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Do superhumans actually exist? Apparently they do, and their DNA could hold the key to solving some of the world’s health problems.

Freakishly strong bones and an alarmingly high pain threshold aren’t the result of falling in a vat of toxic waste, they are caused by genetic mutations. Pharmaceutical companies have not only taken notice, but are investing heavily to produce treatments for a variety of disease indications that could have annual revenue in the billions.

If someone with brittle bones or severe pain can get relief in a pill or an injection, could there be a cure for Rett and other MECP2 disorder unknowingly hidden in someone’s DNA? Twenty years ago, when sequencing DNA took decades and billions of dollars, getting to the answer would have been technologically impossible. But today it’s more than feasible. RSRT is funding several projects in the lab of Monica Justice and Jeffrey Neul aimed at identifying mutations in other genes that make an MECP2 mutation less severe.

Bloomberg Business covered this amazing topic with some great illustrations from Stephanie Davidson.

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

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


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

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

[To share this video on Facebook, etc use this link:]


A video presentation by Monica Coenraads

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

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

As always, I welcome your questions and comments. My email is


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

by Monica Coenraads

Dr. Zoghbi and research assistant

Dr. Zoghbi and research assistant

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

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

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

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

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

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

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

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

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

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

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

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


A video presentation by Monica Coenraads

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

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

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

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

I welcome your thoughts and questions. I can be reached at



A recently published article in the NYT lends support for RSRT’s rationale behind testing FDA approved drugs and compounds in an animal model of Rett Syndrome.

RSRT Project
Sponsor a Drug


With Aid of Drug Library, New Remedies From Old

Some of the more than 3,000 drugs at Johns Hopkins.

Some of the more than 3,000 drugs at Johns Hopkins.

By Kate Murphy
Published: April 27, 2009


Housed in a row of white freezers in a nondescript laboratory at the Johns Hopkins University School of Medicine in Baltimore are more than 3,000 of the estimated 10,000 drugs known to medicine. There is no sign on the door to indicate that this is perhaps the largest public drug library available to researchers interested in finding new uses for old and often forgotten drugs.

Already, researchers have used the library to discover that itraconazole, a drug used for decades to treat toenail fungus, may also inhibit the growth of some kinds of tumors and may forestall macular degeneration. Another drug, clofazimine, used more than a century ago to treat leprosy, may be effective against autoimmune disorders like multiple sclerosis and psoriasis.

“It takes 15 years and costs close to a billion dollars to develop a new drug,” said Jun O. Liu, professor of pharmacology and director of the Johns Hopkins Drug Library. “Why not start with compounds that already have proven safety and efficacy?”

He and his colleagues have been building the collection since 2002 and hope to have it complete by 2011. They acquire the drugs through donations, purchases and sometimes lab synthesis. And they will send researchers a complete set — minuscule amounts of every drug in the library — for $5,000, which covers the cost of shipping and replenishment.

Since the toenail and leprosy drugs are approved for use in the United States and are no longer under patent protection, clinical trials to test their new uses are either under way or close to regulatory approval, Dr. Liu said.

Drugs still under patent protection are more complicated; patent holders seldom allow independent research on alternative uses. “The drug companies haven’t been too keen on helping us,” Dr. Liu said.

There are other drug libraries, both commercial and noncommercial. Commercial suppliers offer considerably fewer drugs than Johns Hopkins (though they may have medicines it does not), and they charge much more. Noncommercial drug libraries include those at the National Institutes of Health; the University of California, San Francisco; and McMaster University in Hamilton, Ontario. But they will usually not send drugs to unaffiliated researchers. And like the commercial libraries, their holdings are smaller and composed largely of compounds from Hopkins.

Regardless of the source, researchers typically order copies of entire collections rather than individual drugs they think may work in their experiments.

“We’ve found drugs that are active in ways no one would have ever hypothesized,” said Marc G. Caron, a professor of cell biology at Duke who is using the Johns Hopkins library to find drugs that might quell the cravings of substance abusers.

Testing of these compounds has become much easier in recent years as a result of an automated technology called H.T.S., for high-throughput screening. The drugs are dissolved in a solution and stored in rectangular, compartmented plates reminiscent of ice trays; they can then be delivered to researchers for testing of their efficacy against various diseases, or disease mechanisms like inflammation.

Computerized droppers, plate agitators and microscope image readers can now accomplish in days what it once took bench scientists years to do.

Although H.T.S. has been around for at least a decade, it is just within the last five years that the technology has been widely available. Previously, only big pharmaceutical companies could afford to screen thousands of compounds; now more public and academic institutions are doing so, and their emphasis tends to be on rediscovering or tweaking the chemical structure of old drugs rather than developing new ones.

“The instrumentation to do sophisticated, large-scale screening of drugs has gotten significantly better and cheaper,” said Michelle Arkin, associate director of the Small Molecule Discovery Center at U.C. San Francisco.

Some institutions, like McMaster in Ontario and Rockefeller University in New York City, allow outside researchers to use their H.T.S. facilities for $10,000 to $20,000, depending on the complexity of the project.

Access to such facilities has increased demand for compounds, particularly already approved and off-patent drugs, to analyze. Johns Hopkins and commercial suppliers report a surge in orders over the last two years — because there are more H.T.S. laboratories, they said, and because of efforts to find cheaper therapies against third world scourges like malaria and tuberculosis.

“Old drugs are the low hanging fruit in terms of finding safe and inexpensive treatments for these diseases,” said Carl Nathan, chairman of microbiology at Weill Cornell Medical College in New York. Dr. Nathan receives plates of drugs from Johns Hopkins as well as commercial suppliers and does high-throughput screening at Rockefeller, which has a partnership with Weill.

“I’m addicted to it,” he said.

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

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

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

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

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

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


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

Nat Heintz, Ph.D.

Nat Heintz, Ph.D.

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

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

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

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

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

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

Skirmantas Kriaucionis, Ph.D.

Skirmantas Kriaucionis, Ph.D.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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



The more we learn about Rett Syndrome and MECP2 the more we are humbled by the complexities. A main function of MECP2 is to silence other genes.  However, the search for these target genes, which began in earnest almost a decade ago, has yielded a paucity of candidates. The most likely, and interesting, candidate, BDNF (brain derived neurotrophic factor), has been implicated in a myriad of neurological disorders. Yet attempts to deliver this trophic factor to the brain have, to date, stumped academic labs as well as pharmaceutical and biotech firms.  MECP2 deficiency seems to create havoc among many neurotransmitter systems (norepinephrine, acetycholine, dopamine, serotonin, substance P) as well as growth factors. Furthermore, MECP2 mutations may change the expression of perhaps thousands of downstream genes.

Despite these challenges the 2007 reversal experiments of Adrian Bird remind us that restoring normal levels of the MeCP2 protein makes the symptoms go away.  Therapeutic approaches aimed at fixing the underlying genetic problem are therefore quite attractive. We don’t necessarily need to understand what MECP2 does in order to explore ways to normalize its expression.

One such approach is to explore turning on the silent MECP2 gene on the inactive X chromosome. All girls have two X chromosomes and they inactivate one very early in development (as the embryo implants into the uterus). Therefore girls with Rett Syndrome have, in every cell in their body, an X chromosome with the mutated MECP2 gene and an X chromosome with the healthy MECP2.  And in every cell one of the two X’s is shut down. In some cells the X chromosome with the healthy MECP2 is activated and the one with the mutated MECP2 is shut down and in other cells it’s the opposite.

Activating the MECP2 on the inactive X could, in theory, cure Rett Syndrome.  RSRT is currently supporting a project in the lab of Antonio Bedalov at Fred Hutchinson Cancer Research Center which will attempt to  identify either drugs/compounds or genes that will activate the silent MECP2.   RSRT is now adding a synergistic project to its portfolio.  Marisa Bartolomei, PhD of the University Of Pennsylvania School Of Medicine was awarded funding from RSRT to identify the mechanisms that keep the MECP2 gene silent on the inactive X chromosome.

Dr. Bartolomei discusses this new effort in her lab in a conversation with Monica Coenraads.

Click here to read the interview.


I begin each morning by pouring through the day’s newly published scientific papers. I relish this part of my day as I scour the titles and abstracts looking for any that may have relevancy to Rett Syndrome and MECP2. I am rarely disappointed.

Papers of interest are compiled and distributed to the Rett Syndrome scientific community via RTT Science Watch, an electronic newsletter with a subscribership of a thousand researchers and clinicians. I follow up with the authors of these papers of interest via email or phone.  Some of these scientists will attend one of our think-tanks, or participate in conference calls, and wind up becoming Rett researchers.

Today I’d like to share a few of the papers that I’ve come across recently that are not specific to Rett Syndrome but demonstrate, instead,  evidence of the natural healing powers of the central nervous system. We saw that healing power at work in Adrian Bird’s 2007 Rett reversal experiments and these papers provide further encouraging examples.

A study published a few days ago in the Proceedings of the National Academy of Sciences showed a surprising ability of cats to restore previously damaged myelin – the fatty insulator or nerves (think of it as the plastic coating around electrical wiring) which is damaged in many neurological disorders including multiple sclerosis.


Another encouraging study was just published in the Journal of Neuroscience and shows evidence that individuals who had lost vision due to a stroke can recover their sight through intense daily visual exercises.


Both of these studies show the remarkable healing ability of the brain, even a severely damaged older brain. They bode well for Rett Syndrome.

A third study that recently caught my attention was published in late February in Nature and identifies a gene called IFRD1, that modifies the severity of cystic fibrosis. By analyzing the genetic makeup of 3000 individuals suffering from cystic fibrosis the scientists found that small alterations in this gene correlated with lung disease severity. Scientists will now determine whether IFRD1 is a reasonable drug target. IFRD1 interacts with a class of drugs called histone deacetylases (HDAC) that are also of interest for neurological diseases, including Rett Syndrome.

It is becoming a well accepted fact that the genetic background of individuals may contain small differences that either protect or worsen an existing condition. In Rett Syndrome, for example, there are patients with common MECP2 mutations and normal X inactivation skewing who, in fact, do not have the disorder. These individuals may walk, talk (some in multiple languages), and have normal hand function. They do have some symptoms that are reminiscent of Rett, like anxiety. Efforts aimed at identifying genetic modifiers of MECP2 are ongoing at RSRT. You can read more about this initiative on our website.

I will continue to share examples of studies that fill me with excitement and optimism. It’s important to note that progress in many areas of science will have direct impact on Rett Syndrome. Following these developments, promoting interactions among scientists and facilitating synergies with Rett Syndrome are vital components of RSRT’s work.

Monica Coenraads
Executive Director – RSRT


A recent article by Nicholas Wade in the New York Times highlights the importance of epigenetic influences on gene expression and the increasing role understanding the epigenome will play in designing medical interventions of the future. Rett Syndrome provides a dramatic example of the remarkable power and control of an epigenetic gene, demonstrated by the restoration of normal function in mouse models of the disorder.


February 24, 2009

From One Genome, Many Types of Cells. But How?


Secrets of the Cell
One of the enduring mysteries of biology is that a variety of specialized cells collaborate in building a body, yet all have an identical genome. Somehow each of the 200 different kinds of cells in the human body — in the brain, liver, bone, heart and many other structures — must be reading off a different set of the hereditary instructions written into the DNA.

The system is something like a play in which all the actors have the same script but are assigned different parts and blocked from even seeing anyone else’s lines. The fertilized egg possesses the first copy of the script; as it divides repeatedly into the 10 trillion cells of the human body, the cells assign themselves to the different roles they will play throughout an individual’s lifetime.

How does this assignment process work? The answer, researchers are finding, is that a second layer of information is embedded in the special proteins that package the DNA of the genome. This second layer, known as the epigenome, controls access to the genes, allowing each cell type to activate its own special genes but blocking off most of the rest. A person has one genome but many epigenomes. And the epigenome is involved not just in defining what genes are accessible in each type of cell, but also in controlling when the accessible genes may be activated.
In the wake of the decoding of the human genome in 2003, understanding the epigenome has become a major frontier of research.
Since the settings on the epigenome control which genes are on or off, any derangement of its behavior is likely to have severe effects on the cell.

There is much evidence that changes in the epigenome contribute to cancer and other diseases. The epigenome alters with age — identical twins often look and behave a little differently as they grow older because of accumulated changes to their epigenomes. Understanding such changes could help address or retard some of the symptoms of aging. And the epigenome may hold the key to the dream of regenerative medicine, that of deriving safe and efficient replacement tissues from a patient’s own cells.

Because the epigenome is the gateway to understanding so many other aspects of the cell’s regulation, some researchers have criticized the “piecemeal basis” on which it is being explored and called for a large epigenome project similar to the $3 billion program in which the human genome was decoded. At present the National Institutes of Health has a small, $190 million initiative, called the Epigenome Roadmap, with the money going to individual researchers.

As is often the case, academic researchers oppose a large, centralized project if the money seems likely to come out of their grants. But it is also true that such projects often fail unless carefully timed and thought out.

“Definitely this is a genome-sized thing, and I believe it will have benefits beyond what are foreseen at present,” says Richard A. Young, a biologist at the Whitehead Institute in Cambridge. But Steven Henikoff of the Fred Hutchinson Cancer Research Center in Seattle says the present methods for studying the epigenome are not yet ready to be scaled up. “It’s too early to mount a technology development that would be large scale,” he says.

The epigenome consists of many million chemical modifications, or marks as they are called, that are made along the length of the chromatin, the material of the chromosomes. The chromatin includes the double-stranded ribbon of DNA and the protein spools around which it is wound. Some of the marks that constitute the epigenome are made directly on the DNA, but most are attached to the short tails that stick out from the protein spools. Marks of a certain kind generally extend through a large region or domain of the DNA that covers one or more genes. They are recognized by chromatin regulator proteins that perform the tasks indicated by each kind of mark.

In some marked domains, the regulators cause the DNA to be wound up so tightly that the genes are permanently inaccessible. The center and tips of the chromosomes are sites of such repressive domains. So is one of the two X chromosomes in every woman’s cells, a step that ensures both male and female cells have the same level of activity of the X-based genes.

In other domains, the marks are more permissive, allowing the gene regulators called transcription factors to find their target sites on the DNA. The transcription factors then recruit other members of the complex transcription machinery that begins the process of copying the genes and making the proteins the cell needs. A third kind of domain must be established ahead of the transcription machinery to let it roll along the DNA and transcribe the message in the underlying gene.

Only a handful of domains are known so far, so it is something of a puzzle that more than 100 kinds of marks have been found in the epigenome, along with specialist protein machines that attach or remove each mark. Some biologists think so many marks are needed to specify a few kinds of domain because the system is full of backups.

The epigenome’s role in marking up the genome seems to have been built on top of a more ancient packaging role. The packaging would have been needed by one-celled organisms like yeast that keep their genome in a special compartment, the nucleus. For multi-celled organisms to evolve, the chromatin’s packaging system presumably adapted during the course of evolution to index the genome for the needs of different types of cell.

The DNA packaging system alone is an extraordinary technical feat. If the nucleus of a human cell were a hollow sphere the size of a tennis ball, the DNA of the genome would be a thin thread some 24 miles long. The thread must be packed into the sphere with no breakages, and in such a way that any region of it can be found immediately.

The heart of the packaging system is a set of special purpose proteins known as histones. Eight histones lock together to form a miniature spool known as a nucleosome. The DNA twists almost twice round each nucleosome, with short spaces in between. Some 30 million nucleosomes are required to package all the DNA of ordinary cells.

For years, biologists assumed that the histones in their nucleosome spools provided a passive framework for the DNA. But, over the last decade, it has become increasingly clear that this is not the case. The histone tails that jut out from the nucleosomes provide a way of marking up the genetic script. Although one kind of mark is attached directly to the bases in the DNA, more than a hundred others are fixed onto specific sites on the histones’ tails. When the DNA has to replicate, for cell division, the direct marks pass only to the two parent strands and all the nucleosomes are disassembled, yet the cell has ingenious methods for reconstituting the same marks on the two daughter genomes. The marks are called epigenetic, and the whole system the epigenome, because they are inherited across cell division despite not being encoded in the DNA.

How is the structure of the epigenome determined? The basic blueprint for the epigenomes needed by each cell type seems to be inherent in the genome, but the epigenome is then altered by other signals that reach the cell. The epigenome is thus the site where the genome meets the environment.

The organization of the epigenomes seems to be computed from information inherent in the genome. “Most of the epigenetic landscape is determined by the DNA sequence,” says Bradley Bernstein, a chromatin expert at Massachusetts General Hospital. The human genome contains many regulatory genes whose protein products, known as transcription factors, control the activity of other genes. It also has a subset of master regulatory genes that control the lower-level regulators. The master transcription factors act on each other’s genes in a way that sets up a circuitry. The output of this circuitry shapes the initial cascade of epigenomes that are spun off from the fertilized egg.

The other shapers of the epigenome are the chromatin regulators, protein machines that read the marks on the histone tails. Some extend marks of a given kind throughout a domain. Some bundle the nucleosomes together so as to silence their genes. Others loosen the DNA from the nucleosome spools so as to ease the path of the transcription machinery along a gene.

Biologists had long assumed that once the chromatin regulators had shaped an epigenome, their work could not be undone because a cell’s fate is essentially irreversible. But a remarkable experiment by the Japanese biologist Shinya Yamanaka in June 2007 underlined the surprising power of the master transcription factors.

By inserting just four of the master regulator genes into skin cells, he showed the transcription factors made by the genes could reprogram the skin cell’s epigenome back into that of the embryonic cell from which it had been derived. The skin cell then behaved just like an embryonic cell, not a skin cell. Until then, biologists had no idea that the epigenome with its millions of marks could be recast so simply or that transcription factors could apparently call the shots so decisively.

But subsequent research has shown the chromatin regulators are not pushovers. Only one in a million of the skin cells treated with the four transcription factors reverts fully to the embryonic state. Most get stuck in transitional states, as if the chromatin regulators are resisting a possibly cancerous change in the cell’s status. “The take-home story is that yes, the transcription factors are really critical players in determining cellular state, but epigenetics is important, too,” Dr. Bernstein said.

The ideal of regenerative medicine is to convert a patient’s normal body cells first back into the embryonic state, and then into the specific cells lost to disease. But to prepare such cells safely and effectively, researchers will probably need to learn how to control and manipulate the chromatin of the epigenome as well as the transcription factors that shape cell identity.

The treatment of many diseases may also lie in drugs that manipulate the epigenome. Rett syndrome, a form of autism that affects girls, is caused by a mutation in the gene for an enzyme that recognizes the chromatin marks placed directly on the DNA. At least in mice, the neurons resume normal function when the mutation is corrected. In several forms of cancer, tumor-suppressor genes turn out to have been inactivated not by mutation, the usual known cause, but by the incorrect placement of marks that invite chromatin regulators to silence the genes.

Drugs developed by Peter A. Jones of the University of Southern California reverse the chromatin silencing of these antitumor genes. Two have recently been approved by the Food and Drug Administration for a blood malignancy, myelodysplastic syndrome.

Besides governing access to the genome, the epigenome also receives a host of signals from the environment. A family of enzymes called sirtuins monitors the nutritional state of the cell, and one of them removes a specific mark from the chromatin, providing a possible route for the genome to respond to famine conditions. Accumulating errors in the epigenome’s regulation could allow the wrong genes to be expressed, a possible cause of aging.

A principal new technique for studying the marks on an epigenome is to break the chromosomes into fragments, which are then treated with antibodies that bind to a specific mark. The DNA fragments so designated are decoded and matched to sites on the human genome sequence. This provides a genome-wide map of how a particular mark is distributed in a particular epigenomic state. The CHiP-seq maps, as they are called, have been very useful but are far from capturing the full detail of the epigenome, a dynamic structure that can change in minutes.
Individual researchers have made considerable progress but may not be able to assemble the comprehensive set of epigenomic marks and states that would be most useful to those developing new approaches to disease and aging. “I think the effort needs to be organized,” Dr. Young said. “It would benefit from being larger than it is.”

Glia in Rett Syndrome: New Findings
An interview with Gail Mandel, Ph.D.

Gail Mandel’s new work reveals not only the important information that MECP2 is expressed in glia as well as in neurons, but the discovery that MECP2-deficient astrocytes (a subset of glia) seem to effectively stunt the development of neurons.


(Copyright © Credit: K. Kasischke,P. Fisher/Cornell University)

Astrocytes in red, neurons in blue. (Copyright © Credit: K. Kasischke,P. Fisher/Cornell University)

Neuroglia, Nursemaids to the Neurons

Parents of children with Rett Syndrome have become accustomed to hearing about MECP2 in neurons, but the very large world of glia may be new to them. Glial cells, which are found throughout the nervous system, comprise the vast majority of cells in the brain, where they outnumber neurons ten to one. They support and interact with neurons in innumerable ways, ranging from structural underpinnings and guidance of the neurons’ processes, which are the axons and dendrites that carry information, to creating protective insulation (myelin) for these processes, to bringing in the groceries and taking out the garbage for the neurons. There is constant “cross-talk” between neurons and surrounding glial cells. The health of the neuron requires healthy responses and support from the glia. There are several different types of glial cells, including astrocytes, oligodendrocytes, and microglia. We will be focusing in this interview on the astrocytes, so named because of their star-like shape.

Ruining the Neighborhood

In the majority of Rett cases, X inactivation results in neurons functioning with a “good” copy of MECP2 scattered among a fairly equal number of neurons with faulty, mutated MECP2. Until now, any special influence the glia might exert on these mixtures of good and faulty neurons, living side by side, was unknown. We now have a very new perspective: even the neurons that aren’t crippled by mutated MECP2 may be, instead, poisoned by malfunctioning astrocytes carrying a faulty copy of MECP2.


In vitro experiments show that damaged neurons can recover normal growth when surrounded by healthy astrocytes.

Gail Mandel, an advisor to RSRT, is a Howard Hughes Medical Institute investigator at the Vollum Institute . She discusses this new work and sudden turn in Rett research in a conversation with Monica Coenraads, Executive Director of the Rett Syndrome Research Trust.

Gail Mandel, Ph.D.

Gail Mandel, Ph.D.

MC: Congratulations on this significant step forward in understanding the far-reaching influence of MECP2, and of the pathology of Rett Syndrome. Until now, it was thought that MECP2 was not expressed in glia. What motivated you to explore glial function in Rett Syndrome?

GM: I got involved in this research from a different perspective all together. My previous work was dealing with neuronal repressors during neuronal differentiation. I’ve worked for a long time on a repressor protein called REST. This is a repressor which is a master regulator of the neuronal phenotype. It ensures that only neurons express neuronal genes, by keeping neuronal genes turned off outside of the nervous system. REST is present for a brief time during the earliest stages of development, including at the embryonic stem cell (ESC) stage. As the ESC differentiates into neurons, REST is lost, and other regulating genes take over.

In stages, our involvement with REST led us toward MECP2 as an important regulator in neuronal maturation. We began to study MECP2, and through the work of Adrian Bird, Huda Zoghbi, Rudolf Jaenisch and others, were introduced to Rett Syndrome.

What didn’t make a lot of sense to us is that MECP2 is found everywhere in the body and yet when you lose it via mutations the deficits are mostly neurological. So we started thinking what else does the brain have that other tissues don’t have, and one thing is glia. My research assistant, Dr. Nurit Ballas and I, decided to look more carefully at MECP2 in glia, and to do this we developed a new and very sensitive antibody which can detect even small amounts of MECP2 protein in glial cells.

When I first started telling fellow scientists that we saw MECP2 in glia they said, “So what?” My response: If defective MECP2 severely compromises glial function, it’s a big “So what!”

MC: Your work suggests that a neuron with normal MECP2 will nevertheless be crippled if the surrounding glial cells cannot support normal growth. Can you elaborate?

GM: We found that MECP2 is present in all kinds of glia. There is more known about the affects of astrocytes on neurons than other types of glia. Astrocytes help neuronal synapses function properly. We’ve known for a long time that astrocytic conditioned medium keeps neurons healthy. (note: “Astrocytic conditioned medium” is comprised of the substances secreted by astrocytes.)

We saw that wildtype (healthy) neurons co-cultured with MECP2 mutant astrocytes exhibited very stunted growth.

MC: Are you saying that, in effect, a healthy neuron may be poisoned by malfunctioning glial cells?

GM: There are two possibilities that could explain what we are seeing. 1) The astrocytes are secreting a toxic factor. This is the scenario that I’m hoping for because it could provide a therapeutic intervention – one could imagine finding a way to neutralize the factor. 2) The astrocytes are depleting a nutrient that the neurons need. This would be a more difficult scenario to deal with.

We did a classic experiment called the mixing experiment: we combined, half and half, conditioned medium from wildtype astrocytes with conditioned medium from the Rett mutant astrocytes. The interpretation is that if normal neurons in the half and half medium resemble neurons cultured in the mutant medium, it’s probably due to a toxic factor. If the astrocytes were depleting a nutrient you would expect that adding in more wildtype medium would help the problem. In our mixing experiment the neurons reacted as if they were in the straight mutant media. These results strengthen the argument that the astrocytes are secreting a toxic factor.

MC: One of the very fascinating aspects of your work is that an MECP2-deficient neuron seems to recover and produce good axonal and dendritic growth in vitro if supported by normal glia. What are the implications of this finding?

GM: It’s an encouraging finding. In theory it suggests that we could treat Rett, at least in part, by neutralizing the toxic factor or by over-expressing the normal factor that wildtype astrocytes secrete to nurture neurons. Given Adrian Bird’s 2007 reversal paper and our culture experiments we would predict that the abnormal phenotype of the neurons should be reversible.

It’s important to note that neutralizing the toxic factor would be a treatment strategy that is not directed at the MECP2 gene itself and would represent a novel approach.

MC: Daniel Lioy, a graduate student in your lab, shared a theory that resonated with me. A girl with Rett is born with roughly 50% wildtype neurons and 50% MECP2– mutated neurons. For a while (sometimes many months) she seems okay. Then the stagnation and regression kick in. Daniel theorizes that perhaps as the toxic factor from the mutated astrocytes poisons the whole neighborhood (wildtype cells as well as mutated cells) the child’s symptoms worsen.

GM: It’s a plausible theory but until we prove it…it’s just a theory. Our lab is currently undertaking several key experiments to further elucidate this proposition as well as to delve more deeply into the question of a toxic factor.

MC: There have been sporadic reports through the years of abnormal findings in the peripheral nervous system in Rett Syndrome. It’s conceivable these are related to some of Rett’s many symptoms. Is there any basis for examining the glial cells of the peripheral nervous system for MECP2 expression?

GM: Yes, I think it’s very important, and we are looking at this, as well.

MC: What are your impressions of the research progress in Rett during the last few years?

GM: I think it’s been really very good, especially when you consider the fact that Rett is a very complicated disease that has a fairly small, albeit growing, community of scientists. There are phenomenal people working in this field and they are making progress. And we don’t just have the Rett scientists in our court; we also have all the other basic scientists working on how genes are regulated in different cells. The body is linked by common solutions to cell functions. Science sometimes works by surprise discoveries that often are fundamental principles that govern how the nervous system works.

MC: Rett shares characteristics of so many neurological disorders, from autism to Parkinson’s. With this new understanding of glial involvement, are there even more disease models where research interests might overlap?

GM: Recent data suggests that toxic astrocytic secreted factors are at the heart of ALS and spinocerebellar ataxia type 7. In fact, it may turn out that the secreted factors may be similar. One could envision a scenario where the sick neurons (whether from an MECP2 mutation or other mutations that cause ALS or SCA7) cause, in turn, the astrocytes to secrete a factor in response to the original insult to the brain. This factor need not be specific to the disease.

I truly hope that my lab can contribute in a meaningful way to the development of treatments. I know the children are in dire need.

MC: On behalf of everyone who loves a child with Rett Syndrome I congratulate you on your discoveries. I look forward to your continued contributions as this work unfolds.


By Monica Coenraads

The trustees, staff and volunteers of RSRT congratulate Dr. Huda Zoghbi on receiving the 2009 Vilcek Prize in Biomedical Science. The Vilcek Foundation was established in 2000 by Czechoslovakian immigrants Jan and Marica Vilcek to raise public awareness of the contributions of immigrants to the sciences, arts and culture in the United States.  Dr. Zoghbi, a world renowned physician-scientist, was selected for this honor for her seminal contributions to neuroscience and genetics, including her discovery, a decade ago, that mutations in MECP2 cause Rett Syndrome.

The Vilcek Foundation celebrates the spirit of immigrants and their will to succeed in a new country, sometimes against all odds. Dr. Zoghbi arrived in the US in 1975, escaping war-torn Beirut where she had been attending medical school.  She had  intended to stay for only a few months, but her parents convinced her to finish medical school in the US after her brother was injured by shrapnel.


Dr. Zoghbi and her first patient with Rett, Ashley.

Dr. Zoghbi found her way to Baylor College of Medicine where, as a neurology fellow, she saw her first patient with Rett Syndrome. She put aside her clinical practice to focus on research. After 16 years of perseverance, the Zoghbi lab succeeded in identifying the mutated gene responsible for Rett Syndrome. During the past 10 years I have witnessed Rett Syndrome go from unknown entity to high-profile disorder. This transformation is due, in large part, to the efforts of Dr. Zoghbi, who has consistently brought awareness of this disorder to the scientific community.

As the mother of a child with Rett Syndrome I am deeply grateful for Dr. Zoghbi’s  patience and tenacity as well as her skill.  It has been my pleasure and privilege over the last decade to have worked closely with and learned so much from Dr. Zoghbi.  RSRT is honored to support her research and to count her as a key advisor.  As I watched her video interview on the Vilcek Foundation website Dr. Zoghbi was asked “What does your future hold?” I was not surprised by her answer:  “There is one more thing I’d like to do…make a patient better.”



Reprogramming Cells

The high-profile journal Science recently named “reprogramming cells” as the 2008 breakthrough of the year. By inserting genes that rewind a cell’s developmental time clock, scientists were able to transform skin cells from patients with a variety of diseases and coax them back into stem cells. These transformed cells will hopefully not only provide novel tools to study the underlying disease process but may, one day, be used to treat patients with their own cells, thereby thwarting potential immunological responses. Several labs are pursuing this approach for Rett Syndrome.  To view a video that explains this exciting development please visit the Science website.


First clinical trial using human embryonic stem cells is approved

Geron Corporation announced last week that the FDA has approved the company’s  Investigational New Drug (IND) application for the clinical trial of GRNOPC1 in patients with acute spinal cord injury.  Geron will initiate a Phase 1 clinical trial to establish safety of GRNOPC1 in patients with acute spinal cord injuries.

“The FDA’s clearance of our GRNOPC1 IND is one of Geron’s most significant accomplishments to date,” said Thomas B. Okarma, Ph.D., M.D., Geron’s president and CEO. “This marks the beginning of what is potentially a new chapter in medical therapeutics – one that reaches beyond pills to a new level of healing: the restoration of organ and tissue function achieved by the injection of healthy replacement cells. The ultimate goal for the use of GRNOPC1 is to achieve restoration of spinal cord function by the injection of hESC-derived oligodendrocyte progenitor cells directly into the lesion site of the patient’s injured spinal cord.”

To read more please visit the Geron website.


RSRT is supporting a project that will screen FDA approved drugs and compounds in a mouse model of Rett Syndrome. The project will take place in the lab of Andrew Pieper at UTSW. To learn more about this project please visit the RSRT website.

In late September we introduced the Sponsor a Drug initiative in conjunction with the launch of our website. As part of that initiative we invited families to recruit their relatives/friends/colleagues to sponsor drugs in honor of their child. The family with the most drugs sponsored by January 15 wins a week-long vacation for two to Ireland.

We are pleased to introduce the winners: Kevin and Dominique Coloton from St. Paul, Minnesota. Their daughter, Catalina, was 21 months old when she was diagnosed in September with Rett Syndrome. The Coloton’s raised over $23,000 for this initiative. We are extremely appreciative of their efforts and for the generosity of their relatives and friends. Dominique, a physician in both internal medicine (adults) and pediatric medicine, and Kevin, an executive at Target Corporation in their Health Care division, comment on their efforts with the Sponsor a Drug effort:

“While we came to terms with Catalina’s diagnosis, we spent significant time learning about Rett Syndrome, resources for families, and ongoing research in areas that could impact Rett Syndrome. During this time we were impressed with RSRT, the mission, and the research that they are funding, so we decided to ask our friends and families to make donations to this organization in honor of Catalina. We composed an email to send to all of our friends and family sharing with them our sadness and grief over lost dreams, yet highlighting our hope for a cure. We enthusiastically talked about how hopeful we are that a cure will be found in her lifetime and how the dedicated researchers around the world, especially those associated with RSRT are working hard to help find the key to unlocking Rett Syndrome. We are so thankful to all those who have chosen to support Rett Syndrome research, although we know that our work is far from complete. We as a family and as a community need to continue to be dedicated to promoting the importance of this research in order to find a cure for our daughters around the world with Rett Syndrome.”


The Colotons will be staying at the Ashley Park Bed and Breakfast in Tipperary County, Ireland. The week-long stay at the B&B is graciously offered by the family of Margaret McKenzie from London. Margaret’s daughter, Katherine, who also had Rett Syndrome, died last year at the tender age of 8. Margaret and her family are hopeful that Rett research will spare future girls the suffering that Katherine endured and that the McKenzie family continues to deal with.

We thank all our families for their participation and in particular Paula and David Southren, Jennifer and Tommy Lopez, Ingrid and Peter Harding, Bridget and Scott MacDonald and Pam and Tony Scarano. We also thank the Israel Rett Syndrome Center, Stichting Rett Syndroom and Mikyla-Cure for their support.

Please know that we continue to need your support. We are 1/3 of the way to our goal with just over 1000 drugs sponsored. While a trip to Ireland is wonderful we all have our eye on the real prize. We still need to recruit 2000 additional drug sponsors. Please consider joining our efforts. Contact us to join our efforts.


We draw your attention to an excerpt from the upcoming memoirs of Harold Varmus, The Art and Politics of Science, (Norton Books, Feb. 2009).  Dr.  Varmus served as the director of the National Institutes of Health from 1993 to 1999, and is now president of Memorial Sloan-Kettering Cancer Center in New York City.  Dr. Varmus was awarded the Nobel Prize in 1989 with J. Michael Bishop for discovering that retroviral oncogenes had a cellular origin. In this excerpt Dr. Varmus discusses the difficulties involved in  setting research priorities. In particular he discusses the disadvantages of designating particular dollar amounts for disease-specific research.  He explains that discoveries in science are often quite serendipitous and that breakthroughs in one area turn out to have unexpected benefits in often unrelated disciplines.

We have a very clear example of this in Rett Syndrome. Pre-1999 no Rett-focused organization would have entertained the notion of providing support to Adrian Bird who was studying methylation.  However, Huda Zoghbi’s discovery a decade ago that Rett Syndrome is caused by mutations in MECP2 put Adrian Bird front and center in the Rett field. He had discovered the MeCP2 protein in the early 1990’s and for years no one knew that “his” protein is responsible for multiple neurological diseases when mutated. There are countless prime examples of the importance of funding high quality basic science regardless of any potential disease orientation.  As the  new administration assumes power it is imperative that increased funding for NIH be a part of reestablishing the economic, intellectual and scientific strengths of this country.


One of the most difficult aspects of the job of running the NIH, or of directing any individual institute, is the designation of research priorities. This is an emotionally and politically sensitive part of the job because it is closely watched by some of NIH’s strongest supporters, who often advocate for the NIH because of a passionate interest in a small fraction of what the NIH does. That fraction is almost always a specific disease or even a subset or facet of that disease.

Shifts in funds assigned to the mechanisms for supporting research, such as the intramural versus the external grant programs, or differential growth of budgets for individual institutes, are often easier to absorb than changes that affect the dollars devoted to specific diseases. Directives to alter allocations for disease-oriented programs are especially problematic if they occur abruptly or come at the expense of research on another disease. The situation may be further complicated if the directives are demands from powerful people rather than consensual decisions.

To read the excerpt in its entirety please visit The Scientist website. (free registration may be required)


To continue our two-part interview with Huda Zoghbi, MD, we have just added these topics to our interview page:

  • Jan and Dan Duncan Neurological Research Institute (NRI)
  • Rett Syndrome and autism

Dr. Zoghbi has recently been appointed as Director of NRI which upon completion in 2010 will be the world’s first comprehensive children’s neurological center.


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



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



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