Letter from the Executive Director

RETT SYNDROME RESEARCH TRUST WEBSITE

Dear Friends,

This October will mark fourteen years since my daughter, Chelsea, was officially diagnosed with Rett Syndrome. On that day I made my then two-year-old daughter a promise: I would do everything in my power to free her from Rett Syndrome.

In pursuit of that promise I co-founded two organizations: first the Rett Syndrome Research Foundation in 1999 (later merged with IRSA to become IRSF) and more recently the Rett Syndrome Research Trust. Through my work I have supervised peer-review for almost a thousand research applications, organized numerous scientific symposiums and think tanks, heard countless science talks and spoken to more scientists than I ever imagined possible.

My work with RSRT is ambitious and often difficult, especially when also dealing with the never-ending challenges of raising a child with complex medical needs. However, working with like-minded trustees, organizers of events both big and small, and the founders of organizations who support our efforts has been a supremely rewarding experience. Their drive to maximize research funds in a no-nonsense, get-the-job-done fashion has been inspiring and energizing.

As I stand on the threshold of the New Year I feel, for the first time in fourteen years, that 2012 may see the efforts of the scientists and the donors who support them begin to bear fruit – a year that could prove to be paradigm-shifting in how we think about fighting Rett Syndrome. A year where we may begin to test, via clinical trials, whether what works in the animal models will actually work in children.

Much work remains to be done, both scientifically and financially. The research that lies ahead needs to be exponentially expanded. Clinical trials will be particularly expensive. We need your help. If you’ve been hesitant about fundraising please consider this your own personal invitation.

In joining our efforts you will become part of an extraordinary group of national and international volunteers – discerning, bold, tenacious and unabashedly intense. Because of their vision and commitment RSRT had a remarkable year. Our young organization, with the tireless work of motivated volunteers and contributors and no staff, beyond myself, moved Rett research forward in 2011:

• RSRT committed $3.6 million to new research in 2011. This is a record amount for any Rett advocacy group in a given year.
• A $1 million gift created the MECP2 Consortium.
• Despite difficult economic times, we saw a 60% increase in donations.
• RSRT launched a 3-month awareness campaign in Times Square seen by millions throughout the holiday season, including New Year’s Eve.
• In 2010 96% of our donations funded our research program – a statistic we expect will hold up in 2011 (our financial statements will be available soon)

As I bend down to lay my 15-year-old daughter gently into her bed each night we often stare intently into each other’s eyes. As her gaze bores into me I feel her holding me to my promise. I invariably ask myself “Did I do right by her today?” It is with serious and deep purpose that I renew my obligation to her and to each person with Rett Syndrome. This sense of responsibility extends also to our supporters and volunteers who donate money, time, and energy. Their confidence in our work reinforces our collective strength and will to defeat Rett Syndrome.

If you know a child or adult with Rett Syndrome please consider making 2012 the year you become more involved with our efforts.

If you are the parent of a child with Rett, perhaps you’ve made a similar promise to your daughter. Help us to fulfill your promise … and mine.

Monica Coenraads
RSRT Executive Director

RSRT Trustees:
Adrian Bird, PhD, Monica Coenraads, Heidi Epstein, Ingrid Harding, Lawrence Mattis, Tony Schoener

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I’d like to support your efforts by making a donation. (Recurring monthly donations also possible.)

I’d like to become involved with an existing annual event.

I’d like to discuss starting my own event.

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The X Factor

 RETT SYNDROME RESEARCH TRUST WEBSITE

Those of you who follow the efforts of RSRT know that one of the treatment strategies we are pursuing is the reactivation of the MECP2 gene on the inactive X chromosome.

A quick refresher for those in need of one: mutations in MECP2 cause Rett Syndrome (and a host of other disorders as well). MECP2 is on the X chromosome. Males have one X (and one Y) and females have two X’s, but in order to prevent duplication of genetic material randomly inactivate one of the X’s in every cell. This means that in females with Rett about 50% of cells have the normal MECP2 gene expressed and 50% have the mutated gene expressed. In theory, if we can find a way to reactivate the normal MECP2 gene on the inactive X chromosome, we may cure the disease.

RSRT funded investigators currently pursuing this line of inquiry include Antonio Bedalov of the Fred Hutchinson Cancer Research Center in Seattle, Marisa Bartolomei of UPenn and Ben Philpot and Bryan Roth of UNC.

The reactivation effort now has a new player – Jeannie Lee, M.D., Ph.D. of Harvard University. She is a leader in the X chromosome field and we welcome the significant intellectual and technological resources that she will bring to this endeavor.

MC: Congratulations Dr. Lee on receiving RSRT funding. Tell us a bit about yourself and how you came to be interested in Rett Syndrome.

JL: Growing up I dreamed of being a physician. While I was in college I got involved in undergraduate research and I realized that I really enjoyed doing research. During my senior year I couldn’t decide whether to become a physician or pursue my new-found interest – science, so I decided to keep my options open and enrolled in an MD/PhD program at Penn. By my third year I realized I wasn’t going to practice medicine and would instead hope to make contributions to medicine via science. My interest in X chromosome inactivation (XCI) began as a graduate student in the lab of Robert Nussbaum.

MC: Dr. Nussbaum was actually one of the first scientists that I connected with in 1998 when my daughter was newly diagnosed. He was very kind and offered lots of practical and helpful advice as I started the Rett Syndrome Research Foundation (which later merged with IRSA to become IRSF).

JL: He was a great mentor. In his lab I worked on Fragile X. While attending various genetics meetings I heard some interesting talks on XCI that really caught my attention. I chose to do my post-doc in Rudolf Jaenisch’s lab at MIT and that is when I began working on XCI. Although the Jaenisch lab was not an XCI lab, all the necessary tools were there. Jaenisch was very well versed in knockout technology and transgenics and the lab was full of very bright people. So for me, it was the perfect place to be.

I set up my own lab at Harvard in 1997 and have been working on XCI ever since. To better understand the mechanics of XCI, I incorporated more molecular biochemistry-driven approaches to the mouse system. During the past few years I’ve been thinking more and more about how to apply the lab’s experience, tools and resources to a clinical problem and Rett is the perfect choice.

MC: Why Rett and why now?

JL: Combination of two things. One, the realization that Rett is curable. There is the beautiful mouse model work of Adrian Bird that shows us that you can be born with this deficiency and be cured through gene therapy or reactivation of the normal copy of MECP2. That is profound. How many congenital diseases can we say that about? Rett is one of those congenital genetic diseases for which a cure could actually happen.

And two, the tools are in place to do the necessary experiments. I feel the time is right to take the platform technologies we’ve developed and use them to identify potential therapeutics for diseases. Rett is definitely one of the targets. I’ve been interested all along in applying knowledge of basic principles to cure disease but needed to develop the tools first. We’d rather start simple and Rett gives us this chance.

MC: I don’t think I’ve ever heard Rett referred to as “simple” but I’m sure glad you think so.

JL: Simple from a mechanistic standpoint because Adrian has already shown us that it can be reversed, and that, together with the fact that Rett is a single gene disorder, which is a huge advantage, gives us hope that we’ll succeed, that we won’t be working in vain. There is actually a huge amount of interest in Rett from the scientific community.

MC: Let’s talk about the experiments you are proposing. Your plan is to develop an assay using mouse cells that will glow when the inactive MECP2 gene is activated. You’ll be using the screening facilities of the Broad Institute in Cambridge, MA, which are quite impressive.

The Broad is really a unique facility – an experiment of sorts about a new way to tackle science. It brings together an eclectic group of scientists from its partner institutions that include MIT, Harvard and the affiliated major teaching hospitals (Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Children’s Hospital, Dana-Farber Cancer Institute, and Massachusetts General Hospital). The combination of some of the best minds, unprecedented technological resources and some pretty deep pockets makes for a fertile working environment.

JL: Yes, that’s right. We are quite excited about the project and our ability to leverage the resources of the Broad. We will work with Stuart Schreiber and Nicky Tolliday and others who run the high-throughput screening group within the Broad Institute Chemical Biology platform. They have the know-how and the necessary robotic devices. We simply would not be able to conduct this screen without the Broad.

MC: Just this week an interesting paper was published in Nature describing a class of cancer drugs called topoisomerase inhibitors that have the ability to activate the silent UBE3A gene in Angelman Syndrome. The work was spearheaded by Ben Philpot and Bryan Roth who now have RSRT funding to pursue a similar approach for MECP2. This work provides strong proof-of-concept that these screens can work.

JL: The paper is exciting and promising. I do believe our screen is going to work.

MC: Dr. Lee, we wish you the best of luck as you begin this project and look forward to hearing about your progress. Happy holidays to you, your family and your lab.

Below is a short video of Nicky Tolliday explaining the Broad’s high-throughput screening capacity.

The Search for Novel Therapeutic Approaches for Rett Syndrome Broadens and Intensifies

RETT SYNDROME RESEARCH TRUST WEBSITE

[GERMAN TRANSLATION]

by Monica Coenraads

Many of you know that my involvement in Rett Syndrome is personal. I have a daughter who suffers greatly from every Rett symptom in the book. She is now 15 years old and every year brings new challenges. In the last six months she has developed severe Parkinsonian symptoms: violent tremors, increased rigidity, difficulty initiating movement.

Despite the increased hardships I cannot help but be optimistic. The news from the scientific community continues to be encouraging and I have not heard one shred of data to dampen my optimism. As I reflect on the state of the current research I am particularly struck by one thing: the number of potential treatment approaches that we are pursuing in parallel.  From gene therapy and exploration of modifier genes to repurposing of drugs, there is certainly no lack of ideas about how to reverse Rett Syndrome or modulate symptoms. That simple fact lifts me up even on those dark “Rett days.”

Today RSRT is pleased to announce that we are adding to our portfolio of potential treatment options with $515,054 of new funding for Huda Zoghbi and her lab. Dr. Zoghbi needs no introduction to anyone familiar with Rett Syndrome. She identified MECP2 mutations as the cause of Rett Syndrome in 1999 and has consistently added to our body of knowledge about the disorder, the animal models and the protein in the years since then. Simply put, the field of Rett would look very different without Dr. Zoghbi.

This latest award, entitled “Investigating Novel Therapeutic Approaches for Rett Syndrome” includes three separate objectives, each of which has potential clinical relevance.

The first objective tests a pharmacological intervention while the other two are aimed at altering the activity of the neural network.

1)   Test drugs on Rett mouse models to enhance the cholinergic pathway.
This neurotransmitter pathway is critical for learning, memory and regulation of the autonomic nervous system. Drugs exist that can be used alone or in combination. If we find the data from mouse models encouraging, then the findings could be immediately transitioned into clinical trials.

2)   Explore deep brain stimulation (DBS) as novel treatment strategy.
DBS has revolutionized the treatment of Parkinson’s and is now also used for depression, OCD, Alzheimer’s and more recently in pediatric disorders such as dystonia and Tourette. The availability of Rett mouse models allows us the opportunity to explore potential benefits of this procedure for Rett. Again, encouraging data can be quickly moved to the clinic.

3)   Boosting Mecp2 levels in normal cells.
Girls with Rett have approximately 50% normal cells and 50% cells which lack the MeCP2 protein. Dr. Zoghbi will explore whether boosting MeCP2 levels in the cells that already have normal amount could enhance the overall neural network activity even though the other 50% have no protein. If boosting levels in normal cells rescues some of the symptoms this would set the stage for a large scale effort to identify targets that can modulate MeCP2 levels.

Please join me in congratulating Dr. Zoghbi on this award and wishing her the very best as she pursues these new lines of inquiry. I’d also like to take this opportunity to congratulate her once again on being awarded the prestigious 2011 Gruber Neuroscience Prize which was presented during last month’s annual meeting of the Society for Neuroscience.

A New Way of Doing Business

RETT SYNDROME RESEARCH TRUST WEBSITE

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[ITALIAN TRANSLATION]
[GERMAN TRANSLATION]

READ FULL PRESS RELEASE

On a chilly day in early spring, an unlikely group gathered in a spacious office at Harvard Medical School – the office of Michael Greenberg, Chairman of the Department of Neurobiology, one of the most respected and prolific neurobiology departments in the world.  Joining Dr. Greenberg was Adrian Bird of the University of Edinburgh and Gail Mandel, a Howard Hughes Medical Investigator from Oregon Health & Sciences University.  These names are well known to anyone who is at all familiar with the Rett research literature, yet none of these distinguished scientists would describe themselves as a “Rett Syndrome researcher.”  The questions that have kept them busy throughout their careers revolve around basic science phenomena such as DNA methylation, gene expression and brain plasticity.

Each of these scientists has been drawn to Rett Syndrome via a different route, and their combined interests will now create a powerful synergy to explore the most basic mystery of Rett:  What is the precise function of MeCP2 in the brain?

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RSRT Invests Record $1.8 million in Three-Way Collaborative Experiments To Speed Path to Drug Development

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Consortium: Profs. Greenberg, Bird and Mandel

Dr. Greenberg called me one day last year and said “I’m coming to you with a far-out proposition.”  He confessed that elucidating the role of MeCP2 was the most challenging problem he had ever worked on (a striking remark, coming from a scientist as accomplished as Dr. Greenberg) and that the chances of success would be greatly increased if he could put his head together with outstanding researchers with complementary expertise. He asked me to explore whether there might be any mutual interest on the part of Drs. Bird and Mandel. I did so, and the response was enthusiastically positive. Synchronicity was on our side. RSRT Trustee Tony Schoener and his wife, Kathy, were interested in funding a high-impact project: the MECP2 Consortium was born.

I recently caught up with the investigators to discuss this novel and non-traditional collaboration.

Coenraads: How would the three of you define the goal of the Consortium?

Bird:  The goal of the Consortium is to bring about a step-change in our understanding of the function of MeCP2 in relation to Rett Syndrome, which we believe will be vital for designing rational treatment therapies. Unlike most other autism spectrum disorders, we know exactly the root cause of this disorder, but explaining in molecular terms just why absence of functional MeCP2 brings about Rett’s particular constellation of symptoms still eludes us.

We already have useful information about what MeCP2 might do in cells – we know it is a chromosome binding protein that targets DNA methylation; we know it becomes chemically altered when nerve cells are active; and we know that other types of cells in the brain apart from nerve cells also need MeCP2 for the brain to function normally – but there is no consensus among scientists about why MeCP2 is needed for the brain to work properly.

Our joint view is that solving this tricky problem calls for cooperation between laboratories with different expertise. Gail, Mike and I have rather different slants on biology due to our training and backgrounds, but we appear to complement each other nicely. Our view is that the next few years will see advances in our understanding of both MeCP2 and the brain. The timing feels right and it will be exciting to see what happens.

Exploring the mystery of Rett

Mandel:   The goal of the Consortium, from my point of view, is to put our heads together to generate new ideas, and to critically evaluate each other’s ideas and experiments, and to collaborate on experiments where the expertise is complimentary.  I also view it as an opportunity to engage our young scientists in training in rigorous translational biology.

Coenraads: That is a good point Dr. Mandel. The Consortium goes well beyond the three of you. It requires the active participation of all of your lab members, who will be interacting with each other on a regular basis.

Consortium with members of the Greenberg lab

Greenberg:  I propose that “speed” is a part of the equation as well. The goal of the Consortium is to gain rapid understanding of the molecular and cellular basis of  Rett Syndrome through a collaborative effort.

Coenraads:  During the 12 years that I’ve been working with the scientific community the concept of consortiums has been discussed from time to time. It strikes me that what differentiates a true collaboration from one that is superficial and in name only is that the desire to collaborate has to come from the scientists themselves.  Collaborations cannot be imposed from above and made attractive with the bribe of money. Meaningful collaborations come from the bottom up and are nurtured by mutual respect and trust and a strong sense that the whole will be greater than the sum of its parts.

How is working with the Consortium different than how you’ve worked in the past?  Has it required any kind of mental shift in your personal working style?

Mandel:  Having had a long-term collaboration with my husband, who is also a scientist, I have first hand knowledge of the virtue of consortiums.  My personal style has also, I think, been open to collaboration.  Similarly, my lab members work very well as a team.

Bird:  Science is normally a competitive activity. Discretion at least is required, if not complete secrecy, if one is to avoid the trauma of being beaten to your goal by other laboratories and scooped by their prior publication. This dog-eat-dog culture among many researchers has its advantages in that it can accelerate discovery, but is often at odds with the needs of a charity like RSRT, which may wish to have scientists putting their heads together to solve pressing, clinically relevant problems.

Our consortium intends to do the latter. We share unpublished data and resources. We speak regularly on the phone and meet several times a year to bring each other up to date on what’s new. The Consortium is still at the beginning, but already it is having an impact on the research going on in our laboratories. To be honest, I find it refreshing to be part of an endeavor that transcends our personal ambitions for a higher purpose.

Greenberg:  I agree. I feel that although the Consortium research effort began just a few months ago we are already seeing a benefit.  The pace of progress in understanding Rett Syndrome is already beginning to accelerate. My expectation is that through collaborative interactions with the Bird and Mandel laboratories we will be able to overcome current obstacles to understanding the molecular basis of the disorder.  I think that we can expect to make key discoveries that will lead to new ideas for therapies for treating Rett Syndrome in the near future.

Coenraads: I think it’s also important to point out that the discoveries that the Consortium will likely yield will help not only Rett Syndrome but also the MECP2 Duplication Syndrome and all disorders caused by alterations in MECP2.

RSRT has committed $1.8 million to the MECP2 Consortium.  The Schoeners have contributed $1 million to the endeavor. It’s an understatement to say that without them it’s unlikely we could have launched the Consortium so quickly. I thank them for their generosity, commitment and frankly, their belief in the scientific process.

To the three of you I wish you much success. I look forward to our monthly Consortium calls and in-person meetings and to keeping our readers apprised of your progress.

Rett Syndrome – A disease of neurons AND glia

RETT SYNDROME RESEARCH TRUST WEBSITE

From today’s Press Release:

A paper published online today in Nature reveals that glia play a key role in preventing the progression of the most prominent Rett Syndrome symptoms displayed by mouse models of the disease: lethality, irregular breathing and apneas, hypoactivity and decreased dendritic complexity. The discovery, funded in part by the Rett Syndrome Research Trust (RSRT) was led by Gail Mandel, Ph.D., an investigator of the Howard Hughes Medical Institute at Oregon Health and Science University.

[READ FULL PRESS RELEASE]
[PRESS RELEASE - SPANISH TRANSLATION]
[PRESS RELEASE - GERMAN TRANSLATION]

LISTEN TO PODCAST  ON NEUROPOD: “MORE THAN JUST SUPPORT?”

 

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INTERVIEW WITH GAIL MANDEL AND DAN LIOY

Brain cells can be divided into two broad categories: neurons and glia. The three types of glial cells are the star-shaped astrocytes, the oligodendrocytes, and microglia. Historically, neurons have received most of the attention, while glia were thought to play a secondary supporting role. During the past several years it  has become increasingly clear that glial cells contribute in very complex and dynamic ways to healthy brain function and are important players in Rett Syndrome.

Monica Coenraads speaks with Gail Mandel, PhD and Dan Lioy, a graduate student in her lab, to discuss their data published online today in Nature, concerning the influence of glial cells on the progression of Rett Syndrome symptoms.

Gail Mandel and Dan Lioy in the lab - Oregon Health and Sciences University

MC:  It’s good to speak with you both again, and congratulations on the new Nature publication.

GM:  Thanks, Monica.

MC:  Let’s go back in time a little bit to give this work some context for our readers. Soon after the discovery that mutations in MECP2 cause Rett Syndrome, a researcher with a longstanding interest in chromatin, Alan Wolffe, organized a scientific meeting in Washington DC. I had just co-founded the Rett Syndrome Research Foundation, which provided financial support for this meeting. It was the first scientific meeting I attended and it stands out very prominently in my mind. And it was there, over a decade ago, that I first met you. After the meeting we stayed in touch, and I remember trying to get you involved in Rett. At first you were somewhat resistant, but eventually you really jumped in with both feet.  What triggered that shift?

GM:  My lab was, and is still today, working on a gene called REST, which is a repressor. We had been doing biochemical experiments and we noticed that MECP2 was one of the proteins that were in the vicinity of the REST binding sites. We didn’t know much about MECP2 so we started reading about it.

This was in 2002.  Nurit Ballas was in my lab at the time, and she and I became interested in where MECP2 was in the nervous system.  And we were perplexed, because it was supposed to be a ubiquitous protein, but people were thinking it wasn’t in glial cells.  Basically, Nurit and I were skeptical, because we know a lot about repressors, and ubiquitous repressors in particular, and from a molecular biology standpoint, it just didn’t make a lot of sense to us that MECP2 would be excluded from glia.

So Nurit did her own experiments to search for MECP2, and she found it in purified glia, and using immunocytochemistry she showed it was in tissue—in glia in tissue. And that made us consider the possibility that MECP2 could be regulating something in glia.

Gail Mandel

MC:  And that finding is a perfect example of why it’s always good in a field to reach out to new people who will bring their own experience, curiosity and fresh ways of looking at a problem. You published your first paper on the subject in early 2009 in Nature Neuroscience. Dan, please give our readers the highlights of the new paper that just came out in Nature.

DL:  The key point of the paper is that in a mouse model that has no MECP2, putting MECP2 back just in astrocytes goes a long way toward correcting the Rett phenotype, especially the respiration problems. We also document that knocking out MECP2 only in astrocytes causes a phenotype, including a respiratory phenotype. But interestingly, and I’ll be the first to admit that I’m not yet clear on why this is—the phenotype isn’t complimentary to the extent of the rescue.  In a simple world one would do an experiment and find that if putting MECP2 back in one cell type corrects the phenotype then removing it from that cell type should, logically cause the phenotype with equal severity.  And so far, that doesn’t seem to be the case.

What I take away from our experiments is that neither MECP2-deficient neurons nor glia alone are sufficient to cause the full-blown Rett phenotype.  But conversely, putting MECP2 back in just neurons or glia can go an extremely long way in correcting the phenotype.  A scientifically interesting question is:   Why is that?

GM:  That was really the unexpected part.

Dan Lioy

DL:  One possibility that we’ve discussed at length is that both cell types, neurons and glia, must be mutated to get the full phenotype.  There is precedence from other diseases, like ALS, that says that neurons and glia contribute to the pathogenesis of the disease, but they do so differently.  And we wonder whether or not this may actually be a general model that’s also applicable to Rett.

MC:  Was this finding surprising?

GM:  Yes, it was. Thankfully we did both experiments pretty much at the same time, knocking it out and putting it back. Otherwise I’m not sure we would have pursued putting it back based on the knockout.  Since the knockout was not as dramatic as the null we might have concluded that glia are not very important and the disease is mostly neuronal. But, luckily, we did them both at the same time.

MC:  Another example of the serendipitous nature of science. Regarding the hypothesis that neurons initiate and astrocytes play a role in the progression of the disease, do you think that’s going to become more of a common theme across diseases?

GM:  That model was presented initially by Don Cleveland for ALS.  I do think it is going to become a more common theme. I think it also means that we need to understand more about how neurons and glia talk to each other.

MC:  Historically glia have not attracted the type of attention that neurons have, but that is changing. Gone are the days where glia were thought of simply as structural components and nursemaids to the neurons.

GM: Yes, that’s right.

MC:  RSRT is funding a collaborative gene therapy project between your lab and Brian Kaspar. You are using a vector called AAV9, which, depending on when you administer it, seems to target astrocytes. If indeed replacing MECP2 in astrocytes is beneficial then this vector might be quite interesting.

GM:  So this project is a big risk for my lab to take on in terms of manpower because I don’t know if it’s going to work.  But I think the project is so interesting and clinically relevant. In terms of targeting the underlying genetic problem in Rett, either we turn the silent MECP2 on from the inactive X, or we have to think about how to add the gene back. That’s why I think AAV9 may hold promise, because it has good expression and it crosses the blood-brain barrier.  There are a lot of labs working on gene therapy approaches so the field is competitive, but I think that is a good thing.

MC:  Well, we are risk-takers—we can’t afford not to be—so we’re delighted that your lab has become so engaged with Rett and opened up new research vistas. I agree with you about the value of competition, and will follow the unfolding of the next developments in your work with great interest. There is certainly no lack of complexities to explore. We hope the Rett community will continue to benefit from your scientific curiosity and perseverance. Thanks for your time with us today, and we look forward to the next updates.

Bringing Justice to Rett

RETT SYNDROME RESEARCH TRUST WEBSITE
GERMAN TRANSLATION

Monica Justice, Ph.D. – Baylor College of Medicine

By Monica Coenraads

Last week the trustees of RSRT voted to award continued funding to Monica Justice of Baylor College of Medicine.  Dr. Justice is a mouse geneticist (yes…there really is such a thing) who is spearheading one of the most unique projects in the Rett research arena today. For background information please read the September 2009 blog interview with Dr. Justice.

This project is a mammoth undertaking – the kind that requires a certain sense of fearlessness on the part of the investigator (and the funding agency). The risks are high but are in line with the potential rewards.

I feel a certain sense of attachment to this particular project as I was present when the idea was first suggested. At the time I was the Director of Research at the Rett Syndrome Research Foundation (RSRF) and I organized the annual Rett Syndrome Symposiums that spanned three days at the end of every June. At the 2006 meeting I cajoled two dozen of the brightest and most creative scientists to join me for an early morning, pre-meeting gathering I called the “knowledge gap meeting”.  I posed the following challenge: develop a prioritized list of high-impact experiments that no one was currently undertaking and that was unlikely to be funded by traditional agencies. After a two-hour discussion the group delivered their top contender: a modifier screen to identify genes that suppress the effects of an MECP2 mutation.

My next task was to find the best possible person to undertake the screen and talk them into taking it on.  I organized a Rett workshop a few months later at a “Mouse Genetics Meeting” (yes…they have those) in Charleston, SC, which attracted a number of candidates.  Bottom line – I courted Dr. Justice and she enthusiastically agreed to pursue the project.

Fast-forward almost five years and I’m delighted that the project is thriving and yielding a wealth of information. I recently caught up with Dr. Justice to discuss how the project is faring.

MC:  Dr. Justice, thank you for taking time away from your work to bring our readers up to date on your fascinating project.  Please tell us how things are going.

MJ:  My pleasure, Monica. I want to start by saying that this project would never have been funded by the NIH [editor’s note: National Institutes of Health] nor would I have proposed this to your foundation, had you not approached me about it.  I knew little about Rett Syndrome when I started this project.

MC:  Tell us a bit about modifiers. Do you think they exist for every disease?

MJ:  I think that most diseases can be influenced by mutations but I don’t think every disease necessarily has modifiers.

MC:  Do you have a sense of how many screens like yours are ongoing right now?

MJ: I know of only a few in the mouse.

MC:  Do you know of any screens that have yielded modifiers that suggest a drug for the particular disease?

MJ:   That’s a great question, Monica. I do not. The goal of most of the modifier screens is not to identify drugs but rather to understand some developmental or biochemical pathway. I think with our screen we are learning a lot about the biology of the pathway, but our hope is to find a drug-targetable pathway.

MC:  Can you summarize the progress and the ups and downs of the project?

MJ:  At the inception of the project we encountered several problems. We really had no idea that the Mecp2 mutant females would be such poor breeders. We tried all sorts of tricks to improve their breeding capacity, because we needed a lot of them to do the screen, and nothing worked.  We kept at it, though, just with basic mouse breeding, and eventually got up to speed. Also, in the beginning we had some communication issues within the lab. I’m not sure we were expecting quite as many modifiers as we found. But we then developed a system, and that system worked very well; then things started moving along beautifully. I also realized early on that I needed to participate in a very hands-on way with this project.

As we isolated each modifier line, we realized that each one was different: that is, none suppressed the disease entirely, but each modifier line appeared to suppress a subset of Rett symptoms.  Even so, each line allowed the mice to live longer, function better and be healthier. However some of them developed other symptoms, such as inflammation and susceptibility to infection, which could also shorten their lifespan.  So, we worked with our veterinarians who helped us decide how to treat these mice. For example, we found that putting them on antibiotics worked extremely well.

And so, there were some unforeseen glitches in the beginning that are moving very smoothly now. We have isolated five modifier lines. We have put the screen on hold for now and are concentrating on understanding these five modifier lines. We have identified three suppressor genes so far and have candidates for the other two.  We feel that the screen and the gene identification have gone extremely well. Each of the modifiers has a different phenotype in that they rescue different symptoms, and we find that each modifier locus is affecting a different gene.  For example, in one line that we named “Romeo,” the suppressor delays the onset of Rett-like symptoms, and the mice have no inflammatory lesions, but eventually, the mice succumb with symptoms.  Therefore, the onset of neurological symptoms is later in their life, making their lifespan longer.  Another line, “Henry” develops almost no Rett-like symptoms, and lives nearly a full long life, with only a few mild inflammatory skin lesions late in life.  Another line, “Cletus”, rescues some of the neurological symptoms so the mice live longer, but the long-lived mice have severe inflammatory lesions, even early in life.  Remember that each of these lines carries the Mecp2 (Bird) null allele, along with a second site mutation that alleviates its symptoms.

MC:  It’s possible to figure out statistically how many mice you have to go through so that you’ve saturated the genome – in other words, ensure that you have a mutation in every gene. What percentage of the genome has your screen hit so far?

MJ:  I think we are between ten and twenty percent of the way through.

MC:  So there is a way to go.

MJ:  Based on our work thus far we could find another 25 modifiers.

MC:  The ideal situation is that the suppressors you find are in pathways that are somewhat known and, ideally, for which there are already drugs associated. But you also have to figure out just how the suppressor inhibits the ill effects of having an MeCP2 mutation.

MJ:  Yes, there are many steps that we have to take after we find a modifier gene, to understand what’s going on.

MC:  One of the surprising things that have already come out of your screen is the mere fact that MeCP2 has so many modifiers. Why do you think that is the case?

MJ:  My hypothesis is that the biological system in Rett is sort of poised on the edge, and it’s not so detrimental that it, for instance, causes death immediately. It’s very easy to tip the scale toward a little bit better—– or a little bit worse.  And my feeling after doing the screens is that MeCP2 creates that kind of situation in the cells, that they’re poised to go one direction or another pretty easily.

MC:  Your hypothesis suggests that there could be lots of things that improve Rett symptoms.

MJ:  Absolutely. And maybe combining them will provide an amazing improvement.

MC:  What is your time frame for restarting the screen?

MJ:  I’m usually an optimist about time; my hope would be that, within a year, we could start the screen again.

MC:  One of my favorite things about the screen is that it is completely unbiased. Preconceptions and favored hypothesis don’t play a role here. The animal tells you what is important and you simply go where the data leads you. I find that very reassuring.

MJ:  I completely agree.  Often, we have been totally surprised, then after generating more data, the mode of suppression makes complete sense.  We are learning a lot from these animals.

MC:  I will leave our readers with one last comment.  Over the past 12 years I’ve overseen peer-review for well over a thousand research applications for funding. So I’ve read my fair share of reviewer comments. Typically reviewers are a conservative bunch; even if they are enthusiastic about a project they tend to be cautious. Your recent proposal, however, generated comments like  “Wow”. That’s truly unusual and a real tribute to your creativity, risk-taking and perseverance. I am thrilled that RSRT can partner with you and hope that together we can deliver some much-needed treatments to kids and adults who are in such desperate need.

Rett Syndrome: Neurodevelopmental No Longer

RETT SYNDROME RESEARCH TRUST WEBSITE
GERMAN TRANSLATION

Huda Zoghbi, M.D.

Huda Zoghbi’s watershed discovery of the genetic cause of Rett Syndrome in 1999 ushered in a new era of research.  The first mouse models for the disease came on the scene in 2001. The male mice are missing the Mecp2 protein completely and are called knockouts; the females, due to X chromosome inactivation, have approximately half of their cells lacking the protein.

These are what most people think of when discussing “Rett mice.” However, in the past few years more types of mouse models have been created, each of them developed to answer a specific question and to teach us something about the disorder. Differences between these various models help form the foundation for much of the current drug discovery efforts.

Data regarding the latest animal model was published today in the high-profile journal, Science.  The model was developed in the Zoghbi lab by MD/PhD student, Christopher McGraw.  Through genetic engineering techniques he created mice that were missing Mecp2 only as adults.

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MONICA COENRAADS, RSRT EXECUTIVE DIRECTOR, INTERVIEWS HUDA ZOGHBI, M.D.

MC:  Dr. Zoghbi, please tell us about your decision to undertake this experiment and the results.

HZ:  There were two main reasons we wanted to perform this study.  We know that Rett symptoms start after birth and we wanted to understand whether there are any developmental components to the disease. In other words, did the Mecp2 protein have some function that is important during early development or childhood?  That was the first question we wanted to answer.

The 2007 experiments from Adrian Bird’s lab told us that if Mecp2 is restored in adult mice that had developed abnormally without the protein, their Rett-like symptoms are reversed. We were curious to see whether brain cells that had properly developed and matured with Mecp2 being present, and had gone through typical experiences of learning and memory and then had the protein removed as adults – would their phenotype be milder? And the answer was a resounding NO. The big surprise for us was how similar the knockout mice that had Mecp2 missing from conception were to the mice that had Mecp2 missing only as adults.  This told us that bypassing the critical period of development did not affect the severity of the symptoms.

The experiment tells us that you need Mecp2 all the time. It also tells us that you need Mecp2 not for development but rather to maintain normal brain function.

MC:   So the timing of the appearance of Rett symptoms has nothing to do with development and everything to do with what happens in the brain after you remove Mecp2.   Can we safely say now that Rett is not a neurodevelopmental disease?

HZ:  Our experiments were done on mice and not humans so we must always be cognizant of that caveat.  But I think you are right.  It’s how long the cells are without the protein that matters.

MC:  Your experiment certainly strengthens the idea that Rett is not neurodevelopmental. The reversal experiments of 2007 provided the first clue. You and I have been at meetings together where the issue has been debated. Some pointed out that the debate was not worth having because it was a matter of semantics.  But I disagree. This is not just semantics; there are clinical implications.

HZ:  You are right. It’s not semantics. I now call Rett a post-natal neurological disorder. Mecp2 is a factor that is critical for the normal function of brain cells. It’s a factor that is constantly needed for normal neurological function and this has implications for therapies.  Therapies will need to be maintained for the long term.
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MC:  Your findings have implications for other diseases that are post-natal, like autism.  Can you elaborate?

HZ:  There are many disorders that show up after birth and we have assumed that, just like for Rett, the absence of a protein was affecting normal development.  I think this paper is telling us that maybe this is not the case.  In the case of Rett the protein affects transcription; in other cases the proteins are doing something different but the end effect is the same – some molecule is not being made in the right amount when it is needed in the brain cell.

So for disorders like Fragile X, Angelman Syndrome, Tuberous Sclerosis, if we take away their particular protein the cells are sensitive to the deficiency, but if we bring the protein back the chances for recovery are high.

MC:  The key is that Rett symptoms are not hard-wired since the same symptoms can be found also in the adult knockout. That is hopeful, encouraging news.

It’s quite fascinating to me that despite being a rare disorder and having relatively small number of investigators working on Rett, the field seems to be tearing away at some long- standing neuroscience dogma.

Your discovery in 1999 made Rett the first sporadic neurological disorder that had a gene associated with it.  Rett was the first childhood neurological disorder to be shown to be reversible, thereby teaching us about the plasticity of the brain.  We now know that Rett is not developmental and this fact calls into question the neurodevelopmental status for other disorders such as autism, Fragile X, Angelman Syndrome, Tuberous Sclerosis and others. It’s quite remarkable.

It’s been almost 12 years since you discovered the genetic cause of Rett.   Are we as far along as you would have expected in our search for treatments?

HZ:  In many ways things are going well, as we’ve learned so much about the disease. We know the anatomy of the brain is normal, we know the cells can recover if you bring back this protein.  Our challenge is that the protein is so essential for so many cells. Finding a pharmacological intervention that can hit a great majority of the cells will be key. I don’t underestimate the difficulties; it will take some very good pharmacology to bring the symptoms under control.

MC:  I know I speak for every Rett family around the world – we are tremendously grateful that you are working on behalf of our children. Thank you for your commitment, your determination and your hard work.

Fragile X and Rett Syndrome – Opposite Ends of the Bell Curve?

RETT SYNDROME RESEARCH TRUST WEBSITE

Mark Bear, PhD of MIT

Mark Bear, Ph.D. of MIT is the most recent addition to RSRT’s portfolio of funded scientists. Prof. Bear studies synapses, the gaps between nerve cells where chemical or electrical signals are exchanged. The strengthening and weakening of synapses contributes to learning and memory but when impaired can lead to neurological disorders.

Much of the excitement in the Fragile X community comes courtesy of the Bear lab. His discoveries have spawned a series of clinical trials.
Forbes
New York Times
Bloomberg

Monica Coenraads, Executive Director of RSRT, recently caught up with Prof. Bear to discuss his Fragile X research and how it might extend to Rett Syndrome.

MC: Prof. Bear, thank you for taking time to discuss your research with us. Many of our readers will have heard of the ongoing Fragile X clinical trials and are eager to understand how your research might also impact Rett Syndrome. Please explain the so called “mGluR Theory of Fragile X” which was discovered in your lab.

MB: Sure. Synaptic function requires the synthesis of proteins in the synapses, so that supply can keep up with demand.  Demand is registered, in part, by activating metabotropic glutamate receptors (mGluR).  So the more active the synapses are, the more glutamate is released and the more protein is made. Like in many systems there are checks and balances, and one of those is the negative regulation of protein synthesis by FMRP, the protein made by the Fragile X gene, FMR1.  Normal synaptic function requires a sense of balance between driving protein synthesis through mGluRs, and inhibiting protein synthesis through FMRP. In Fragile X the FMRP protein is missing so it’s like driving a car with no brakes – your foot is on the gas but there is no way to stop. So there’s excessive protein synthesis which leads to a myriad of deleterious consequences. The approach that holds a lot of promise is to inhibit mGluR which in essence takes your foot off the gas.

Now that theory has been pretty widely validated and at least in the animal models of Fragile X  many features of the disorder can be corrected by inhibiting mGluR.

MC:  You theorize that Rett Syndrome is at the other end of the spectrum, instead of too much protein synthesis, there’s too little protein synthesis. What’s behind this hypothesis for you?

MB: Once we had the success in Fragile X, we started thinking more broadly about other single gene disorders that are characterized by autism, seizures, and impaired learning. I was influenced by a paper that was published by Christian Rosenmund and Huda Zoghbi. They analyzed synaptic connectivity of hippocampal-cultured neurons that either were over or under expressing MeCP2, the Rett Syndrome protein.  They found that reducing expression of MeCP2 reduced the connectivity, and over expressing it increased the connectivity.

We think about Fragile X as a hyper-connectivity disorder: too much protein synthesis, too many synapses, or too much synaptic turnover…and so, the Rosenmund/Zoghbi results made me think about Rett in terms of diminished protein synthesis. Also, in terms of morphology in Rett tissues we see signs of reduced connectivity –for example too few spines on dendrites.

MC: You were recently at a Fragile X meeting in Edinburgh where you spent some time discussing your theory with Adrian Bird. Tell us a bit about that.

MB: I was starting to mull this theory over then I ran into Adrian and had a great conversation with him. He was very encouraging – he didn’t think that this was a ridiculous idea. So that really got me charged up.  We agreed that the most exciting thing is that we have drugs that can correct both excessive and diminished protein synthesis.

MC: Prof. Bird called me after you and he had this discussion – he was charged up too. I organized a conference call and the three of us rather quickly decided on a collaboration and a division of labor with regards to experiments. Please tell our readers a bit about the drugs that are in existence.

MB: There are two types of mGluR drugs that have been developed. One of them is the negative modulators that will inhibit mGluR. These would be used for Fragile X. The others are positive modulators that will promote mGluR activation – these might be helpful for Rett.  The negative modulators were developed originally as a potential treatment for generalized anxiety disorder  with the goal of creating the next generation of anxiolytics. That’s what motivated industry and  they invested hundreds of millions of dollars into developing these compounds. We are really lucky in that there’s already a lot of great chemistry around our target. The positive modulators were developed for schizophrenia.

MC:  Novartis recently released data on a phase 2 clinical trial for Fragile X.  What did you think of the outcome of that trial?

MB: I think the best news is that they’ve decided to go forward into phase 3. Overall I think there is tremendous hope for disorders like Rett and Fragile X even for interventions in adults. So we are extremely optimistic and very energized to help people affected by Rett. And we thank RSRT for giving us funds to explore the disease and for facilitating a collaboration with Adrian.

MC: Talk to us about Seaside Therapeutics, the biotech that you started to develop drugs for neurodevelopmental disorders.

MB: When we first realized that mGluR inhibitors might be beneficial for individuals with Fragile X we reached out to big Pharma and we got a very cool reception. In those days, about ten years ago, big Pharma had very little interest in rare genetic disorders. As a consequence, I founded Seaside. So far we have been pretty successful in advancing a drug that shows great promise in both Fragile X and autism.  Seaside is committed to tackling the single gene disorders. And although we do not currently have a Rett program, there easily could be if we get a promising lead, so we are eager to get to work.

MC: I remember sitting in your office at MIT 6 or 7 years ago talking to you about Rett Syndrome. It’s taken a bit of time but I’m so pleased that you are now working on Rett. Our readers and I wish you much luck. We hope to hear of your success soon.

In From the Cold

Excerpted from: Special Educational Needs Magazine
Wednesday, 06 April 2011

Author Rachael Bloom is Co-founder & Chair of Rett Syndrome Research Trust UK and the mother of a fifteen-year-old daughter with Rett syndrome:

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Rachael Bloom explains the chilling reality of Rett syndrome and sees signs of hope in a major scientific breakthrough.

Ever since Rett syndrome was first identified in 1966, this has been a diagnosis associated with negative outcomes. The initial tragedy of the condition is undeniable; Rett most often occurs in previously healthy little girls, just after they have learned to walk and say a few words, and begins to drag their development backwards.

Most of these children completely lose the ability to speak. Most retain little, if any, use of their hands and are left instead incessantly wringing them. Over time, roughly half of the girls who are able to walk will lose their mobility as well.

“There is just so little that the majority of these girls and women are able to do for themselves.”

Sadly, this is only the beginning of the story. Rett is a condition which becomes increasingly complex with age. As girls move into their school years, symptoms cascade. Apraxia sets in, rendering the combination of impairments increasingly stifling. Layer upon layer of multiple, sometimes externally very subtle symptoms, descend and often go unrecognised, leading the people around the child to believe that her understanding is extremely limited.

Aside from the disabilities inherent in a Rett diagnosis, there are also a number of medical implications. The majority of these children will develop seizures. Many are plagued by autonomic disturbances which throw their physiology into disarray. Breathing dysfunctions, orthopaedic and severe digestive problems are common. Low stamina, sleep disturbances, high-levels of anxiety, spatial disturbances, reflux and constipation can often cause unexplained discomfort and distress and inhibit her ability to focus.

If you know a girl with Rett, you will know that the complexity of her condition is too elaborate to adequately describe here. If you have been caught in her gaze, you might already be familiar with that fleeting moment of undeniable coherence which calls so much into question. Why can she scratch an itch when she can’t touch a switch on demand? Why does she glance at something when you mention it but not when you ask her to?

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Huda Zoghbi Takes the Helm of the World’s First Pediatric Neurological Research Institute

RETT SYNDROME RESEARCH TRUST WEBSITE

The recently opened Jan and Dan Duncan Neurological Research Institute (NRI) in Houston, Texas is dedicated to scientific exploration of childhood neurological disorders. Director Huda Zoghbi, whose laboratory established that mutations in MECP2 cause Rett Syndrome, envisioned a center where researchers with diverse interests could work within an environment of ongoing, cross-disciplinary dialogue.  The soaring new structure is located in the heart of the Texas Medical Center, close to the basic science campus of Baylor College of Medicine and Texas Children’s Hospital.  At full capacity the NRI will provide laboratory facilities for 50 to 60 investigators.  All NRI investigators are Baylor College of Medicine faculty.

Jan and Dan Duncan Neurological Research Institute

Below are excerpts from a recent conversation between Dr. Zoghbi and Monica Coenraads, RSRT Executive Director.

MC: Dr. Zoghbi, it was wonderful to witness the recent opening of the NRI, the culmination of a lead fifty million dollar gift by the Duncans, an outpouring of support from the local community and years of work. The unique architecture reflects a specific functional goal: the creation of a powerful center for collaborative research on children’s neurological disorders.  In shepherding this concept from an idea to a most impressive reality, I know you were involved in every aspect of its development. Congratulations are in order! And now that this beautiful facility is open for business, tell us how the next steps are progressing.

HZ: I think there are really two phases now that are moving in parallel. One is the recruitment of talented faculty to occupy the laboratories of the first five floors that have been completed. The second will be to continue our expansion, which is being built by stimulus money and will hopefully be ready for additional recruits in 2012.

MC: I know the physical layout of the building goes beyond its striking appearance.  You had a particular vision in mind.  In fact, you coined a new descriptive term: collaboratory.

HZ: Yes.  The design is specifically intended to promote and enhance interaction between investigators within the building, and communication with adjoining faculties.  We have tried to structure this within individual labs as well as the institution as a whole.  In an age where most people will text or send an e-mail message rather than walk across the hallway to talk to someone, we have arranged work areas that are conducive to actual conversation, and social spaces that invite and encourage movement and exchange.  Investigators with different areas of expertise will be able to access shared resources.  The collaboratory is a beautiful, very open glass tower, modeled after the DNA double helix; the stairwell is very spacious and pleasant.  People will be drawn here, moving from floor to floor to lunch, have a cappuccino, take a break, use the exercise machines, and in doing so will naturally be interacting with fellow scientists from labs on different stories.

So this collaboratory, this getting together people of different disciplines is still rather new, a kind of paradigm-changing shift from traditional science boundaries. As you recruit faculty, I imagine personality will have to play an equal role with intellectual excellence in considering a candidate.

HZ: Yes, it is really important that the scientists we recruit be generous and receptive.  Generous means they are willing to help and to share their ideas and contribute to others’ projects if their skills would be useful in a particular area. Receptive scientists are open to hearing input about their work.  These are very important qualities and are key for an interactive research environment; we dream of a generation of scientists who really cherish such a philosophy.  We are also establishing programs to help scientists transition to independence as soon as they are ready.  Toward this end we will be creating NRI fellowship positions, to give brilliant young PhD graduates (two per year) the opportunity to work within an unusually supportive and nurturing environment.  If their projects are successful, they will then be well positioned for highly competitive faculty appointments.

MC: And this philosophy of the collaboratory is expanded even beyond the architecture of the new building, by the way the site was chosen.  I know the location was very critical to you.

HZ: The NRI is a Texas Children’s Hospital building, but I wanted it in a location where scientists from very different disciplines would have access to it.  I also wanted our own scientists to be only steps away from institutions where the focus and expertise are on scientific problems that are quite different from problems seen in childhood neurodevelopmental disorders.  For example, a researcher at Mitchell research building at MD Anderson (attached to NRI) who studies cancer and the epigenetics of cancer might make a discovery that has relevance to epigenetics in the nervous system.   You really don’t know where the breakthroughs will come from, and so this cross-cultivation of work and ideas from different institutions has great potential value.

MC: Tell us about the potential of this approach to accelerate and validate new work.

HZ: If you know one technique very well, or even have multiple skills in one discipline, this is still not enough when you are trying to understand something as intricate as brain development and brain function.  Somebody might come here with expertise in basic synaptic biology and neurophysiology, but is very willing to engage and think about how they could maximize the impact of their work by collaborating with someone who might be studying a model of Rett Syndrome or Fragile X.  You truly need a great variety of specializations, including those from the physical sciences, to begin to tackle complex problems.  Even with all of the expertise you can begin to put together, these problems are still challenging.

MC: The readers of this blog are of course interested in Rett Syndrome.  Can you speak about the kinds of resources that you envision being allocated for Rett research?

HZ: We’ve recruited eight faculty members so far, and one of our first recruits was somebody who works in Rett Syndrome, Jeff Neul.  In addition, we’ve really strengthened the physiology core.  Our colleagues in neuroscience are doing some work using two-photon imaging of cortical neurons in animal models of Rett, so the NRI has purchased equipment for these experiments. (Editor’s note: Two-photon imaging is a type of microscopy that allows researchers to look in depth at living tissue.)  Our behavioral core is designed to address the needs of large scale preclinical trials in Rett mouse models so we can expand the number of trials we do and expand our behavioral assays.  Some of our new recruits will be investigators who bring in a skill set to look at Rett from different angles.  Since Rett encompasses so many symptoms, the more we learn about it, the more we’ll gain knowledge that may be applicable to a very large range of neurological and neuropsychiatric disorders.

MC: Along those lines, many children with neurological disorders suffer from seizures, chronic GI problems, and orthopedic issues.  The approach thus far has been to try to ameliorate symptoms, but often standard treatments don’t work well and they really don’t address the underlying causes.  Will existing faculty members or new recruits be focusing on looking more deeply into the mechanisms of these problems across different diagnoses?

HZ: Yes, absolutely.  One of the ways information will be exchanged at the NRI will be through series of regularly scheduled seminars, and some of these will focus on a specific symptom. We bring together clinicians with basic scientists, presenting problems from both points of view. We will invite GI experts, bone experts.  The very serious problem of uncontrolled epilepsy may be the first topic we explore in this way. A symposium on this topic is currently in the planning stage.

MC: And this leads into the situation of children who have symptoms but no diagnosis. There are girls who have a clinical diagnosis of Rett but no MECP2 mutations have been found for them. Will the NRI be a resource for these families?

HZ: Sequencing costs are coming down, so it’s feasible to look not only at the children but the parents as well. We are beginning an initiative between our NRI investigators and the genome center to do large-scale medical sequencing for these patients.

Mark Wallace (President and CEO of Texas Children's Hospital), Jan Duncan, Huda Zoghbi, Cynthia and Tony Petrello

MC: On all fronts, then, the NRI is gearing up: Creative collaborative strategies, fresh angles of approach, in-depth examination of the symptoms that children suffer from in Rett and many other neurological disorders, and genomic investigation. You are really launching a powerful new interdisciplinary model for 21st century medical research. Thank you so much for your dedication to Rett research all these years, and for this interview. We hope to check in with you periodically for updates and anticipate great work from the Institute.