An Interview With John Crowley, The Father Who Inspired “Extraordinary Measures”

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John Crowley’s life was bright: a recent MBA from Harvard Business School, a young family, and a blossoming career…the world was his oyster. And then John and Aileen received the shocking news that their toddler and newborn were both afflicted with Pompe Disease, a fatal neuromuscular disease. John’s fearless actions as he fights to save his children’s lives are portrayed on the big screen  in the new film by Tom Vaughan, Extraordinary Measures starring Brendan Fraser, Harrison Ford and Keri Russell.

VOTING OPPORTUNITY TO HELP RETT SYNDROME RESEARCH

The Extraordinary Measures website is highlighting video stories of hope and inspiration. One video will win $10,000 from CBS Films. Please visit and vote daily for “Reverse Rett Syndrome – Give Our Girls a Voice.”

Below is an excerpt from a recent conversation between RSRT Executive Director, Monica Coenraads and John Crowley, currently President and Chief Executive Officer of Amicus Therapeutics.

Visit the Crowley Family Website

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MC John, congratulations on the movie. As can be expected, news of the film and your story have already attracted attention in the special needs community.  Your spectacular success inspires all of us who are dealing with rare childhood disorders. For me personally, the key message of the film is that parents can be instrumental in helping to move the science forward.

Let’s go back to when you and your wife received the diagnosis. Megan was a toddler and Patrick just a newborn. Many of the readers of this blog know how it feels to be hit with a terrible diagnosis. Was your first step to approach existing Pompe organizations or medical centers? How did you go about gathering information and how were your questions received?

JC This was in March of 1998 and the internet was a pretty new phenomenon but that was the first place we went.  We learned of the small but dedicated group of researchers around the world as well as numerous Pompe families that shared a lot in common with Aileen and I.  We were surprised by the abundance of information that was out there. We quickly realized that it fell on our shoulders as parents, more than anyone, to collect and to synthesize the scientific data as well as the clinical information that was available.

MC Your accomplishments bring to mind some parallels with another non-scientist father who advanced research— Augusto Odone, the father portrayed in Lorenzo’s Oil. In my conversations with  Mr. Odone a decade ago we shared our common experiences in being repeatedly told that parents cannot drive the science. What kinds of difficulties did you encounter as you decided to move forward on your own?

JC At times we were viewed as interfering with the established plans that some people had. We didn’t pay much attention to that. We felt that we could only add and not detract from the debate as we pushed for treatments for Pompe.  I was surprised by the competitive nature of academic research and the lack of communication and coordination between the different efforts. I don’t think that is something you can fix but you can incrementally improve the situation.

MC Academic research is indeed competitive; on the other hand, it’s the very nature of that competition that often yields progress and results. Do you think that as an advocate with a personal mission, your background in business and law has been a greater asset, actually, than if your degrees had been in science?

JC I think so. You don’t have to be a scientist to run a biotech. In fact most CEOs of biotech firms are not scientists, but business people and they bring a different skill set.  But you must possess the ability to understand and articulate your science, and your technology and your disease area as well as a Ph.D. or you will not have credibility. That was a steep learning curve for me.

MC How do you think the urgency that only a parent of afflicted children can bring to bear has impacted drug discovery efforts for Pompe Disease?

JC I think the science would have gotten there eventually but I believe that Aileen and I accelerated the timetable quite a bit by bringing focus to the existing resources as well as bringing additional resources to the table.

MC How important a role does public awareness or lack of awareness of a certain disease play in drug discovery?

JC We got approval for a treatment for Pompe without many people in the US knowing what the disease is. What I do think is hugely important however, is increased awareness about rare diseases in general. There are 7000 rare diseases that collectively affect over 30 million people. That is more than everyone who suffers from all cancers and AIDS combined. So taken together these diseases are not rare at all – in fact they are remarkably prevalent.  While the symptoms and severity of these rare diseases may vary, there are commonalities with regards to a framework of development for novel therapies that can and should be applied to all these disorders.

MC That’s an excellent point. Single gene disorders like Pompe Disease and Rett Syndrome give scientists the ability to work out the biology of a disease, which can sometimes be applied to more common disorders where the underlying cause is unknown.

JC I agree. I believe that rare diseases will unlock cures for a whole host of more prevalent diseases.

MC What role do you think research foundations run by people with a personal stake in the disease play in drug development?

JC They play a very critical role.  Research foundations absolutely accelerate the timeline to drug development.

MC I think one reason their role is so critical is that they often fund a different caliber of research. They are often less risk adverse and therefore willing to support projects that more conservative funding agencies, like the NIH, won’t touch.

JC I completely agree. The Cystic Fibrosis Foundation, as the prime example, puts hundreds of millions of dollars into cutting-edge research. The result is thirty drugs in the pipeline.

MC Let’s talk about the science, and your perspective on future developments for Pompe.

JC We have small molecule chaperone technologies in the pipeline at Amicus Therapeutics, the biotech firm where I am CEO. We are looking at monotherapy as well as combined approaches with these chaperone drugs in conjunction with the existing enzyme treatment. Furthermore, there are several next-generation enzyme replacement therapies at various companies. There are also gene therapy studies that we hope to get underway this year.

MC What are some things you know now about drug discovery that you wished you knew 10 years ago?

JC The list is too long. I’m glad that 10 years ago I didn’t know what I know now because I probably wouldn’t have taken the risks that I did!

MC Your kids must be very proud of you. Have they seen the film? How are they doing?

JC We saw the film together a few weeks ago. They are very excited. Megan and Patrick still have remarkable special needs but they also have remarkably special gifts. Megan just turned 13; Patrick will be 12 in March. Megan was able to blow out her birthday candles. The fact she could do that while on a ventilator is a gift, let alone the milestone of reaching her 13th birthday. The enzyme replacement medicine that we helped to discover, and which they have been taking for almost 7 years, stopped and reversed the life threatening enlargement of their hearts. They are still ventilator-dependent and in wheelchairs but the quantity of years and quality of life that the medicine bought us is extremely valuable.

MC Megan and Patrick are very lucky to have you as their father and their advocate.

You are played by Brendan Fraser in the movie. I actually knew Brendan when we were kids, because I was good friends with his older brother Kevin. The Fraser family lived in Holland as I did at the time and we attended the American School of The Hague. I lost touch with Kevin when I moved to the States, but perhaps you’ll intercede with Brendan and help me get to get back in touch with Kevin.

JC I’d love to.

MC John, thank you so much for taking the time for this conversation. We wish you continued success and look forward to updates as the work progresses. I can safely speak for the entire Rett family community when I say that your story inspires and lifts us.

JC Thank you, Monica. I hope that the film helps to raise the collective awareness of rare diseases and the struggles of families around the world.

RSRT Partners for Cures

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by Monica Coenraads

Recently, RSRT Professional Advisory Council member Jonathan Epstein and I participated in the Partnering for Cures meeting in New York City organized by FasterCures, a think-tank of the Milken Institute. In attendance were over 600 people, including heads of medical research organizations, executives from pharmaceutical companies and biotechs, policymakers, philanthropists and representatives from NIH. The goal of the meeting was to identify the challenges involved with delivering treatments and cures and to brainstorm about possible solutions.

Information was shared with participants via plenary sessions as well as panel discussions on focused topics. Forty-two research organizations, including RSRT, were selected to present their innovative strategies. I was delighted and honored to brief this elite group on Rett Syndrome and RSRT’s efforts.

The meeting also provided opportunities to schedule one-on-one “partnering” meetings. I took full advantage and met with a variety of representatives from biotech and pharma. It was also an opportunity to reconnect with people who have been mentors and advisors to me during the past decade. People like Richard Insel, EVP of Research for JDRF, and Katie Hood, CEO of the Michael J. Fox Foundation. In some cases I finally met, face to face, people with whom I’ve been speaking on the phone for years.

A common theme throughout the meeting was the fact that the most innovative and ambitious science is not being done at pharmaceutical companies or biotech, nor is it being funded by NIH. Rather, it’s being driven by disease-specific research organizations like ours.  Why is this?

• First, because we have a single, urgent agenda – to make the patient better.  We are not encumbered by concerns over who gets the credit or the profit as long as our constituency is healed.
• Second, we often have the most comprehensive and accurate information on the state of research for our particular disease. From that elevated knowledge base we are often in the best position to make well-informed decisions.
• Third, we are prepared to fund risky and ambitious projects – the kind the NIH and many other funding agencies shy away from.

RSRT is proud to be part of this game-changing scientific movement.

At the crossroads of epigenetics and neurobiology, the Trust and our research projects are gaining traction. We look forward with hope and determination to the research developments of 2010. On behalf of our trustees, scientific advisors and professional advisory council we wish you and yours a wonderful holiday season.

Down Syndrome – A Possible Treatment in Sight?

William Mobley, the newly appointed chairman of the Department of Neurosciences at UCSD published a paper today in Science Translational Medicine showing that boosting levels of the neurotransmitter, neuropinephrine, in a particular part of the brain, the locus coeruleus, reversed some of the cognitive deficits in a mouse model of Down Syndrome.  This work adds to the fascinating data in recent years showing that neurodevelopmental disorders such as Down, Rett Syndrome, Fragile X, and others may be treatable.

UCSD Press Release
The Scientist – A Fix For Down Syndrome Brains?

Rett Syndrome Awareness Video

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McCann Erickson graciously created this 90-second awareness video.  We are indebted to Steve Levit and Kenny Gilbreath for the pro bono effort.  Steve, who is chief creative officer of McCann Erickson recently joined the RSRT Professional Advisory Council (PAC).

The awareness video was launched at the recent Hope for Hannah event which was held in the home of FOX CEO, Jim Gianopulos and his lovely wife Ann, both members of the PAC.

[To share this video on Facebook, etc use this link: http://blip.tv/file/2756182]

Where and How Does Rett Research Happen?

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A video presentation by Monica Coenraads

On September 9, 2009 the Rett Syndrome Center at The Children’s Hospital at Montefiore in the Bronx hosted its second Parent Gathering. The Director of the Center, Dr. Aleksandra Djukic, gave a presentation entitled Rett Syndrome: What Went Right in the Brain?   Dr. Chhavi Agarwal, the pediatric endocrinologist of the Rett Center, gave a talk entitled Osteopenia in Rett Syndrome.

In this presentation, I address some basic questions regarding Rett research. The focus of the presentation is not the actual scientific data but rather the logistics.  What are the fields of expertise who are involved in the current research?  How does the data get communicated? Where do scientists find funding? How do NIH, pharma and biotech fit into the picture?

As always, I welcome your questions and comments. My email is monica@rsrt.org.

Podcast: Mt. Sinai researcher interviews Monica Coenraads

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Monica Coenraads, Executive Director of RSRT, was interviewed on October 1st by John Fossella, PhD, MBA, a neuroscientist at Mount Sinai in New York City.

Click here to visit his blog and access the podcast (15 min)

The Upside of Genetic Mutations

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by Monica Coenraads

Last week I attended a scientific meeting held in Stresa, Italy and organized by a parent group, Pro Rett Ricerca. One of the most well received talks of the speaking program was presented by Monica Justice, PhD of Baylor College of Medicine, who discussed data collected from her RSRT-funded project. What follows is an excerpt from a recent conversation between the two Monicas following the Italian meeting.

MC: Dr. Justice, it was great to see you in Italy. I thought it might be helpful to give our readers some insight into your project. But first I’d like to start with you, the soul behind this impressive undertaking. How did you end up in science?

MJ: My grandfather was a vet and I had an uncle who was a physician. I have always had a deep love for animals so as a child and young adult I wanted to be a vet.  My father thought that was not an appropriate career for a woman and he and my uncle encouraged me towards the medical field. Early on, however, I realized that my true passion was in basic research.  I went to graduate school thinking I would focus on immunology and microbiology but my very first class would change my career path forever. My professor was switching into the mouse genetics field and invited me to join his lab.  I loved mouse genetics from the very start and knew immediately this was exactly where I wanted to be.

MC: Most lay readers of this blog will not have realized that mouse genetics as a field exists.  Can you elaborate on this specialty?

MJ: When I entered the field most mouse genetics was being carried out in a few labs, The Jackson Laboratories being the primary one in the US, and research centered around a few mouse mutations that primarily altered mouse coat color.  I think the perception from the science community at large was that we weren’t doing particularly important work. That perception changed with the introduction of very powerful research tools.   One such tool was the ability to alter genes in mouse embryonic stem cells to engineer DNA mutations at will. The second was the ability to use a strong mutagen, called N-ethyl-N-nitrosurea or ENU, to do forward genetics – more on that later. This was also the time when molecular biology was exploding.  Rather quickly the mouse became THE model organism of choice. I’ve ridden that wave since my graduate student days. Today nearly every institution that is doing cutting edge research has a mouse genetics core.  I suspect there are now about 2000 true mouse geneticists worldwide.  Nearly every person who works on human disease now works with mouse models.

MC: Please tell our readers the basics behind your Rett project.

MJ: Our Rett project is based on two discoveries:  1) that you could make the symptoms of Mecp2 mutant mice better if you  introduced brain derived neurotrophic factor (BDNF) and 2) Adrian Bird’s  finding that you could actually reverse very severe symptoms in the mice by reintroducing the gene. Because of those two findings I believe that Rett symptoms can be altered by other genetic mutations. I felt strongly that the genetic approach that I was familiar with would be an ideal strategy to try and identify suppressors of the symptoms of Mecp2 knockout (ko) mice.

So let me tell you a bit about the screen. I use a powerful mutagen, ENU, that induces mutations in mouse sperm at a very high rate. We give the mutagen to wildtype (normal) male mice and then mate them to female Mecp2 knockout mice. A certain percentage of their offspring will have no Mecp2 and a sporadic mutation somewhere in their genome.  We then analyze the mice very closely and look for any that appear healthier than your typical Mecp2 ko mouse.  For example, a Mecp2 male ko mouse is dead by 6-14 weeks. If a mouse in our screen lives much longer than that, we hypothesize that there is a mutation in another gene that suppresses the ill effects of having no Mecp2. We currently have mice that are over a year old and still do not show signs of Rett.

MC: How many mice has your project generated?

MJ: We have used about 10,000 mice at this point and envision needing 5,000 more to find and understand the current genes of interest. To reach saturation for our screen, meaning that we are confident that the mutagen has generated mutations in every gene that could potentially be a suppressor, we would need to screen through five times the number of males that we have done thus far. Statistically, I estimate that there are 25-50 suppressor genes that we would expect to find were we to hit saturation.

MC: What kind of precedents are there for success using ENU modifier screens?

MJ: The first successful modifier screens were done in bacteria and yeast. The technique gained momentum in the late 1980’s early 1990’s when Gerry Rubin carried out a modifier screen in the fruit fly for genes that would interfere with a particular pathway. Dr. Rubin is a famous scientist who now is the Director of the Howard Hughes Medical Institute Janelia Farm Research Campus.   Historically, people thought that fruit flies were the only organism that you could do this with. It’s clear now that the mouse is an equally powerful organism.  My graduate mentor, Vernon Bode, did a screen in mice for PKU modifiers, which was finished by Bill Dove at the University of Wisconsin Madison.  And an Australian group that works on diseases of the blood did an ENU mouse screen looking for genes that influence platelet counts.   Each of these screens was very successful.

MC: Is there data to show that modifier genes are the rule or the exception in disease?

MJ: That’s a very interesting question. I work in the Department of Human and Molecular Genetics at Baylor. What I see from many of my colleagues’ work is that genetic modification of disease is the rule and not the exception.

MC: Can you envision a situation where you find modifiers in the Mecp2 ko mice but those genes are not implicated in the human disorder?

MJ: I do not think that we will find modifiers that are mouse specific only. I believe that because the mouse model for Rett Syndrome is amazingly similar to the human disease.  Also, DNA methylation (which is critical to MECP2) and some of the possible functions of the MECP2 gene are highly conserved between species. So it’s very likely that the MECP2 gene in people and in mice is doing the same thing.

MC: What do you foresee as the best possible outcome?

MJ: I foresee finding a molecule that would help forge neuronal connections, and help these connections be maintained and molded.
Furthermore, whatever molecules we find that suppress Rett symptoms may also give us important biochemical information on other genes that may interact with Mecp2.

MC: Did being at Baylor, a Rett hotspot, impact your decision of taking on this Rett project?

MJ: I have been very much aware of Rett since I moved to Baylor in 1998, a year before Huda Zoghbi identified the gene. I have been on the student committee of some of Dr. Zoghbi’s students, which kept me up- to- date on the ongoing work. MECP2 is a transcription factor and I’ve always been interested in transcriptional regulation. What really brought me into the project was when you called me up with a proposition.

MC: When I was the Director of Research at the Rett Syndrome Research Foundation (several years before the merger with IRSA to form IRSF) I piggybacked an early morning think tank during the RSRF Rett Syndrome Symposium in Chicago. About two dozen creative thinkers were kind enough to drag themselves out of bed and brainstorm with me about potential key experiments that could significantly move the field forward.  At the top of that list was an ENU mouse modifier screen. The group also gave me a list of potential people who could undertake such a laborious and intense project…it was a small list and your name was on it.  As you well know, RSRF then organized a workshop at the Mouse Genetics meeting, which took place in Charleston, SC in 2006. Those discussions led to the funding of your project.

MJ: I was so thrilled when you called. There was a time when I would have turned down this project.  But the timing of your call was perfect. The project appealed to me very strongly as a geneticist but also as a compassionate person who wants to make a difference in the life of others.

Your readers should also know that this is a project that the NIH would never have funded.  It was too risky and too “out there”.  I knew this was a viable technique and I was confident with the expertise of my lab with regards to mouse breeding, husbandry and handling that would move this project along quickly so I am very grateful to have had the funding to pursue this.   People should be aware of how much private foundations such as RSRT move the field forward by funding high risk, but high impact projects.

MC: Speaking of compassionate person, at the end of your talk in Italy you got a little emotional.  I was quite touched by that. Can you tell our readers what was going through your mind?

MJ: Yes, I got a little “verklempt” and I got teased quite a bit at dinner for that. I take this project very seriously because I feel that what we are doing could have an impact on people’s lives – an impact that perhaps wouldn’t happen without the screen – I guess as I was up there in front of scientists and the organizers of this meeting who have children suffering from Rett – the importance of our efforts hit me hard.

MC: Are you able to give our readers a hint at the data that your project has thus far yielded?

MJ: The project is at an exciting point.  We are close to identifying our first suppressor gene and we have a few more potential genes that we are pursuing as well.  Once they are identified we will begin experiments to confirm that they are indeed interacting with Mecp2m, first in the mice and then in people.  I also think the modifiers we have so far are just the tip of the iceberg.  So we have a lot more screening ahead of us.

I love this project, it’s fun, it’s exciting, and each new piece of data that we identify brings us closer to our goal.

MC: On behalf of families everywhere who love a child with Rett Syndrome we wish you Godspeed. We look forward to hearing about future progress.  Thank you also to Pro Rett Ricerca and especially Rita Negri and Laura Rassetti for their tireless work to organize this meeting.

MJ: It was my pleasure and honor to attend the meeting in this most beautiful area of Italy, near where you were born.

Drug Discovery for Rett Syndrome: A Fresh Angle

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Stavros Lomvardas, a young investigator at the University of California San Francisco, has just been awarded funding from RSRT for an innovative project which has the potential to not only help to clarify the function of the MeCP2 protein but also discover drugs to reverse the deficits incurred when the protein is mutated. Below are excerpts from a recent conversation with Dr. Stavros.

MC: I am always fascinated by how scientists end up in their chosen career. Was it a relatively late decision for you or did you know as a boy that you were destined for science?

SL: I guess in my heart I always knew. Even when I was a very little kid I was always designing little experiments. I grew up in Athens, Greece.  My father was dentist who had a deep interest in biology.  I found his love for biology very inspiring. He would always bring me books and talk to me about experiments and help me to design my own. So from a very young age I knew I wanted to be a scientist.

MC: It’s my impression that most scientists go into this field for the love of basic science and not with the goal of understanding or treating disease. Would that be a fair statement with regards to you?

SL: Yes, it would be fair. To be quite frank until 5 years ago I was completely dedicated to basic science and did not have any real interest in applying my knowledge to treat disease. I thought it was utopic to expect that basic science could be used, at least in the near future, to treat diseases.  But the last 5 years have changed me dramatically. Maybe it has to do with having my own children. Or maybe dealing with health issues that have cropped up in my extended family and realizing that there are people out there who are really suffering. I realize now that scientists cannot sit at our lab benches preoccupied only with the joy of doing pure science. We have an obligation to also help people. The idea of doing experiments that might actually have medical applications is very appealing to me right now. Maybe I’ve just matured but I find the concept very fulfilling.

MC: For a young investigator you have a very impressive training and publication record.  In fact, you have worked with not one but two Nobel Laureates.

SL: I came to the U.S. as a graduate student in 1998 and trained in the lab of Dimitri Thanos at Columbia University. The Thanos lab and the lab of Nobel Laureate, Eric Kandel, also of Columbia had an extensive collaboration that lasted a number of years. It was a very interesting experience for me personally. After I received my PhD in 2002 I transferred to the lab of Richard Axel for my post-doc training.
Dr. Axel, together with Linda Buck, shared the Nobel Prize in 2004 during my second year in the lab for solving the question of how we recognize and remember thousands of different smells. They discovered a large gene family comprised of about 1500 different genes that correlate to an equal number of olfactory receptors, each of which detect a small number of smells.  These receptors are located on the olfactory receptor cells which in turn are located in the upper part of the nasal epithelium.
Interestingly, each olfactory receptor cell has only one type of odorant receptor, and each receptor can detect a limited number of odorant substances.

MC: Did the Nobel Prize make working in the Axel lab any different?

SL: Dr. Axel was an extremely admired scientist among his peers. I don’t think receiving the Nobel Prize changed how his peers viewed him. While the prize brought lots of attention from the outside community it did not change his already existing celebrity status in the scientific world.  What did change is the demands on his time – for a number of years, and to some extent still now, he was insanely busy.

I will always remember the call I received from him while he was in Sweden receiving his Nobel. He was eager to know how an important experiment that I was undertaking was proceeding. The call is an example of Dr. Axel’s philosophy – science first. For me the experience was quite surreal.

Overall I was very fortunate to have trained in labs where the bar of what is considered good science and ground-breaking research was set very high.

MC: How did your research come to include MeCP2?

SL: Toward the end of my post-doc I had started working on DNA methylation and other epigenetic modifications of olfactory receptors. I was a fellow of the Helen Hay Whitney Foundation and at a Foundation meeting I saw a friend, Joe Zhou, who worked on MeCP2 in Michael Greenberg’s lab at Harvard. I had certainly heard of MeCP2 and knew of its involvement in Rett Syndrome but had never considered working on this protein myself. Joe gave an interesting talk which enticed me to do some preliminary experiments. I asked Joe for some antibodies against MeCP2 and I quickly noticed a peculiar expression pattern in the olfactory epithelium. Also the Ronnet lab in John’s Hopkins had published some very interesting results regarding MeCP2 function in the development of the olfactory epithelium, so I got really interested. We then ordered the knockout mice and started working seriously.  So my entry into the Rett field was, like many things in science, quite serendipitous.

MC: Please give our readers some insight into your RSRT funded experiment.

SL: My experiment leverages the discovery that MeCP2 deficient olfactory receptor neurons (ORN) have a very robust readout. They co-express molecules that are never expressed in the same neuron in wild type mice. Part of our experiment will capitalize on this finding to screen for drugs that can reverse the deficit – in other words find drugs, using high throughput screens (HTS) that can turn off one of ectopically expressed molecular markers.

MC: The reviewers of your proposal as well as our advisors had a common observation. They commented that the leap to the HTS was exceptionally clever and unconventional.

SL: The idea to undertake a HTS came to me last December during at a scientific meeting organized by RSRT.  As you know RSRT brought together about two dozen scientists, including the top minds in epigenetics and Rett Syndrome, to brainstorm about MeCP2 function. During the stimulating discussions it hit me that as far as I could tell there were no existing straightforward assays for MeCP2 deficiency.  It occurred to me that our finding could be leveraged to develop an assay for drug screening. At first it seemed like a crazy idea. But the more I spoke to people the more they liked the idea.   I am quite hopeful that we can find some molecules that can turn off one of the two markers and be effective also in vivo.

MC: This is a prime example of translational research – in other words a logical next step of taking a basic science discovery and designing an experiment with clinical applications – that most individuals outside the science arena believes happens naturally – but actually needs to be pushed, facilitated and funded – often by research organizations such as RSRT.

SL: Yes, absolutely. For me the first key turning point was reading Adrian Bird’s reversal paper. It was a beautiful paper; the experiments were so elegant and the results so dramatic. The second key turning point was attending the RSRT meeting which led to the idea of the HTS.

MC: You’ve been studying MeCP2 for about 3 years now. Has anything surprised you?

SL: Before I started working on MeCP2 I could not understand why people were struggling so much to understand the function of this protein. After all, there is a knockout, with a severe set of symptoms. So why don’t we have a clear list of target genes that are regulated by MeCP2. Now that my lab is focused on this protein I am realizing that we are not dealing with a traditional molecule. MeCP2 is not a traditional repressor or activator in that when you remove it you do not see huge effects on other genes.  It’s a very intriguing molecule indeed.  My personal hypothesis is that MeCP2 is a modulator involved in the fine tuning of nuclear processes. This is where my lab as an edge in choosing the olfactory epithelium because we can work on a very pure population of neurons.

MC: Parents reading this who have children with Rett Syndrome are probably wondering if their child has problems with smell.

SL: I don’t know. We are doing experiments now to delete the protein in the olfactory epithelium and will test whether there are olfaction deficits in the mice. I would expect that there may be subtle problems of discriminating between smells.

MC: This is a pretty difficult time economically for young scientists. Are you also feeling the impact?

SL: Yes I am certainly feeling the impact, especially being in CA.  My first two years of having my own lab have been very rough.  I had serious problems attracting funding from anywhere. It was a very painful experience because I was establishing a lab, recruiting and training people and trying to get enough funds to stay afloat. Fortunately my department and the UCSF supported me during this very difficult phase. Things have improved slightly but the situation remains challenging. Funding from RSRT is greatly appreciated.

MC: Over the past decade I have administered peer review for almost 1000 Rett grants.  I have seldom seen the kind of unanimous enthusiasm that your application generated. I wish you success and look forward to updating our readers about your progress.

Rett Gene Discovery: Ten-Year Anniversary

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Tenacity, talent and pure luck coincided ten years ago this week in a crucial experiment that forever changed the landscape of Rett Syndrome research.

by Monica Coenraads

Dr. Zoghbi and research assistant

Dr. Zoghbi examined  her first patient with Rett Syndrome  in the mid 1980’s and was so emotionally and intellectually hooked that she decided to put her nascent neurology clinical practice on hold and move instead into basic science. Her ambitious goal to locate the gene mutations responsible for this puzzling disorder was successfully realized sixteen years later.

Because Rett Syndrome is a sporadic disorder “gene hunters” could not employ traditional strategies to identify the culprit gene.  Fortunately significant clues came courtesy of several families with multiple affected members and the location was narrowed to a specific section of the X chromosome – Xq28. What followed was a painstaking candidate gene approach analyzing each of the hundreds of genes located on Xq28. Visit an earlier blog post to read in Dr. Zoghbi’s own words the details of the gene discovery.

During the summer of 1999 my daughter, then three years old, had been diagnosed for less than a year.  As any parent of a newly diagnosed child will testify the year had been marked by a rollercoaster of emotions.  With the shock and the grief came also the urgent desire to understand the lay of the land in current Rett research and how I might help to speed things along.  I spent my days juggling Chelsea’s therapy visits, caring for my 5-month-old son and speaking to as many scientists as I could.

Late one night in early September I received an instant message from a fellow mom who had taken her disabled child to see a well-known autism spectrum disorder neurologist in the Boston area earlier that day. The doctor mentioned that the “Rett gene” had finally been found. I had heard similar claims in the past year that turned out to be unsubstantiated rumors,  so I spent the next few days doing detective work.  To my surprise and delight, this time it was true.  A few days later I spoke to Dr. Zoghbi and she confirmed the wonderful news.  A few excruciating weeks followed during which the discovery had to be kept under wraps until the embargo was lifted, and the paper was published in Nature Genetics on October 1, 1999.

I spent hours on PubMed learning about this gene/protein with the strange name, methyl CpG binding protein 2. Eager to identify the leading labs, I poured through every publication on the subject. Two names flew out at me:  Adrian Bird and Alan Wolffe. That same week I called them both and a few months later had an opportunity to meet them at Rett Syndrome meeting in Washington DC.  Both quickly became cherished mentors. I was devastated to learn in May of 2001 that a traffic accident in Rio de Janeiro had claimed the life of Dr. Wolffe at the age of 41, leaving behind two young children and a devoted wife.

It is hard to convey to parents and relatives whose children were diagnosed after the gene discovery the excitement felt by the Rett community.  For me it was the realization that the limited world of Rett research  was about to burst wide open and that we would soon welcome scientists from the fields of epigenetics, DNA methylation, X inactivation, gene therapy and more.  It was exhilarating to think that Rett might be able to leverage decades of research already underway in these many laboratories.

It was this excitement and promise that prompted me and five other parents to start the Rett Syndrome Research Foundation in the fall of 1999. During the next eight years RSRF’s funding contributed to nearly every major publication in the field culminating in Adrian Bird’s reversal experiments of 2007.  I left shortly thereafter to establish RSRT.

Scientists and their institutions and funding agencies often trumpet any progress as a breakthrough. In reality true breakthroughs are few and far between. They are always unpredictable and they indelibly change the course of research.  The Zoghbi Lab’s discovery on that hot, humid Houston day in mid-August certainly fits the bill.

The Rett community owes a tremendous debt of gratitude to Dr. Zoghbi, not only for her fortitude during the difficult 16-year search for the gene, but also for the plethora of key scientific papers she has written since.

I often hear Dr. Zoghbi described as one of the most accomplished female neuroscientists of our time. Her impressive body of work and the respect she commands on the international scientific world stage have played an enormous part in making Rett Syndrome a high-profile disorder.

Over the ensuing years I have been fortunate to count Dr. Zoghbi as an advisor and a friend.  I ask the Rett community to join me in congratulating her and her colleagues, in particular Ruthie Amir, on the 10-year anniversary of their momentous discovery.

May we all have much to celebrate before another decade has passed.

Curing Rett Syndrome: How Do We Get There?

RETT SYNDROME RESEARCH TRUST WEBSITE

A video presentation by Monica Coenraads

On June 28, 2009 the Rett Syndrome Center at The Children’s Hospital at Montefiore in the Bronx hosted a Parent Gathering. The Director of the Center, Dr. Aleksandra Djukic, warmly welcomed the audience and introduced the first of what will be quarterly Gatherings. Dr. Djukic introduced R.E.T.T. (Rethink Education, Therapy & Technology) an engaged group of parents who have designed a survey to gather information to better assess what programs, techniques and settings are most effective for educating individuals with Rett Syndrome. Darcy Minsky followed with some IEP tips to get next year’s educational year off to a good start. The next Gathering will take place on September 27th.

I spoke about an issue that is dear to the heart of anyone who loves a child with Rett Syndrome: How do we get to a cure? The presentation, which is about an hour in length, highlights the key research discoveries of the last decade and lays out the current thinking on treatment/cure approaches in easy to understand language. The presentation is divided into four sections:

• Genetics of Rett Syndrome
• Functions of MECP2
• Reversal
• Treatments and Cures

If you are the parent, relative or friend of a child with Rett Syndrome, I hope this video will give you a glimpse of the excitement that the scientific community feels about the possibilities that lie ahead for our children.

I welcome your thoughts and questions. I can be reached at monica@rsrt.org.

CLICK HERE TO DOWNLOAD SPANISH TRANSCRIPT OF PRESENTATION