind of capsule that can be put in to the eye via minor surgery. The capsule then releases the CNTF over time.

They have begun phase I clinical trials and Dr. Sieving presented the preliminary results. Ten patients were involved in the study. Five got a limited dose of CNTF and five got a higher dose. All patients in the trial had very limited vision. Not all of them had Usher syndrome but there were Usher syndrome type II patients in the study.

The results are still being collected and analyzed, but it seems like it helped improve the vision in at least some of the patients, who were able to read more letters on an eye chart after the treatment.

Why you care

This is about as exciting as the science of Usher gets. This is a potential treatment for the vision component of Usher syndrome that is in clinical trials right now and has demonstrated, at least initially, that it might help. There are still more phases to go before this is available as a treatment, but it’s promising enough that the Director of NEI wanted to talk about it.

Neuroprotective Effects of TUDCA and Safranal
Nicolas Cuenca
University of Alicante, Spain

Like CNTF, TUDCA and safranal both seem to have the ability to protect photoreceptor cells from degenerating. TUDCA is bear bile and has been used in traditional Chinese medicine as a treatment for eye and liver disease for centuries. Safranal is the stuff that turns rice yellow in paella (can you tell I was just in Spain?). Dr. Cuenca has found that treatment with TUDCA and safranal has slowed cell death in rat’s with retinal degeneration.

Why you care

This, too, is pretty exciting stuff. The research is farther away from helping families than the CNTF research and the doses used in the study were very, very high. Much higher than you’d want to take. But it did help. More studies need to be done, but it’s promising. However, until more studies are done, please don’t stuff yourself or your kid full of TUDCA. We don’t know enough about it. You might want to think about adding some more yellow rice to your diet, however. Any excuse to eat more paella is good with me.

The Use of Aminoglycosides as a Therapy for Usher Syndrome
Tamar Ben-Yosef
Technion-Isreal Institute of Technology, Haifa, Israel

Let me see if I can do this topic justice. Usher syndrome is caused by mutations in DNA. DNA contains the instructions on how to build certain proteins. If the instructions are wrong, you get a bad protein and cells don’t work properly. There are different ways to screw up instructions (just ask my wife when she sends me to the grocery store). One particular type of mutation is called a nonsense mutation. Basically these are periods in a sentence where they shouldn’t be. So when my wife says ‘pick up milk and bread PERIOD’ I hear ‘pick up milk PERIOD’ and screw up the instructions.

Aminoglycosides are drugs that allow a ‘read through’ of that misplaced period, hopefully allowing the full instructions on how to build a particular protein to be read.

There are some aminoglycosides that are commercially available today. The problem is that they are often toxic at the levels necessary to get the desired read-through result. Dr. Ben-Yosef has found some compounds that are more effective in getting a read through effect while reducing the toxicity. Unfortunately at the moment none of these compounds seem to work with nonsense mutations in Usher.

Why you care

If you or your family member has a nonsense mutation, you care a lot. This has the potential to treat your Usher syndrome by simply taking a pill. However, this is still in the theory stage. It hasn’t even helped treat Usher in an animal model yet.

Gene Therapy for Usher syndrome Type 1B
David Williams
Jules Stein Eye Institute, UCLA School of Medicine

Jennifer has explained gene therapy much better than I can here and here. Just to give a quick synopsis, gene therapy is the act of overriding bad instructions within DNA by supplying a new set of good instructions. So going back to my wife example, she could override the entire bad instruction of ‘go sit on the couch and watch TV’ with the good string ‘go downstairs and do the laundry’.

This is accomplished by using a virus to ‘infect’ the cells with the new DNA. The problem is that different genes are different sizes and viruses are like airplanes in that they have a limited payload that they can carry. There are also only a limited number of viruses that can be used in gene therapy. The virus has to be safe and not cause other problems.

One virus known to be safe is the HIV-1 lentivirus. Dr. Williams and his team have found that this virus can be stuffed with a good copy of the MYO7-A gene that causes Usher type 1b and that it can deliver that gene to cells.

Why you care

I care a lot because my daughter has type 1B. This proves that a safe virus can be used to deliver a good copy of the type 1B gene. This is an important step in moving toward clinical trials. In fact, there aren’t too many more steps before we get there. Right now the hope is that Phase I clinical trials will begin in mid-2011. By the way, this estimated date was not discussed at this conference but comes from a discussion had with Dr. Stephen Rose in a Coalition for Usher Syndrome Conference Call a while back. In other words, don't write it in your calendar just yet.

USH1C Therapy Strategies in the Retina
Kerstin Nagel-Wolfrum
Johannes Gutenberg University of Mainz, Germany

The two previous subjects, those of aminoglycosides and gene therapy, were both discussed in this session as potential therapies for Usher type 1C. Preliminary data show that the gene can be delivered via a virus, which is good news for gene therapy as an option. Also 20% of all Usher cases are nonsense mutations and a particular aminoglycoside called PTC124 seemed to show promise in clinical trials for non-eye diseases.

Why you care

This is similarly good news for Usher 1C patients. While no particular date for clinical trials of gene therapy for Usher 1C were discussed, things are looking as promising for gene therapy in type 1C as they are for type 1B. On the aminoglycoside front, this just reiterated much of what Dr. Ben-Yosef had said but with a focus on Usher 1C.

Stem Cell Therapy for Usher 2a
Peter Francis
Casey Eye Institute, Oregon

Jennifer discussed Stem Cell Therapy and this particular study at length in a previous post, so I won’t go in to detail about it. A quick summary, though, is that stem cell therapy is the method of taking stem cells, essentially baby cells that could grow in to any other type of cell, and getting them to grow in to a healthy cell, in this case photoreceptor cells for Usher type 2A.

Two interesting things came up in this discussion. The first was that they have developed a way to test the vision in mice with Usher 2a and those tests have revealed vision loss in the mice. This is significant because historically we’ve had a hard time developing a mouse model that displays the vision loss phenotype. Dr. Francis found that the mice were losing their vision prior to any noticeable loss of photoreceptors. This is good news for testing potential treatments.

Those tests found that the mice treated with stem cell therapy had little functional deterioration of their vision during the ten week test period.

Why you care

This is great news for two reasons. First, a functional mouse model is critical to testing treatments and we hadn’t really had one before. These tests could potentially be used with other Usher mouse models as well. Second, the stem cell treatment seemed to work, at least in mice. No schedule for clinical trials was discussed, but this was an important step in the process. It’s also important for other types of Usher syndrome which may also be treated in the same manner some day. Stem cells are the best bet for reversing vision loss in the long run, though, obviously, that’s a long way off.

Gene Therapy in Usher Syndrome Type 3
Eeva-Marja Sankila
University of Helsinki, Finland

More gene therapy, this time for Usher type 3. As with Type 1B and Type 1C, it appears that Usher Type 3 genes can be delivered via a virus.

Why you care

Same as we discussed earlier. This is good news for using gene therapy as a treatment for Usher Type 3. Again, no dates for potential clinical trials were discussed.

Most of the morning of the first day was exciting news for families with Usher syndrome. I will caution our readers once again, though, that wheels of science turn slowly. There will be more of these every other year science conferences before any of these are regularly administered treatments for families with Usher. That said, we are definitely headed in the right direction and, as you’ll read in the next post about the psychosocial aspects of Usher syndrome, the treatments are coming none too soon.

More Gas for the Fire

2010-06-03T09:22:00.003-04:00

by Mark Dunning

Editor’s note: This is a planned public debate between Mark Dunning and Jennifer Phillips, the two primary contributors to this blog. The ideas expressed in the posts during this debate will be purposely provocative and unfinished to invite a response from the other party. We hope you find the discussion valuable.

“You Can’t Handle the Truth!” – Jack Nicholson as Colonel Nathan Jessup in ‘A Few Good Men’

Sorry I’m late in responding to Jennifer, but I was over in Spain at the Usher Syndrome and Related Diseases symposium. You know what? Jennifer was right. The researchers DO talk to each other. They use big words and often seem to be speaking a different language, but they do actually talk to each other. More than that, they seemed really excited to share information. In fact, there were a number of presentations that thanked our dear Dr. Phillips for her assistance. But here is where the aforementioned dear Dr. Phillips misunderstood my original post. I merely said that researchers give the impression that they don’t talk to each other. So why do families with Usher syndrome have this impression?

The Researchers Are Too Distant From Their Real Purpose

I was one of only two parents at the conference. The other was a researcher. He was there in a professional capacity because, and this could be a whole posting on its own, he happened to be working in the field when his daughter was diagnosed with Usher. There were a couple of adults with Usher there as well, but again they were both professionals working in deaf blind programs in their home countries. So few families actually saw what was going on or heard any of the presentations.

The information was also brutally technical and scientific (protein structures, Jennifer?). This was exacerbated by the fact that many of the researchers used English as a second language. (A quick side note: It was truly amazing to hear these folks talk coherently about extremely technical topics in their second language when I had a hard time ordering dinner in Spanish. There are smart people working on Usher syndrome.) Further there were no interpreters or CART present at the event, so anyone with hearing loss would have had a hard time even accessing the dense information being presented.

None of this is meant as a criticism of the organizers of the event, who were fantastic, but rather to point out that families with Usher syndrome often felt very distant from the discussions. The researchers were very enthusiastic about their mice and their protein chains and their alleles, but very few seemed outwardly cognizant of the fact that those were a means to an end and that we, the families with Usher syndrome, were that end. To the everlasting credit of the organizers, they did an excellent job of including sociologists, behavioral studies, and social workers among the presenters to try to tether the scientists to the patients, but the researchers often got the same glassy look in their eyes when social data was discussed that I got when any study Jennifer was involved in came up (Sorry Jennifer. I really did try.)

Let me pause here for a moment to make clear it is NOT that the researchers don’t care about families. They were all appropriately appalled by the social data, especially the suicide rate (frighteningly high). Indeed, when my daughter showed up at one coffee break, they were all thrilled to see her, many commenting on how important it was that they be reminded she and others like her are the reason that the function of the whirlin protein matters at all. But I got the sense that a child with Usher was a rarity in their lives when, in truth, they probably should all have a picture of a patient with Usher taped above their door. In the end, the families are all that matter. Even if you were an empty hearted researcher you would have to recognize that without Usher families, you don’t have a job. No one cares about developing an Usher syndrome animal model if no one has Usher syndrome.

The Researchers Aren’t the Only Ones That Need the Information Presented

I agree with Jennifer that the media doesn’t do a good job with science content, but I’m not asking that the conference be broadcast on C-SPAN. I only want some thought given to how to communicate the news of the conference to families. This is not a criticism of this conference (again, our hosts were wonderful) but of these scientific conferences in general. I know you can go to the ARVO web site and find abstracts on the conference and I know that if you were to contact the organizers of the conference in Spain that they would happily share the information with you. All of that assumes, of course, that you knew these conferences were happening. But how would the average family know that?

Further, what, exactly, would they read? Here’s a sample e-poster available from the ARVO conference.

Um, yeah.

The point is that not only does there need to be some way to dumb down this information and pass it on to families, that should be one of the priorities.

Information is NOT Freely Shared by Everyone

And that leaves me flummoxed most of the time, downright angry at others. Let’s start with flummoxed. I was at the conference in Spain and heard the talks. The abstracts are printed in the book I took home. I want to communicate out the contents of the presentations I saw to other families. But I’m nervous because I don’t know what the researchers consider privileged information and what they don’t. In other words, even though I heard it and know it could help families, I might upset some folks if I share it. That frustrates families. It is research for us. Heck, it’s often research about us and yet we’re not allowed to know it? How can that be?

One doctor presented a database of genetic information that she had created. The idea was to share genetic discoveries about Usher syndrome with the wider researcher community. Awesome idea. But researchers could enter their findings and mark it private if they so chose. The doctor strongly urged people not to do this, but the fact that she felt it was necessary to include such a feature to get other researchers to use the database speaks volumes about the mindset of many. It is their discovery, their research, and the rest of the research community and the families themselves are not welcome to it.

That makes me angry. Not only could they possibly be withholding information that could help my family but they may very well be stunting the research done by others in the process, further slowing the overall search for a cure.

We CAN Handle The Truth

I understand the concern around sharing certain information with families. I feel it now as I prepare to write about what I learned at the conference. I learned, for instance, that if you shoot a rat with retinitis pigmentosa full of so much TUDCA that the rat eventually dies from the dosage, that rat’s vision does not deteriorate while the vision in similar rat’s with RP does deteriorate. I am worried that parents will buy an oil drum full of TUDCA and hook it via IV to their infant. But does that mean that families shouldn’t be told that TUDCA has protected the vision of rats with RP in monstrous doses. I mean, I’m a parent and I’m not going to be shooting up my daughter with the stuff.

I only felt compelled to speak up once during the meeting. That was when a debate opened up about the merits of withholding or delaying the delivery of a diagnosis to families found through the newborn hearing screen. The idea was to ‘protect’ them from the emotional trauma of an Usher diagnosis so soon after they receive a hearing loss diagnosis. My response was something along the lines of ‘Parents are adults. Treat them like adults.’

The point here, to misquote Jack Nicholson, is we CAN handle the truth. Please, please, please don’t protect me from information because you don’t think I’m big enough to handle it. If a doctor or a researcher I respect tells me to please, whatever you do, don’t stuff your kid full of TUDCA, I’m not going to do it (and please, whatever you do, don’t stuff your kid full of TUDCA). However, if you want my respect, you’ll tell me all you know and trust that I can handle it.

The Big Problem

More than once I talked to doctors who lamented the fact that desperate patients had ignored their advice and gone to Cuba or China to have some cockamamie treatment ‘guaranteed’ to save theirs or their child’s vision. They were understandably appalled by this and I could see that it drove their fear of mentioning any untested treatment (like TUDCA) to any family. They don’t want desperate, frightened families to do something rash. They are right. We don’t want that to happen.

But when doctors and researchers always stress what we don’t know while not openly sharing what we do, it opens the door for these scam artists to step in. What doctors fail to realize is that they contribute to the problem when they withhold information from families. It makes them seem ill informed. (You mean you hadn’t heard that TUDCA helped rats see better?) It also understates what we do know and exaggerates the possibility that Jennifer’s hated ‘pseudo-science’ could hold merit. I mean, they laughed at Columbus when he said the world was round, didn’t they? That, in turn, makes families wonder if maybe, just maybe, those doctors in Cuba know a little bit more or the doctors in China are a little more open to sharing information.

This is about trust, and trust starts with the open sharing of information. Tell me what you know in a format I can understand. I can handle the truth.

Friendly Fire

2010-05-14T13:39:00.004-04:00

by Jennifer Phillips, Ph.D.

Editor’s note: This is a planned public debate between Mark Dunning and Jennifer Phillips, the two primary contributors to this blog. The ideas expressed in the posts during this debate will be purposely provocative and unfinished to invite a response from the other party. We hope you find the discussion valuable.

"Each of us is entitled to his own opinion, but not to his own facts.”
Daniel Patrick Moynihan

Mark began this debate by airing some grievances against the scientific and medical communities. The central charges as I read them (from my anti-hope enclave) are as follows:

1. Through their perceived reluctance to communicate and network on Usher-related research projects, scientists are impeding progress toward a cure and engendering mistrust and betrayal among patients and families.

2. By limiting patient education to well-established medical facts, and/or neglecting to educate themselves on the latest research, doctors are failing to give hope to families reeling from a diagnosis of Usher syndrome.

Formidable challenges, indeed. So, here’s my attempt at rebuttal, from the top:

Just as Mark uploaded his last post, I was preparing to travel to Ft. Lauderdale, Florida for the Annual Meeting of the Association for Vision Research and Ophthalmology. From May 2nd to the 6th, more than 11,000 scientists and clinicians convened under one roof to speak, listen, learn and share ideas about this year’s topic: “For Sight: The Future of Eye and Vision Research”. Mind you, not all 11,000+ were there to talk about Usher syndrome, but there were literally hundreds—hundreds!—of presentations on developing techniques for better diagnosis and treatment of RP. I spoke with a huge number of people, laid the groundwork for some new collaborations, and came back to Oregon bubbling over with ideas for new research directions to pursue. Coincidentally, as that meeting was underway, a paper was published in the Journal of Clinical Investigation presenting collaborative work between myself and clinician-scientists at the University of Cologne in Germany. Thus, I was practically wallowing in a vat of collaborative goodness as I read the words of my esteemed co-blogger:

"Researchers are loathe to discuss any research that is currently underway because until the results are not only in but have been peer reviewed, they can not be trusted to be fact. Understandable. This is especially true when discussing research done by someone else because, obviously, if you’re not doing the research and the results have yet to be published, you can’t possibly know the results.”

My first thought was “Whoa, dude, you are so wrong”. But then I started to wonder what might have led him to form such an opinion. I mean, Mark is a smart guy. More to the point, he’s a proactive guy who’s taken the initiative to build a network of families and physicians and researchers working toward the common goal of fighting back against Usher syndrome. He hobnobs with some pretty heavy hitters in the Usher research community, the kind of people who never remember my name—probably because I devolve into a groveling, insignificant puppy in their presence…but I digress. My point is, if someone like Mark, who’s really got the inside track on the research angle, has this impression of the research world, what are we scientists are doing wrong?

The answer, while multi-faceted, boils down to communication lag:

Disconnect between the routine interactions within the research/clinical community and the extent to which patients and families are aware of these goings on.

While I was at the ARVO meeting I asked a nice lady at the information desk about mainstream press coverage of the meeting. I mean, nearly 12,000 people converging on South Florida to talk about eyes has to be newsworthy, right? She looked at me as if I had sprouted tentacles, and an awkward conversation ensued, during which I tried (in vain, I think) to convince her that my question was only meant to acquire general information and not some ego-driven attempt to pimp my own highly important research findings. My take-home message from that encounter was that, in general, teeming nerd hordes don’t make very provocative headlines. Go figure. The good citizens of Ft. Lauderdale had no idea what we were up to in there, and all over the world similar stories are playing out on a regular basis. Large scientific and medical conferences with attendance well into the thousands are commonplace. We talk to each other a LOT—we share boatloads of unpublished data, swap cool reagents, and forge integrative collaborations, all on an astonishingly frequent basis—and you’d never know it. Because it isn’t ‘news’. Which brings me to:

Mainstream media ~~bungling~~ handling of scientific news

Unlike scientists, who tend to err on the side of understatement and uncertainty (because after all, a hypothesis can never be proved—it can only be disproved), many journalists trend the other way, often favoring sensationalism over nuance. Most scientists, while perfectly willing to share details of their work with one another, are somewhat more wary sharing similar details with the media until the peer-reviewed publication process is complete. There are exceptions from time to time. Occasionally, a researcher will engage in what has been termed ‘science by press release’. Usually this is accomplished by holding press conferences in conjunction with or in anticipation of a publication, whereby the researcher may use the public forum to speculate or opine on findings that go beyond the peer-reviewed data. The press, therefore, tend to report on a rather unbalanced view of the topic, and it usually takes the larger scientific community some time to put the findings in context. The hype over the ‘Ida’ fossil published last year is one such example; the utterly unfounded ‘link’ between autism and the MMR vaccine is another.

Point being, it is not generally in the best interest of science or the medical applications thereof to make public pronouncements that can’t be backed up by good hard data. You, the patients and families, may wish to hear more preliminary reports, and we may wish to provide them, but in reality it would be difficult to do so on a large scale without creating a lot of misunderstanding and false hope.

Competetive research environments

I don’t mean to suggest that the research community as a whole is 100% transparent about everything we do all the time. When researchers discover they’re working on similar projects, they will often agree to pool their findings and collaborate—but not always. Obtaining and retaining funding is a competitive process, after all. Research grants are in relatively short supply and are awarded based on the uniqueness and feasibility of the proposed experiments. Furthermore, far from being a mere benchmark of personal achievement, funding is essential not only to finance the research materials, but the personnel doing the experiments. Running a research program is in many ways like running a small business, and getting—or keeping—a research grant is often the difference between hiring on an extra technician and having to let some lab members go. A small business owner wouldn’t play fast and loose with trade secrets that could bankrupt his or her company—is it fair to expect research scientists to take a similar risk?

Are there things we, as scientists can do to combat this perception of paranoid isolationism? Sure—in fact, that’s one of the reasons I began to contribute to this blog. That said, I hope the above points have helped to illustrate that a) unpublished results are shared freely in professional settings and b) there are necessary and legitimate limits to how and when a researcher should divulge these unpublished results.

Now, on to defend the poor doctors who have been painted with the same anti-hope brush. Again, Mark correctly identifies one motivation for sticking to hard facts when delivering a diagnosis, namely the ethics involved in leveling with patients and families about bad medical news, which actually goes quite a bit beyond ‘do no harm’. Doctors are schooled pretty hard on this. On a personal level, they may long to soft-pedal the news, but they are ethically compelled to tell the whole truth, however grim or devastating it might be, because of all the ramifications of informed consent and the general trend away from a paternalistic practice model to one in which patients are encouraged to be active participants in their own health care choices. Mark, speaking from the patient/family perspective, made the point that the delivery of such news would go down a lot better if combined with hopeful news about nascent treatments, etc. As reasonable as that sounds, there are, again, a number of difficulties in making it a reality. And once again, it boils down to communication:

Bedside manner

Some doctors, while excellent clinicians, are wretched communicators. This is a ‘soft’ skill that can be difficult to teach.

The limits of specialized care

The health care provider who delivers a diagnosis of Usher syndrome may not be a specialist in this disease. Usher syndrome is a fairly rare and exceedingly complex disease. It would be onerous indeed to expect every clinician who was ever likely to see an undiagnosed case of Usher syndrome to keep pace with the published research on the topic, let alone stay current on unpublished research endeavors.

Differences of opinion

Different doctors give different ‘weights’ to new experimental findings based on their comfort level with the techniques and/or technology. As such, a doctor might initially choose not to discuss a nascent therapy when first delivering the diagnosis. However, I must add that I feel this choice would only be valid on a temporary basis.

Doctor-Patient communication

Bedside manner notwithstanding, what a doctor says and what the patient (or family) hears can sometimes differ to an astonishing degree. Dr. David Gorski, a breast cancer surgeon and scientist (and most excellent medical blogger) recently discussed this phenomenon:

“A while back, I saw a patient with breast cancer in her hospital room, a woman I had operated on the day before. I thought I had calmly laid out the situation, reassured her that her tumor was treatable, and told her that she might not need chemotherapy. About an hour later I got a frantic page from the floor. The patient was in tears, and the family was in an uproar. I don’t know how I had done it, but I had somehow given this patient the impression that her situation was hopeless and that she was going to die. When her family arrived to take her home she was crying. Apparently she had interpreted my telling her that she might not need chemotherapy (mainly because of her age and tumor characteristics) as telling her that it was pointless to treat her more. I relearned a valuable lesson that day, one I (and, I daresay, most doctors, no matter how experienced) need to relearn periodically, namely that patients don’t always interpret what I tell them the way I think they will and that sometimes how I view a conversation with a patient may be very different than how the patient viewed the conversation.”

This experience, which is far from unique, argues in favor of delivering a diagnosis in concise, clear, unambiguous terms, and saving details such as treatments on the horizon for subsequent visits.

The lag between research results and clinical applications

I spent about 12 hours of my 5 days at ARVO attending lectures on emerging therapies for retinal degeneration—the majority of which were either stem cell based or gene therapy based. I saw some truly impressive clinical trial results and extremely promising preclinical studies with animal models of RP. Importantly, even as they revealed what were likely the most ambitious achievements of their careers to date, the majority of presenters concluded their talks with cautionary words about extrapolating too much from these findings. Most advocated proceeding with great caution with thorough clinical trials. These are cutting edge therapies, tested under extremely narrow, controlled experimental conditions. History has demonstrated that mainstreaming such treatment options without adequate safety testing across broader patient demographics can have unfortunate consequences. So, as anxious as we all are for a cure, there are extremely good reasons for proceeding in a prudent, science-driven manner.

Again, there are certainly some areas for improvement in communication between physicians and patients, between scientists and physicians, and within each of these groups, but at the end of the day, the facts are what they are. When one speaks of facts, one is referring to informational pieces of objective reality. Factual information is the bread and butter of science and medicine, and scientific research is, essentially, a steadfast embrace of one’s own ignorance of a sought after set of facts. Sure it can be frustrating at times--as Mark (and David Byrne before him) lamented, facts often don’t do what we want them to do. What we have to realize as scientists, and I think, as humans, is that we must allow reality to tell its own story. If we superimpose our hopes for a particular outcome on top of newly discovered ‘facts’, we lose objectivity and risk misinterpreting the findings.