You are currently browsing the tag archive for the ‘Michael Greenberg’ tag.

ZylkaHeader

In March of this year, the lab of Michael Greenberg at Harvard Medical School published data showing that the MECP2 gene lowers the expression of genes that are physically long.The scientists found that the MeCP2 protein acts as a dimmer switch, dampening the expression of long genes. When the MeCP2 protein is absent, as in the case of Rett, with no dimmer switch to regulate it, long gene expression goes up. This work suggests that drugs that can rebalance the expression of long genes might have therapeutic benefit in Rett.

Mark Zylka from the University of North Carolina at Chapel Hill, working independently on a non-Rett project, discovered that a class of drugs called topoisomerase inhibitors reduces the expression of long genes. Almost by accident, this raised the possibility that this class of drugs could be clinically relevant for Rett. One such drug is topotecan which is FDA approved for cancer. The Greenberg lab is now testing Topotecan in Rett mice models.

However, Topotecan may not be the ideal drug since it doesn’t get into the brain easily and would be toxic for long term use. As a result, RSRT has awarded Mark Zylka $400,000 to screen for other compounds that can rebalance expression of long genes safely.

Advertisements

Every cell in our body contains the same genes. Yet a brain cell is distinctly different from a heart cell or a liver cell. What differentiates these cells are the genes that are either silenced or active and the degree of activation of the genes, also known as expression.

Scientists have known for many years that the “Rett protein”, MeCP2, regulates the expression of other genes. The big question has been, which genes?

Michael Greenberg of Harvard University, and his lab members Harrison Gabel and Benyam Kinde, may have an answer: long genes. The journal, Nature, is publishing this finding today.

Genes are made up of nucleotides (think back to high school biology: A,T,C,G) The average gene has about 20,000 nucleotides, but some have as many as a million. The scientists in the Greenberg lab found that the MeCP2 protein acts as a dimmer switch, dampening the expression of long genes. When the MeCP2 protein is absent, as in the case of Rett, with no dimmer switch to regulate it, long gene expression goes up. Any deviation from the normal expression pattern causes problems.

From this finding, the scientists suggest that Rett Syndrome may be caused by a widespread overexpression of long genes.

You may be asking yourself, why does this matter? It matters because there is a drug that can rebalance the expression levels of long genes. The Greenberg lab has already tested this drug in cells missing the MeCP2 protein with encouraging results. Experiments are now underway to test the drug in Rett mice.

This is a promising development. We are providing the following resources to help you understand the progress being reported today.

press

 
 
 
 
 

Animation of Findings

 

Interview with Greenberg Lab Members

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)
gabel
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.

adrian-bird

Adrian Bird (left) and Matt Lyst
University of Edinburgh

michael-greenberg

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

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

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


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.