by Monica Coenraads

Chelsea is 18 years old today. It’s a milestone birthday that parents of special needs children face with mixed emotions. My heart is full with love and pride for the beautiful, emotive, tender yet determined young woman that Chelsea has become. But today I am also mourning. Mourning for a childhood never lived and forever lost.

Chelsea beach

When Chelsea was a toddler I made her a promise – that I would do everything in my power to heal her. With little science background, zero drug development knowledge and no fundraising experience I did not appreciate the enormity of my promise. Ignorance, at times, can be a blessing.

The Rett research landscape in the year Chelsea was diagnosed, 1998, was dismal. The disorder was practically unknown in medical and scientific circles, there was no known gene and therefore no diagnostic blood test, there were no animal models, and there was little research beyond trying to pinpoint the genetic cause.

My conviction that treatments and a cure for Rett were possible came from both visceral intuition and a mother’s love. Today that conviction is based on science.

But when will that cure come? Is it really “around the corner” as I so often read on facebook and other social media? I do not know the timeframe associated with “around the corner” (is it weeks, months, years?) but I am confident that a number of treatments will become available to our children in the coming years that will improve certain symptoms. The Potential Rett Syndrome Therapeutics chart on the RSRT website provides insight into the numerous interventions currently being pursued.

As parents we will take any improvement in our children’s symptoms that we can get. But what about the “like it never even happened” cure? (My all-time favorite catchphrase from the disaster restoration company, SERVPRO) For now we do not know whether the cure will be gene therapy, or protein replacement or activating the silent MECP2 (or the entire X chromosome) or a drug that modulates a modifier gene or perhaps a combination of some or all of these approaches. And we don’t know what a cure for someone like my daughter, who is now an adult, will look like. Will she be able to speak, to walk, to use her hands?

I do not focus on these questions because they are, for now, unanswerable. I concentrate only on the facts and these include:

  • The reversal experiments originally done in Adrian Bird’s lab and repeated over and over again in many labs gives us solid proof-of-principle that dramatic reversal of symptoms should be possible. I have yet to hear one piece of scientific data that would dampen my optimism that a cure is possible.
  • Scientists are making progress on many fronts including gene therapy.
  • Rett researchers are collaborating and sharing information in real-time in a way that is unprecedented. Examples include the MECP2 Consortium, the Gene Therapy Consortium, and researchers focused on reactivating the silent MECP2.
  • Technologies exist today that are enabling experiments that only a few years ago would be impossible.
  • Rett has become a high-profile disorder in scientific circles.
  • Biotech and big pharma, for the first time, are showing an interest in Rett Syndrome.
  • Science is not linear. We do not know what might lie around the corner that can dramatically accelerate the development of a cure.

Those of you who know me will know that I am aggressive when it comes to pushing the science forward but I am conservative in how research progress is relayed to families. I prefer facts over hype.

Could a cure for Rett be around the corner?  The answer to that question will come when we have a clearer picture of what form that cure will take.  I can assure you that I will not rest until we accomplish that.

Love alone cannot cure Rett but love and research will. It’s been 16 years and I am more than ready to deliver on my promise.

Monica Coenraads interviews Michael Green, MD, PhD of the UMASS School of Medicine about his newly published paper in Proceedings of the National Academy of Sciences.  The work was funded, in part, by RSRT.  He has identified a number of genes that when disrupted can reactivate the silenced X chromosome in females. Some of these genes lie in pathways that are druggable which makes this work potentially clinically relevant not only for Rett Syndrome but also for other X-linked disorders.

Prof. Green’s paper was covered by SFARI.org. in an article written by Jessica Wright.


Rousing silenced X chromosome may treat Rett syndrome

Drugs that activate the silent copy of the X chromosome in women may be able to undo the damage from mutations in genes located there. The study, published 2 September in Proceedings of the National Academy of Sciences, offers hope for treating Rett syndrome and other disorders linked to the chromosome1.

One copy of the two X chromosomes women carry is randomly silenced in each cell of the body. This occurs when the chromosome makes small pieces of RNA, called X-inactive specific transcript, or Xist. A cloud of Xist coats the chromosome and blocks its expression.

Female mice lacking Xist die in utero, so X inactivation was thought to be required for survival. The new study suggests otherwise.

The researchers identified 13 genes required for X inactivation. Female mice missing STC1, one of these genes, show expression of genes from both copies of X and have no obvious symptoms.

“The mouse findings suggest that you might be able to survive without X chromosome inactivation,” says lead researcher Michael Green, professor of molecular medicine at the University of Massachusetts Medical School.

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Frank Menniti Chief Scientific Officer  Mnemosyne Pharmaceuticals

Frank Menniti
Chief Scientific Officer
Mnemosyne Pharmaceuticals

Discovering drugs to treat diseases of the central nervous system is a formidable task.  Our brains are easily the most complex machines on the planet and the more we learn about this machine, the more daunting seems the task of fixing it when things go wrong.  This point is brought home for me when meeting people with some of the CNS disorders I hope to help treat.  I’m new to Rett Syndrome but have now been to a couple of events along with girls suffering Rett and their families.  How can a mutation in a single gene result in such a complex outcome?!  There is a specific answer to this question, because MeCP2 mutation causes Rett, a specific disease.  Yet it is a long and winding road from MeCP2 to that characteristic hand wringing and the many other symptoms Rett girls experience over a lifetime.  Where to step in with a drug therapy and what to expect as an outcome?

The best way to deal with such complex drug discovery problems is head on – identify the root cause of a disorder, fix that, and relief from even the most complex symptoms should follow.  For Rett, there is very good basic science data to suggest that if we restore MeCP2 function then we will restore brain function, and so with habilitation therapy achieve a cure.  Encouraging research along this line is ongoing and we can hope for success.

However, many, if not most, of the drug discovery efforts around Rett syndrome target the consequences of MeCP2 mutations to provide a therapeutic benefit. Put another way, these approaches aim to mend the damage done to the brain that results from lack of functional MeCP2.  In fact, this is the most common approach in CNS drug discovery, where root causes are seldom clear.  Such approaches can be quite effective. Perhaps the best example is in Parkinson’s disease, where dopamine neurons in the brain die off.  We don’t know why dopamine neurons die or how to prevent this die off, that is, how to fix the root cause of Parkinson’s. But we have a pretty good understanding of the dopamine system and from this knowledge drug therapies, and more recently deep brain stimulation therapies, have been developed that compensate for the loss of dopamine neurons.  Take a look at this YouTube video of the effect of deep brain stimulation in a Parkinson’s patient.  Clearly, this patient is being enormously helped by his therapy, even though the therapy does not fix the root cause of dopamine neuron loss.

Can we fix the Rett brain and anticipate that complex symptom relief will follow? I think the answer is ‘yes’.  And, there is a guidepost on how we may go about this in the efforts being made to discover new therapies to treat cognitive defects in schizophrenia.  Schizophrenia, like Rett, is a neurodevelopmental disorder that results in an incredibly complex and variable array of symptoms.  Of these, the cognitive deficits are the most debilitating, keeping patients out of school and work even after their more florid symptoms are under control.  But these cognitive deficits are complex, as are their outcomes (that’s an understatement!).  How would we know that a new therapy had a meaningful effect in the face of such complexity, let alone how to prove a benefit in a Phase II clinical trial?  The schizophrenia research community, NIMH, FDA, and the pharmaceutical industry, took this problem on and the result was the MATRICS and CNTRICS Initiatives.  In MATRICS, complex global cognitive deficits in schizophrenia were broken down into simpler components like working memory, for example as measured in the ability to remember a short word list.  The idea is that improving a patient’s working memory, coupled with habilitation therapy, would make the patients better able to keep track of tasks and so hold a job or finish school.  CNTRICS takes this one reductionist strategy one step further by trying to identify the fundamental physiological brain abnormalities that underlie the simpler cognitive components.  For example, associating an EEG abnormality with a working memory deficit.  The logic now is that, if we fix the EEG abnormality, we will fix working memory, and the patient has an improved cognitive toolbox to use in daily life.  Clinical trial follows this progression – first, fix the EEG abnormality, which is most quantifiable and requires the smallest number of patients; second, take the learnings on drug dosing etc. from the EEG trial to prove a reliable drug regimen that fixes working memory; third, use this drug regimen, in combination with habilitation, to explore the potential for ‘real life’ benefits.

I think a structured approach following a MATRICS/CNTRICS model could be very impactful in developing drug therapies for Rett. But the devil is in the details.  The most obvious and immediate questions are scientific- what to measure first, second, third?  Less obvious but no less important are questions around clinical development strategies and timelines for such an approach.  Where along such a path does such a drug become approved and so commercially available?  These latter issues will require significant thought and discussion among all in the Rett community.  More of my thoughts on the science and these broader issues in future posts.

 

by Monica Coenraads

Anyone who knows anything about Rett Syndrome knows that the disorder is primarily seen in girls. The disorder is caused by disruption of the MECP2 gene located on the X chromosome. Girls have two X chromosomes one with the disrupted gene and one with the healthy gene. Having some healthy MeCP2 protein allows girls to survive but at the expense of severe impairment that comes with Rett.

1623703_516732648427830_2098385048107441333_n

Since boys only have the one X chromosome they have no healthy MECP2 at all. These boys typically have a more severe form of the disease and often die in early childhood. (There are genetic situations that allow boys to present like classic girls with Rett, for example if they have Klinefelter Syndrome which gives them two Xs.)

The fact that boys only have one X is the reason most often given for why Rett is seen in girls. However this is not accurate. While having the sole X is the reason boys often succumb to the disease it is NOT the reason why Rett is primarily a woman’s disease. That reason has to do with where the MECP2 mutation originates.

Many studies over the past decade have provided evidence that the vast majority of MECP2 mutations originate in the sperm. Since fathers give an X to their daughters and a Y chromosome to their sons the MECP2 mutation can only be transmitted from father to daughter. This is the reason why Rett is seen primarily in girls.

y-chromosome

Boys, on the other hand, get their MECP2 mutations from their mother, a situation that arises only rarely. (Mutations can also originate in a single cell as the male embryo is developing.)

Scientific papers over the years have hypothesized that because male fetuses only have one X their disease would be so severe that they might not even develop to full term and the mothers might miscarry. There is no clinical data to support this hypothesis whatsoever.

Due to the sheer volume of sperm that is continuously made it is likely that all men produce sperm with MECP2 mutations. One in about 20,000 eggs will be fertilized with a sperm that has an MECP2 mutation in it – the cruel reality of genetic roulette.

Dear Friends,

Tim and his daughter Eleanor

Tim and his daughter Eleanor

A year ago today I started as program director for RSRT.  I thought I would share a few reflections about the people I’ve met and what I’ve experienced and learned over that time.

Before starting at RSRT I had met two girls with Rett Syndrome—my own daughter and Monica’s daughter.  Now, in my travels to events and meetings with families, I have met 47 girls and young women with Rett.  Each of them, often despite terrible symptoms, has tried to engage me in some way, sometimes just through a flash of the eye or a smile.  I met a teenage girl at an event who had been seizure-free for six months.  But midway through the event she had a seizure.  I watched as she trembled and her muscles seized; a single tear rolled down her cheek.  Was it pain, frustration, fear?  It was so clearly all of those.  Her father and mother cried too.  So did I.  Of all I have learned and experienced over the last year, nothing sticks in my memory or keeps me awake at night like the faces of these girls and women and the strength I have seen in them and in their families.  Our daughters have reminded me again and again without saying any words that it’s imperative that we change their lives.

MacDonald Family at this year’s Quest for a Cure

Tim and MacDonald family at the
Quest for a Cure event

I have also learned that it’s we—the families of girls and women with Rett—who are going to make this happen. We are the leaders in this cause. I’m not at all suggesting that we families have to throw money at this. I am well aware that we all have plenty on our plates; we have to live our lives, and the daily challenges of Rett Syndrome add emotional and financial stresses that most people don’t even have to think about. So we can’t be expected to shoulder the full burden of supporting Rett research on top of everything else. But, we all can make a critical difference by getting friends and contacts to support RSRT. Thanks to the efforts and outreach of some Rett families, many people who are not directly affected by Rett have generously and happily supported the research and have made it a priority for their giving. We, all of us families, have to continue and expand this outreach to our friends and contacts. Our daughters’ futures depend on it, and we all must get involved if we are to turn the possibility of a cure into a reality.

My respect for Monica and for RSRT as an organization, already great when I started, has only grown.  I wanted to work for RSRT because I knew it did one thing and one thing only—supported research to find a cure.  This is what I want.  This is what we all want.  I’ve worked in the non-profit world long enough to know that a 4% administrative cost rate is remarkable.  The fact that RSRT spends 96 cents of every dollar directly on research is a reflection of its dedication, efficiency, and integrity.  This is not an organization that is flashy or that spends a lot of time or money promoting its accomplishments; instead it focuses on finding a cure for Rett Syndrome.  The result is, well, results.  It is RSRT-supported scientists who are accumulating the knowledge needed to take the next steps in gene therapy and other promising approaches.  I can talk about RSRT this way because I’m still new and in a way I’m looking from the outside in, as a parent.  I have had nothing to do with this organizational culture myself; it is driven by Monica, by the RSRT trustees, and by the families that support us.

I have learned a lot about the science behind Rett Syndrome.  I have much more to learn, but I know enough to say definitively that a cure is much more than a dream.  It is a very realistic possibility.  But it’s not going to happen unless we grow RSRT’s financial resources above and beyond the funds we raise from existing events.  Money matters in scientific research.  The more money RSRT has, the more resources it can put into projects like the Gene Therapy Consortium, and the faster and more efficiently these projects are likely to lead to a cure.

I know this has turned into a pitch—not for your dollars, but for your involvement. I am somewhat of a shy person by nature, so I guess I’ve also learned over the last year not to be shy about asking for help. There is so much to gain by it. We need more of you—as many Rett families as we can get—involved and supporting RSRT. Whether you are a parent, grandparent, aunt or uncle, cousin, or sibling—start an event of your own; support an existing event and get friends to join you; do a letter writing campaign. I know all of our lives are busy and full of the challenges of Rett Syndrome. If you can’t do a lot, do a little. But do something. It all makes a difference.

To all of you reading this who are involved already, this is a big thank you.  None of what RSRT does would be possible without you.

I have one further thought.  I know it’s hard to consider ourselves fortunate. My wife and I often find ourselves asking why us—why did our beautiful, bright-eyed daughter get such a bad roll of the dice? But when I take a step back and look at the bigger picture, I see that we are very fortunate.  We’re fortunate that scientists have pinpointed the cause of Rett Syndrome; we’re fortunate that Adrian Bird demonstrated that Rett is a reversible condition; we’re fortunate that the best geneticists and neurobiologists in the world are now attracted to Rett research and are taking the next steps on Prof. Bird’s discovery; we’re fortunate that we have RSRT to lead, support, and push forward the science; and we’re fortunate that we have a cause that speaks to people so compellingly and with so much promise. Most of all, we are fortunate to have our daughters; to love them and to be loved by them in such a profound and special way; and to see brightness in their futures.

I look forward to hearing from you. Thank you.

Tim Freeman

 

We need your help!  With promising new research projects underway such as the Gene Therapy Consortium, now more than ever RSRT needs families affected by Rett Syndrome to get involved and raise funds.  Here’s what you can do:

  • Start a new event.  Anyone can start an event—parents, grandparents, brothers and sisters, aunts and uncles.  Events can be whatever you want them to be—a gathering in a home, a picnic in a park, or a big gala.  We can help you with ideas and planning.
  • If you live in an area that already has an RSRT event, please get involved.  Come to the events and get friends to join you, ask for sponsorships, and donate auction items.
  • Do a letter-writing campaign to your friends and contacts.  This is easy to do, and we can help.  Most people are thrilled to support our cause.  But they need to learn about it and be asked.  A thoughtful letter from you can do this.  We can help you draft it and even mail it out for you.
  • Raise funds online.  This is easy and fun to do.  Go to FirstGiving and click on “Start Fundraising.”  You can do this for an occasion like a birthday or anniversary, for a run or a walk, or in honor or memory of someone.

We need all hands on deck.  Rett research is poised for breakthroughs, but we need help from the entire Rett community.  To get started, contact Tim at 609.309.5676 or tim@rsrt.org.  Thank you!

by Monica Coenraads

There is no mystery about why a girl suffers from Rett Syndrome. The cause is the mutated copy of the MECP2 gene inhabiting her cells.  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 by reawakening its silenced counterpart? If we could wake up MECP2 in enough cells we could conceivably reverse Rett symptoms.

healthy-mutant

This is an approach that RSRT has championed since our launch in 2008. We are funding seven labs that are pursuing this line of work.

You may ask why do we need multiple labs working on the same goal. Isn’t that a waste of effort and money? The answer is a resounding “NO”. While the end game is the same each lab is using a different strategy to get there.

For example, the types of cells that labs are utilizing are different. Ben Philpot and colleagues at UNC are working with mouse neurons, Toni Bedalov and Jeannie Lee are using fibroblast cells, others still are using human cells. Each cell type has its own set of advantages and disadvantages.

The labs are also using different “reporters” – meaning how the cells are designed to detect activation of MECP2. Different compound libraries at different concentrations are being screened. Compounds are also being screened at various degrees of high and low throughput. And finally different criteria are being employed to define a “hit” (drugs that reactivate MECP2).

Bryan Roth

Bryan Roth gives us a tour of his robotic high-throughput
screening facility at UNC Chapel Hill

Having multiple labs attack this problem gives us more shots on goal and added assurances regarding the quality of any potential hits.

Two weeks ago we gathered everyone tackling this approach and brought them together for two intense days of talks and discussions.

Targeting MECP2 as a Treatment Strategy for Rett Syndrome
Chapel Hill, NC
May 12-13, 2014

Seventeen scientists from eight labs plus advisors from NIH and industry at RSRT meeting.

Seventeen scientists from eight labs
plus advisors from NIH and industry participate at meeting in Chapel Hill, NC.

 

Over the past 15 years I’ve organized dozens of meetings and before each one I worry – will the discussions be forced or will they flow naturally? will collaborations ensue? It was no different with this meeting.  The first few talks of the day however quickly put me at ease.  While a number of common hits were reported in multiple labs much validating and further screening remains to be done.  At the meeting, and in emails and phone calls since, the scientists are working out the logistics of validating each others hits, trading cell lines and compounds.  Exactly the outcome I was hoping for.

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by Diana Gitig

Clinical trials are designed to make sure that new therapeutics are both safe and effective. They can also be used to identify side effects, to compare how well different drugs work relative to each other and to see if certain populations react differently to different treatments. In order for doctors to prescribe the most appropriate drugs to their patients, they need to know the results of such clinical trials. Unfortunately, that information is not always so easy to come by.

Publication bias means that negative results generally do not get published. This is problematic because it skews the publication record. If only positive results get published, showing that a given drug is effective in assuaging a certain condition, people assume that that is the full story. Even if ten studies have been done showing that that same drug is useless, since negative data does not usually see the light of day no one knows about them and people think the published positive results are “fact.” Approximately half of all clinical trials performed globally have never been published in academic journals, and trials with positive results are twice as likely to be published as those with negative results. No one wants to publicize that their drug doesn’t work. Because if doctors don’t know that a drug doesn’t work – or a more realistic scenario, that a new, expensive drug doesn’t work better than the old generic – then why on earth wouldn’t they prescribe that drug to their patients? Moreover, it has been perfectly legal for pharmaceutical companies and universities to withhold the results of clinical trials as proprietary information.

To mitigate the misperceptions caused by publication bias and the withholding of trial data by the pharma industry, the Food and Drug Administration Modernization Act of 1997 created ClinicalTrials.gov. All clinical trials with at least one testing site in the US are supposed to register there before the trial starts. It went online in 2000 but only really became a force in 2005, when the International Committee of Medical Journal Editors made registration a prerequisite to having a trial published in a journal. Since researchers must register before the trial begins, they must lay out their initial hypothesis and thus cannot “move their goalposts” – claim to have always been looking for whatever it was they found. In 2007, the FDA added the requirement that results must be published on the site within a year after a trial is completed. Thus even if results are not published in journals doctors and patients have another place to search for them, and it should, in theory, be more difficult for researchers to hide negative results, since there is a record of the trial having taken place.  However, neither the requirement to register trials nor the requirement to report results have been rigorously enforced or followed. So often not only do doctors still not know the results of trials – they might not even know that a trial has been done.

On April 2, 2014, the Members of the European Parliament voted to adopt the Clinical Trials Regulation. This regulation makes it law in the European Union that clinical trials be registered before they begin, that results be published somewhere within a year after the trial ends, and that a summary of results written in lay terms be published on the publicly accessible register. Failure to comply with these new requirements will be punishable by a fine. It also dictates that information contained in Clinical Study Reports will no longer be considered commercially confidential. These reports contain many details that are often omitted in academic papers but are nonetheless important, like research methodologies.

This new European law is expected to come into effect in mid-2016 at the earliest. It is an enormous stride forward, but most of the medicines currently in use went through trials that have already been done. Results of these trials can still legally be withheld, so doctors must still make prescribing decisions without complete, accurate, and up-to-date information about which drugs now available are best for which patients.

Those with rare diseases can be particularly impacted by the transparency, or lack of it, in clinical trials. Pooling results from different studies into meta-analyses can often reveal the most telling effects of a drug; since fewer people have these disorders fewer studies can be done, and thus withholding data from any one of them can thus have an outsize effect. Moreover, subjects who participate in such trials often do so to benefit their fellow patients in addition to themselves, and withholding the results that they helped provide is a betrayal of their trust.

http://www.alltrials.net/

http://www.badscience.net/

http://www.thepharmaletter.com/article/meps-vote-for-more-transparent-and-simpler-european-clinical-trial-rules

http://www.bmj.com/content/348/bmj.g213?ijkey=5aXoYcMGOETixKf&keytype=ref

http://www.nimh.nih.gov/funding/opportunities-announcements/clinical-trials-foas/changing-nimh-clinical-trials-efficiency-transparency-and-reporting.shtml

http://www.nimh.nih.gov/about/director/2014/a-new-approach-to-clinical-trials.shtml

 

Last year RSRT awarded a $750,000 grant to Michael Green,  PhD of University of Massachusetts to pursue an unconventional approach to reversing Rett: reactivating the silent X chromosome.  UMASS just released the piece and video below highlighting Dr. Green’s work.  We are struck by the following quote from Dr. Green:  “With NIH funding, you pretty much have to be doing mainstream research. The NIH doesn’t fund bold and innovative projects often. By contrast, organizations like RSRT are willing to take on high-risk projects that have controversial hypotheses and rationales, because these are the ones that really may have a great impact on disease.”

We thank all of our supporters who make it possible for us to fund innovative, out-of-the-box projects that we believe will move us towards a cure for Rett by leaps rather than small incremental steps.

From the UMASS Med NOW website:

UMMS scientist aiding a mother’s quest for rare disease cure
With a $750,000 grant from the Rett Syndrome Research Trust, Michael Green is working to reverse a debilitating neurological disease

By Lisa M. Larson and Bryan Goodchild (UMass Medical School Communications)

Monica Coenraads is discussing work with two business associates in the living room of her Trumbull, Conn., home on a recent spring morning, when the conversation turns to the benefits of face-to-face communication over reliance on electronic devices.

Suddenly, a squeal of laughter erupts from the other side of the room, where her 17-year-old daughter, Chelsea, has been relaxing on the couch, quietly listening to her mother’s every word.

“Chelsea thinks it’s funny, because she believes her mom spends too much time on her phone,” explains Coenraads, who works from her house.

In homes across America, parents and kids are debating texting, cell phones and screen time.

But for the Coenraads family—Monica, husband Pieter, and sons Alex, 15, and Tyler, 14,—the focus is on discovering any method by which Chelsea can communicate. The slender, brilliant-blue-eyed girl, who bears a striking resemblance to her mother, has Rett syndrome, a rare, genetic, neurological disease that locks her thoughts inside her head, as she is unable to speak or to use her hands. With great determination and without speech or hand gestures, Chelsea expresses herself by focusing her gaze on pictures in a three-ring binder of the words she’d like to say.

“A child with classic Rett syndrome is in a wheelchair, unable to talk, fed through a feeding tube, with seizures, anxiety, orthopedic issues, scoliosis, contractures and no hand function,” said Coenraads, co-founder and executive director of Rett Syndrome Research Trust (RSRT) and its director of research. The former restaurateur is credited with helping to raise more than $37 million for research into Rett syndrome since her daughter’s diagnosis 15 years ago.

“They’re really trapped,” continued Coenraads, explaining the disease, which affects approximately 16,000 girls across the country. “They can understand what is going on; cognitively they are quite on track.”

UMass Medical School scientist Michael R. Green, MD, PhD, globally known for his work in gene regulation, keeps the image of Chelsea and that of other girls who suffer from Rett in mind as he works toward finding a drug that would reverse the disease. Dr. Green, a Howard Hughes Medical Institute Investigator, the Lambi and Sarah Adams Chair in Genetic Research and professor of molecular medicine and biochemistry & molecular pharmacology, received a $750,000 grant from RSRT for research aimed at reversing the underlying cause of the disorder. He is one of several dozen researchers around the world, recruited by Coenraads, who have met children with Rett and their parents, and are working on therapies, a cure or a reversal of the disease.

Rett syndrome is caused by a mutation of the gene on the X chromosome called MECP2 that causes numerous devastating symptoms that worsen over time. The symptoms begin in early childhood and leave Rett sufferers completely dependent on 24-hour-a-day care for the rest of their lives. While the function of MECP2 remains elusive, scientists know that it acts globally and impacts numerous systems in the body.

Female cells have two X chromosomes and therefore two copies of the MECP2 gene, and mutations occur in only one of the two copies of the gene. In females, however, one of the two X chromosomes is randomly turned off (or silenced), a phenomenon called X chromosome inactivation (XCI). As a result, in patients with Rett syndrome, half of the cells express a normal copy of MECP2 and the other half express the mutant copy. Importantly, in those cells that express the mutant MECP2, the normal copy is still present—just silent. Green is testing drugs that modulate XCI to reactivate the silent normal MECP2 gene in these cells as a strategy to reverse the disease.

“He is taking a somewhat unconventional approach, as he is attempting to reactivate the entire X chromosome and not just MECP2,” saidCoenraads. “His work first came to RSRT’s attention in 2009. We learned that he was conducting a screen to identify genes that control XCI. As his work matured over the next few years he did indeed identify factors that control XCI, some of which belong to molecular pathways for which there are drugs. These drugs can now be tested in culture and in vivo in Rett syndrome mouse models.”

Green praised the support he has received from RSRT and said the work that Coenraads and her colleagues do is inspirational.

“With NIH funding, you pretty much have to be doing mainstream research,” said Green, who was recently elected to the National Academy of Sciences. “The NIH doesn’t fund bold and innovative projects often. By contrast, organizations like RSRT are willing to take on high-risk projects that have controversial hypotheses and rationales, because these are the ones that really may have a great impact on disease.”

Read in its entirety

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The Milken Institute Global Conference, which explores solutions to pressing challenges including healthcare, took place today in Los Angeles.  FasterCures reported on the conference proceedings with the blog post below – two facts caught our attention:

  • Only 1 of every 10,000 academic discoveries make their way into the hands of patients….
  • Industry has 0.1% of scientists in world.  They are as good as any other scientists, but they’ll only have 0.1% of ideas. 

These facts truly bring home the message that academia and industry must work together.  And advocacy groups such as RSRT can play a major role in catalyzing these interactions.

FasterCures Blog

“We don’t just want to chase cures, we want to catch them,” said National Institutes of Health (NIH) Director Francis Collins at the Milken Institute Global Conference today in Los Angeles.  His comment aptly captured the prevailing sentiment of a panel of life science experts who came together to discuss creative strategies for speeding and improving medical progress across diseases in the face of limited resources. 

As moderator Melissa Stevens (Deputy Executive Director, FasterCures) pointed out, our knowledge of disease has never been deeper, but our need for cures has also never been greater.  Only 1 of every 10,000 academic discoveries make their way into the hands of patients, and the cost of developing a new therapy can soar as high as $1 billion. But it’s not all bad news.  With greater cross-sector collaboration and increasing levels of openness in research, we are poised to capitalize on the scientific opportunities before us.  “But we have to stop playing like solo artists, and start playing like a band,” said Stevens.

When asked how that band could best jam together, Collins gave the example of NIH’s Accelerating Medicines Partnership. A new venture between the NIH, 10 biopharmaceutical companies – including Johnson & Johnson and GlaxoSmithKline, both represented on the panel – and several non-profit organizations, it seeks to transform the current model for developing new diagnostics and treatments by jointly identifying and validating promising biological targets of disease.

Melinda Richter, Head of Janssen Labs, talked about industry’s commitment to sustaining innovation through collaboration, citing Johnson & Johnson’s role as key architect of Transcelerate and creator of the YODA project, as examples. “Jannsen labs enables scientists to think about their science in a commercial way, and creates a financial marketplace where people with money looking for technology and people with technology looking for money can find each other.” She went on to note that industry has a duty to make sure there is a strong investment profile for individuals looking to put money into the field. 

“There is a new level of humility within industry,” said Moncef Slaoui, Chairman, Global R&D and Vaccines at GlaxoSmithKline, who noted that the private sector recognizes the need to embrace open innovation and collaboration to solve medical challenges. “Industry has 0.1% of scientists in world.  They are as good as any other scientists, but they’ll only have 0.1% of ideas.  The other ideas are happening elsewhere so we need to figure out where and how to combine forces.”

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by Diana Gitig

Science, Nature, and Cell, The New England Journal of Medicine, The Lancet – these most prestigious of scientific and medical journals are published on a weekly basis, each week’s issue brimming with amazing new discoveries claiming to expand the state of knowledge in their respective fields, or better yet, to shatter current paradigms and shift future research to a new direction. Yet not every published paper stands the test of time; few manage to actually shatter paradigms, and there are those whose results even fail to be replicated by other scientists. The process of peer review is the method most journals use to vet their papers, to try to ensure that the results they publish are correct more often than not.

It works like this: after years of toil by graduate students and postdocs, a lab head prepares a manuscript describing their hypothesis, the experimental methods they used to test the hypothesis, the results of those experiments, and their interpretations of those results. Sometimes results prove the hypothesis to be true, and sometimes to be false. Either way, the results often suggest avenues for future research. Then the researchers must choose a journal, and send their manuscript off to the editors.

If the paper is obviously terrible or fraudulent, the editors will reject it outright. And if it is obviously earth shattering – and has well-controlled experiments, and an argument that flows logically from the results – they will accept it immediately without reservation. Since in the real world neither of these things ever actually happens, editors usually send the paper out for peer review, asking two to four scientists familiar with the field their opinions of the paper.

These peer reviewers must assess if the experiments used were the most appropriate ones available to test the hypothesis in question; if the experiments were performed properly; if the authors’ conclusions are consistent with the results obtained; and if the findings are significant – i.e. new and sexy – enough to warrant publication. Often, the reviewers will suggest that the authors modify wording, or  perform additional experiments, before the paper is published. This back and forth can take up to a year. These reviewers are anonymous, so the authors don’t get to engage with them directly. And the reviewers don’t ultimately decide if the paper gets published; the editors of the journal make that decision, based on the reviewers’ recommendations. If the paper is rejected, the authors are free to try the whole process again at a different journal.

Like most things in this world, peer review is not perfect. Reviewers must obviously be familiar with the topic at hand, so they are often colleagues – and can be competitors – of the researcher whose work they are reviewing. They can hold up the publication, or utilize the ‘insider information’ they glean from the paper to advance their own research. But on a less nefarious level, they are busy scientists who are not being compensated for their time reviewing this new paper, so it is often not their top priority. Nor have they had any training as to how to review a paper, since it is not built into science education. They also never get an assessment of their reviews, so they don’t know if they were helpful or if they need to improve. And peer review is not designed to pick up fraud or plagiarism, so unless those are really egregious it usually doesn’t.

Funding requests, like those submitted to RSRT, are subject to a very similar system. Just like journal editors, the people handing out research money rely on expert opinions to decide who gets how much. A grant is slightly trickier than a paper submitted for publication, though, because nobody knows a priori if the proposed experimental methods will work as hoped, or how significant the results might be.  As mentioned above, these things are difficult enough for reviewers to assess once the results are in – and in a grant application, the experiments haven’t even been done yet.

To minimize this risk RSRT employs a fastidious peer review. Reviewers are selected with painstaking attention to fields of expertise and potential conflicts of interest including philosophical or personality conflicts. Proposals are judged for relevancy to RSRT’s mission, scientific merits of proposed experiments and strength of the investigator.

There are stirrings of change to deal with these problems. Many scientists think that established journals have a chokehold on research by deciding what gets published, and are playing with a more open system whereby scientists publish their findings online – often for free, in contrast to traditional journals which charge a hefty fee for publishing a paper – where they are then subject to a more transparent post-publication peer review. Some examples are PLoSOne, BioMedCentral, and F1000Research. Other researchers think pre-publication reviews should be signed, so the reviewer has some accountability.

Forums that allow for ongoing critiquing of papers after publication are gaining momentum.  Examples include PubMed Commons, PubPeer, Open Review. RSRT is a fan of post publication peer review and has long employed this approach to evaluate papers in the Rett field.

One way scientists assess the relative importance of an academic journal is by its impact factor, a way to measure a journal’s prestige. It measures the average number of times recent articles published in the journal have been cited in a given time period, usually a year. Journals with higher impact factors – like those that began this piece – are deemed more important than those with lower ones. Impact factors have been published annually since 1975 for journals that are indexed in Journal Citation Reports and have been tracked by Thomson Reuters (ISI) for three years.

No scientific paper is intended as the be all and end all of truth. That is how the scientific method works, and where its beauty lies; each discovery is “true” only until new experimental evidence comes along that refutes it. Peer review cannot guarantee that a paper’s results will be reinforced over time. But it does act as a gatekeeper or first responder, trying to ensure that papers that are published in scientific journals are experimentally and logically sound.

References/ Further reading

http://arstechnica.com/science/2010/11/the-vagaries-of-peer-review/

http://boingboing.net/2011/04/22/meet-science-what-is.html

http://www.wired.com/wiredscience/2012/02/is-the-open-science-revolution-for-real/

http://blogs.scientificamerican.com/the-curious-wavefunction/2013/01/29/peer-review-pitfalls-possibilities-perils-promises-scio13/

http://johnhawks.net/weblog/topics/metascience/journals/tracz-interview-f100research-2013.html

http://wokinfo.com/essays/impact-factor/

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