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The NIH Grant Package For CFS - "Neuroimmune Mechanisms and Chronic Fatigue Syndrome":  Making the Difference or More of the Same?
Part IV: Conclusion - Assessing the Grants by Cort Johnson

As an introduction to a series of papers exploring the state of CFS funding at the NIH I focused my attention on the NIH’s big effort in this regard; the $4,000,000 grant package on Neuroimmune Mechanisms in CFS. While $4,000,000 doesn’t go all that far in medical research this was a significant endeavor; the RFA had the potential to double NIH funding for CFS research.

Three years, one conference and - according to Dr. Hanna, the leader of the CFS research program at the NIH - a lot of hard work later, this effort culminated in these 7 grants. The NIH RFA is a good test case for the NIH; it is the first major initiative by the Office For Research into Women’s Health (ORWH) to implement its new multidisciplinary approach to CFS and it was widely trumpeted as proof that the ORWH and the NIH are serious about re-invigorating CFS research. Given the decline in NIH funding for CFS - now reduced to early 1990's levels - the RFA couldn’t have come at a better time. Given the kinds of studies the NIH likes to fund - complex, innovative, expensive, multi-systemic studies – a fully funded RFA would be a considerable breakthrough for CFS research.

In this four part series we have charted the positives (the purely biological approach, a focus on some important issues) and the negatives (the possibility of non-CFS grants being funded, the few CFS researchers at the conference or on the review committee, the inclusion of some peripheral issues in both, etc.). Now, we ask, how did the NIH do? Was the RFA a success? Did the NIH pick good grants? Did they include CFS patients? Did they use CFS researchers? It's been suggested these grants are an exciting development. Are they? Let’s find out.

Researcher Interest - One purpose of the RFA was to spark investigator interest. Officials at the NIH have repeatedly said that one reason CFS has not been better funded has been a lack of researcher interest. The research community responded well to the RFA; at least 29 grant applications – enough for the NIH, even with a high rejection rate, to fund 10 or so grants. The response was good enough, in fact, for Dr. Hanna to state at one point that $4,000,000 was the floor, not the ceiling, and speculate that the funding level could increase if the Institutes found more projects they wished to fund. The CFS research community appears to have kept its part of the bargain.

Analysing the Grants - Each grant gets scored on its applicability to CFS pathophysiology. The type of grant it was funded and the Institute funded it are noted. The scores are

Plus the type of grant is noted. This RFA involved two different kinds of grants

The Funder -.The CFS research program is in an unusual position in the NIH; most diseases have a base within one of the 28 Institutes and Centers that make up the institution, but the CFS research program does not. CFS is based in the Office for the Research into Women’s Health (ORWH), an organization with little funding ability itself which lobbies Institute representatives to get the funds on a project by project basis. Identifying which Institutes stepped up to the plate at this RFA may give us some insight into which Institutes are willing to support CFS research.

The NEUROIMMUNE GRANTS OF 2006

‘The Autonomic Nervous System in Chronic Fatigue Syndrome’

Italo Biaggioni, Vanderbilt University – RO1 Grant – National Institute of Neurological Disorders and Strokes (NINDS) – Score 33 – $382,500 - 2006

CFS Experience – none, well published author focused on autonomic nervous system research

This study ties together several prominent areas of interest in CFS; the sympathetic nervous system, inflammation, oxidative stress, nitric oxide, low blood volume. Dr. Biaggioni proposes that the low blood volume seen in some CFS patients occurs when their sympathetic nervous system (SNS) stops the cells lining the blood vessels from producing a substance called nitric oxide (NO). Since NO is a vasodilator low NO levels would lead to blood vessel narrowing (constriction) and host of problems including low blood flows to the muscles and brain and other organs. In this study Dr. Biaggioni will measure indices of SNS activity, inflammation and oxidative stress. This is just the kind of complicated, multi-dimensional study that we need the NIH for. This is an excellent study. Score 1 for the NIH!

‘Neuropeptide Y and Dipeptidyl-peptidase IV (CD 26) in Chronic Fatigue Syndrome’

Mary Fletcher, University of Miami – R21 Grant – National Institute of Alcohol Abuse and Alcoholism (NIAAA) – Score 33 - - $200,321 - 2006

CFS Experience – extensive, leader of the group that characterized natural killer cell dysfunction in CFS

Mary Fletcher has led efforts to characterize natural killer cell dysfunction in CFS. Over the past 10 years her team uncovered poor NK cell functioning in CFS, developed a test to measure it, determined that levels of the main cytotoxic factors in NK cells, perforin, are low in CFS, and has recently found a subset of CFS patients who have particularly low NK cell functioning. She has an impressive track record and is an important CFS researcher.

In this study Dr. Fletcher extends her NK cell research to the sympathetic nervous system. A substance called neuropeptide Y (NPY) produced by the sympathetic nervous system suppresses NK cell functioning. NPY production is controlled by a regulator on our lymphocytes called CD 26 (dioeptidyl-peptidase IV). Evidence from her lab suggests that CD 26 concentrations in CFS are low. In this study Dr. Fletcher will determine if abnormalities on CFS patients’ lymphocytes result in both sympathetic nervous system and immune problems. This is another excellent study - Score another for the NIH.

This study seemed like such a natural fit for the National Institute of Allergy and Infectious Diseases (NIAID) but it ended up being paid for by an Institute - the National Institute of Alcoholism and Abuse – that has absolutely no interest in CFS. Why the NIAID – traditionally a large funder of CFS research – stepped away from this study is unclear but it suggests that there’s more to the funding process than meets the eye.

‘Mast cells, Antidepressants and Chronic Fatigue Syndrome’

Theoharis Theoharides, Tuft University – R21 Grant – National Institute of Alcohol Abuse and Alcoholism (NIAAA) – Score 33 - $275,906 - 2006

CFS Experience – none, extensive publications on mast cells

This study appears to have been fated to be funded. This subject, mast cells and anti-depressants, was the focus of a presentation at the Neuroimmune Mechanisms Conference  and was specifically mentioned in the RFA. Never mind the fact that mast cells have never been investigated in CFS, and except for one paper by the author, have never to my knowledge have been mentioned with regard to CFS, or that there is no evidence that anti-depressants do anything other than ameliorate symptoms in those CFS patients with depression.

To add injury to insult, the central hypothesis of this project, that CFS is caused when high corticotropin releasing hormone (CRH) levels activate central nervous system mast cells, is contraindicated by the fact that CFS patients have low not high CRH levels. This project is not aimed at CFS patients – who have a hypoactive HPA axis - but at depressed people who  have a hyperactive HPA axis. This project doesn't involve CFS patients – it’s purely a laboratory study – but then again how could it? They don’t fit the bill.

The fact that this study made it suggested the review committee was unfamiliar with the neuroendocrine literature on CFS. Dr. Hoffeld reviewed the grants before hand and reportedly threw out a number of grants that he felt didn't fit the parameters of the RFA. He should have thrown this one out as well. The only consolation was that it was a smaller R21 grant not a full RO1 grant.

Here again we have the NIAAA  (the 'Alcoholism Institute) not the NIAID or the NINDS (National Institute of Neurological Disorders and Stroke) funding a neuroimmune study. 0 points for the NIH

‘Cognitive Behavioral Stress Management for Chronic Fatigue Syndrome’

Micheal Antoni, University of Miami Coral Gables – R01 Grant – National Institute of Neurological Disorders and Strokes (NINDS) – Score 22 – $343,219 - 2006

CFS Experience – no published papers on CFS, recipient of former NIH CBT grant

Neither cognitive behavior nor other behavioral approaches to CFS were mentioned in either the Neuroimmune Conference or the RFA. The discourse in both was unfailingly biological and the title ‘Neuroimmune Mechanisms and CFS?’ bore out this emphasis. So how did a behavioral study show up here?

It turns out there is a rationale for fitting this particular study into this RFA. If CBT works, it should change the physiology of its recipients and this is the first CBT study I have seen that examines whether it does so. In this study Dr. Antoni, an associate of Dr. Klimas, will examine cortisol and pro-inflammatory cytokine levels before, during and after the CBT treatment. This is not the kind of grant we wanted to see here; it’s not focused entirely on CFS pathophysiology and it’s a major grant – a 4 year RO1 project – that will eat up a lot of money, but if we’re going to have a CBT grant this is the kind of grant we would want to see and the researcher we would want to see doing it. .5 points for the NIH

Proteomics of Cerebrospinal Fluid in Chronic Fatigue Syndrome

James Baraniuk, Georgetown University – RO1 Grant – National Institute of Environmental Health and Sciences (NIEHS) – Score 22 – $379,720 - 2006

CFS Experience – author on allergic rhinitis and a protein signature in the cerebrospinal fluid of CFS patients

This study seeks to replicate and expand Dr. Baraniuk’s stunning brain proteome study of 2005 (Phoenix Rising ‘Paper of the Year’). That study suggested that protein aggregation (amyloidosis) was occurring in the blood vessels of CFS patients’ brains. This project expands that study by extending the number of sample sets, by attempting to identify not only a protein signature but a unique protein biomarker as well and by attempting to correlate specific proteins with specific symptoms.

This is a great study but it’s not ‘new’ research. The RFA was intended to spark new initiatives and bring in new researchers and this study has neither. Given the success of Dr. Baraniuk's previous study it seems hardly possible that this study wouldn’t have been funded by the regular CFS SEP. Given the Institutes’ reluctance to support CFS research, one wonders if it knocked another study off the list. Still it's an excellent study that could reap many benefits for CFS patients. This is a fully funded four year grant (RO1). Score another for the NIH

Yet here we have another strange funder; the National Institute of Environmental Health and Sciences. This is the first CFS study the NIEHS has ever funded. Does this mean the ORWH is having difficulty getting funding from institutes that have funded CFS in the past?

Stress and Neuroimmune Dysregulation in Chronic Fatigue Syndrome

Light, Kathleen, University of Utah – R21 Grant – National Institute of Neurological Disorders and Strokes (NINDS) – 11 - $154,395-2006

CFS Experience – none, well published author on endocrine subjects

This is two studies in one. One examines cardiovascular, sympathetic nervous system, endocrine and immune (cytokine) activity during exercise and mental stress in CFS patients. Encouragingly this study examines these parameters during exercise and in the post-exercise period. It is another excellent multi-systemic study.

The second part of this grant will determine if there is a familial predisposition to CFS; i.e. if CFS runs in families. If this study is successful researchers will begin to look for genes that predispose one to CFS. It is a good study but it doesn’t have anything to do with neuroimmune mechanisms. Half a point for the NIH

Human Spinal Cord Glial Cytokines and Chronic Pain

Diane Lorton, Sun Health Research Institute – R01 Grant – National Institute of Arthritis and Muscoskeletal and Skin Diseases (NIAMSDS). $296,311-2006

CFS Experience – none, no research papers found

This project aims at forming a fibromyalgia tissue bank of cerebrospinal fluid, spinal cord and brain tissue. The researchers will use these tissues to study glial cell production and pro-inflammatory cytokine production in fibromyalgia patients. This kind of study was made possible when the Neuroimmune RFA left the door for this ‘CFS grant’ to fund studies into other diseases. To make matters worse, since this is a RO1 grant it eats up a lot of funds. It’s certainly a worthy project but it doesn’t belong in a RFA grant intended for increasing research into a poorly funded disease like CFS. O points for the NIH.

Finally we have a  funder - the 'Muscoskeletal Institute' - that makes sense.

ANALYSIS - The 2006 NEUROIMMUNE GRANT PACKAGE

Overall Grant Package - Seven grants totaling $2,032,372, or half the projected total, were funded. Four grants were focused on CFS pathophysiology, one was on a process (HPA axis hyperfunction) not found in CFS, one was on FM and one was on cognitive behavior therapy with a neuroimmune component.

Two of the four ‘good grants’ were R21’s – short 2-year studies. Two of the three ‘losers’ on the other hand, were RO1’s, costly 4-year grants. Instead of $2 million the NIH actually ended spending $1,116,937 on studies of CFS pathophysiology. Thus only about a quarter of the projected $4,000,000 was spent on studies directly focused on CFS pathophysiology, a rather stunning disappointment given the good response from the CFS research community. Unfortunately this is what one has come to expect from the NIH; in the last couple of years, only about half the funds they attributed to CFS research actually went to CFS projects.

NIH officials have stated new researchers are needed to revitalize the CFS research  program and it was hoped that the RFA would begin this process. The RFA ended up, however, rewarding researchers who were already accomplished at negotiating the grant review process at the NIH. All had recieved NIH grants before.

Individual Grants - The final grant score was 4 out of 7 points; a C. There are some excellent projects here; the Biaggioni, Fletcher and Baraniuk and half of the Light study, are all excellent studies and they are a cause for celebration. It was very welcome to see several studies emphasize the sympathetic nervous system; an important subject that was mostly ignored in the Neuroimmune Conference and RFA. This suggested the review committee had the flexibility to look outside the guidelines of the RFA.

Still if one considers that the Baraniuk grant was probably already a ‘given’, a close examination of the grants indicates that this long process actually yielded only three grants the CFS community might not otherwise have seen. Given its available funding the grant package had the potential to yield four times as many studies.

How did a project that appeared poised to succeed falter so badly at the end? This is not an easy question to answer. Dr. Hoffeld, the administrator of the CFS SEP that reviews CFS grant proposals has described the NIH grant process as a kind of ‘black hole’. NIH rules preclude us from learning much about the rejected grants; we can’t learn who submitted them or find out how they were scored or what comments they were given. Indeed it can be difficult even to determine how many grants are submitted. (This was a rare occasion when it was publicly announced.)

A review of the grant process suggests some possible culprits.

Lack of Agency Support - The success of any grant process in CFS is dependent upon the willingness of the 14 Institutes that make up the Chronic Fatigue Syndrome Working Group (CFSWG) to fund CFS projects. These Institutes fund a wide variety of medical research topics involving the immune system, cardiovascular and nervous systems and others. Some Institutes (NIAID - immune, NINDS – nervous system) have close ties to CFS research subjects but the connections of most of the other Institutes (e.g. NIAAA, NIEHS, NINR) on the CFSWG are tenuous. A successful CFS research program will need the support of the Institutes (NIAID, NINDS and NHLBI ) with the mandates to study CFS related subjects.

The NINDS did fund several of the grants in this package but the other major funders did not. Most surprising was the inability of the 'Immune Institute', the NIAID, to fund a single CFS grant in a Neuro-Immune Grant. Instead, two Institutes that between them have funded only a single CFS grant over the past 15 years, the National Institute of Alcohol Abuse and Alcoholism (NIAAA) and the National Institute of Environmental Health and Sciences (NIEHS) stepped up to fund almost half the grants in this package. T

Another warning sign concerns the amount of time the ORWH needed to find the funds for the RFA. Dr. Pinn, the director of the ORWH, told me that grant package was the lowest she felt she could put forward without being embarrassed. Yet it still took two years and a congressional outcry to get the Institutes 'on board' and the grant package moving. This was doubly disappointing since it  took place during a time when the Institutes were funding less CFS research than they had for at least a decade and just after the NIH budget had undergone an unprecedented increase. Even with their coffers flush and the CFS research program faltering the Institutes still balked at supporting a small grant package for CFS. 

Dr. Hanna recently stated that the CFS research program has two options; it can either have a research grant program or have a Centers of Excellence program – the Institutes would not support both. Six years ago, however, they were supporting both. This suggests that institutional support of CFS has declined dramatically under the ORWH.

Lack of Researcher Support – It’s possible that the CFS research community simply did not rise to the occasion. NIH officials have long said that most CFS research grants have lacked innovation. Did the rejected grants not meet the test of innovation? This is impossible to tell but at least one researchers experience suggests not.

Dr. Andrew Lloyd has an extensive resume; over the past 10 years he has co-authored approximately 40 papers on CFS, hepatitis C, fatigue states in cancer, HIV and others. He is the leader of the groundbreaking Dubbo project examining the physiological changes occurring as people come down with CFS following infection.

The Dubbo project’s next course was to be an examination of the neuro-immune interface in CFS. Despite Dr. Lloyd’s resume, the success of the past Dubbo projects, the innovative nature of these projects, and the fact that they fit the parameters of the Neuroimmune RFA, neither of two grants he submitted were funded.

A Failed Process - Unfortunately we don’t know where in the process the Lloyd grants failed. Poor scores by the initial reviewers or a lack of institute support could have sealed their fate. The grant review panel has been a point of contention almost since a special panel was formed to review CFS, FM and TMD grant proposals. The CFIDS Association appealed in vain for an administrator other than Dr. Hofford to overview the review process. While the RFA panel Dr. Hofford assembled was a step up from others before it, it did not include many CFS researchers and had a number of poorly qualified reviewers (click here).

Special grant mechanisms like RFA’s give NIH officials a justification for overlooking poor review scores and funding studies they believe have value. Dr. Hofford has, in fact, stated the Institutes regularly pass over more highly scored grants and fund less well scoring ones. Given the Dubbo project’s record of success, its innovative nature (something NIH officials say again and again they do not see from CFS researchers), and the faltering CFS research program, an alert and pro-active CFS research program would have found a way to fund these projects.

Conclusions: Given the opaqueness of the NIH grant process, it is impossible  to know why this RFA sputtered so badly at the end. If we go back to the beginning, however - the Neuroimmune Conference in 2003 - plenty of warning signs are evident. The few CFS presenters, the lack of discussion on CFS, the presentations on other diseases, the focus on ancillary subjects such as antidepressants all suggest that the NIH has an institutional difficulty focusing on CFS.

The RFA was strong - it emphasized CFS pathophysiology and provided many opportunities for CFS researchers but itallowed for projects on other diseases. The choice of Dr. Hofford – someone the CAA actively lobbied against – as the review panel administrator was not encouraging. The long lag time between RFA's announcement and its actual funding date suggested the ORWH had trouble getting the Institutes on board. The fact that the ORWH had to take funds out of other programs to pay for the RFA suggested a lack of support for the CFS research program at the Office of the Director. These warning flags suggest the CFS research program at the ORWH faces many hurdles that impair it from mounting a strong effort.

The NIH is a very, very important part of the CFS research effort. It is one of the few institutions that can fund the kind of expensive, multi-dimensional studies that CFS desperately needs. They NIH has and is doing vital work in CFS; many of the brain studies, most of the cardiovascular studies, the natural killer cell studies and most of the twin studies came out of the NIH. Even when the NIH fails it can succeed in ways other funders cannot; few institutions are able to fund studies as complex and expensive as the Biaggioni or Baraniuk ones.

Making the Difference or More of the Same?  In several ways the process appeared to exemplify a more-of-the-same approach. The inability of an experienced CFS researcher to be awarded grants for an ongoing project aimed squarely at the focus of the RFA is inexplicable and alarming. The grant package unveiled several problems the CFS research program at the ORWH  faces including poor institutional support at the research and funding levels and a failed review process.  

  Neuro-Immune RFA Intro / The Neuro-Immune Conference / The RFA Grant / Reviewing the Reviewers