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The Solve ME/CFS Initiative’s webinar with Dr. Avindra Nath revealed again what an extraordinary study the NIH intramural study at its Clinical Center is.  The Webinar started off with Dr. Nath stating that it was “such a pleasure” to talk to the chronic fatigue syndrome community, and that he was “absolutely thrilled” to be leading the study.

Nath said he was thrilled to be working on ME/CFS

Nath said he was thrilled to be working on ME/CFS

His interest in ME/CFS derives from the patients he’s seen over the years (he’s an MD) as well as patients he’s seen in the multiple sclerosis clinic. Fatigue, he noted, is the most disabling part of MS. Given the immune nature of that illness as well as the effects MS drugs can have on fatigue, he thought it was likely there was an immune basis to ME/CFS.  (He also mentioned the Rituximab studies.)

On that note be sure to check out, if you haven’t, one ME/CFS patient’s rather amazing  response to an MS drug:  A Chronic Fatigue Syndrome/POTS Patient Responds to a Multiple Sclerosis Drug – What Does It Mean?

Note that this is Nath’s study. He’s the one Collins came to and he’s the one putting the study together.  Because he’s a neuroimmune infectious specialist the study is heavy on nervous system and immune studies but because he also studied the literature (and talked to a lot of people) there are also exercise, autonomic nervous system and other components.

Given Nath’s background it’s no surprise that the study focuses on people with infectious onset. He believes an infection triggered the immune system to whack the brains of ME/CFS patients.

Nath didn’t put together just a study, though; he put together a three phase series of studies that he hopes will end up in treatments for ME/CFS. In its duration and scope the NIH study resembles the Open Medicine Foundation’s End ME/CFS project.

Both first deeply examine a limited number of patients, then test their results in a larger number of patients, and finally both envision finding/developing immunomodulatory or other treatments based on those results.

Both, furthermore, are employing top researchers and cutting-edge equipment at two of the top research centers in the world.  Nath repeatedly pointed out in his presentation that several of the techniques being used were developed by the researchers who are actually participating in the study. Ron Davis’s lab at Stanford has developed many new technologies over time. During the course of his interest in ME/CFS he’s created a new, more accurate (and cheaper) way to study HLA genes.

The Nath Study

Note that the NIH could have played “small- ball” as they reinvigorated ME/CFS research. They could have brought in a  junior investigator, had him do a couple of tests and pronounced themselves done. Instead they brought in one of their top investigators who put together not one study but a series of studies that will take probably five years to finish and could culminate in a treatment or treatments.

Metabolic and Brain Studies

Each patient will stay overnight in one of the NIH Clinical Center’s “unique” metabolic chambers. These chambers, which were developed at the NIH decades ago, have  been refined over time and allow for extremely accurate measurements of metabolism and energy production.  Nath said the overnight chamber stay will provide an enormous amount of information on energy use in ME/CFS patients.

brain MRI

Two different MRI’s will be employed in the study; one looking at brain structure and one looking at brain functioning

The functional MR’s will measure blood/oxygen and glucose uptake (metabolism) flow during tasks. These will be able to tell what happens to ME/CFS patients brains when they’re stressed. Will their blood flows be adequate?  Will different parts of their brains be activated?  Will they produce normal metabolic activity?

Then comes another brain scan called transcranial magnetic stimulation. TMS is mostly used to evaluate a key topic in ME/CFS – the ability of the primary motor cortex in the brain to move muscles. It’s widely used to evaluate brain damage occurring in multiple sclerosis, stroke, ALS, movement disorders, etc..  Nath said he was excited that world class experts who developed this technology were participating in the  study.

Autonomic nervous system testing is, of course, of huge interest in ME/CFS, and it was another area in which Nath reported that “world class experts” would be working.

Immune System

The study will compare immune factors in the spinal fluid and the blood – something that’s rarely been done in the same patients.  First, they will look at 1500 cytokine and immune factors, and then they will do flow cytometry.

Those two studies will set up what comes next as they double down on abnormalities found.  If B-cells pop up they’ll dig deep into the B-cells. If NK cells pop up they’ll do the same with the NK cells. Any unusual immune pattern Nath finds, he’s pretty sure he can find an expert to study it given the size of the immune intramural team at the Clinical Center.

experts

Again and again Nath referred to the world class experts who will be participating in the study

They will look at antibodies (autoimmune factors) in his lab and cerebral spinal fluid proteins, where they have, yes, more “world class” experts who will do the analyses.  Nath will later say his lab has developed a unique way of examining autoantibodies.

Nath said the immunology program at the Clinical Center is the largest and best in the world and they have a wealth of information from other diseases they can compare to ME/CFS.

Gut samples will be sent to Ian Lipkin and they will examine viruses as well.

The Solve ME/CFS Initiative’s Avindra Nath Webinar

The Woo- Woo Section: Getting at the Central Nervous System Problems.

The most cutting-edge, woo-woo type type of inquiry comes in the nervous system side of the study.  Referring again to a technology developed  at the NIH – in fact, in his laboratory – Nath will take blood cells and transplant them into pluripotent stem cells  and then make neurons out of  them.

neurons

In one part of the study Nath will use stem cells to grow ME/CFS patient neurons outside of their bodies

That will allow him to grow ME/CFS neurons outside their body and test them.  Interestingly, he referred to the possibility of uncovering mitochondrial dysfunction in ME/CFS patients neurons but he said many very sensitive kinds of tests can be done to determine what might be going wrong in these neurons.  For instance, he can add blood samples to the neurons to see if some sort of factor in the blood is tweaking them. If a factor is present he’ll identify it and it could provide a prime target for a drug.

Nath considers this a critical component of the study.

They will also create “humanized ME/CFS mice” generated from immune cells that are added to them. They will test them in several ways including using cerebral spinal fluid and/or antibodies and determine if they become fatigued, etc.  If they do they will try to determine what in those substances is making them fatigued, etc.

Study Population

Nath reiterated that one of the tests used for the Reeves criteria will be used to quantify symptoms but that the criteria itself will not be. Instead, the study participants will have to meet the Fukuda and Canadian Consensus Criteria, have a documented infectious onset and have the disease less than five years.

filter

This study has the best filter that can be devised; the participants come from ME/CFS experts

From his perspective there is no such thing as a perfect criteria for ME/CFS (or other diseases) but that’s not a problem. He expects to be adjusting the study as he goes along. If a phenotype (version of the disease) stands out, he’ll hone in on that, and noted that it can be helpful to identify outliers. Disease heterogeneity is something the intramural center deals with all the time, he said, and we’re very good at it.

(In truth, though, this study is set so that there won’t be many significant outliers – as least from outside the ME/CFS patient community. The participants will be coming from ME/CFS expert physicians and they’ll have to meet the criteria.)

Nath went over some of this research including studies on numerous viruses including Ebola and now the Zika virus. He said he comes from a virological background and that he’s an expert on the clinical side in neuro-infectious diseases and neuro-immunology, and in basic sciences as well. He said not many people have that kind of background. He believes that his team has a special kind of expertise that could be valuable for working on ME/CFS.

He noted, though, that his goal is to find something in ME/CFS and pass it on to other researchers. The study design he emphasized is quite flexible and the study ultimately will evolve depending on what they find.

Everyone  except for a few full time people everyone else (about 150) are lending their time in addition to everything else they are doing.

Push Back

The scrutiny that some researchers have come under, however, has caused, he said,  “a lot” of people to say that they don’t want their names associated with the study, and some have even said they don’t want to have anything to do with the study. He also said some researchers who haven’t said no, are apparently saying no by not answering his emails.

He suggested that patients “be a little careful” about how critical they become for fear of antagonizing people who might not end up helping.  The criticism of Brian Walitt and perhaps Dr. Saligan, Gill and even Dr. Unger has apparently gotten around, and it’s had the unintended effect of making some of the researchers we do want working for us leery of doing so.

Nobody can be forced, Nath said, to study a disease – it doesn’t work that way at the NIH. Plus these researchers are already busy and are volunteering their time; i.e. they don’t have to participate in this study. .

stop

Some researchers have become leery of being associated with the study

. Someone recently related to me that some researchers she was interacting with  were at first shocked at the intensity of the ME/CFS community.  That rang true. We’re an unusually intense group. I don’t think we realize how intense we probably are relative to other groups. I imagine that critique’s of study members are almost unknown at the Clinical Center. I imagine that very few patient communities know about, let alone research the backgrounds of the investigators involved in studies done there

Of course, this is a huge moment for us. We’re hopefully on the cusp of finally making it in the research world and everything is under scrutiny. We don’t have the history of successes that other diseases have.  This is our big moment. I hope Dr. Nath and the other researchers understand that, and we should understand that we are probably subjecting him and the NIH to stresses they’re not used to as well.

I remember Suzanne Vernon saying the researchers aren’t the most social of animals; they do, after all, spend their lives in labs.  They’re probably not used to their comrades being questioned.

The NIH has been responsive. Dr. Nath has been quite gracious to talk to the ME/CFS community, now three times. (I wonder if he’s ever done that with a disease group before?) Lines of communication are being set up that I imagine are new to both him and the NIH as well. They didn’t get rid of Walitts but they did axe one problematic study.

With regard to bias, Nath reported as he has before, that the solution to potential bias is to design a study so that bias is not an issue. It’s not possible, he argued, for him to do a litmus test or reach inside everyone’s head and understand what they are thinking. He has produced a study, though, which he believes eliminates any  potential problems with bias.

Nath handled, I thought, a touchy situation well. The push back is something to think about. The one potentially psychological aspect of the study – the functional disease subset – has been dropped at the patient communities request. You wouldn’t know it from some of the objections, but all the research being done in this study is pure pathophysiology with a strong neuro-immune thrust.  Because no portions of the study are examining psychology or psychosomatism there’s no literally no way available to inject those into the study.

Ironically, none of  the individuals that have been objected to are doing any research in the study, yet the criticism against them appears to be effecting the participation of researchers we do want in the study.

Questions

Bias – When asked about preventing the personal biases of the investigators effecting the kinds of patients entering the study Nath said he’s gotten this question many times.  Again, he said that because you can’t eliminate bias you design a study so that bias is irrelevant.  He did that by ensuring that the patients first come from ME/CFS experts, then by ensuring that they meet the specified criteria at the site.

He anticipates that if they get a patient or two that doesn’t fit, that that will become obvious quickly.

Somatization  – When asked to clarify the problem of somatization (i.e. Walitt) Nath repeated that he’s only interested in neuroimmunology, that he doesn’t know anything about psychosomatic illnesses, is not interested in them or learning about them, and again, he’s designed a study that doesn’t pertain to them.

Exercise Testing – With regard to 2-day exercise testing and using the Stevens Protocol Nath said his goal was basically to get his patients fatigued and see what happens.  He appears to regard exercise testing mostly as a means to an end.

maverick

Nath isn’t worried about a patient or two without ME/CFS slipping through. He believes he’ll be able to quickly identify them if they do

Consulting With Outside Experts – When asked whether the NIH would be open to consulting with experts in that area? Dr. Nath said he will begin a seminar series that will bring experts in.  When asked if he had contacted Dr’s Fluge and Mella, Dr. Nath sounding a bit peeved now, stated that if he finds what they have found (or perhaps what the Rituximab study suggests they have found; i.e. problems with B-cells)  he will do a much, much more extensive study than they have the capability of doing.  He did say he would contact them about giving a presentation to the study team.

Autoantibodies – Will he test for the adrenergic and muscarinic autoantibodies recently found in POTS patients? Dr. Nath said he has developed a unique way of examining autoantibodies for the brain which involves mass spectroscopy. If there’s an autoantibody to anything in the brain he’s confident they’ll be able to find it.

Timeline – When does he believe the timeline for phase I will end? With 80 patients it could easily take two years.

Patient Participation – Dr. Nath said he was very eager to have patient participation but it’s turned out to be much more complicated than he thought (which patients, how many, etc.). He said they will use the participation structure the extramural (Working Group) structure is setting up.

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