Reprinted with the kind permission of Cort Johnson and Health Rising
By Cort Johnson
And then there were three.
Almost two years after Dr. Collins announced that the NIH would reinvigorate ME/CFS, the NIH has finally provided funding for three research centers and one data center.
Earlier this year the ME/CFS research community surprised by submitting no less than 10 applications, including one from a research group new to the field.
The Center for Enervating Neuroimmune Disease (Cornell) – Maureen Hanson
The Center for Infection and Immunity – Ian Lipkin
The Genome Technology Center at Stanford – Ron Davis + Bob Naviaux
The Institute For Neuroimmune Medicine – Nancy Klimas
Lenny Jason at DePaul University – Lenny Jason
The Nevada Center for Biomedical Research – Vincent Lombardi
Pain and Fatigue Study Center – Dane Cook
Stanford Chronic Fatigue Initiative – Jose Montoya
The Jackson Laboratory (Connecticut) – Derya Unutmaz
Beth Isreal Deaconness Medical Center – Associated with Harvard Medical School – Dr. Janet Mullington
That number guaranteed that the competition was going to be stiff – and that some perfectly good projects were going to get stiffed. Of course, there was probably going to be controversy. The NIH seemingly can’t sneeze around ME/CFS without creating something controversial. Even its good stuff creates controversy. From the IOM report to the extramural study and now to the research centers, something controversial always seems to show up. I think that’s partially the result of an unusually active and informed disease community.
As Vickie Whittemore explained in a Solve ME/CFS Initiative article, each grant was scored for five factors (significance, investigators, innovation, approach and environment) by at least three reviewers. The final review was done by Institute and Center National Advisory Councils or Boards composed of both scientific and public representatives.
The applications included research groups relatively new to the field (Lipkin, Hanson, Davis, Unutmaz, Mullington) and research groups that have been associated with ME/CFS for longer (Klimas, Jason, Natelson, Montoya, Lombardi).
The three winners, all on the eastern side of the U.S.: Dr. Ian Lipkin of Columbia, Maureen Hanson of Cornell and Derya Unutmaz are all relatively new to the field. They have a few things in common: they all entered the field in the last five years or so, and most are associated with top labs employing cutting-edge technology. They’re all taking a deep look at the immune system, and, this wouldn’t have been true even a couple of years ago, two will be studying the metabolism and metabolomics and/or the microbiome.
Ian Lipkin – Pathogens, Immune Disruption and Metabolism
Ian Lipkin, of course, is internationally known for his pathogen work, runs an enormous and well-respected lab, regularly creates new technologies, and has been a passionate advocate for ME/CFS. He was widely expected to be a front-runner, and it was no surprise that he won out.
Lipkin will finally be able to dig into the hundreds of ME/CFS samples he and Mady Hornig collected which have been lying fallow in his lab for a year or so. They’ll do a complete array of pathogen and immune testing to try and figure out how a simple infection turned so devastating in so many people with ME/CFS. Lipkin will also explore gene expression and metabolic changes before and after exercise. More on Lipkin and his work in an upcoming blog.
Maureen Hanson – The Exercise Center
Coming from a plant biology background, Maureen Hanson entered the field with a bang, scoring one of the few XMRV grants and then moving on to win several other grant awards. A nimble researcher, since 2012 Hanson has published no less than six studies covering a wide variety of factors in ME/CFS including the gut, mitochondrial DNA, exercise and metabolomics. Hanson, who has a son with ME/CFS, has shown the ability to knock her studies out in timely fashion – a rather rare commodity in ME/CFS – and something that is greatly appreciated.
Hanson has personal experience (her ill son) with the costs ME/CFS wreaks on those who have it and their families.
“Being awarded an NIH ME/CFS Center means we have taken on a huge responsibility to the more than one million people affected by this life-limiting disease that has no FDA-approved drugs and a poor prognosis for recovery.”
In what is probably some sort of record, Hanson is on the Scientific Advisory Boards of the Simmaron Research Foundation, the Open Medicine Foundation and The Solve ME/CFS Initiative (SMCI). A vocal advocate, Hanson is well-respected by all, and is clearly an excellent choice.
The Cornell Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Collaborative Research Center
The new Cornell Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Collaborative Research Center will include researchers and doctors from the Weill Cornell Medical College, Ithaca College, the Boyce Thompson Institute, the Workwell Foundation, EVMED Research, the SOLVE ME/CFS Initiative and private ME/CFS medical practices.
“The ultimate goal of all this is to find the fundamental disruptions, so that we can discover treatments to mitigate those disruptions and restore people to health,” Hanson
Hanson will be highlighting the “disruption” occurring in ME/CFS by featuring the most effective disrupter possible – exercise – to bring out the most telling problems in ME/CFS patients’ systems. Closely affiliated with ME/CFS exercise physiologists (Betsy Keller, Workwell) Hanson’s is the only center to so completely integrate stress produced by exercise into all aspects of her studies.
Hanson’s will also be the only center to examine the brain. Using MRI and PET scans, she and Dr. Shungu will look for markers of neuroinflammation and oxidative stress in the brains of ME/CFS patients and healthy controls. Finding out what happens after exercise to the reduced antioxidant and increased lactate levels in the brains of ME/CFS patients Shungu has found thus far will be fascinating.
Hanson will bring something absolutely new to the field with a project on “extracellular vesicles”: free-floating membrane-surrounded blobs containing proteins, lipids, hormones and RNA’s. These “cargo carriers” release their products into cells when they fuse with them, and appear to play a role in many functions including how the immune system (including B-cells) react to pathogens. Hanson believes exercise may be causing these vesicles to release inflammatory factors that contribute to the PEM in ME/CFS. Since extracellular vesicles are new to ME/CFS research, my guess is that she’s gathered some nice pilot data on them.
Hanson’s third project will sequence the RNA in individual white blood cells before and after exercise. Since RNAs are the messengers the cell uses to produce proteins, this third leg will examine how exercise alters the activity of immune cells.
Derya Unutmaz – The Integrater
Derya Unutmaz is the dark-horse candidate here. With no ME/CFS publications under his belt, and the latest arrival to the field, Unutmaz clearly had his work cut out for him. Unutmaz, though, is affilated with a top lab, and presumably has some hot pilot data that helped him win out.
After getting turned onto ME/CFS by Suzanne Vernon (then at the SMCI) around 2014, Unutmaz, an immunologist and T-cell specialist, became intrigued by what he was seeing in his lab. Whatever he found was intriguing enough to score him a rare NIH ME/CFS grant.
Suzanne Vernon was overjoyed at Unumatz’ success
I’ve had to pinch myself ever since Dr Unutmaz became intrigued with ME/CFS and integrated ME/CFS immune profiling into his large immunology research program. For the longest time we (the ME/CFS research and patient community) have said we should and could learn from other immune dysfunction diseases. Now we have one of the world’s top immunologist who has researched and published extensively on HIV, chronic diseases and aging working to decipher ME/CFS. Unutmaz embraces the biological complexity and this is one of the reasons it was easy for him to say “yes” to ME/CFS research and take a comprehensive system biology approach in his funded CRC.
Check out the SMCI webinar Unutmaz gave to the ME/CFS community on his work in 2014
Unutmaz has said he’s been particularly intrigued by two things in ME/CFS – the immune data he’s been seeing and b) the possibility of making a huge difference in an under-researched field.
Taking samples at different time points during the year, Unutmaz’s Center will employ a longitudinal approach to ME/CFS that will look at how three systems interact with each other to produce ME/CFS.
Immune system – using his state of the art flow cytometer, Unutmaz will determine which parts of ME/CFS patients’ immune systems are perturbed.
Gut – given the microbiome’s enormous impact on the immune system (Unutmaz referred to thousands of gut species impacting it) Unutmaz will attempt to determine what microbiome problems are present and if they are throwing the immune system off.
Metabolism – everybody it seems is into metabolomics now, and so is Unutmaz.
Unutmaz will use computational and statistical techniques to determine how these different systems impact each other. Could a problem producing energy, for instance, effect how the immune system is functioning? Are gut issues causing immune problems? Could low energy production be associated with poor immune regulation; i.e. an ongoing autoimmune process?
Ultimately, Unutmaz, who’s finding ME/CFS patients to be quite heterogeneous, will attempt to uncover biological signatures which stratify patients and produce new hypotheses to test. Unutmaz has been tweeting up a storm since the announcement. Check out his tweets here
The Missing Centers
It was clear from the get-go that some good proposals were not going to get funded. I was surprised, for instance, that Nancy Klimas, given her long research history and the big team she’s built at Nova Southeastern, was not funded.
That said, the exclusion of Ron Davis was the other big story. Davis was clearly the patient community’s favorite. A 13-page thread on the Research Centers on Phoenix Rising
was dominated not by expressions of glee that the Research Centers were finally underway, but more by dismay that Davis’ Center was not selected.
On the face of it Davis’ rejection is hard to understand. Davis has lead major projects before. He’s the biggest name in the field, and has extensive connections, and his application showed that. Mark Davis, Stanford immunologist, Mike Snyder, the Chair of what’s considered the best genetics department in the world, Craig Heller, William Robinson (immunologist/rheumatologist) 12 publications thus far this year, Lars Steinmetz (genomics technology pioneer), Bob Naviaux, Lucinda Bateman and Sue Levine and many others certainly made Davis’ application top-heavy with big names.
Davis’s application didn’t make it though. Janet Dafoe, Ron Davis’s wife, took the unusual step of publicly reporting some of the reviewers concerns about the Davis grant on Phoenix Rising. She did this because
He (Ron Davis) thinks it’s important for people to know that because his grants have been rejected it doesn’t mean it’s bad science, because if people think that then the private donations will be negatively affected. He has to rely on private donations. We need them. It’s good science. It was an excellent grant.
Lack of Publications – She noted that Davis’ application was marked down for his having no ME/CFS publications and for not having ME/CFS experts on it. There was no escaping the publication issue for Davis. He has not published and so was destined to score low on this criteria.
The publication criteria does seem to be of diminishing importance at this point, however. The NIH’s main goal – to invigorate the field and bring in new researchers who will apply for and be successful at getting grants – is at odds with a criteria that supports those already in the field. Davis doesn’t have publications yet, but his research center would have brought in a stable of top researchers new to the field – the NIH’s key goal.
No ME/CFS Experts? Davis’ main team is not filled with ME/CFS experts, but Dr. Bateman, Dr. Levine and Bob Naviuax have all published on ME/CFS, and Davis himself spent a year going over thousands of studies for the Institute of Medicine project. Being appointed to an august body such as the Institute of Medicine to prepare a report on ME/CFS surely qualifies Davis as an ME/CFS expert.
Mediocre Institution (???) – In what must have been a jaw-dropping moment for Davis and for Stanford itself, the institutional environment for Davis’ grant – one of five major factors in Davis’ score – was rated “mediocre”. Stanford, of course, has one of the top medical schools in the world. Dafoe reported that the Stanford grant review office stated they have never seen in their entire history anywhere near that low of a score. This score is a big red flag that something went very wrong with this review.
Conflicts of Interest? – In another jaw-dropper, the reviews also suggested that Davis’ work with a non-profit (the Open Medicine Foundation) was a conflict of interest, despite the fact that each applicant was required to work with a non-governmental organization (NGO) and that the NIH lauds its private-public partnerships.
Having his wife, Janet Dafoe, on the community outreach portion of the grant was considered a negative. Janet also had a conflict of interest because her son has ME/CFS (Maureen Hanson’s son has ME/CFS as well).
Nano-needle – Davis’ application had at least one significant hurdle in the science area to overcome. A portion of the grant was dedicated to improving and validating the work of the nano-needle – a new instrument with vast possibilities – but whose fate, because it is still under development, is uncertain. Davis, of course, has been very effective at creating biological technologies. His lab has birthed dozens of companies. One might have thought that if, after decades producing breakthrough technologies, Davis thinks the nano-needle has a good shot, that might mean something. It turned out that it didn’t.
Instead a reviewer cited the fact that nano-needle wasn’t “government-certified” for medical use in patients as a problem. Since the goal of the project was to develop the nano-needle so that it could be used in patients, that criteria automatically eliminated it from consideration.
Unproven Technology – The project to produce induced pluripotent stem cells (iPS) was rejected because it used unproven technology – yet Janet Dafoe noted that the ME/CFS Intramural Study run by the NIH is using that very technology.
Some of the reviewers’ considerations regarding the Davis application seem petty and just plain wrong. While Davis has been the most public with his dismay, he wasn’t the only one shocked at his poor score. Reports from people associated with five of the applications, none of which made the cut, suggested that other groups were surprised at how poorly they scored.Two groups wondered, if their scores were so poor, if anybody was going to make the cut.
We’ll probably never know what happened, but here are two suggestions: unprepared reviewers and sour grapes.
Not the Best Reviewers: It’s possible that some of the reviewers were not up to the task. Reviewing an ME/CFS research center grant proposal is not exactly a job that most researchers probably jump at.
Sour Grapes: Through their outreach, Davis and the OMF have won the hearts and minds of much of the ME/CFS community, and they’ve been effective fundraisers to boot. It’s inevitable that some backlash has occurred. Davis has been honest from the beginning that his goal has not been to produce papers, but his lack of publications really grates some in the community.
Some of the reviewer comments – perhaps from ME/CFS reviewers (?) – suggest some hostility at OMF’s success could be present. (I have not seen and don’t have any knowledge of the reviews other than what I’ve read. This is pure conjecture.)
On the other hand, it must be noted that the reviewers did pick three excellent research centers. Whatever happened with Davis and other groups, the research center review was largely a success.
Could it have turned out better? I would have loved to see the NIH go out on a limb a little and given Ron Davis the opportunity his career suggests he should have in this field. Davis’ project is the most risky, but if successful, it appears to have the ability to move the field forward very quickly. The nano-needle could potentially provide a diagnostic test, help determine factors in the blood that are hurting people with ME/CFS, and even become a drug-screening tool.
Also lost was funding for Bob Naviaux, Mark Davis’ intriguing new immune findings, and Mike Snyder’s stem cell work. For me, it’s a lost opportunity.
Overall A Big Win for the ME/CFS Community
The research centers aren’t perfect. Several researchers believed the heavy reporting burden and the need to provide for extramural funding was going to hamper their performance. One researcher decided to go apply for single grants instead of a center because of those factors. While the research centers may be a little “skinny”, they still constitute a major infusion of funding for chronic fatigue syndrome over five years – @ $35 million.
While many dearly wanted Ron Davis’ application to win out, the NIH’s research center grant was a success overall. Ian Lipkin will finally get the funding (or at least some of it ?? needed to get his long-hoped for big ME/CFS projects going; Maureen Hanson ‘s “exercise center” will be determining how exercise effects the brain, the immune system, and gene expression, and Derya Unutmaz is going to use his big lab to see if he can figure out how immune, gut and metabolism problems fit together to produce ME/CFS. These efforts should produce some nice big, well-formed studies, the results from which no one can argue with.
Plus, there’s a silver lining. The biggest problem at the NIH has been the lack of ME/CFS grant applications. The NIH, after all, can’t fund grants it doesn’t get applications for, and Koroshetz has warned that diseases cannot rely on research centers. Most NIH funding is in the form of individual grants. The ME/CFS research community met the “research center challenge” with its ten applications. Now it needs to meet the “individual research grant challenge”; i.e. ME/CFS researchers need to start applying for individual research grants in volume.
The Research Center application has already begun to resolve the low individual research grant application problem. In fact, that problem should basically disappear for the next year. The seven groups that didn’t win out should have from 15-20 individual grant applications ready or nearly ready to present.
The next grant review, which begins in October, will hopefully be one of the biggest in the history of this disease. Ron Davis, Nancy Klimas and Vince Lombardi have all said they will be submitting grant applications. By next year we could/should have five or more big studies adding perhaps $7-10 million or more in grants to the funding pie. We should at least expect the Research Center process to lead to a significant uptick in extramural funding next year.
About the Author:
Cort Johnson has had ME/CFS for over 30 years. The founder of Phoenix Rising and Health Rising, Cort has contributed hundreds of blogs on myalgic encephalomyelitis, chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort's and other bloggers' work at Health Rising