by Monica Coenraads

This past November in a peaceful New York City suburb, twenty-eight scientists gathered for a three-day meeting organized and sponsored by RSRT.

In the age of email and Skype and webinars and GoToMeeting and a plethora of ways to connect people from across the world with a click of a mouse why does RSRT spend hard-earned money to bring scientists together for face-to-face meetings?


Science Magazine Editor-in-Chief, Bruce Alberts, addresses this question beautifully in a recent editorial. “Part of the answer is that science works best when there is a deep mutual trust and understanding between the collaborators, which is hard to develop from a distance. But most important is the critical role that face-to-face scientific meetings play in stimulating a random collision of ideas and approaches. The best new science occurs when someone combines the knowledge gained by other scientists in non-obvious ways to create a new understanding of how the world works. A successful scientist needs to deeply believe, whatever the problem being tackled, that there is always a better way to approach that problem than the path currently being taken. The scientist is then constantly on the alert for new paths to take in his or her work, which is essential for making breakthroughs. Thus, as much as possible, scientific meetings should be designed to expose the attendees to ways of thinking and techniques that are different from the ones that they already know.”

I’ve organized dozens of scientific meetings since 1999. In recent years I’ve come to favor small, invitation-only meetings on clearly defined topics, hosted in quiet locations far away from distractions. I find that more intimate and focused meetings catalyze deeper discussions and are better equipped to ensure participants of confidentiality, allowing them to share data long before publication, a process that can unfortunately take many months and sometimes years.


The success of a meeting is measured in part by how effectively the exchange of ideas, scientific tools and ensuing projects and collaborations move the field forward. It may take considerable time for the impact of a meeting to be known. Sometimes, however, success is instantaneous, with collaborations initiated before the meeting has even concluded.  The concept for the modifier screen currently underway in the lab of Monica Justice, in which we have invested $1.5 MM, was born at a meeting I organized a number of years ago. The MECP2 Consortium evolved from interactions between Gail Mandel, Mike Greenberg and Adrian Bird at our science meetings over the last decade.


As the Rett/MECP2 field has matured, so has the nature of the science meetings. This year we heard a large number of presentations with clinical relevance; that certainly was not the case even a few short years ago. Where will the research take us in the next few years? I can’t wait to find out.

facebook  View our Facebook album to see all the pictures from the meeting and to put names to the faces.

Photo credit:  Kevin Coloton


by Monica Coenraads



monica-chelseaFor almost 15 years now, I’ve been immersed in the science behind Rett Syndrome. As Executive Director of RSRT I understand that the work is methodical, that good research takes time, that breakthroughs often come after many tiny, incremental steps. And yet, as a mother witnessing my 16-year-old daughter deteriorate a little more each year, I feel a great urgency to push the research harder and faster. All families with intimate, daily experiences of Rett Syndrome’s harsh rule know the longing for their children to be free and well. RSRT is one-hundred-per-cent focused on that ultimate goal – and that’s what guides our choices about where to invest not just our hard-won funds but our hopes and dreams.

2012 gave us reason to be hopeful. We are grateful for the active engagement of our trustees, the unwavering commitment of the families who fundraise for us and the generous contribution of a wide range of people who give their time and talents freely to help us achieve our goal. We wouldn’t be where we are without the unique global partnerships that we enjoy with Rett Syndrome Research Trust UK and the Rett Syndrome Research & Treatment Foundation (Israel), and with national organizations such as GP2C, Kate Foundation, RMRA. Together you have produced an investment in science that will create a better future for our children.

But that future won’t just happen. Before Rett entered my life, I had never given much thought to the drug development process. Like most people, I assumed that academic scientists, industry and government worked together seamlessly to discover effective therapies for the horrible ailments that afflict us.  Nothing could be further from the truth.

There is no “Department of Cures.” Laboratory breakthroughs don’t naturally bubble up and become drugs.  The reality is that progress must be relentlessly driven, managed, nurtured and prodded, not to mention funded. It’s a messy, difficult and expensive process that can be slowed and derailed by a multitude of hurdles.

Disease-specific organizations such as RSRT cannot afford to be spectators, passively reviewing proposals and granting money. It is incumbent on us to set the research agenda and to facilitate its execution while staying nimble and vigilant to new opportunities.

Two such opportunities would not currently exist without RSRT: reactivating the silent MECP2 on the inactive X chromosome, and gene modifiers.  Following the 2007 reversal, RSRT carefully evaluated the state of Rett research and made the decision to champion these explorations before others had even realized they were, in fact, promising approaches.

Will they lead to a cure? Ongoing research and clinical trials will tell. But in the meantime, RSRT will continue to encourage and support the research that holds the greatest promise to truly change our daughter’s lives.  For we have the most to win if we succeed, and the most to lose if we fail.




There is no mystery about why a girl suffers from Rett Syndrome. The cause is that mutated copy of the MECP2 gene inhabiting her every cell.  But since MECP2 is on the X chromosome and all females have two X’s, beside each mutated gene rests a healthy but silenced twin. What if we could replace the flawed gene with its perfect counterpart?

That’s the question Ben Philpot of the University of North Carolina at Chapel Hill has asked. RSRT has awarded Philpot, Bryan Roth and Terry Magnuson $2.2 million to answer it.

Philpot’s recent paper in Nature describes successful reactivation of the silenced gene in Angelman Syndrome, demonstrating that replacement is possible.

Joining Philpot and Roth in this effort is Terry Magnusson, a world-renowned leader in X-inactivation. The award will fund a team of three full-time post-docs and two technicians.


The goals of the 3-year project include:

  • Screening of 24,000 compounds
  • Performing whole genome analyses to test for drug specificity to help predict potential side effects (e.g. what other genes might be affected by the drug)
  • Identifying the mechanism of MECP2 unsilencing, which will allow the prediction and design of additional therapeutic targets
  • Optimizing drug efficacy through medicinal chemistry (e.g. by designing drugs to maximize transit through the blood-brain-barrier while minimizing off-target effects)
  • Advancing lead candidates into preclinical trials.  The project will be milestone-driven, with a set of pre-established deliverables. This will allow us to monitor progress utilizing a team of advisors with relevant expertise.

Interview with Benjamin Philpot Ph.D. from RSRT on Vimeo.


Along with activating the silent MECP2, RSRT has championed a second exciting approach.

In her Baylor College of Medicine laboratory, Monica Justice set out to identify modifier genes – altered genes able to dampen the ill effects of an MECP2 mutation.

The common belief has been that these genes would be hard to find.  The reality? With the screen just 15% complete, Justice has already found five. What she is seeing in mice implies that Rett-like symptoms are unstable, and consequently easier to revert to a normal state than anyone had suspected.

None of the modifier genes can suppress the disease entirely, but each reduces a subset of Rett-like symptoms.  While we had originally thought that the modifiers were specific to the central nervous system, it turns out they may operate elsewhere in the body. At least one of the modifiers suggests an alternative therapeutic target, using drugs already FDA-approved.  With RSRT funding Justice is now testing the drugs in mice and has a manuscript currently under review.  A clinical trial is being explored.


At RSRT we’re excited about will happen once the screen is completed. Justice is likely to find many more modifiers, some of which may point to tractable pathways. In support of this goal, RSRT has committed an additional $800K to the Justice lab, bringing its total commitment to the modifier screen to $1.5 million. This funding should provide sufficient resources to allow Dr. Justice to reach the 50 percent mark in the screen within two years – at which point she will propose a plan to us for completing the project. Many more modifiers await discovery. Further surprises are likely in store.


We have also awarded funding of $720K to the lab of Jonathan Kipnis at the University of Virginia. Kipnis and colleagues hope to gain better understanding of the immune system’s involvement in Rett by analyzing patient blood.  The hope is that immune-based therapies can be developed.


Previous work from the Kipnis lab suggested that bone marrow transplants could be beneficial. Before proceeding to clinical trials with a procedure that is extremely serious and risky, RSRT committed funding in 2012 for independent corroboration of these findings.


We are also supporting Huda Zoghbi’s work to explore whether symptoms of the MECP2 Duplication Syndrome can be reversed once the protein level is normalized. $236K was awarded to this project via the MECP2 Duplication Syndrome Fund through the fundraising efforts of the duplication/triplication families.



RSRT is supporting work at John Bissonnette’s lab at OHSU (Oregon Health & Science University) to explore serotonin 1a agonists for their ability to reduce apneas, and Andrew Pieper’s lab at UTSW (University of Texas – Southwestern) for ongoing drug screening.


Finally an award of $65K was made to Dr. Sasha Djukic for her work at the Tri-State Rett Syndrome Center in the Bronx, NY with the majority of the funds coming from the annual Reverse Rett NYC event.


Please join me in wishing all of our scientists Godspeed. I look forward to keeping you apprised of their progress.  One last heartfelt thank you to everyone who raises research funds for RSRT. These projects are your money and your effort at work.

Photo credit: Kevin Coloton


A non-scientific magazine, The New Yorker, recently published a great article by NYU professor, Gary Marcus, on some of the challenges facing science and suggestions on how to tackle them.  It’s an informative article and relevant to anyone who has a vested interest in disease research.

Cleaning Up Science
by Gary Marcus

A lot of scientists have been busted recently for making up data and fudging statistics. One case involves a Harvard professor who I once knew and worked with; another a Dutch social psychologist who made up results by the bushel. Medicine, too, has seen a rash of scientific foul play; perhaps most notably, the dubious idea that vaccines could cause autism appears to have been a hoax perpetrated by a scientific cheat. A blog called RetractionWatch publishes depressing notices, almost daily. One recent post mentioned that a peer-review site had been hacked; others detail misconduct in dentistry, cancer research, and neuroscience. And that’s just in the last week.

Even if cases of scientific fraud and misconduct were simply ignored, my field (and several other fields of science, including medicine) would still be in turmoil. One recent examination of fifty-three medical studies found that further research was unable to replicate forty-seven of them.

Read article in its entirety.


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.



Podcast with Skirmantas Kriaucionis


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.


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

HHMI Press Release


The current issue of Businesweek includes an interesting article on the challenges of drug discovery.  The quote from Margaret Anderson really resonates “The challenge in medical research is that there ultimately is no one in charge.”  In one simple sentence she gets to the root of why RSRT and other disease specific non-profits exist:  someone needs to be in charge!

Illustration by 731; Pills: Dwight Eschliman/Getty Images  |  One out of every 5,000 to 10,000 potential treatments discovered in the lab makes it to market.

Illustration by 731; Pills: Dwight Eschliman/Getty Images | One out of every 5,000 to 10,000 potential treatments discovered in the lab makes it to market.

Speeding Up the Discovery of Drugs

By on November 29, 2012  |  Businessweek

When Scott Johnson read an article about a potential breakthrough that restored nerve function in mice with multiple sclerosis, he assumed it would soon be turned into a treatment. That was in 2001. Johnson, who was diagnosed with MS at age 20 in 1976, is still waiting.

A Silicon Valley entrepreneur who has led startups in areas as diverse as food processing and simulated helicopter flights, Johnson founded the Myelin Repair Foundation in 2002 with the goal of halving the time it takes to develop new MS treatments. Now he’s part of a growing movement to fix the messy, uncoordinated way new medicines are created. “I realized that it was literally a totally dysfunctional system,” says Johnson. “It’s not surprising no drugs come out.”

The distance between a scientific discovery and a commercial treatment is known in the drug industry as the “valley of death,” and that’s where most medical innovations end up. For every 5,000 to 10,000 potential treatments discovered in the lab, only one makes it to market, according to the Pharmaceutical Research and Manufacturers of America (PhRMA), the drug industry lobby. And while total spending on research and development by the industry and the National Institutes of Health has increased from about $50.3 billion in 2001 to $80.4 billion in 2011, according to PhRMA data, the number of new drugs approved each year has remained roughly constant at 20 to 30.

“The challenge in medical research is that there ultimately is no one in charge,” says Margaret Anderson, executive director of FasterCures, a Washington nonprofit trying to speed up medical breakthroughs. “It’s not like building the atomic bomb or mapping the genome, those big scientific projects where there was one goal everybody’s trying to get to.”



This week’s issue of Nature contains a provocative article (see below)  suggesting that the National Institutes of Health is missing the mark by funding “safe” science rather than novel and potentially game-changing research.  The claim is hardly new.  In fact scientists often joke that in order to get NIH funding one needs to have already completed the experiments and have data in hand.  The Nature article now backs up the charge with data of its own –  the majority of the nation’s most influential scientists are not receiving NIH funding.  Why this is happening may be easy to explain. How to fix it is likely to be problematic.

While this issue will be the topic of ongoing discussions for months and years to come at NIH, Congress and academic institutions around the country one thing is starkly clear: there is a great need for organizations like RSRT that do not shy away from high-risk projects.


“Capecchi got the grant and put all the money into the part the reviewers discouraged. “If nothing happened, I’d be sweeping floors now,” he said. Instead, he discovered how to disable specific genes in animals and shared the 2007 Nobel Prize for medicine for it.”

“Conformity,” “mediocrity” win biomedical funding, say critics
By Sharon Begley for Reuters

NEW YORK (Reuters) – Accusations that the leading U.S. funders of biomedical research “ignore truly innovative thinkers” and “encourage conformity if not mediocrity” are seldom heard in the polite precincts of top science journals. Yet they are front and center in a paper published Wednesday in the journal Nature, which concludes that fewer than half of America’s most influential and productive biomedical scientists now receive funding from the National Institutes of Health.

Critics have long argued that NIH, which spends some $30 billion a year on biomedical research at universities and medical centers worldwide, funds conventional, incremental science rather than swing-for-the-fences studies more likely to produce breakthroughs. But the new analysis goes further: It marshals data to show that U.S. biomedical researchers who make the most influential discoveries are not getting NIH support.

“I was astonished” by the findings,” said Jack Dixon, vice president and chief scientific officer of the nonprofit Howard Hughes Medical Institute (HHMI), who was not involved in the study. “It’s just amazing that most of NIH’s $30 billion is going to scientists who haven’t had the greatest impact.” (continue reading on


by Kelly Rae Chi

In September of 2011, RSRT met with the National Institute of Neurological Disorders (NINDS) and other public and private organizations that fund Rett Syndrome research to discuss crucial knowledge gaps in the field. The main findings of the workshop were published recently in Disease Models & Mechanisms.

In particular, the meeting focused on how the research community can improve its chances of success in clinical trials. Preclinical studies require a huge investment of time and effort studying disease in rodent models. Even then, for a variety of reasons, drugs that show promise in preclinical studies will often fail in the clinic.

Here are a few big hurdles in preclinical animal studies — some that are specific to Rett research — and how experts are meeting those challenges.

1. Studying female mouse models of Rett.

“It’s important that when we do a drug trial, that we really impact features that are clinically meaningful, features that are going to impact patients,” Huda Zoghbi of the Baylor College of Medicine in Houston, Texas, told RSRT in a recent interview.

Like girls with Rett, however, female mouse models of the disorder vary in the type and severity of their symptoms, which makes them harder to study than males.

That’s because the gene missing or mutated in Rett, MECP2, is located on the X chromosome.  Female mice — which, like girls, have two X chromosomes, only one of which is active — will have either mutated protein or normal protein levels, depending on which copy is expressed in the cell. Rarely are they missing all of their MeCP2 protein.

In contrast, male mouse models missing the Rett gene have no protein at all. Although these mice have paved the way in understanding the protein’s role in the brain, when it comes to treating Rett, results from studies of male mouse models may not be the ideal model to work with.

More researchers are turning to female mouse models. Zoghbi and Rodney Samaco, also at Baylor, for example, published a study in October in Human Molecular Genetics, describing two different female mouse models of Rett in detail. Detailed characterization of these mice will help lay the groundwork for preclinical studies.

2. Unknowns about how an animal’s environment affects therapeutic efficacy.

No two research labs are alike. The ways in which they differ, including animals’ access to food, housing, lighting or other environmental factors, might well influence an animal’s response to a drug.

What’s more, an individual mouse’s genetic environment — meaning the genetic background on which Rett mutations are made — affects some of its symptoms, such as obesity and abnormalities in social behavior. These genetic differences may also affect how animals respond to treatment.

Variability in genetic and environmental conditions plague scientists studying many conditions, not just Rett syndrome. One way to help address this obstacle, according to Rett researchers in the Disease Models & Mechanisms workshop summary, is to study symptoms and potential therapies across a variety of models and in many lab settings. Those mouse models that show consistent results across different environments will be most useful for translational studies.

3.  Recapitulating speech problems in mice.

Of the many symptoms seen in Rett, loss of speech is among the most challenging to study in a mouse model. Some groups have shown that Rett mouse pups produce unusual vocalizations when they’re separated from their mothers in early postnatal life. These sounds are either more or less frequent than in healthy controls, depending on the mouse model studied. Future work will need to sort out these conflicting results and identify a mouse model that best captures this hallmark symptom of Rett, researchers say.

4. Avoiding bias, which can prevent preclinical errors.

Unintended biases can creep into animal studies. This can lead researchers to conclude a treatment is effective when it isn’t, or it can cause overestimations of a drug’s efficacy.

In recent years, researchers across numerous fields have stepped up efforts to improve study rigor. In June of this year, NINDS convened a panel of scientists, funders and journal editors to talk about how researchers can do a better job reporting methods in preclinical animal studies; both in grant applications and journal publications. At the very least, the panel concluded in a perspective published October in Nature, researchers should report on the following practices:

  • Randomization, where animals are randomly assigned to receive either treatment or placebo;
  • Blinding, where researchers doing the experiments or analyzing the data are unaware of whether of which animals are receiving treatment or placebo;
  • Sample-size estimation, a calculation of an appropriate sample size at the study’s outset;
  • And how data is handled, for example, deciding on study’s primary endpoints, or how to handle missing data points or outliers, before starting the study.

Not reporting such details has, in the past, been linked to overestimations of therapeutic efficacy, according to the NINDS report.

Now Rett researchers have added their voices to the mix in the Disease Models & Mechanisms report, voicing their support of NINDS’s recommendations and emphasizing the need for rigorous experimental design.

by Monica Coenraads

In January of this year a gentleman who has a granddaughter with Rett Syndrome introduced me to his neighbor, David Scheer, a 31-year veteran of the life sciences industry. I was eager to meet David, whose entrepreneurial focus lies at the intersection of finance and science. Our planned hour of conversation turned into a three-hour discussion as we delved into David’s network, experiences, and the potential synergies we might explore. Over the past 9 months I’ve come to rely on David’s insights, perspective and advice. I’m delighted that he has agreed to serve on RSRT’s Professional Advisory Council and look forward to working closely with him on our drug development strategies.

MC: David, please start us off by telling us a bit about your background.

DS: I began with an undergraduate degree in biochemical sciences from Harvard and went on to study cell and molecular biology and pharmacology at Yale. While in graduate school during the early 80’s, I started doing consulting work in the emergent fields of molecular biology and biotechnology. This became a life sciences consulting practice that brought together venture capital, transactional advisory services, and corporate strategy. Scheer & Company is best known for having launched a series of companies spanning the fields of infectious disease, cardiology, oncology, and neurology, to name a few. We’ve had some pretty significant successes among the entrepreneurial enterprises we have launched and built. One of our companies launched a product that was ultimately acquired by Johnson & Johnson; another, a company called Esperion Therapeutics, developed a product in HDL (good cholesterol) therapeutics which was sold to Pfizer in 2004 for $1.3 billion. In the roles of founder and director of numerous companies, I have been involved in identifying technology, recruiting people and raising capital. In most of my more recent companies, I have served as Chairman of the Board.

MC: David, one of your companies, Aegerion Pharmaceutical, operates in the ultra-orphan disease world. Can you tell us a bit about that company?

DS: Aegerion has developed a drug for a very rare disease present in only one in a million people: Homozygous Familial Hypercholesterolemia (HoFH). The disease causes very high bad cholesterol that confers high risk for cardiac events like strokes or heart attacks, even in individuals as young as teenagers, for those who are untreated. We are pursuing approval with both FDA and European regulatory authorities, and we have put in place management and commercial infrastructures in the US and Europe to make the drug available to patients in need, when there is the proverbial regulatory green light. As Chairman of the Board of this company, I have become quite interested in the area of rare diseases.

MC: Lately, pharmaceutical companies seem to all be starting rare disease initiatives. This is in stark contrast to the traditional focus on blockbuster and “me-too” drugs. What is driving this change?

DS: The traditional view has been if there are not enough patients, it’s not really worth developing a drug. However, pioneering companies such as Genzyme, BioMarin, and more recently, Alexion, have successfully developed life-saving drugs to treat rare diseases while providing a return on investment for their shareholders. In so doing, they have opened the eyes of people in the pharmaceutical industry. This shift holds clear potential for organizations working toward the development of therapies for rare diseases, such as the Rett Syndrome Research Trust.

I suspect that rare diseases may also provide an easier path for drug approval. Much of the cost of drug development comes at the end, during the extremely large and expensive clinical trials that are needed for blockbuster drugs. In the rare-disease space, due to the small population sizes, trials will be much smaller, and therefore less expensive. Also, the regulatory process may be fast-tracked for a rare disease, as the FDA recognizes the enormous unmet need and cooperates with sponsors and patient advocates to provide new agents sooner.

So interest in innovation in the rare disease category has turned bullish, which makes this an exciting time for someone engaged in your work, Monica, and frankly also for people like me who are really interested in efficient and effective development of new drugs.

MC: Are large pharmaceutical companies set up to tackle drug development for rare diseases?

DS: I think the answer depends on the drug company. The bulk of the rare-disease experience in drug development has traditionally come from innovative smaller companies. For example, Genzyme, which started off as an idea on the back of an envelope, became a multimillion-dollar pharmaceutical company with a large number of products in its portfolio, and was recently acquired by Sanofi-Aventis. Sanofi now has a franchise that is very capable and active in the rare-disease field. Other companies have either built from scratch, made smaller acquisitions, or are making partnerships or deals with companies that have assets or programs in rare-disease drug development. Pfizer and GlaxoSmithKline have done this, and both now have rare-disease units.
I think it is too early to predict the success of these larger companies. Can the big companies be as effective as some of the smaller companies have been? Will the entrepreneurial spirit of a Genzyme in the early days be retained or lost as part of a larger company? We shall see.

MC: How do FDA drug reviews for a rare disease differ from those for a common one?

DS: The FDA has really had to modify its approaches to adapt to the needs of the rare-disease community. In fact, there is an orphan-disease unit within the FDA that is specifically tasked to review rare-disease drugs. These people are very familiar with how to evaluate a drug through a very different lens than is ordinarily used. It is important to keep in mind that regulatory decisions are always based on a favorable risk-benefit relationship.

MC: The Rett community, including families, clinicians and researchers, is highly concerned—-and properly so—with rigorous validation of pre-clinical advances and the complexities of developing solid protocols for outcome measures. Though Rett patients are a small population, the range of symptoms is staggering, so there are many issues to address.

DS: There are no perfect drugs – even Tylenol can have dreadful side effects if taken in excess, such as liver failure. The FDA must balance the solemn task of making available new and important therapies, while ensuring that such agents demonstrate safety and efficacy commensurate with the condition being treated.

MC: You were only recently introduced to Rett. What have you found most interesting thus far?

DS: That it has attracted some very talented individuals. The scientists, thought-leaders, and patient advocates involved in Rett Syndrome research represent an incredibly impressive group. Perhaps this is because Rett Syndrome is believed to be scientifically very tractable. It certainly helps that it is a single-gene disorder. The number of chronic conditions that can be attributed to a single gene is relatively low. So if I may say this, those in need of therapeutics for Rett Syndrome, may be fortunate in that there is an important foundation for discovery of potentially novel, disease-modifying therapeutics.

MC: I think the 2007 proof-of-concept reversal has also helped put Rett on the map; it had been a much more obscure disorder before that breakthrough.

DS: I agree. Each year in my not-for-profit work, I organize and chair a conference in New Haven, in conjunction with Yale and the Long Wharf Theater, called Global Health and the Arts,. For the past four years, this conference has promoted examination of important disease topics in public health and global health. This past May, we explored the neuropsychiatric disease arena. We had a major scientific symposium, with some of the most well known academic and industrial thought leaders from around the world, who were able to give us an update on relevant areas of science and technology, drug development, genetics, genomics, and translational medicine. In the middle of this event we actually had several individuals comment on the importance of the work being done in Rett and related disorders.

Monica, you need to continue doing what you do so well: ensure you have the best information from scientists at the cutting edge of this field, and then position that knowledge in a way it can be most effectively translatable. The more quickly drug development gurus can bring their expertise to the table, the better the chances of a successful outcome. I am very much looking forward to help you achieve that success.

MC: Thank you, David, and on behalf of every Rett family, welcome.


Ever wondered why most labs use male Rett mice for their experiments even though the females are the better model? What human symptoms are replicated in the Rett mice? What are some of the surprises these mice have in store for us? What are the complexities of doing well-designed and executed trials in mice? What are some of the pitfalls that the Rett field needs to avoid? What is the potential for the newly unveiled Rett rat? Listen and find out….

This past week, more than 30,000 neuroscientists convened in New Orleans for the annual Society for Neuroscience meeting. Here are some of their interesting (unpublished) findings on Rett Syndrome.

Rett rats

Recent progress in genetic engineering has made it possible to model Rett Syndrome in rats – whose behavior is easier to study than mice. Researchers led by Richard Paylor from the Baylor College of Medicine in Houston, Texas, designed a set of behavioral tests to capture the animals’ social interest, anxiety, vocalizations and sensory and motor abilities. The team found that male rats whose Mecp2 (the gene that is missing or mutated in girls with Rett Syndrome) is disrupted were less active, showed impairments in a memory task, and behaved in a way that suggested they have disrupted connections between sensory and motor brain areas.

IGF-1 on trial

Researchers administered a full-length version of insulin-like growth factor 1 (IGF-1) — which is now under clinical investigation for treating Rett Syndrome — to mice lacking Mecp2. This particular form of IGF-1 boosted neuron-to-neuron signaling and the ability of neural connections to change in strength, compared with untreated mutant mice. According to a report by, however, treatment did not improve mutant mice’s performance on a task of motor coordination and learning.

In a separate study of mutant mice, led by Jeffrey Neul’s team at Baylor, scientists administered a slow-release form of IGF-1, or PEG-IGF1, finding that it only slightly lengthened lifespan but did not improve heart rate, body temperature, breathing, motor function, or behavior. And a higher dose of PEG-IGF1 cut the lifespan of mice, the group found.

Neul is planning a clinical trial in adult women with Rett with a shorter, tripeptide form of IGF-1, which in 2009 scientists found delayed the onset of several symptoms of the disorder in a mouse model.

Selective expression

In 2010, Huda Zoghbi and her colleagues at Baylor showed that neurons that dampen brain signals through their production of the inhibitory chemical GABA (gamma-aminobutyric acid) play an important role in the development of Rett.

For a preliminary study presented this week, Zoghbi’s group found that reactivating Mecp2 expression exclusively in GABA neurons well into adulthood (6 and 9 weeks) improved two symptoms of Rett — obesity and ataxia — in male mice missing Mecp2. Her group is also measuring cognitive and breathing symptoms after selectively reactivating the gene in GABA neurons.

Reprogrammed Rett cells

Alysson Muotri at the Scripps Research Institute in La Jolla and his collaborators took cells from human males with Rett and converted them into induced pluripotent stem (iPS) cells, which have the ability to form any other cell in the body.

The group found that several molecular signaling pathways differ between the iPS cells of healthy people and individuals with Rett as their cells begin to form neurons. These early changes may underlie neuronal features of Rett. The scientists are working to validate the biochemistry, but report that the new findings suggest that iPS cells derived from people with Rett may help identify new drug targets.

Progress on point mutations

Two years ago, researchers from the Barrow Neurological Institute in Phoenix, Arizona, described a new Mecp2 mouse — the A140V model —that reproduces a point mutation (meaning a single “letter” of the DNA code is replaced).

Male mice with the mutation survive, though they have X-linked mental retardation and show some brain abnormalities — such as less intricate neuronal branching and more tightly packed cells – compared with healthy mice. Unlike other mutants, however, the A140V has a normal lifespan and weight gain and no seizures or trouble breathing. The same group presented a detailed protocol to characterize the shape and size of brain cells of female mice that carry the mutation.

Monica Coenraads, Executive Director of the Rett Syndrome Research Trust, interviews David Katz, PhD about his Journal of Neuroscience paper published 10/3/2012 and entitled “Brain Activity Mapping in Mecp2 Mutant Mice Reveals Functional Deficits in Forebrain Circuits, Including Key Nodes in the Default Mode Network, that are Reversed with Ketamine Treatment.”

David Katz Interview from RSRT on Vimeo.

Yesterday (October 8) Shinya Yamanaka of the University of Kyoto, Japan, was awarded the 2012 Nobel Prize in Physiology or Medicine for his discovery that a person’s cells can be reprogrammed to pluripotency – meaning they have the ability to form most other cell types in the body. Yamanaka shares the prize with John B. Gurdon of the Gurdon Institute in Cambridge, UK, who is known as the “godfather of cloning.”

After stem cells were initially isolated from mice, Yamanaka’s team found four genes that, in combination, could be introduced to adult cells to turn them into embryonic-like cells. The resulting so-called induced pluripotent stem (iPS) cells could in turn be coaxed into mature cell types such as neurons and gut cells. Yamanaka’s findings, published in 2006, gave way to new cell-based models diabetes, Parkinson’s disease, and other disorders.

Yamanaka’s reprogramming technique has also allowed researchers to study the early development of neurons derived from people with Rett syndrome. In 2010, Alysson Muotri’s research group at the University of California, San Diego, turned skin cells from people with Rett into pluripotent stem cells using Yamanaka’s methods.

“The data is already revealing a new biology,” writes Muotri in an email. The group has uncovered differences between human Rett neurons and those derived from animal models of the disorder, for example. “I believe this is a complementary new tool that will allow us to understand the molecular and cellular mechanism leading to the Rett condition,” he adds.

Importantly, Yamanaka’s fundamental discovery and the subsequent iPS cell work on Rett syndrome will also speed drug discovery, by allowing researchers to test candidate medicines directly on human neurons, Muotri says. Yamanaka’s winning the prize was “well deserved,” he adds.

RSRT has an amazing opportunity over the next 2 weeks to show the internet community the importance of Rett Syndrome research.  We have been nominated for a $250,000 grant, and need your support to win.

Any Facebook user, anywhere in the world, can vote.

Voting is open from 9/6 through 9/19. This is not a daily vote.

BONUS VOTE: Share a link to the Chase Community Giving app on your FB timeline and if a friend links back to the app and casts a vote of their own you will earn an extra vote.

SPREAD THE WORD: Ask your friends, family, neighbors and co-workers to vote, too!

CHASE CUSTOMERS: You have 2 extra votes. Just go to, log in, search charities, and cast your ballots!

The charity that gets the most votes over this two-week period will win the money – funds that will be immediately invested in RSRT’s research projects.

It’ll take a few seconds of your time – and could make all the difference.

NOTE: In case of a tie, the winner will be the organization who got the highest number of votes the earliest in the voting period. So…

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.


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.


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.


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.


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.

hotos courtesy of Kevin Coloton


Last month brought me to Houston, Texas to attend a fascinating meeting organized by Huda Zoghbi and Morgan Sheng and co-sponsored by RSRT. Entitled Disorders of Synaptic Dysfunction, the event was the inaugural symposium of the recently established Jan and Dan Duncan Neurological Research Institute, directed by Dr. Zoghbi.

The two-day meeting brought together a heterogeneous group of scientists from academia (senior and junior faculty as well as post-docs and graduate students), industry, NIH and other funding agencies.

The focus was not on  a single disease but rather on a group of disorders (Rett, Angelman, Fragile X, autism, Tuberous Sclerosis) that share a common cellular phenotype: abnormal synapse activity.

It’s no surprise that some of the talks that generated the most buzz came from labs that are doing very clinically relevant research. These include the labs of Mark Bear at MIT, working on Fragile X, and Ben Philpot at UNC whose lab works on Angelman Syndrome.

Like Rett Syndrome, Fragile X is a single gene disorder, caused by mutations in a gene called Fmr1. When Fmr1 is mutated, protein synthesis fails to shut down, leading to excess. Some years ago Dr. Bear proposed that compounds which can block a certain type of receptor, mGluR5 (which triggers the burst of synaptic protein synthesis) might counteract over-expression of protein and thereby cancel out the damaging effect of Fmr1 deficiency. His theory has proved correct, and clinical trials of mGluR5 antagonists are currently ongoing at multiple pharmaceutical companies.

I first met Dr. Bear almost a decade ago, when he was just beginning to formulate what is now commonly known as the mGluR5 theory of Fragile X.  His lab is currently funded by RSRT to explore protein synthesis in the Rett mouse models. Dr. Bear hypothesizes that Rett may be due to under-expression of proteins. If his hypothesis holds up, pharmacological manipulations of mGluR signaling will be pursued.

Ben Philpot’s talk also generated excitement. He discussed a high-throughput screen that has yielded a compound which can activate the silenced Angelman Syndrome gene, UBE3A. Dr. Philpot is currently funded by RSRT to pursue a similar approach for the silent MECP2 gene on the inactive X chromosome.

Mike Greenberg spoke about MECP2 and shared unpublished data that has come about from his collaboration with Adrian Bird via the RSRT funded MECP2 Consortium. (More on that in the months to come.)

Jackie Crawley of the NIH gave a brilliant talk on how “autistic mice” are being characterized to yield a plethora of new information.  For me the highlight of her talk was hearing recordings of mouse “speech”. She shared a variety recordings and I was taken aback by the complexity and richness of the sounds, which left me yearning for an analysis of Rett mouse vocalizations.

After a lively cocktail hour it was back to work with dinner plates in hand. Drs. Zoghbi and Sheng divided the attendees into three working groups: 1) dysfunction of proteins of the synapse 2) dysfunction of nuclear/cytoplasmic proteins 3) young investigators and junior faculty.  Masquerading as a 30-something I happily joined the third group.  I was struck by the fearlessness and boldness of these young scientists. There were not shy about criticizing the status quo and what could be done differently to enhance the research progress. I came away feeling buoyed and reassured that science is in good hands with this new generation.

The following several hours of discussion, led by Rodney Samaco and Mingshan Xue and facilitated by NIMH Director, Tom Insel, were intellectually stimulating and entertaining. Below is a visual output of our intense discussion.

A few personal reflections on the symposium

  • Over and over again throughout the meeting I heard comments from autism researchers such as: “Where would we be without the syndromic autism animal models like Rett and Fragile X? We’ve learned so much from them”.  More than once I found myself thinking that as horrible as Rett is at least the genetics of the disorder are clear-cut – Rett’s silver lining.
  • The meeting provided an opportunity to meet some scientists with whom I had communicated by email and/or phone, but never met in person. People like Pat Levitt, Freda Miller and Michael Palfreyman.  It was a reminder of how many people over the years have taken the time to discuss their work and possible synergies to Rett Syndrome.
  • Drs. Zoghbi and Sheng kept everyone busy from the moment the meeting started to the moment we left, including an intense working dinner. I tend to do the same thing  at meetings that I organize, but always feel like I’m being a bit of a slave driver. Never again, however, will I feel guilty. If Dr. Zoghbi thinks it’s acceptable, then so do I!

Kudos to Drs. Zoghbi and Sheng for a stimulating meeting and thank you both for inviting me.

Science Translational Medicine, which co-organized the meeting, will be publishing a white paper on the proceedings.
RSRT will let you know when the paper is available.

Jonathan Kipnis and his lab members Noel Derecki and James Cronk authored the  recent Nature paper entitled Wild type microglia arrest pathology in a mouse model of Rett Syndrome. Watch the videos below for some insight into what makes them tick.

Jonathan Kipnis, Ph.D.

Noël Derecki, Ph.D.

James Cronk


The recent publication of the Kipnis paper in Nature has generated understandable excitement and questions in the Rett community. Email and Facebook are difficult vehicles for providing proper answers. Rett Syndrome is complex, and so is the research; this work doesn’t lend itself to sound bites. I know Rett mothers and fathers are often tired and overworked, but I encourage you to find fifteen minutes to sit down together with a cup of coffee, listen carefully to what these researchers are discussing in the video interview, and come away more deeply informed.

The paper has already been euphemistically coined the bone marrow transplant paper. I’ve occasionally called it that myself, sometimes in the presence of Dr. Kipnis, who promptly says, “Please don’t call it that. There is so much more information in that paper than just the bone marrow experiments.” He’s right. In fact, there is enough material to have generated multiple publications.

The paper is attracting an unusual amount of attention in the scientific community, and this is bound to stimulate more interest in Rett Syndrome and the role of the immune system in neurological disorders. The bone marrow transplant result is understandably what families gravitate to because of the potential for clinical application, but it’s important not to ignore the other findings, because they too could point to eventual treatments. In fact, it is my fervent hope that in time, new discoveries will make it possible to manipulate the immune system through a safer route.

Bone marrow transplants (BMT) have been used since 1968 to treat an increasingly wide range of disease, including cancers, metabolic diseases, inherited red cell disorders and immune disorders. The treatment can be lifesaving. It can also be fatal. Accompanied by chemotherapy and/or radiation treatment, BMT is a serious and grueling procedure with significant side effects. The combined expertise of specialists in pediatric BMT, as well as in Rett Syndrome,  together with basic scientists is crucial to minimizing risk as much as possible.

As part of a fact-gathering process, RSRT has been facilitating talks between top pediatric transplant centers and Sasha Djukic, Director of the Rett Syndrome Center at the Children’s Hospital at Montefiore, Jonathan Kipnis and his lab members and, most recently, NIH. Discussion includes defining the data needed to consider clinical trials. This must be completed and thoroughly evaluated in order to design the best possible treatment protocol. Independent confirmation of the results achieved by Dr. Kipnis and his team is a standard requirement; this work is already underway. Further experiments in the Kipnis lab itself are ongoing, and we can expect more new information to emerge.

It is perhaps timely for me to reiterate that RSRT is very aggressive about research, and conservative about clinical application. I want to be crystal clear on one thing – parents should not take it upon themselves to pursue BMT for their child. As the mother of a severely afflicted daughter, I understand all too well the desperation for treatment. As Executive Director of RSRT, I understand equally well the importance of applying meticulous due diligence. RSRT does this in all the work we undertake, the projects we review, our financial decisions, and certainly in our approach to clinical trials.

I share your excitement, your urgency and your trepidation, and RSRT will continue to inform you of new developments as they unfold.

– Monica Coenraads
Executive Director, RSRT


Click Here to Read Press Release

A paper published online today in the high-profile journal, Nature, describes the results of using a bone marrow transplant to dramatically stop the development of symptoms in pre-symptomatic male and female mouse models of Rett Syndrome.  The work was undertaken in the neuroimmunology laboratory of Jonathan Kipnis, Ph.D. and his team at the University of Virginia.

That a bone marrow transplant could arrest such a severe neurological syndrome such as Rett is quite unexpected and provides us with yet another strong example of how tractable this disorder appears to be – at least in the animal models.   Experiments are now underway in the Kipnis lab to test whether reversal of advanced symptoms via bone marrow transplants and other modulation of the immune system is also possible.

This work was funded by the Rett Syndrome Research Trust and the Rett Syndrome Research Trust UK.

Jonathan Kipnis and Noël Derecki

Jim Cronk and Noël Derecki

The clinical relevancy of this work makes this paper of obvious and significant interest. But the authors don’t stop there. The paper describes data that could help us better understand how MeCP2 deficiency leads to symptoms.  They introduce the concept of a powerful connection between the immune system and Rett Syndrome and open the door not only to bone marrow transplants as a treatment modality but potentially to other immune therapies as well.

To help you understand the key findings and implications we invite you to watch the videos below. Please watch the animation of the experiments first followed by the interview.

We would like to take this opportunity to thank Jeff Canavan of NewsAnimation for volunteering his time and effort to create the beautiful animation below. Jeff has a daughter with Rett Syndrome and founded, with his wife Sarah, the Kate Foundation for Rett Syndrome Research.


We thank Jeff Bemiss for donating his filmmaking expertise, substantial time, energy, equipment and editing resources to film the interview below. He comes to our cause through his friendship with the Canavan family.


A recent issue of BioWorld Insight, the weekly newsletter that provides behind-the-scenes analysis and commentary on the biotechnology industry, included a feature article on Rett Syndrome.  The piece explored how recent interest in rare diseases on the part of pharmaceutical/biotech industry may impact research in disorders such as Rett Syndrome and Fragile X.

Science, Rare Disease Push Help Developmental Disorders

By Anette Breindl
Science Editor

In its last issue of the year, Science – one of the premier  journals for peer-reviewed scientific research – published both what it considers to be the biggest breakthrough of the past year, and areas to watch for the next year. For 2012, one of those hopeful areas was “treating intellectual disability.”

According to the story, “the cognitive deficits and behavioral problems caused by Rett, Fragile X and Down syndromes have long been considered irreversible. In each syndrome, a genetic glitch causes brain development to go awry even before birth. But recent work with mouse models of those conditions suggests, remarkably, that some cognitive and behavioral symptoms may be reversible.”

For Rett syndrome, Monica Coenraads traces the realization that developmental disorders do not necessarily mean a lifetime of disability, to a paper published almost exactly five years ago, in the Feb. 8, 2007, issue of Science. In that paper, researchers reported that when they replaced the mutated MeCP2 protein with a normal one in adult mice with full-blown Rett syndrome – animals whose life expectancy without medical intervention could be measured in days – the mice could be rescued, and many of their symptoms reversed.

Posted with the permission of AHC Media, publishers of BioWorld Insight,

Professor Adrian Bird needs no introduction to anyone who follows Rett Syndrome research. His list of accomplishments includes discovering the MeCP2 protein, developing multiple animal models for the disease and authoring the seminal 2007 Science paper which introduced the startling concept that Rett Syndrome and other MECP2-related disorders are curable.

He was the Guest of Honor at the Reverse Rett London event hosted by RSRT UK which took place on December 1, 2011. Below is a video of his remarks on the vitality of Rett research, the importance of maintaining global efforts in the field, and the possibilities that lie ahead.


02/10/2012 –

Turning loss into hope, family offers inspiration — and a few lessons about drug discovery

A poignant story in Thursday’s Boston Globe describes how the O’Donnell family of Boston channeled their love of a son, Joey, who died tragically at the age of 12 from cystic fibrosis, into a successful mission to develop impactful new treatments for this terrible affliction.

The narrative – expertly told by Brian McGrory (see here for my favorite example of his wonderful writing) – is a testament to devotion, persistence, the power of parental love, and the resiliency of the human spirit.  It is essential reading for these qualities alone.


Rett Syndrome Research Trust Website

Doris Tulcin – A Mother’s Love Raises the Bar For All Non-Profits

Half a century ago, a mother whose baby daughter was diagnosed with a life-threatening genetic disorder decided to fight it. Doris Tulcin is that mother, and Cystic Fibrosis is the disease against which she went to war. First identified in 1938, Cystic Fibrosis affects roughly 30,000 children and adults in the United States and is therefore, like Rett, classified as a rare disease. In 2010 the Cystic Fibrosis Foundation generated donations in excess of $300 million, $120 million of which was raised from the general public. Now, Vertex Pharmaceutical’s VX-770, the first drug that treats not just symptoms but the underlying genetic cause of Cystic Fibrosis, has been fast-tracked through FDA approval.

Doris Tulcin has been a valued advisor to RSRT since our inception three years ago. The following in an excerpt from a recent conversation between Mrs. Tulcin and RSRT Executive Director, Monica Coenraads.

MC:  Congratulations! You must be thrilled with the early FDA approval—it’s been a long road and I know CF families are rejoicing today!

DT:  It’s mind-blowing!  VX-770 is for a small group of patients that have a rare mutation but will literally change the disease and these kids completely.  And that’s what we are working on now for 90% of the patients with the major mutation.  Things are moving really well.

MC:  CFF provided substantial scientific, financial and clinical support for the development of VX-770, including the investment of $75 million.  When I think about the vast amount of money CFF raises, with a patient population similar to Rett, I can’t help but ask myself, How have you done it?  Are there specific decisions that you think have been pivotal?

DT:  Well, you must remember that we have a long history; we’ve been in business since 1955.  So it took over fifty years to get to where we are today.  Going back in time, it is so hard to pinpoint any one thing.  But we really focused on research, as you are doing.

MC:  Of course, the scientific tools and knowledge that were available fifty years ago are so very different from research today.  Everything has accelerated.  Yet I know that getting to this point with Cystic Fibrosis has been a process with many components.

DT:  From 1980 on is where we really took off with developing research programs with major universities, and by the 1990’s we became increasingly business-oriented and
focused on working with the biomedical community and pharmaceutical companies for drug development.

MC:  As with Rett syndrome, the Cystic Fibrosis population is small.  You know RSRT has a PSA that’s running in Times Square, the same screen that was used for the CFF.  So 1.5 million people will see it every day for three months.  How important do you feel it is to raise general public awareness, in terms of the ability to raise research funds?

DT:  Name recognition is very important.  The general public doesn’t have to understand the disease but they certainly have to recognize the name.  You know, people will say “I’ve heard of Cystic Fibrosis”— well, what do you think it is?  They can’t describe it.  They haven’t the vaguest idea, but they’ve heard of it.

MC:  And you think that correlates to the amount of money you raise?

DT:  I do. Our chapters raise roughly $100 million a year. But keep in mind that it took decades to get where we are today.

MC:  For RSRT, at the three-year mark, most of our revenue comes directly from affected families and their networks.  Do you think the same applies to you, or do you have people just spontaneously donating to CFF without any personal connection?

DT:  I think now we do, yes. But what we started with and built on was indeed that personal commitment and involvement to develop networks of family and friends.  The activism of those who are personally affected is crucial.

MC:  How would you compare the current philanthropic landscape to what you’ve seen in past decades?  These are difficult economic times for many.

DT:  Yes, we are still in a bad economy now and that reflects on contributions, there’s no doubt. It’s tough, and there’s always competition and distraction.

MC:  On a personal note, how is your daughter doing?

DT: Oh, thank God, she’s doing well.  She’s a grandmother!  My grandchildren have introduced me to Facebook, so we communicate in that way, because they’re all grown up and don’t have time for other things. But we do that too with the foundation, we’re on everything you can think of— Facebook, Twitter, YouTube.  Everything now is sent electronically.  The website is being updated all the time, you can get every bit of information at any time off that website.

MC:  Yes, the fact that electronic media is now ubiquitous worldwide has really changed the flow of information in important ways for families dealing with something like a rare disease. The ability to be in instant communication with others who really understand relieves some of the isolating strain of constant and intense caregiving, as well as keeping people informed of current developments. That families can so easily connect and learn from each other is vital and sustaining.  The day-to-day struggles can be so overwhelming sometimes for Rett parents that there’s not always a lot of energy left for what I feel is truly going to change our children’s lives—the research.  What are your thoughts?

DT:  There is no doubt that you really have to find ways to stay focused, and I think that was one of our biggest successes.  Care has been important but it is research that’s absolutely critical; it’s the only way to move forward.

MC:  Research has always been my commitment, and I hope the work of RSRT will prosper as brilliantly as that of the CFF. Congratulations again on VX-770 and
thank you for your guidance and inspiration.

DT:  Monica, I know how tremendously devoted you are to this fight. The Rett community is very blessed to have you.

MC:  Thank you, Doris.


Dear Friends,

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

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

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

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

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

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

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

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

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

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

Monica Coenraads
RSRT Executive Director

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


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

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

I’d like to discuss starting my own event.

I would like to learn more about RSRT and how I might contribute.


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

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

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

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

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

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

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

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

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

MC: Why Rett and why now?

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

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

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

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

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

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

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

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

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

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

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


by Monica Coenraads

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

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

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

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

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

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

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

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

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


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.


From today’s Press Release:

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




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

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

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

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

GM:  Thanks, Monica.

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

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

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

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

Gail Mandel

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

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

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

GM:  That was really the unexpected part.

Dan Lioy

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

MC:  Was this finding surprising?

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

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

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

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

GM: Yes, that’s right.

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

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

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


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

By Monica Coenraads

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

MC:  So there is a way to go.

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

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

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

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

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

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

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

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

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

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

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

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


Huda Zoghbi, M.D.

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

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

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


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

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

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

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

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

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

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

HZ:  You are right. It’s not semantics. I now call Rett a post-natal neurological disorder. Mecp2 is a factor that is critical for the normal function of brain cells. It’s a factor that is constantly needed for normal neurological function and this has implications for therapies.  Therapies will need to be maintained for the long term.

MC:  Your findings have implications for other diseases that are post-natal, like autism.  Can you elaborate?

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

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

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

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

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

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

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

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