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Sir Adrian Bird has been a trustee of RSRT since our launch in 2008.

If you care about Rett Syndrome then you undoubtedly know about Adrian Bird. He discovered the Rett gene, MECP2, and he made the first animal model of the disease. And if that wasn’t enough his reversal experiments suggested to the world that Rett may be curable.

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Listen to the podcast from The Naked Scientist as Prof. Bird discusses his research and his hopes for a cure.

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by Monica Coenraads

As always at RSRT, our funded projects are aimed at developing effective treatments and a cure for Rett Syndrome. But one of the key roadblocks to achieving this has been a lack of knowledge about the MeCP2 protein and how it functions. In 2011 RSRT decided to conduct an experiment of our own. Take three world-class laboratories and give them the necessary financial resources ($5.5 million awarded to date) and infrastructure to tackle a question that no one yet has been able to answer: what does the MeCP2 protein do?

Almost four years later the labs of Gail Mandel (Oregon Health and Science University), Michael Greenberg (Harvard University), and Adrian Bird (University of Edinburgh) are getting closer to that answer and have made the following discoveries along the way— discoveries that could prove to be invaluable to how we will ultimately change the lives of girls and women afflicted with Rett:

  • It was known that MeCP2 binds to DNA in brain cells, but the Consortium showed that MeCP2 has a binding partner, called NCOR, that is known to silence genes. Importantly, the Consortium showed that mutations that disrupt the ability of MeCP2 to bind to NCOR are associated with Rett in people, thus lending support for the essential nature of this interaction.
  • MeCP2 is modulated by phosphorylation for normal nervous system function.
  • The Consortium has shown that gene therapy can reverse symptoms in symptomatic female Rett mice. This work is being actively followed up by a dedicated “Gene Therapy Consortium” also funded by RSRT.
  • As yet unpublished work is shedding light on the crucial question of which genes in the brain are controlled by MeCP2. It may be possible to target these genes via specific drugs.
The MECP2 Consortium meets in Boston twice a year and holds conference calls in between the meetings. The meetings at first included only Professors Mandel, Bird and Greenberg but have grown over time to include many of the lab members. The middle and right pictures are from the last meeting in October 2014.

The MECP2 Consortium meets in Boston twice a year and holds conference calls in between the meetings. The meetings at first included only Professors Mandel, Bird and Greenberg but have grown over time to include many of the lab members. The middle and right pictures are from the last meeting in October 2014.

Recently I posed a few questions to the three investigators about the important work they are tackling.

Why is uncovering the function of MeCP2 important?

adrian-birdDespite much effort, there is little consensus among scientists regarding what MeCP2 actually does in the brain. Needless to say it helps greatly when fixing something to know exactly what has gone wrong, so this is an issue that badly needs addressing. Fortunately the research tools for getting at the problem have gotten much better over the past few years and we are now in a good position to nail this problem down.

gailIt’s important to know why the loss of MeCP2 gives rise to Rett as well as helping to determine a minimally active form that might be better suited to gene replacement approaches.

Is it necessary to know the function of MeCP2 to discover treatments?

greenIt is hard for me to imagine a treatment for Rett that isn’t based on an understanding of MeCP2 function. Based on what we already know about MeCP2 it is clear that it’s function in neurons is quite complex and difficult to understand. That together with the complexity of the brain makes me think it is unlikely that a therapy that isn’t based on a deep understanding of MeCP2 function is likely to work. Nevertheless, I wouldn’t rule it out.

adrian-birdIf we could correct the genetic changes that cause MeCP2 to dysfunction in Rett so that the defective gene is replaced by a healthy one, then we would not need to know how MeCP2 works. This ideal scenario is becoming less of a fantasy, but is still some ways from being a reality. Knowing precisely what pathways MeCP2 regulates offers the prospect of treating downstream effects of the mutation as an alternative to correcting the gene. It is too early to say at the moment which approach is more likely to bear fruit so it is important to try both.

How has being part of the Consortium impacted your lab’s research?

gailI think investigators in other disciplines would love to have what we have built together. The Consortium is a wonderful stimulus for new ways of thinking critically about how to study and/or cure Rett. Two heads, or in this case three heads, are always better than one, particularly because we have different expertise and backgrounds. And we can build on each other’s discoveries much more quickly.

adrian-birdThe Consortium is a new way of working that has benefited our lab’s work greatly. Being able to thrash out ideas and explore different ways of looking at Rett with top class scientists from different backgrounds has sharpened up everybody’s research. All the partners have fully committed to the Consortium idea and as a result no one feels inhibited about robustly questioning the others. This kind of free and frank exchange keeps us on our toes and always makes research better. As well as ideas and data, we share materials and equipment, which speeds up our work and reduces costs.

How would you describe the experience of working collaboratively? Has anything surprised you?

adrian-birdScience is usually built on a competitive model where PIs compete for funding and try to make and publish discoveries ahead of their peers. Sharing data and plans for experiments with people who were once competitors is a different way of working – but one that is also liberating. It requires trust and a recognition by everyone that a higher goal is at stake. This Consortium really works. Hopefully we are poised to advance our knowledge of MeCP2 in ways that will make a difference therapeutically.

gailIt has been very rewarding. Nothing really has surprised me because I knew Adrian Bird and Mike Greenberg pretty well beforehand and I had ultimate confidence in the high quality of their science and their collegiality.
 

 

 

Participating in the Consortium and working collaboratively with the Mandgreenel and Bird labs has been a wonderful experience. The rigor and pace of scientific progress is much greater with the three labs working together than would be possible if each lab were working alone. Monica has been essential to keeping the Consortium on target and helping make sure the scientists in the Consortium continue to work together effectively over time.

The lab members from the three labs have thoughts of their own about the MECP2 Consortium.

Consortium Research Projects Reflections on Meeting
Harrison Gabel
(Greenberg lab)
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Benyam Kinde, Caitlin Gilbert, William Renthal and myself have been studying how MECP2 functions when it is bound to DNA in neurons and how it might control the levels of many proteins important for the function of neurons in the brain. This exciting work may provide an answer to the long-standing question of exactly what goes wrong in individual neurons in the Rett Syndrome brain when MeCP2 is lost. I described recent results from experiments using cultured mouse neurons that lack MeCP2 to test whether drugs can correct the defects in these neurons. Promising results from these experiments suggest that a drug can at least partially correct these defects. We are now beginning to explore if this drug can improve symptoms in mice with Rett Syndrome by delivering the drug to the brain of these mice. In general it is truly unprecedented to have three powerhouse labs that work on the mechanism of MeCP2 get together for a meeting and share their most recent data. The reality is that under any other circumstances we would be competing (hopefully in a congenial way!) and largely keeping secrets from one another until the data were published. This Consortium breaks down these walls and as a result the science moves much faster. I commend Adrian, Gail, and Mike for being willing to share so much, all of the lab members for trusting in the other Consortium members to treat them fairly, and most of all RSRT for creating such a unique and effective Consortium. Thanks!
Benyam Kinde
(Greenberg lab)
At the meeting I spoke about experiments that provide insight into the mechanism of MeCP2-mediated gene regulation. Through a series of biochemical, genetic and genomic experiments, I described how DNA methylation, specifically occurring in the CA dinucleotide sequence context in neurons, serves as a critical site for MeCP2 binding and regulation of gene expression in the developing brain. The Consortium has provided a unique opportunity to share novel findings, which ultimately has led to invaluable discussions that provide critical insight into the design and interpretation of experiments. In this way, the Consortium has allowed all three laboratories to develop projects at an exceedingly rapid pace.
Matt Lyst
(Greenberg lab)
Last year we published evidence for a model where the primary function of MeCP2 is to recruit the NCoR/SMRT co-repressor complex to chromatin.
At the last Consortium meeting I presented work aimed at further testing this hypothesis, and also investigating which components of this complex are most relevant to Rett Syndrome.
Sharing current data between labs means we all receive input from people in the field but outside of our own labs at a much earlier stage than would normally happen.
Sabine Lagger
(Bird lab)
MeCP2 is classically described as a methyl DNA binding protein exerting its function by exclusively binding to methylated CpG dinucleotides. It became obvious in recent years that MeCP2 can not only bind to methyl CpG dinucleotides but has been suggested to bind to other forms of modified DNA in in vitro experiments broadening its DNA binding sites. My work aims at establishing in vivo models to analyze MeCP2 binding patterns in brain cells. I therefore sort neuronal and glial cells from mouse brain and subject them to DNA methylation analysis to the single base pair resolution level. I can then overlay these maps with MECP2 binding profiles and identify the true in vivo MeCP2 targets. This analysis will help us to understand how MeCP2 is acting on chromatin and what the necessary signal for its binding are. I was invited to the RSRT Consortium meetings in Boston twice and both times I could not wait to get back to the lab and start working again. The possibility to present and discuss my work with like- minded and enthusiastic experts on MeCP2 is extremely beneficial and made me look at scientific problems from different angles. Meeting Rett Syndrome patients’ parents was very interesting for me and made me realize even more how important it is to keep working on understanding this devastating disease and to ultimately find a cure.
John Connelly
(Bird lab)
The MeCP2 protein acts by interacting with DNA at many locations inside cells. It is not clear however exactly what DNA sequences MeCP2 binds to on chromosomes. My work aims to identify what these sequences are.
My hope is that understanding how the protein works in greater detail will aid the design of an effective therapeutic strategy.
I was really pleased to be able to attend the recent MeCP2 Consortium meeting in Boston as it was really nice to meet and talk to the parents of children with Rett syndrome and discuss my work with them and the other scientists present. When in Boston I found that other members of the Consortium had, reassuringly, reached similar conclusions and this gave me the impetus to continue my particular avenue of investigation.
Hume Akahori-Stroud
(Greenberg lab)
I talked about a series of experiments on understanding the role of DNA methylation patterning in the brain. DNA methylation is a chemical modification of DNA that is abundant in neurons, and regulates MeCP2 function. Understanding the molecular mechanisms of DNA methylation in regulating MeCP2 is important to understand how MeCP2 works. It was great getting to know what other laboratories were up to, and I think the meeting has increased my understanding on MeCP2 a step further.
John Sinnamon
(Mandel lab)
Many of the mutations in MeCP2, which cause Rett Syndrome are single nucleotide changes known as point mutations. Our goal is to harness the catalytic activity of an enzyme already found in cells to target and correct these mutations in MeCP2 RNA. We have been able to edit MeCP2 RNA in vitro and are working towards testing our strategy in a mouse containing a point mutation, which has been identified in several Rett patients. Attending the RSRT Consortium meetings is a wonderful experience. There is a collaborative atmosphere you do not see at large scientific meetings and everyone is focused on understanding the biology of MeCP2 so that we can understand Rett Syndrome. For me personally, it is very powerful to meet parents of girls with Rett and to talk to them about my research. It provides a reminder of what I am working towards and I think gives the families an opportunity to talk one on one with the scientists they support.
Ruth Shah
(Bird lab)
My project involves modeling Rett – causing mutations in human neurons. Model systems are a great way to elucidate the molecular mechanisms behind diseases and to understand how a protein works in a cellular context. I really hope these human neurons will help us to understand the details involved in Rett, they may even provide a useful tool for testing gene therapy ideas in! Being part of the Consortium meeting gave me the opportunity to meet neuroscientists and gain advice and ideas from them on how to improve my project and my research. The flexibility to present my project in detail to an experienced audience without fear of my project being torn apart is a great thing. It provides the freedom for open chat and encouragement and an exchange of thoughts and ideas in a positive manner, rather than having a competitive undertone to the day. This is the environment that is needed in scientific research to encourage advances in knowledge. It allows for collaboration in a productive manner, for example as a result of the Consortium, I now have a list of genes whose expression I should look into from one of the other attending labs. If it weren’t for the Consortium I doubt information like this would be shared among labs in such an open manner.
Jackie Guy
(Bird lab)
Using information we have about the MECP2 mutations found in girls with Rett we have been able to identify two important regions of the protein: the region that binds to methylated DNA (MBD) and a small region which binds to a repressor complex, NCoR/SMRT. I am producing a number of different mutations in mouse embryonic stem cells in order to investigate why they cause Rett Syndrome. This may lead to a better understanding of the function and/or structure of MeCP2. I enjoyed hearing about the work of the other two groups in the Consortium. Each group has its own particular view of what MeCP2 is doing and I found it refreshing to think about things from a slightly different angle.
Rebekah Tillotson
(Bird lab)
Missense mutations that cause Rett are almost all located in either the region of MeCP2 protein that binds to methylated DNA or the region that interacts with the NCoR/SMRT repressor complex. This suggests that the function of MeCP2 is to form a ‘bridge’ between chromatin and the repressor proteins, and loss of this bridge results in brain dysfunction in Rett. I am testing this hypothesis by manipulating the MeCP2 gene in mice, and then carrying out behavioral tests to determine whether they exhibit the symptoms observed in the mouse models of Rett. The RSRT Consortium was a great opportunity for me to meet other scientists in the field, to learn about and discuss their work, and to get valuable input on my own project. The informality and openness of the discussion made it a thoroughly rewarding and stimulating experience.
Kyla Brown
(Bird lab)
Rett Syndrome severity varies partly because of the nature of the MECP2 mutation. My project focuses on making animal models of “milder” mutations to see if there are specific functions of MeCP2 that these mutations affect. The Consortium provides a unique opportunity to communicate findings within a group of expert researchers as well as to forge collaborations. I enjoyed being able to appreciate others’ perspectives on the same clinical and biological problem and seeing how this can result in advances in the MeCP2 field.
Martha Koerner
(Bird lab)
I am working on MeCP2 duplication syndrome. I am trying to understand what happens if you do have too much MeCP2 and what we can do to counteract the symptoms caused by excess MeCP2. The Consortium meeting in October was the first one I’ve attended. I’ve found it incredibly helpful to be able to talk to other scientists who work on the same gene, to learn about novel findings of others that will impact my research and also to get input from experts into the work I’m doing.
Susan Su
(Greenberg lab)
I am interested in examining the ultrastructural changes underlying the altered cellular morphology and synaptic connections of a mouse model of Rett Syndrome. I enjoy our lively, intellectual discussions at the Consortium meetings where we all share a common goal of gaining a deeper understanding of MeCP2. The Consortium meetings are wonderful opportunities to reflect on preliminary data and to share helpful reagents and insights for our experiments.
Jim Selfridge
(Bird lab)
My work in the Bird Lab focuses on the production and analyses of genetically modified animal models of Rett. These models have proved invaluable to Rett research over the years and the novel models continue to increase our understanding of MeCP2 function and the underlying molecular basis of Rett. I am also committed to using these Rett models to investigate potential therapeutic strategies. Although I never actually presented any of my research in person at the last meeting I was still able to benefit hugely by attending. The Consortium meetings and in particular the relaxed, open and friendly format provide a great focus for Rett researchers. It gives us a perfect opportunity to have our work critically assessed by experts in the field, even in the early stages of a project. This often affords us extra insight that we might not get from the sometimes insular environment of our own individual groups.
I look forward to being part of many more meetings!
Will Renthal
(Greenberg lab)
Rett is characterized by profound synaptic dysfunction. I am studying the role MeCP2 plays in coordinating the gene programs responsible for normal synaptic responses to neuronal activity. Specifically, our laboratory has found that neuronal activity drives the rapid phosphorylation of MeCP2 at serine 86, so my current efforts are aimed at identifying the functional significance of this event. I think the Consortium was a fantastic opportunity to share ideas with people from a variety of backgrounds to accelerate Rett research. We were having technical difficulties with some of our experiments and the collective wisdom of the Consortium has been crucial for overcoming them.
Justyna Cholewa-Waclaw
(Bird lab)
The aim of my project is to define primary transcriptional consequences of MeCP2 depletion. In order to do that I use an in vitro system based on immortalized human neural precursors which can be differentiated into dopaminergic neurons. I generated cells with reduced amount of MeCP2, entirely depleted MeCP2 and increased levels of MeCP2. Gene expression changes in these cells with different levels of MeCP2 will be studied additionally in the context of gene body methylation and hydroxymethylation to provide the molecular basis of MeCP2 function. I think the Consortium meetings are great.  The informal nature is very beneficial. I had brilliant opportunity to discuss my work with people working on the same problem. I could also ask questions more openly and know what other people are doing.

by Monica Coenraads

[Italian translation]
[Spanish translation]
[Press Release]

Faced with the complex problem of discovering the elusive function of the Rett protein, RSRT set out to conduct an experiment of our own. We shook the conventional practice of laboratories working in isolation and instead convened three scientists to work collaboratively: the MECP2 Consortium. We gave them the necessary financial resources and provided infrastructure including in-person meetings. The results surprised us all.

Adrian Bird

Adrian Bird

Michael Greenberg

Michael Greenberg

Gail Mandel

Gail Mandel

The MECP2 Consortium was launched in 2011 with a $1 million lead gift by Tony and Kathy Schoener.
RSRT has committed an additional $3.4 million of funding to the Consortium.
We are extremely grateful to the Schoeners for their second $1 million pledge to support this effort.

The Consortium quickly reported significant advancements. The Mandel and Bird labs showed, for the first time, a dramatic reversal of symptoms in fully symptomatic Rett mice using gene therapy techniques that could be utilized in people.

The “Rett mouse” moving around received healthy Mecp2 via gene therapy. The immobile mouse did not receive treatment. The video was taken four weeks after treatment.

The Bird lab discovered that the function of the Rett protein, MeCP2, depends on its ability to recruit a novel binding partner, NCoR/SMRT to DNA. Disrupt that ability and the symptoms of Rett ensue.

The Greenberg lab built on the work of the Bird lab and discovered that adding a phosphate group to MeCP2 alters its ability to interact with NCoR/SMRT and affects the expression of downstream genes.

While the clinical implications of the gene therapy experiments are obvious some may think “so what?” when it comes to the NCoR experiments.

I suspect that in the mind of many Rett parents the best evidence of research progress is clinical trials. However, this is often not the best measure of progress.

Thomas Südhof, recent Nobel Laureate, recently commented  “I strongly feel that attempts to bypass a basic understanding of disease and just to get to therapies immediately are a misguided and extremely expensive mistake. The fact is that for many of the diseases we are working on, we just don’t have an understanding at all of the pathogenesis. There really is not much to translate. So NIH and many disease foundations are pouring money into clinical trials based on the most feeble hypotheses.”

So I will argue that investing in a better understanding of MECP2 – a primary goal of this Consortium – is money well spent, as it will add to our current arsenal of strategic approaches to combat Rett.

A repurposed drug may partially treat some of the symptoms, but to achieve the kind of dramatic improvement that most parents and I ache for will likely require attacking the problem at its very root.

As Rett parents will attest to the symptoms of the disorder are numerous and devastating. Whatever MECP2 is doing, it’s acting globally on many systems in the body. A repurposed drug may partially treat some of the symptoms but to achieve the kind of dramatic improvement that most parents and I ache for will likely require attacking the problem at its very root.

There are multiple ways to achieve this end goal: gene and/or protein therapy, activating the silent MECP2, modifier genes. These are all areas in which RSRT is financially and intellectually engaged with.

In parallel, however, it is imperative to understand what MECP2 does. RSRT has therefore committed an additional $3.4 million of funding to the MECP2 Consortium. We are extremely grateful to Tony and Kathy Schoener for their second $1 million pledge to support this important project.

I recently discussed the experiences of the past few years and what lies ahead with the Consortium members.

Greenberg: Research in neuroscience is undergoing a revolution. We now have the technologies in hand to solve some of the most difficult neurobiological questions. However, progress towards answering these hard questions requires scientists working together. A single lab working alone doesn’t have the expertise or the resources to make significant progress when the scientific problem is particularly challenging.

The MECP2 Consortium is a model for something much bigger: how neuroscience overall needs to operate so that we can find therapies and cures for disease.

The MECP2 Consortium is a model for something much bigger: how neuroscience overall needs to operate so that we can find therapies and cures for disease.   We are scientists in different parts of the world, working together, sharing their results long before publication, and brainstorming openly on a regular basis.  The different perspectives of the three labs allow for a wonderful exchange of ideas to advance the science. I believe this is what the Consortium is all about.  We have ignored the typical barriers of geography and have brought together scientists from Edinburgh, Portland, and Boston on a regular basis.  The results have been stunning.  There has been much more rapid progress than would have been made by the individual labs.

Consortium meeting in Boston in November of 2013.

Consortium meeting in Boston in November of 2013.

Bird: I agree. An over arching goal of the Consortium is to understand the way the MECP2 protein works at the molecular level.  We are at last starting to make real progress on this and will be testing some of the new ideas in cellular and animal models.  Our ultimate aim is to use this new knowledge to provide rational approaches to therapy.

Mandel:  Front and center is always our goal to find a therapy for Rett. This guides our experiments and keeps us focused. The fact that financial support comes from families who have a child with Rett and their networks makes us work harder.

Coenraads: In your opinion what are the elements that have made this consortium “work”?

Greenberg:  Trust and openness, a willingness on the part of all three Principal Investigators to talk through any potential problems immediately as they come up.  A willingness to check egos at the door so that we can work together for something that is more important than our individual advancement. Importantly the participants, Mandel, Bird, Greenberg and Coenraads like and trust each other.

consortium4Bird: We all have different backgrounds and interests, but we share a commitment to understanding Rett Syndrome.  We compliment each other surprisingly well.

Mandel:  The regular meetings and exchanges and the quality of the scientists involved have been key factors as well as the availability of sufficient funding for each of us to follow our scientific noses.

Coenraads:  Fortunately science is not linear. There are technologies available now that weren’t available when the Consortium started. How does this impact your Rett research?

Greenberg:  There are a lot of new technologies available – in particular Cre lines that will allow us to study the effect of MeCP2 loss in a relatively homogeneous population of neurons, CRISPR and Talen technology that will facilitate gene correction, and genomic technologies that are providing a new understanding of the role of methylation in the control of neuronal gene expression.  Also, better equipment, such as microscopy will help.

Bird:  The technologies for genetic modification have existed for a decade, but the advent of CRISPR has made this facile.  Being able to edit genetic mistakes in patients is no longer a science fiction dream, but has become a real possibility.  Exploring this option will be an important focus for the Consortium.

Coenraads:  Harrison Gabel from Mike’s lab recently shared with me in an email:  Our group meetings are essential to critically assessing our work. Each lab group has its own “world view,” and having that view shaken up every six months is very constructive.

So I look forward to lots more critical assessments and worldviews getting shaken as together we get to the bottom of what MeCP2 does.


* Due to the success of the MECP2 Consortium, and its positive gene therapy findings, RSRT has just announced funding for a second consortium: the MECP2 Gene Therapy Consortium. Read more about this newly formed second collaboration.

by Monica Coenraads

[Italian translation]
[Spanish translation]
[Press release]

The videos below are perhaps the most well-known in the Rett community. If you love a child with Rett then chances are you’ve watched them obsessively.

This work published in 2007 by Adrian Bird, declared to the world that Rett is reversible, but did not tell us how this could be done in people.

Fast-forward six years and the video below from the RSRT-funded labs of Gail Mandel and Adrian Bird may have given us an answer: gene therapy.

The mouse moving around was given gene therapy treatment and received healthy Mecp2 gene. The immobile mouse did not receive treatment. The video was taken four weeks after treatment.

So how do we make the giant leap from recovered mice to recovered children?

To move us towards this goal, RSRT has launched their second collaborative group – the MECP2 Gene Therapy Consortium. This new group comes after the success of RSRT’s MECP2 Consortium, established in 2011, that led to the initial encouraging gene therapy findings. With a budget of $1.5 million the members of this international gene therapy collaboration are charged with tackling the necessary experiments to get us to clinical trials as quickly as possible.

I recently caught up with the investigators to discuss this novel collaboration:

Brian Kaspar (Nationwide Children’s Hospital)
Currently working on gene therapy clinical trial for Spinal Muscular Atrophy

Stuart Cobb (University of Glasgow)
Neurophysiology lab and co-author on 2007 reversal paper with Adrian Bird

Steven Gray (UNC Chapel Hill)
Currently working on gene therapy clinical trial for Giant Axonal Neuropathy

Gail Mandel (OHSU)
Member of MECP2 Consortium and author of gene therapy paper published this summer

Brain KasparNationwide Children's Hospital

Brain Kaspar

Stuart CobbUniversity of Glasgow

Stuart Cobb

Steven GrayUNC Chapel Hill

Steven Gray

Gail MandelOHSU

Gail Mandel



Coenraads:  Let’s jump right in. Why Rett? Why now? 

Cobb: While there have been major advances in understanding the molecular actions of the MeCP2 protein, it is still difficult to conceive of a small ‘traditional’ drug molecule being able to mimic its function. While traditional drug approaches will likely be restricted to correcting specific aspects of what goes wrong in Rett it is conceivable that gene therapy can correct the cause of Rett at its very source and thus provide a profound recovery of function.

While traditional drug approaches will likely be restricted to correcting specific aspects of what goes wrong in Rett it is conceivable that gene therapy can correct the cause of Rett at its very source and thus provide a profound recovery of function. – Stuart Cobb

Mandel:  It has been known for some time now that when MeCP2 is expressed genetically in cells throughout an MeCP2-deficient mouse, major Rett symptoms are reversible in mice.  Two of the big outstanding questions then are: 1) Will this be true for humans and 2) Can we add MeCP2 back to patients and also achieve reversal?  The first question is currently still an open question, although upcoming experiments using human neurons and astrocytes derived from iPSCs and xenografts (transplanting human cells into mice) may provide some important clues. The second question is challenging because currently there are no reliable ways to introduce MeCP2 throughout the brain, although recent studies in mice, funded through RSRT consortiums, suggest that AAV9-mediated transduction (delivery via a virus) might have potential. Therefore, two advancing technologies, iPSCs and AAV9 viruses, are converging to compel us to jump right in now.

Kaspar: A major advantage in Rett is that the genetic target is defined for us: MeCP2.  Another advantage is that it’s not neurodegenerative – neurons don’t die.  And importantly, we know that restoring the proper level of MeCP2, even later in life, at least in a mouse, results in dramatic improvements.

Why now? Because the gene therapy field now has an arsenal of powerful new tools.  We have at our disposal a tool kit that can express genes for long periods of time and that can target many cell types efficiently throughout the entire nervous system. Our challenge will be to utilize our toolkit to hit the precise cells at the right expression levels.  I’m certain we can accomplish this goal.

Gray: That said, the devil is in the details.  We have to get MeCP2 broadly distributed throughout the whole brain, which is something that has been done in animals but not yet in humans.  Just as important, we have to be very careful to get the level of MeCP2 correct – too little may not work well enough and too much could cause a different spectrum of disease.

Coenraads: What have we learned thus far regarding gene therapy for Rett?

We’ve learned that a single one-time administration of a gene therapeutic can have a clinically meaningful result in the workhorse rodent model of this disease, even when delivered later in life. The results have been quite promising, and now multiple laboratories have similar promising results, it’s not just an isolated manuscript happening in one laboratory. – Brian Kaspar

Kaspar: We’ve learned that a single one-time administration of a gene therapeutic can have a clinically meaningful result in the workhorse rodent model of this disease, even when delivered later in life.  The results have been quite promising, and now multiple laboratories have similar promising results, it’s not just an isolated manuscript happening in one laboratory.  Using similar approaches, multiple groups have encouraging results.  That’s good for science and that’s good for Rett patients.

Steve Gray (far right) and Stuart Cobb (second from the right) at an RSRT science meeting in late 2012.

Steve Gray (far right) and Stuart Cobb (second from the right) at an RSRT science meeting in late 2012.

Cobb:  The studies have also shown that the level of MeCP2 protein produced by the gene therapy is not producing any obvious defects in its own right and it therefore seems possible to deliver protein within limits that are tolerable to cells.

We have also learned that it is not necessary to ‘hit’ all cells with the virus, this is never going to be achievable in practice anyway. Fortunately, a substantial therapeutic impact may be achieved by delivering the gene to a subset of cells. Of course the absolute number of cells, the types of cells and location in the brain is likely to be very significant. These are important issues that will be investigated by the MECP2 Gene Therapy Consortium.

Gray: Finally, the studies tell us that we have to be very careful how we target the MeCP2 gene, to make sure too much isn’t delivered to a particular organ, such as the liver.

Coenraads: Have you ever worked in collaboration with multiple labs?  What do you think are the advantages?  Could there be disadvantages?

Mandel: I have been fortunate enough to be part of a productive collaboration funded by RSRT to work on how MeCP2 functions normally, and in mutants, and to do, with Kaspar’s group and Adrian Bird, the initial pilot proof of principle for gene therapy for Rett, using AAV9 vectors.

Gray:  Most of my work is done in collaboration with other labs, and I’m very comfortable doing research that way.  I have a small and fairly specialized lab.  We aren’t experts at everything, and it is much more efficient to collaborate with someone that has expertise than try to develop it on your own.  This speeds things up and raises the quality of the work.  The keys to making it work are that everyone has to be fully committed, and there has to be a level of trust across the members of the consortium.  Trust that you can share data openly, and trust that the work is being carried out to the highest standards.  If one investigator isn’t doing their part or does sloppy science then things can fall apart.

Stuart Cobb (right) with David Katz.

Stuart Cobb (right) with David Katz.

Cobb:  I have enjoyed a number of successful bilateral collaborations in the past but the formation of the four-lab Consortium is going to be a new venture for me. Clearly there will be big advantages in terms of pooling complementary expertise to make swift progress. However, there will also be challenges, one being the necessity to maintain very good communication within the Consortium to coordinate our efforts and work together efficiently.

Kaspar:  My laboratory is engaged in a number of collaborations and they are a major reason we have been successful.  Our international collaborations have given us access to patient samples as well as opened the door to new ideas and interactions that just couldn’t be accomplished sitting in isolation. Collaborations bring everyone’s experience and expertise to the table and allow the participants to rapidly answer difficult questions. We don’t always have to reach consensus but the right team will be open to sharing ideas and comfortable with hearing criticism as well as be aligned on goals and focused on the patients.

Coenraads: What are the strengths your lab brings to the table?

Steve Gray in his lab at UNC Chapel Hill

Steve Gray in his lab at UNC Chapel Hill

Gray:  We are part of one of the best gene therapy centers in the world, with a vector core facility that makes hundreds of research preps and several clinical preps each year.  My lab in particular has, as its primary goal, a mission to develop nervous system gene therapy platforms.  We’ve made enormous strides using existing vectors to their full potential, and also leading the way to develop newer and better vectors.  Also, our experience bringing our Giant Axonal Neuropathy project to clinical trial gave us experience on the process of moving a biological from the bench to the bedside. 

Cobb:  My own lab brings expertise in the neurobiology side in terms of accurately mapping out Rett syndrome-like features in mice and within the brain and being able to assess in detail the ability for gene therapy to improve aspects of the disorder.

Mandel:  I am a basic science lab and I have strengths in applying state of the art molecular tools to questions related to gene therapy.  My lab also has much expertise in histology of the brain.

Kaspar: We have successfully navigated two programs from bench research to human clinical trials.  We have flexibility to focus on complex basic biology questions, while keeping in mind our goal to advance therapies towards human clinical trials.

Coenraads:  Gene therapy has had a rocky road. How do you view the field at the moment?

Kaspar:  Expectations and promises were far too high in the early days of gene therapy. I think transformative therapies go through this track of failing and then triumphing. One simply has to look at the field of organ transplantation as an example. I think gene therapy will triumph, but we still have much to learn and pay attention to. There is a great deal of excitement and hope in the field today.  We have to be good custodians of this technology with laser focus on safety and design of human clinical trials.

Gray:  There are a lot of good things happening in the field right now with patients seeing major improvements in their lives as a result of gene therapy.  The first gene therapy product received full regulatory approval last year in Europe.  Biotechnology companies are taking an interest in gene therapy.  Frankly, it is a good time to be in the field.

Modern, safer, approaches to gene therapy are developing very rapidly and it is one of the most vibrant fields in the genetics and molecular medicine arena at the moment. – Stuart Cobb

Mandel: I think that there is a large and growing momentum now for gene therapy because of the huge advances in molecular biology and viral technologies.

Coenraads: I find that the gene therapy area is polarizing – people love it or hate it – have you encountered a similar response?

Cobb:  Yes, I have indeed encountered such contrasting views. Even within the community of Rett clinicians, I have had views of gene therapy being ‘the obvious route to follow’ versus others expressing great skepticism. Interestingly, the view within industry has been more accepting, perhaps due to the massive shift towards biologicals (alternatives to classical small molecule drugs) that has occurred in recent years.

Kaspar:  Typically those that are not fans of this technology focus on past failures. With any transformative findings there will be disbelievers.   I’m reminded by a quote from Alexander von Humboldt:  There are three stages of scientific discovery: first people deny it is true; then they deny it is important; finally they credit the wrong person.

Gray:  I can’t blame some people for hating it.  Gene therapy promised a lot early on, before the technology was very developed.  Expectations should have been tempered somewhat while the science was worked out, but instead the field moved too fast and people got hurt.  That said, I don’t think you should turn your back on a potentially revolutionary medical technology because of mistakes made over a decade ago when the field was in its infancy.  If you take a fresh look at the things happening today, there is a lot of real and well-founded optimism.

Gail Mandel at a recent RSRT meeting.

Gail Mandel at a
recent RSRT meeting.

Mandel:  As in any area of science, there are proponents and detractors.  There are technical issues with gene therapy, such as scaling and side effects that need to be addressed before more people will lose some skepticism, although some skepticism is quite healthy and pushes us to be as rigorous as possible.



Coenraads: Dr. Kaspar, tell us a bit about your experience bringing the Spinal Muscular Atrophy project to clinical trial.   How long did it take from mouse experiments to trial? How much money was invested from your lab?

Brian Kaspar (middle) at an RSRT workshop.

Brian Kaspar (middle) at an RSRT workshop.

Kaspar:  Our SMA program is quite exciting. We discovered the unique capacity for AAV9 to cross the blood brain barrier in 2009, in 2010 we were in progress to have the longest living SMA mouse in the world. We further tested safety and navigated the regulatory process including the NIH Recombinant Advisory Committee, the Food and Drug Administration and our institutional review board.  Late in 2013 we were granted approval from the FDA and we will be injecting our first patients in a Phase 1/2 clinical trial early this year.  It was a hectic 3-year process that cost $4 million and counting.  We are excited and hopeful to help children with SMA type 1.

Coenraads:  Dr. Gray, you are developing a gene therapy treatment for a disease called Giant Axonal Neuropathy.  Can you tell us about your experience with that project? How far from clinical trials are you?   How long did it take from mouse experiments to trial? How much money did it cost?

Gray:  My GAN project has been life changing.  This was the project that made the connection for me to patients and changed the way I think about research.  Before then it was just about getting a good paper, or a grant, or doing the right things to advance my career.  Now it is about making a real difference in the lives of people I’ve come to know and love.  We’re on track to treat the first patient in the first half of 2014. We developed the treatment about 3 ½ years after starting the project, which included testing the treatment in the laboratory and developing an approach that should translate to humans.  It’s taken another two years to start the trial. Our preclinical supporting studies were approximately $1.5 million.  The FDA-required safety studies were another $0.75 million.  We are budgeting another $1.5 million for the clinical trial. Most of these funds were provided by a small grass-roots foundation called Hannah’s Hope Fund.

Coenraads:  I’m delighted that you have all agreed to collaborate. I look forward to our bi-monthly phone calls and in-person meetings twice a year.  Parents all over the world will be waiting anxiously to hear about your progress. As you know, there is a lot at stake.

We are starting the New Year with the wonderful news that Professor Adrian Bird has been Knighted for his services to science.  For anyone following Rett research Prof. Bird needs no introduction. His list of contributions to the Rett field are numerous starting with the discovery of the MeCP2 protein in the early 1990’s to the development of the first animal  model in 2001 to the unexpected discovery that Rett symptoms are reversible.  We congratulate Sir Adrian Bird and wish him the best for 2014 – may the discoveries continue!

AdrianBird

Professor Adrian Bird

Prof Bird with fellow trustees Heidi Epstein,
Monica Coenraads and Marci Valner

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At the end of every year the Simons Foundation announces its list of most notable papers from the autism field. Among these are two RSRT-funded papers: the gene therapy paper from Gail Mandel and Adrian Bird and the statin paper from Monica Justice.

To profoundly impact a disorder with as many varied and debilitating symptoms as Rett Syndrome, it is likely that intervention must be directed toward the very root of the problem. There are several ways to do this: activate the silent back-up copy of the Rett gene; target modifier genes; explore gene therapy.

Today, we announce a study funded through the MECP2 Consortium suggesting that gene therapy may indeed provide a feasible approach to treat Rett Syndrome.

The work was led by Gail Mandel at Oregon Health and Sciences University in collaboration with Adrian Bird of the University of Edinburgh and Brian Kaspar of Nationwide Children’s Hospital.

Gail Mandel with lab members Dan Lioy and Saurabh Garg

Gail Mandel with lab members
Dan Lioy and Saurabh Garg

Adrian Bird and post-doc Hélène Cheval

Adrian Bird and post-doc
Hélène Cheval

In the past sixty days, four key papers have been published detailing research advances supported financially and intellectually by RSRT. Three of those papers are funded through the MECP2 Consortium, a unique alliance launched by RSRT in 2011 among three leading labs: Bird, Greenberg (Harvard) and Mandel. If you are a donor to RSRT, the accelerated research these projects represent is the result of your money at work.

We wish to express our gratitude to all of our generous supporters and the parent organizations that make this progress possible. Special thanks to our funding partners, the Rett Syndrome Research Trust UK and the Rett Syndrome Research & Treatment Foundation.

Below are some resources to help you understand today’s announcement.

Press Release [Spanish Translation] [German Translation]


Video interview with Dr. Mandel & lab members

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Adrian Bird (left) and Matt Lyst
University of Edinburgh

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Michael Greenberg (right) and Dan Ebert
Harvard Medical School

It stands to reason that in our battle to cure Rett Syndrome it would be of great benefit to understand the function of the “Rett protein”, MeCP2. Towards this end RSRT launched the MECP2 Consortium in 2011, a unique $1.8 MM collaboration between three distinguished scientists, Adrian Bird, Michael Greenberg, Gail Mandel.  On June 16th the first two publications from this collaborative effort are published in Nature Neuroscience and Nature. Together these papers provide further clarification of the elusive function of the MeCP2 protein and how mutations within it contribute to Rett.

We thank Kathy and Tony Schoener whose visionary $1 MM gift made the Consortium possible. We thank all of our donors and parent organizations worldwide who support us, in particular our funding partners Rett Syndrome Research Trust UK and the Rett Syndrome Research & Treatment Foundation.

We are providing a variety of resources to help you understand the progress being reported today.

Press release

Animation of Nature Neuroscience Paper (courtesy of Jeff Canavan)

Chinese Translation

Interview with Matt Lyst, post-doc in Bird lab

Interview with Michael Greenberg and Dan Ebert,
post-doc in Greenberg lab

RETT SYNDROME RESEARCH TRUST WEBSITE

by Kelly Rae Chi

Rett Syndrome is caused by a variety of mutations in the MeCP2 protein, but in some instances, MeCP2’s end is missing.  A graduate student in Developmental Biology at the Baylor College of Medicine in Houston, Steven Baker, who is also in the medical scientist training program, was sifting through the clinical literature on boys with such mutations when he noticed that a tiny difference in how much of the protein’s tail is shortened—by just three amino acids—seemed to make the difference between decades of life (albeit with Rett-like deficits) and death in infancy.

Steven Baker

Steven Baker

Baker asked his adviser, Huda Zoghbi, whether she thought those extra few amino acids could so dramatically change the clinical progression of Rett.

Huda Zoghbi

Huda Zoghbi

“I don’t know,” Zoghbi, Howard Hughes Medical Institute Investigator and director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, recalls telling him, because other genetic factors could be contributing the dramatic difference in the progression of Rett. “The only way to know is to make mice that have the two different mutations.”

So they did. One mouse had the end of its MeCP2 cut off at the 270 mark (‘R270X’ mice) while another’s protein was shortened at the 273 mark (‘G273X’ mice). The stories of these mice were reminiscent of the boys Baker had noticed. The R270X mice died prematurely, around the same time as mice with no MeCP2. In contrast, the G273X mice, with their extra three amino acids, survived longer and showed symptoms later, although these features became more severe and the mice died before healthy mice did.

What do those amino acids do? In trying to find out, the scientists have refined their understanding of how MeCP2 works. Their results are published this week in Cell.

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A first look at DNA binding:

Researchers know that MeCP2 binds throughout the genome, coating the DNA in neurons more heavily than in other cells, but what exactly it does after that is less clear. It’s thought to turn genes on or off, or alter the overall structure of DNA.

Zoghbi’s team thought that the two truncated forms of MeCP2 might bind to DNA differently — in a way that would help explain the different clinical progressions of the boys — but when they initially looked at several spots within the genome they saw that both forms bound to those spots similarly.

In fact, looking more broadly across the genome the group found that overall binding of the MeCP2 was pretty much the same, and it looked normal. (The latter wasn’t too surprising, though, because the front end of MeCP2 was already known to bind to DNA.) Both mutations also interfered with the normal ability of MeCP2 to repress genes.

Looking more closely at gene expression at various time points in brain development, however, the group found a key difference in the two mutants: at 4 weeks of age, a small group of genes was improperly expressed in the R270X mutant but not in the G273X mutant. Interestingly, most of those genes eventually became misregulated in the G273X group by 9 weeks.

The hook from the animal kingdom:

Meanwhile, the scientists asked evolutionary biologist, Olivier Lichtarge, a Professor at Baylor College of Medicine who uses computational tools to study the evolution of protein sequences, to help them compare the sequences of the protein’s tail across different species (the idea being that any regions of the protein that were highly similar across species might be important for the protein’s function). “We worked with Angela Wilkins in the Lichtarge lab and asked, ‘Is there something in this domain that’s really unique?” says Zoghbi, who is also a Professor at Baylor College of Medicine.

They found that three clusters of MeCP2’s tail were highly conserved across fish, frog, rat, mouse, and human. Shortening MeCP2 at the 273 mark removed the third of those conserved clusters, whereas cutting the tail at the 270 mark deleted the second and third clusters.

What are these clusters in MeCP2’s tail and what do they do? It turns out that they’re called AT-hooks. In 2005, a study by Adrian Bird’s group described the first of those three AT-hooks (which is the one still present in both of Zoghbi’s new models), though its function was unclear.

AT-hooks are regions of a protein that are already well known to bind DNA, however, so the team went back to the idea that the two truncated proteins might differ from one another in how they attached to the genome, even though their initial results had shown that binding was similar. Using a different assay, they found that missing the second AT-hook domain impaired the ability of the R270X to steadily interact with certain sequences in the genome.

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The interaction between MeCP2 and DNA:

Our genomes are wound tightly around spool-like proteins called histones; the DNA and histones (together, called chromatin, which looks like beads on a string) are then packed in even more so that it can all fit inside cells. Using an experimental model of compaction in vitro, the team found results suggesting that R270X mice (which, remember, are missing an two AT-hooks instead of one) don’t pack up chromatin as well as 273X mice do.

The initial finding that both mutated forms of MeCP2 bind to DNA are still important though, Zoghbi says. “It tells us that the major binding to DNA happens. That’s the first step.” The researchers think that once the front end of MeCP2 sits on DNA, the AT-hook clusters on its tail come in manipulate the DNA further, likely bending or altering the structure to help it pack further into the cell.

“There were hints previously that MeCP2 might cause a change in the overall conformation of DNA. The new study is probably the most direct evidence,” says Howard Hughes Medical Institute Investigator Gail Mandel, at the Oregon Health and Science University in Portland, who was not involved with the study.

The protein partner ATRX:

When the MeCP2 sits on DNA, and likely alters the way it packs into a cell, there are other molecular partners that come and join it. One of those is the protein ATRX—whose mutations have been linked to Alpha-thalassemia mental retardation syndrome—and Adrian Bird’s lab has previously shown that its interaction with DNA is disrupted in mice missing MeCP2. Zoghbi’s team decided to look at this protein in their new mutant mice.

Compared with the healthy mice and the G273X mice, ATRX goes missing from the tightly packed DNA of neurons earlier in life for the R270X mouse, and this loss mirrors the quicker onset of Rett symptoms. “To us, that was really interesting,” Zoghbi says, “because this change is not because the neurons are sick, it’s because you don’t have MeCP2 functioning properly.”

Studying female mutant mice that are missing a copy of MeCP2, the researchers found those brain cells with no MeCP2 also had less ATRX bound to tightly packed DNA compared to controls. In female mutants with too much MeCP2, an excess of ATRX latched on to DNA. MeCP2’s absence from liver and non-brain organs didn’t affect ATRX binding in those organs, suggesting that MeCP2 has a mechanism that’s specific for the brain.

Future directions:

Taken together, these results suggest that in the brain, the AT-hook clusters on MeCP2’s tail are manipulating DNA in a way that’s crucial for the other protein partners to bind and do their jobs, Zoghbi says.

“This new paper is beginning to shed light on the complexity of this interaction between MeCP2 and ATRX,” says Mandel. In addition, “we don’t know all the other proteins that bind to MeCP2, but the guess would be that there are likely more partners affecting whether genes are on or off.”

Zoghbi’s team hopes to understand how shortening MeCP2’s tail changed chromatin structure without dramatically changing gene expression — as well as the mutation’s affect on brain activity. They also plan to do biochemical and molecular experiments to figure out where ATRX is going and what it’s doing when its distribution is altered in the brain cells of the MeCP2 mutants.

For Zoghbi, the new findings underscore the importance of going back to patients to look for clues about MeCP2’s function. In 1999, Zoghbi first showed that various mutations in MeCP2 caused Rett. “Here we are 14 years later, some of these human mutations are teaching us lessons,” she says. “The variety you get and the breadth of human features you can dissect and go back and study in the mouse are really very humbling.”

RETT SYNDROME RESEARCH TRUST

Kelly Rae Chi

[links to podcasts are below]

That mutations in the MECP2 gene cause Rett Syndrome has been known for over a decade. But what exactly the protein does is not yet clear.

In the early 90s, Adrian Bird’s group purified MeCP2—which stands for methyl-CpG binding protein 2—and named the protein for its ability to bind parts of the DNA with a chemical tag called a methyl. Methyls tend to dampen the expression of genes, suggesting that MeCP2’s function is to silence genes.

Studies published since then suggest MeCP2 activates or represses the expression of many genes. Other results suggest that the protein binds throughout the genome, influencing the way DNA packs into a cell.

New evidence, published today (December 21) in Cell, shows that MeCP2 binds to spots throughout the genome that are tagged with the chemical, 5-hydroxymethylcytosine (5hmC) in mice, and that this interaction may be important for understanding Rett Syndrome.

“[The study is] a very interesting new development in studying the functional significance of MeCP2, which we have to understand if we’re going to understand Rett Syndrome,” says Bird, professor of genetics at the University of Edinburgh in Scotland who was not involved with work.

Abundant in the DNA of certain brain cells, 5hmC seems to be a signpost of sorts for active spots within the genome — that is, the regions that are churning out new protein — the study found. MeCP2’s latching onto these sites supports its potential role as a gene activator, though it’s clear that the case of what MeCP2 does is far from closed.

“Whether or not [MeCP2 is] directly involved in activation is still a matter of further investigation. But we know that it can localize to a region that contains 5hmC and active genes,” says Skirmantas Kriaucionis, group head in the University of Oxford Nuffield Department of Medicine, who co-led the study with Nathaniel Heintz of the Rockefeller University in New York.

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heintz-skiri

Podcast with Skirmantas Kriaucionis

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Figuring out 5hmC

As a postdoctoral researcher in Heintz’s lab, Kriaucionis found 5hmC in 2009 by accident when he was looking at how a closely related chemical, 5-methylcytosine (5mC), influences genome structure in brain cells. Anjana Rao’s group, then at Harvard Medical School, working independently from Heintz’s lab, confirmed the existence of 5hmC in the same issue of the journal.

Researchers consider 5mC a fifth base, and 5hmC a sixth base, of DNA, which is traditionally thought of as a string of four different chemicals called nucleotides. 5mC and 5hmC resemble the traditional base cytosine, but with a methyl group added on, making 5mC, and a hydroxy group added to the methyl, creating 5hmC. The new study confirmed that patterns of these chemical modifications to the genome are different in each cell and influence which genes are turned on or off and when.

The discovery of 5hmC opened up a new area of work—and hundreds of new papers—focused on where the nucleotide is in the genomes of different cell types, and what it’s doing.

In the new study, using an explorative molecular assay to fish for a binding partner for 5hmC, the group identified the molecule as MeCP2, and nothing else. “It was really a surprise,” Kriaucionis says.

“This paper is the second paper to suggest a candidate binding protein for 5hmC,” says Rao, now a professor of signaling and gene expression research at the La Jolla Institute for Allergy and Immunology, who was not involved with the new study. Other findings have proposed a different molecule, MBD3, as a candidate, but those and the new results need further investigation, she adds.

“So far, both candidates — MBD3 and MeCP2—also bind 5mC, so an exclusive binding protein for 5hmC has not yet emerged,” Rao says.

Indeed, contradicting the new evidence that MeCP2 binds 5hmC and 5mC equally, some previous studies show that MeCP2 much prefers binding to 5mC over 5hmC. For example, a study published earlier this year shows that says MeCP2 is nearly 20 times more likely to bind 5mC than 5hmC.

Relating to Rett

In the new study, Kriaucionis and his colleagues observed that a certain Rett-causing mutation, called R133C—which is responsible for a relatively milder form of the disorder—disrupts MeCP2’s binding to 5hmC.

“[The R133C mutation] is really interesting because it allows us to speculate that MeCP2 binding to 5hmC is important as a part of the function which causes Rett Syndrome,” Kriaucionis says.

The evidence now “strongly suggests” the potential involvement of 5hmC in Rett, says Peng Jin, an associate professor of human genetics who was not involved with the new study. A study his group published last year in Nature Neuroscience found that patterns of 5hmC are altered in mouse models of Rett.

Interestingly, the R133C mutation only slightly dampens MeCP2’s interaction with 5mC, suggesting that MeCP2’s binding with 5mC serves a different purpose than that of MeCP2 and 5hmC.

Other Rett-causing mutations in MeCP2 examined by the group don’t seem to affect binding to 5hmC, meaning 5hmC binding does not fully explain the symptoms of Rett.  “It will be important to test further the contribution of 5hmC to Rett Syndrome,” notes Jin, adding that there are mouse models available to do so. Those mutant mice lack the enzymes needed to convert 5mC to 5hmC.

In the new study, researchers studied only a few types of neurons, but there are hundreds of cell types in the brain. Kriaucionis thinks that MeCP2 binds to 5hmC in other cells.

The 5hmC patterns themselves are cell-specific, however, perhaps further complicating the story of MeCP2.

“We really need to get more data to understand whether or not, how different 5hmC and MeCP2 localization would be in different cell types,” Kriaucionis says. “It’s an important component to understand MeCP2 function,” and how scientists might think about future treatment.

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Cell podcast with Nat Heintz    (click on Paperclick on right)

HHMI Press Release

Rett Syndrome Research Trust Website

by Monica Coenraads

It would be difficult to overestimate the importance of what we have learned from the mouse models of Rett Syndrome.  After all, without them we would not know that Rett is reversible.

It may come as a surprise that there is no single mouse model of Rett but rather a variety of genetic models, from “KO” or “knock-out” mice, which have no MeCP2 at all, to those in which the precise MeCP2 mutations that are seen in humans suffering from Rett Syndrome have been duplicated.

Jackson Laboratories in Bar Harbor, Maine currently distributes almost a dozen mouse models of Rett. Jackson (or Jax, as most scientists refer to it) is a non-profit organization that specializes in this work to advance the understanding of human disease. Although no animal model perfectly capitulates human symptoms or responses, 95% of our genomic information exists also in rodents. Maintaining an extraordinary level of care and attention to detail in this sensitive field, Jax conducts its own research as well as breeding and managing colonies of thousands of models.

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To learn more about Jax please read an earlier blog post, Of Mice and Men…Or in the Case of Rett…Of Mice and Women.

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Having access to the various models of Rett Syndrome is crucial to the advancement of research and this is an area that RSRT and its predecessor, RSRF, have been actively involved in since the first animal models were published in 2001 by RSRT Trustee and advisor, Adrian Bird and by Rudolf Jaenisch.

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From the Jax website:  “Partners in the fight against Rett syndrome,” a story about how Monica Coenraads, the mother of a daughter with Rett syndrome and co-founder of two organizations focused on treating it, is working with Dr. Cathy Lutz to develop and distribute new mouse models of Rett syndrome.

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Sharing mouse models is not always the norm as this article about a mouse model for Angelman Syndrome illustrates. We are extremely fortunate that researchers in the Rett field have been stellar about quickly sharing their models. Adrian Bird, Rudolf Jaenisch and Huda Zoghbi have set an exemplary high bar when it comes to making their own mouse models available as soon as they publish.

In some cases sharing the mouse has even preceded publication. Last year Nature reported on a situation regarding a Rett mouse that had been developed by Novartis. The model had been engineered so the Rett protein glowed so it could be tracked visually.  Many researchers were eager to access the model but could not due to legal issues. (Nature article – Licence rules hinder work on rare disease.  Animal model off-limits to Rett syndrome researchers.)  I knew that Adrian Bird after being denied access had created his own model and I asked him whether he would be willing to share it through Jax. He agreed immediately even though he had not published yet. The mouse is now available to any researcher worldwide that needs it.

Besides teaching us about the molecular underpinnings of disease, mouse models may be effective to test treatments.  We have all heard many stories about how drugs tested in mice with success are found to be ineffective in humans. The next few years will be extremely interesting as we begin to explore how predictive the Rett mice models really are.

Rett Syndrome Research Trust Website

Adrian Bird and colleagues recently published  their latest paper on MeCP2 in the journal Human Molecular Genetics. The series of experiments described in the paper were designed to explore what happens when the MeCP2 protein is removed from mice of various ages, including in a fully adult mouse. This work was funded in part by RSRT with generous support from RSRT UK, Rett Syndrome Research & Treatment Foundation (Israel) and other organizations who financially support our research effort.

Below are excerpts from a conversation with joint first authors Hélène Cheval and Jacky Guy.

Jacky Guy (far right), Hélène Cheval (2nd from right) with Adrian Bird and other lab members. University of Edinburgh, Scotland

MC  Dr. Cheval, you trained as a neuroscientist. What attracted you to the Bird lab, which is very biochemistry-based, and where you are the sole neuroscientist?

HC  My previous lab, run by Serge Laroche,  was a pure neuroscience lab focused on learning and memory. However, I was actually doing biochemistry and I was very much interested in how to get from molecule to behavior, and I was also quite interested in chromatin.  I had read the Bird lab reversal paper of 2007 and thought it was one of the most exciting papers I had ever seen. Upon receiving my PhD I applied for a post-doc position, convinced that it would be a great experience for me but also thinking that perhaps the lab would benefit from having someone with a neuroscience background.  I joined the lab in 2009.

MC  Dr. Guy, you co-authored your first paper on Rett Syndrome in 2001. That was the paper that described the MeCP2 knockout mouse model made in the lab, one that is now used in hundreds of labs around the world.

JG  I joined the lab in 1997. My first project was to make the conditional mouse models of Mecp2, meaning mice where the protein can be removed at will.  At that stage we didn’t yet know about the link between MECP2 and Rett Syndrome.  That came about as I was working on the project. It was a very exciting time.

MC  It’s unusual for people to stay in a lab so long. This gives you an amazing depth of uninterrupted knowledge about the field.

JG  I took a rather unconventional path. I’m very happy to do bench work and being able to work in the same field has been wonderful.

MC  Dr. Guy, perhaps you can start us off. What are the key questions you were trying to answer with this series of experiments?

Jacky Guy

JG  This was actually an experiment we had been wanting to do for a long time.  We have always been interested in defining when MeCP2 is important.  Rett had been thought of as a neurodevelopmental disease. Since we were completely new to Rett, we thought maybe it’s not neurodevelopmental. So we set out to remove the protein at different ages and see what happens.  Removing the protein is not quite as simple as reactivating the gene, which we had already done in the reversal experiment. When you reactivate the gene it makes protein right away. In this experiment, however, when you deactivate the gene you have to wait for the protein to decay away. We found it takes about two weeks for the amount of MeCP2 protein to fall by half.

HC  Jacky’s reversal experiment suggested that MeCP2 is implicated in adulthood. But many papers were still describing Rett as a neurodevelopmental disease.  We also wanted to confirm a hypothesis that we all shared in the lab that MeCP2 is required throughout life.

MC  That is a hypothesis that was also put forth in Huda Zoghbi’s 2011 Science paper. She showed that removing Mecp2 in adult mice aged 9 weeks and older caused Rett symptoms. Do you think that her paper and your new data have definitively put to rest the notion that Rett is neurodevelopmental?

HC  To my mind it’s clear that it’s not merely neurodevelopmental.

JG  I think “merely” is the key word here. The phenotypes we analyze in mice are those that are quite easy to see; for example, lifespan, breathing, gait. There might be more subtle things that we are not observing, or that are not affected by knocking out the protein in adulthood.  And we are not analyzing cognitive aspects. So we can’t completely rule out the possibility that there could be some things that are indeed of a neurodevelopmental origin that we are not seeing in these experiments.

JG  Mecp2 can be deleted by treating the mouse with tamoxifen in the same way the protein was reactivated in the reversal paper.  In this paper we picked three different time points to turn off the gene: three weeks (which is when mice are weaned and begin to live independently) eleven weeks and twenty weeks.   In all three scenarios the tamoxifen was able to delete Mecp2 in about 80% of the cells.

What you might expect is that at whatever age you delete the gene, there will be a certain amount of time for the protein to disappear and then the effects of not having the protein will appear.

In fact, what we found is that the time it took for symptoms to appear varied with the age at which we inactivated the gene.  It took longer for the symptoms to appear when we deactivated Mecp2 at 3 weeks.  When we removed MeCP2 in older mice, the symptoms appeared more rapidly.  So it seems that younger mice are able to live symptom-free without MeCP2 for a longer period of time. There is a certain period when the need for MeCP2 becomes more important in mice. This is the first critical time period that we talk about in the paper; it happens around eleven weeks.

Drs. Cheval and Guy with Prof. Bird and other lab members

As we followed the mice treated at all three time periods, eventually they all started to die at about the same age, approximately thirty-nine weeks, regardless of when MeCP2 was removed. We concluded that this time period centered around thirty-nine weeks represented a second critical period for MeCP2 requirement. This is a time in a mouse that roughly coincides with middle age in humans. We think that maybe MeCP2 is playing a role in maintaining the brain as it ages.

Interestingly, this time frame of thirty-nine weeks is when female mice that are MeCP2-deficient in about 50% of their cells from conception begin to show symptoms. The male mice which have zero MeCP2 can’t make it past the first critical time period of eleven weeks. When you delete MeCP2 in 80% of the cells, the male mice show symptoms at 11 weeks and die at 39 weeks. So having about 20% normally expressing cells allows you to survive the first critical period but not the second.

MC  I’ve heard clinicians say that women with Rett in their 30s and 40s and beyond look older than they are. I wonder if this has anything to do with your hypothesis that MeCP2 may play a role in aging. Of course we don’t know if the premature aging is primary or secondary.  It may have to do with the effects of dealing with a chronic illness for many years.

JC  We are quite interested to learn about  a potential late deterioration in women with Rett but there is very little published on the subject.

MC  There are two potentially critically relevant points made in your paper. One is the fact that the half-life of the MeCP2 protein is two weeks. That could be relevant and encouraging for a protein replacement approach.

JG  We certainly had this in mind when we were doing the experiment.  The half-life of MeCP2 is longer than we expected. And could in fact bode well for protein replacement therapy. One caveat, ours was a bulk brain experiment. It could very well be that if you looked regionally in the brain or by cell type you might find varying results.

MC  The other potentially clinically relevant information comes from comparing the severity of symptoms seen in the mice in this study versus the adult knockout done in the Zoghbi lab and correlating symptoms to amount of MeCP2 protein. Your experiments yielded 3% more protein and resulted in less severely affected animals. Can you elaborate?

HC   That such a small difference in protein could have such a significant impact on survival is unexpected and indeed may be relevant for therapeutic interventions. We may not need to get the protein back to wildtype levels to have an effect. It may be possible that even small increases may be helpful.

MC  Congratulations to you both on this publication. The Bird lab has made numerous seminal contributions to the Rett field. The Rett parent community doesn’t typically have a chance to glimpse the researchers behind the experiments, doing the day-to-day work, so I’m delighted to provide an opportunity for our readers to get to know you a bit.  I look forward to the next publication. Best wishes for your ongoing work.

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P
hotos courtesy of Kevin Coloton

RETT SYNDROME RESEARCH TRUST WEBSITE
[SPANISH TRANSLATION]
[ITALIAN TRANSLATION]
[GERMAN TRANSLATION]
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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?


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


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 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.

RETT SYNDROME RESEARCH TRUST WEBSITE

On April 18, 2010 the Rett Syndrome Center at The Children’s Hospital at Montefiore in the Bronx hosted the third Parent Gathering.

I presented the second part in a series explaining RSRT’s research strategies and the very interesting scientific tools and discoveries on which they are based. [SEE BELOW TO WATCH VIDEO PRESENTATION]. I want to make this work comprehensible to parents and other interested members of the lay community, so that families have a perspective on research that is grounded in clear understanding of some unique and very hopeful possibilities. Several of the topics discussed are also the focus of RSRT’s most recent scientific meeting, which yielded a rich exchange of ideas and is catalyzing new partnerships and directions to explore. I will discuss RSRT’s dynamic approach to meetings in an upcoming blog. Viewers who have questions or comments about the video presentation are encouraged to contact me.

Three other presentations at the April 18 gathering will be online shortly. Director of the Rett Syndrome Center, Aleksandra Djukic M.D., Ph.D, summarizes a recent scientific workshop, organized by Dr Djukic and sponsored by RSRT, convened to brainstorm about appropriate clinical trial design. Dr. Shlomo Shinnar, a clinical trialist and Professor of Neurology and Pediatrics at Montefiore will share his vast experience on the topic.

Michael Beloff of the Barnum Financial Group, an office of MetLife, discussed aspects of legal planning with our children in mind, in a talk entitled Family Dynamics of Special Needs Planning.

These discussions will be available at the Montefiore website so that parents unable to attend in person can always have free access to this information.

Monica Coenraads

TO VIEW PART ONE and other RSRT VIDEOS – CLICK HERE
PART TWO IS BELOW

[blip.tv ?posts_id=3691861&dest=-1]

Rett Syndrome Research Trust Website
GERMAN TRANSLATION

Anyone who keeps up with Rett research knows that the different mouse models of the disease have given us a rich knowledge base. But have you ever stopped to think of how scientists get access to these crucial models?  Today we share with you a conversation between Cathleen Lutz of  The Jackson Laboratory in Bar Harbor, Maine, and Monica Coenraads, Executive Director of the Rett Syndrome Research Trust.  Jackson is the gold standard for the colonization and distribution of mouse models of disease.

MC: Thank you, Dr. Lutz, for spending some time with us. Tell us a bit about the background behind Jackson Laboratories.

CL: Jackson Laboratories was established by Clarence Cooks Little and Roscoe B. Jackson in 1929 as a genetics institute. Financial support came from Detroit industrialists such as Edsel Ford and Roscoe Jackson, president of the Hudson Motorcar Company, with land donated by family friend George B. Dorr.  Of course, Bar Harbor has a long history of philanthropic summer residents who supported the Laboratory, for example the  Rockefellers had settled on Bar Harbor.

Off the coast of Maine may seem like a strange place to have a genetics facility. The advantage to the location is that at the time there wasn’t any air conditioning, so the ocean breezes really kept the animal facilities cool. In the early years we didn’t have the ability to do genetic engineering, so essentially we relied on spontaneous mutations that resulted in interesting things to study.

MC: I’ve recently learned of veterinary schools setting up facilities to diagnose animals with spontaneous genetic mutations. For example, it’s possible that a dog with a mutation in MECP2 would be taken to vet and a bright geneticist might be able to diagnose the animal. This would allow different species to be studied without having to do all the expensive and time consuming genetic engineering involved with making models.

CL: In fact I just attended a seminar on this. Recently a naturally occurring form of ALS was identified in dogs.  What is particularly interesting is that the canine form of ALS progresses slowly, unlike the human ALS where patients usually die within 5 years of diagnosis.  The key question is what is genetically protecting these dogs?

MC: The hope is that genetic modifiers are protecting these dogs from their mutations in SOD1, an ALS gene.  And if you can identify these modifiers it may open up avenues for intervention. We have the same situation in Rett. Currently RSRT is funding a project in the lab of Monica Justice at Baylor to look for genetic modifiers in the Rett mice models.
How many disease models would you estimate that Jackson has?

CL: We have over 5000 different strains here at the Jackson Laboratory.

MC: How many new strains are imported every year?

CL: We’re importing about 600 new strains every year.

MC: Is Jackson struggling to keep up given such large numbers?

CL: We have over 1300 strains live on the shelf and over the years have worked to meticulously manage the supply and demand of the strains so investigators can get a jump start on their experiments.  We also scale up our colony sizes for individual investigators who need a larger supply of animals than we currently may have.  For strains that have low demand, those mice are available from our cryopreserved stocks.  Cryopreservation involves either freezing embryos or sperm.   Dr. Robert Taft at Jackson has been on the cutting edge of that technology and recently published his technique that helps recover sperm much more easily.  Animals can then be recovered from cryopreserved stocks as needed.

So instead of having to super ovulate 50 or 60 females, fertilize, and bring embryos to the two cell stage for cryopreservation, all we have to do is take two males and freeze down the sperm and that particular model is completely archived. We cut down on shelf space and cost.

MC: When a laboratory needs a particular strain which is cryopreserved, that means you don’t have a live colony; what do you actually send them?

CL: It depends on where the requesting laboratory is physically located and the level of their expertise.  Cryopreservation is still a rather novel technology so some labs are not equipped to handle the technique of thawing sperm and doing in vitro fertilization (IVF). In those cases we can take the sperm, thaw it and do an IVF to donor females and then we’ll send them live mice.  Alternatively we can send frozen viable embryos. This works well especially if the lab is an international customer because we have all kinds of handcuffs regarding transportation of live animals and tissues outside the country.

MC: How many scientists do you estimate have purchased from Jackson?

CL: Last year over 19,000 investigators from 50 countries purchased 2.7 million mice.

MC: That is unbelievable! How is Jackson funded?

CL: We are a not for profit organization with three prongs. We are a research organization; a resource organization, that’s the mouse distribution portion of our institution; and we run courses and conferences where we teach people the latest technologies.

Most of the research and courses are funded mainly through NIH grants.  A large portion of our Mouse Repository is also funded through NIH program grants.  The rest of the funding required for running the Repository comes from the fees we charge for the mice we distribute.   The proceeds go right back into the operation to acquire more mice and outfit new facilities to expand the program.   It’s very expensive to distribute mice because we have to maintain high health standards so that any institutions can receive mice knowing that they are free of viruses and pathogens that could contaminate their facility. We also have philanthropic donations.

MC: When I was the Director of Research at the Rett Syndrome Research Foundation we financially supported the importation and colonization of several Rett animal models at Jackson. That was money very well spent as those mice have now been distributed to hundreds of labs and have formed the foundation of much of what we have learned about Rett Syndrome.

You shared that in 2009, 95 different labs ordered Rett mice. The first Rett mouse model made by Adrian Bird was published in 2001, so Jackson had it ready for purchase in 2002.  So eight years later almost 100 researchers bought this mouse.

CL: Yes, there is still a lot of demand for that animal, partly because it’s one of the better models of neurological disease.  But it’s always going to take more than one model to really dissect what it is that you’re looking for.  So if you want to ask specific questions it’s very helpful to be able to utilize more than one type of mouse model.  So one model may have a point mutation, another may have a complete exon deleted, yet another may be a conditional mutation so you can just make that mouse gene defective in certain tissues and not others. When you put the collection all together it makes for a really good research resource…your toolbox, so to speak.

MC: I want to acknowledge the scientists who have developed the Rett mouse models:  Adrian Bird, Rudolf Jaenisch and Huda Zoghbi. All of them quickly deposited their mice with either Jackson or the Mutant Mouse Regional Resource Center, thereby giving the research community at large access to the mice.  This type of sharing does not always happen and I’m so grateful that they set a high standard for our community in terms of accessibility to these models. I hope that it’s a standard that others will follow.

MC: The recent ability to manipulate rat embryonic cells now makes it possible to create rat models of genetic disease. Does Jackson plan to expand into rat models?

CL: We’ve really talked about it a lot as genetic engineering in rats has come a long way in the last few years.  One problem is that sperm cryopreservation in rats is still not as efficient as it is in mice. And the housing of rats is so much more expensive because they are so much bigger than mice.

So we have to realize analyze what the advantages of working in rats versus mice are.

MC: Rats are considered smarter than mice.

CL: Yes, they are. They are probably a better model for studying behavior, as well as learning and memory, which will be important in many neurological diseases.   But the advantages of studying diabetes in a rat versus mice, for example, is less clear.  There is a rat repository in Missouri run by John  Critser.   I think that Jackson will basically rely on the Missouri repository, working with them when and if needed..  But certainly we’d like to see the cryopreservation and the sperm recovery be just as easy and cost effective and efficient for rats as it is for mice so that we could we could cut the cost and make the process feasible.

MC: I wonder then how many labs would purchase rats.  It would be a big learning curve to switch and the costs would be so much higher.

CL: Yes.  That’s absolutely true.  So there again I think researchers will really need to ask themselves what the advantage to using rats is for their particular research.

MC: Jackson also does its own research and has some high profile scientists on staff.

CL: We have 35 staff scientists on site working right now in a variety of areas. We have cancer biologists, neuroscientists, bioinformaticians. We have investigators  who specialize in metabolic diseases like diabetes and obesity.  We try to be as diverse as we possibly can in that respect.

MC: And why do you think the scientists would choose to work at Jackson and not at an academic institution?

CL: There are many factors but I think one of the attractions is the availability on site of all of the different mouse models. Also the sheer size of our operation means we can offer economies of scale. The per diem costs of mouse experiments are much lower than they would be at other institutions. That is a very attractive feature for scientists.  If researchers need large numbers for their studies then this is the place to do it.

MC: Is there anything you would like to say to families of children with Rett Syndrome?

CL: I’d Iike to let people know that our mission at the Jackson Laboratories is really for the families, for the patients, and for biomedical research.  We have, as I described, the repository and the disease model resources.   It is quite an undertaking and we really feel that it is within our scientific mission to be collecting these animals and to be making them as readily available to the scientific community as we possibly can.  That’s why we’re here and we feel that over the years we’ve really developed the expertise to do that and to manage the sheer numbers of strains that we have live on the shelf.

MC: Jackson truly provides an important resource for the scientific community. Thank you, Dr. Lutz, for sharing some of your knowledge with us today.

RETT SYNDROME RESEARCH TRUST WEBSITE
[SPANISH] Redefiniendo la Función de la Proteína del Síndrome de Rett

[ITALIAN] Ridefinire le Funzioni della Proteina Chiave della Sindrome di Rett
[GERMAN SUMMARY] MeCP2 – Neudefinition der Funktion des Rett-Syndrom Proteins
[GERMAN TRANSLATION]

Just before the holidays I had an opportunity to discuss with Adrian Bird the new data reported in his latest paper, published today in Molecular Cell. Most readers of this blog will know that Prof. Bird discovered the MeCP2 protein in the early 1990s while working at the Research Institute for Molecular Pathology in Vienna. Almost a decade later, Huda Zoghbi’s finding that mutations in MeCP2 cause Rett Syndrome propelled Prof. Bird into the realm of neuroscience. He found himself working, for the first time, on scientific issues with great relevance to human disease. In 2007 he published the dramatic reversal experiments.

We’ve come to expect novel and significant insights from the Bird lab; this new paper redefines our concept of both the scope and function of MeCP2. In the words of co-author Peter Skene, it may be “the watchdog of the neuronal genome.”

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Dr. Adrian Bird

MeCP2 Goes Global

MC: I found the data in your latest paper regarding the high levels and broad distribution of MeCP2 to be quite striking.

AB: Yes, MeCP2 is exceptionally abundant. Most transcription factors, proteins that turn genes on or off, exist in 10,000 to at most 100,000 molecules per cell. We are seeing 100 to 1,000 times more than that of MeCP2.  In fact, there is almost as much MeCP2 in the nucleus as there are nucleosomes, which are the fundamental repeating structural units of chromatin. That means that there is enough MeCP2 to potentially cover nearly all of the genome.

MC: I was intrigued by the fact that MeCP2 binds to non-genes as well as genes.

AB: As far as MeCP2 is concerned it doesn’t seem to care whether it binds to genes or not. It simply binds everywhere there are methyl groups.

MC: So MeCP2 follows methylation across the genome.

AB: Indeed, and this tracking of DNA methylation could explain the reversibility of severe Rett symptoms that we see in mice.  The important developmental step is to establish the correct pattern of methylation, and that appears to happen normally in Rett patients.  Once you have that pattern set down, and you put MeCP2 back in, as we did in our reversal experiment, the protein simply goes where it’s told by methylation and resumes its function.

The Genome – It’s Not All About Genes

MC: This is probably a good time to remind our readers that only 5% of the genome is made up of genes.  The rest comprises what is still sometimes referred to as “junk DNA” because scientists have not been able to ascribe any function to it. I’ve always found the term “junk DNA” a bit arrogant – I doubt that 95% of our genome is junk and in fact recent work has suggested that the junk might in fact have important regulatory functions.

AB: You are absolutely right; we shouldn’t dismiss any of the genome as junk.  Much of this so- called “junk DNA” has actually been conserved over many millions of years and that fact alone suggests that there is a good reason for that “junk” to be there.

MC: In recent years the idea that MeCP2 binds to methylated DNA has been questioned a bit. This paper reaffirms and expands on that. Where is this leading us?

AB: I think this confirmation, combined with an abundance of MeCP2 sufficient to cover all the methyl groups in the genome, is telling us something about the function of MeCP2.

MeCP2 Redefined

MC: So can we still say that Rett symptoms are caused by faulty repression of downstream genes by MeCP2?

AB: That remains a hypothesis that needs proving. We are still waiting for evidence that particular genes, when misexpressed due to mutated MeCP2, are causing Rett. We have a lot of work yet to do to figure out the connection between the absence of repression by MeCP2 and the symptoms of Rett.

MC: So what about the papers that claim particular genes are targets of MeCP2?

AB: Indeed, there have been quite a lot of papers – some written by our lab- which say that certain genes appear to be changed when MeCP2 is missing. The finding is followed up with biochemistry experiments which show that MeCP2 binds to these genes, so the data seems to make sense. However, once you find that MeCP2 binds absolutely everywhere, the concept of target genes becomes a bit less interesting and perhaps less relevant.

MC: If MeCP2 is not a transcription factor, as previously thought, what would you call it?

AB: I would call it an alternative linker histone 1.  Ages ago we showed that MeCP2 and the linker histone, HI, compete with each other to assemble chromatin on methylated DNA.  In this paper we show that when MeCP2 is absent, the amounts of HI, which are normally very low in the brain, go up dramatically.  In that sense MeCP2 clearly resembles a histone.

MC: Let’s give a bit of background for our readers. Histones are proteins which act as spools around which DNA is wound. This winding, or compaction, allows the 1.8 meters of DNA material to fit inside each of our cells. There are two classes of histones – core histones and linker histones.  Core histones form the spool around which DNA winds – resembling beads on a string. And linker histones are the DNA separating the beads. HI is one of two linker histones.  So, in effect, linker histone is the string between the beads of a necklace.

Might It Be Simpler?

MC: Yet another observation of your paper is that MeCP2 is likely performing the same function throughout the brain.  Please elaborate.

AB: Some think that MeCP2 does different things in different neurons.  Our data suggests that the pattern of MeCP2 binding is similar regardless of the brain region.  My emphasis has turned to the idea that, in the absence of MeCP2, there is a generic problem with neurons and that the regional effects have something to do with what those neurons do in the brain and not so much that MeCP2 does different things in different places.  In other words, MeCP2 does the same thing everywhere but its consequences are different.

Currently there is a lot of data from many labs pulling us in multiple directions. I would like to see if we can slice through all that complexity and say, in all these neurons this is what is wrong.  I’m excited about the possibility that perhaps it’s not that complicated after all.

MC: That would be an elegant and welcome scenario. Thank you, Prof. Bird, for discussing your latest paper.  I look forward to bringing our readers an update soon regarding your work.

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ROCKEFELLER PRESS RELEASE
HEINTZ LAB
Isolated nuclei from cerebellum. Blue color represents DNA. Green spot is the nucleolus of a Purkinje cell. (photo from Heintz lab)

Isolated nuclei from cerebellum. Blue color represents DNA. Green spot is the nucleolus of a Purkinje cell. (photo from Heintz lab)

The readers of this blog will have noted the frequent mention of epigenetics – a young but hot area of research which holds promise for novel therapeutic interventions for a myriad of diseases.  The term epigenetic means over and above the genome. It refers to changes in gene expression caused by mechanisms other than changes in the underlying DNA sequence.  It helps to think of epigenetics in terms of the charm bracelet analogy – the DNA is the charm bracelet and epigenetic modifications are the charms that can be added to or removed from the bracelet.

Every cell has about 30,000 genes. What distinguishes a heart cell from a liver cell is the pattern of gene expression (what genes are on and what genes are off). Considering the vast number of cell types in the human body it’s easy to appreciate how the instructions for turning genes on and off must be finely tuned and exquisitely calibrated.  When missteps occur – disease often follows.

Epigenetic modifications catalyze gene expression changes. The best known epigenetic modification is methylation.  Adding methyl “charms” to DNA leads to gene silencing. MeCP2, the protein that is mutated in Rett syndrome as well as a variety of other disorders, binds to DNA that has already been methylated and plays a role in regulating downstream genes.

The excitement surrounding epigenetics is that it’s dynamic. “Charms” can be added and they can be removed. The ability to catalyze these modifications through drugs has already led to some treatments for cancers. The hope is that these treatments are the mere tip of the iceberg.

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The latest breakthrough in epigenetics comes to us from the laboratory of RSRT advisor Nat Heintz of Rockefeller University. The connection to Rett Syndrome, however, does not end there. The post-doc in the Heintz lab who made this discovery is Skirmantas Kriaucionis. As a graduate student, he spent five years in the lab of RSRT trustee Professor Adrian Bird who in 2007 announced the dramatic Rett reversal experiments. The Heintz and Kriaucionis paper was published online, April 16th, in the high profile journal Science.

Nat Heintz, Ph.D.

Nat Heintz, Ph.D.

We all remember the four nucleotide bases (A-adenine, T-thymine, G-guanine, C-cystosine) from high school biology. Together these four bases make up DNA. If we were taking high school biology today we would also learn about a fifth nucleotide, methylcytosine (mC) that replaces cytosine depending on whether a gene needs to be turned on or off. Kriaucionis has now added a sixth, hydroxymethylcytosine (hmC), a nucleotide base previously observed only in the simplest of organisms, bacterial viruses.

Drs. Heintz and Kriaucionis discuss their findings with Monica Coenraads.

MC: It’s not every day that a new nucleotide is discovered. Congratulations! Were you surprised by this finding?

NH: Yes, I was. I like to think that in most cases I know where my research is heading. But, in this particular case, the finding was completely unexpected. Broadly speaking, I think these experiments validate that it’s worthwhile spending time analyzing detailed properties of cells as they exist and operate in vivo, rather than studying their properties after they have been adapted for growth in culture.

Ironically, as a graduate student in David Shub’s lab I worked on bacterial viruses carrying modified nucleotides in their genomes. Now, many years later, that research has come full circle.

MC: As is often the case in science, the discovery was rather accidental. Dr. Kriaucionis, can you tell us what kind of research you were undertaking and how you stumbled on hydroxymethylcytosine (hmC)?

Skirmantas Kriaucionis, Ph.D.

Skirmantas Kriaucionis, Ph.D.

SK: The discovery of hmC can be traced back to several key reasons. One, we were interested in investigating chromatin structure (DNA/protein material which makes up the chromosomes) in different brain cell types. A finding which attracted our attention is that certain cell types have distinct looking chromatin. A dramatic example is Purkinje cells which have a very open chromatin configuration, in contrast to cerebellar granule cells which have very condensed looking chromatin (see above picture) We wanted to investigate this further. Second, was the availability of technological tools in the Heintz lab, which not only gave us access to these specific cells but allowed us to isolate very pure material to investigate. Thirdly, was the rather outdated technique that I was using to quantify the absolute levels of the different nucleotides. Scientists rarely use this technique now because it does not tell you where in the genome the nucleotides are. Since location gives insight into biological function this technique is rarely employed. But the decision to use this method turned out to play a large part of how I was able to identify the hmC.

At first I didn’t believe my results, and it took several months to reproduce the results many times using different experimental conditions to give us the necessary confidence that indeed, we were seeing a novel nucleotide and not an artifact of the experiment.

MC: So hmC is an example of a further modification to a nucleotide base, cytosine, that has already been modified by a methyl group. Has your discovery added more complexity to the process by which genes are regulated?

SK: Yes, indeed it does add a layer of complexity to what sort of biological message is being encoded by these modifications. The next important step will be to figure out what outcome is expected when DNA sequences have unmethylated cytosine, methylated cytosine or hydroxymethylated cystosine.

It’s interesting to note that while histone proteins have many epigenetic modifications mammalian DNA had, until now, only one – methylation. This finding is totally unexpected. Although RNA has plenty of modifications, its functional repertoire is complex as well including structural, enzymatic and coding roles.

MC: Do you have any hypothesis about what hmC might be doing?

SK: hmC is very abundant in brain so this gives us confidence that it’s doing something biologically significant. We currently have two hypotheses regarding its function. One hypothesis is that the hmC might be an intermediate step to get methylated cytosine back to its original unmethylated state.

MC: So in essence hmC might transform a silent gene (methylated) to an active gene (unmethylated).

SK: Correct. Another possibility is that hmC is a stable final modification. It could still activate a silent gene without demethylation. We see different amounts of hmC in different cell types so it may be that in some cell types hmC is an intermediate while in other cell types it’s a stable modification. And obviously we are keeping open mind as there may be an unpredicted function of hmC.

MC: There was a second paper in the same issue of Science as your paper that identified the enzyme that catalyzes the conversion from mC to hmC. Can you elaborate on the synergies between these two papers?

NH: The second paper is from the laboratory of Anjana Rao at Harvard. We were unaware of her ongoing research until very recently. Our papers complement and actually help each other quite a bit. The Rao lab identified an enzyme which catalyzes the conversion from mC to hmC. This is a very significant finding. A criticism that our paper was receiving was that hydroxylation of methyl groups could be a spontaneous reaction that was happening due to the oxidation of DNA. We addressed this question in our study, but the accompanying paper completely puts this criticism to rest since the group found the enzyme catalyzing the conversion of mC to hmC. So in that respect their paper was helpful to us. Our data strengthened their paper because we showed that hmC was highly enriched in brain, providing a link to the biology of neurons and, perhaps, neurological disease. Taken together, the two papers establish the importance of hmC in the mammalian genome, and suggest that this new epigenetic mark will provide an entry into a previously unanticipated and important field of biology.

MC: Dr. Kriaucionis, previous to your post-doc position in the Heintz lab you were in Adrian Bird’s lab for five years. Prof Bird’s lab focuses on DNA methylation and discovered MECP2, the “Rett gene” in the early 1990s. You co-authored 5 papers on MECP2 and Rett Syndrome with Prof. Bird. Do you think there is any possible connection between MECP2 and hmC?

SK: I think there is indeed a connection. As your readers know, MECP2 binds to methylated DNA. There is data showing that MECP2 resists binding to DNA that contains hmC. If these findings hold up, then hydroxylating mC could release MECP2 from the chromatin and influence for example nearby gene expression. Finding genomic MeCP2, mC and hmC distribution in neuronal cell types will provide us with valuable insights into the biological function of MECP2 and the role of DNA modifications.

NH: So Skirmantas’ hypothesis implies that hmC can modulate the distribution of where MeCP2 binds in the nucleus. There is an alternative scenario in which a different and, as of yet, unidentified protein binds to hmC. My theory is that this protein is likely not a repressor, like MeCP2, but perhaps is acting as an activator. The beauty of science is that we can test these hypotheses. I suspect we’ll have our answer in a relatively short amount of time.

MC: What are the next steps that the lab is pursuing?

SK: Of utmost importance is to answer the following question: where is hmC and what is it doing? To answer that question we are developing a new set of tools which will allow us to adequately map where hmC is in the genome. I hope that having a clear understanding of location will provide clues as to its role.

MC: Dr. Heintz, you are known in the scientific world as a “big idea man” who identifies and then develops the necessary tools to go after key neurobiological questions. Can you elaborate on the development of the novel tools to which Dr Kriaucionis just alluded?

NH: The fact that as currently applied bisulfate sequencing techniques,which are used to detect sites of methylation in the genome, do not distinguish between a cytosine that is methylated or hydroxymethylated is a major problem. We hope to develop new methodology that will allow us to map the precise sites of genomic hmC and mC separately.

Our strength as a laboratory fits in nicely with the task ahead. We have at our disposal gene expression data that is specific to a large variety of specific cell types. This information will be very useful as we begin to map where in the genome hmC is found. These two separate but very complementary sides of our lab will help elucidate not only the function of hmC but perhaps also the function of the proteins that bind to it.

MC: Dr. Heintz, your lab does not have a history of working on epigenetics and yet you made a remarkable discovery. Given this finding do you envision changing the focus of your lab in any way?

NH: Yes, I think it will change our focus somewhat. We feel this discovery is a critically important finding and the role of hmC in neurons will be of high interest both fundamentally to understand brain function and also for investigation of epigenetic influences on disease states. So we will be focusing a lot of our attention on what the biological role of hmC is in the healthy and diseased brain .

MC: You are not a “Rett researcher” yet you have kept up with the literature, attended a number of Rett scientific meetings that I have organized over the years and have been a highly respected advisor to the field. Do you have any insight on recent progress and where you think the field is heading?

NH: I’m very enthusiastic about the developments of the last few years. Adrian Bird’s reversal experiments are stunning. It has also become very clear, largely as a consequence of Huda Zoghbi’s work, that the impact of MeCP2 in different brain cell types is distinct. This means that strategies aimed at treating particular symptoms of the disease can be devised in the nearer term while approaches to reversing the entire phenotype, a much taller order, are explored.

MC: On behalf of our readers I thank you both for your time and wish you the very best for your ongoing research. I look forward to staying in touch and hearing how this work unravels. Congratulations again on your paper.

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Our inaugural post includes interviews with Huda Zoghbi, M.D. and Adrian Bird, Ph.D. — two people whose names have become almost synonymous with Rett Syndrome.   It was due to Dr. Zoghbi’s tenacity and commitment that the Rett gene, MECP2, was identified in her lab in 1999. After seeing her first Rett patient in 1983 she became determined to find the disorder’s genetic cause. It took 16 years of hard work and determination.  Dr. Zoghbi’s efforts ushered in the appearance of Professor Adrian Bird.  He had discovered the MeCP2 protein earlier that same decade, years before anyone knew it was related to a human disease. During this decade they have both made many key contributions to the Rett field. Rett Syndrome is high-profile disorder in the neuroscience community, in large part, due to their efforts.  They play a key role at RSRT as trustee and advisors.

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HUDA ZOGHBI, M.D.

Huda Zoghbi, M.D. is an internationally renowned physician-scientist at Baylor College of Medicine and an investigator of the Howard Hughes Medical Institute. Click here for the first part of a two-part interview.

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ADRIAN P. BIRD, PH.D.

Adrian Bird, Ph.D. is the world’s leading expert in the gene MECP2.  He is the Buchanan Professor of Genetics at the University of Edinburgh and the Deputy Chair of the Wellcome TrustClick here to read his interview.