Update

In June, longtime Stanford professor and Director of the Stanford Chronic Fatigue Initiative, Dr. Jose Montoya was terminated from Stanford University for “multiple violations of University policy” which, according to women from his ME/CFS clinic who were involved, included “extensive allegations of sexual misconduct, assault and harassment” and “many other instances of harassment and misconduct”. After an investigation by an outside attorney, Dr. Montoya received the strongest possible punishment the University could provide – his employment was terminated.

Dr. Montoya, who’s worked at Stanford for the past thirty years, stated that he’s always acted “with the respect, professionalism, and the affection proper of my Hispanic culture”. He asserted that his inability to sufficiently appreciate the difference “between the social norms of his homeland and those of the U.S.” led his employees to “experience his behaviors as attempts at unsolicited sexual acts, harassment, and misconduct.”

Since his termination, Dr. Montoya has received several letters of support: one from 72 physicians and academics working in Dr. Montoya’s home country, Colombia, and one from 33 academics and physicians; 15 working in Colombia, 18 elsewhere, and three currently working at Stanford University.

The three women supporters who worked with Dr. Montoya at Stanford appear to have either worked in the Sutter Health Toxicology Reference Lab, which Dr. Montoya directed, or with him on toxoplasmosis projects. None worked in his ME/CFS clinic. While Dr. Montoya has received an enormous outpouring of support from his colleagues in Colombia, it’s clear he’s received much more limited support from his colleagues at Stanford.

The Impact of Dr. Montoya’s Termination

Dr. Montoya’s termination and its potential effects on the small ME/CFS medical and research community prompted a fuller look at Dr. Montoya’s work on ME/CFS. At first glance, it seems like nothing good could come of this situation, but the situation does, in fact, present some interesting possibilities which could, if they were acted on, end up being beneficial. Attempts, by the way, to get Dr. Montoya to respond to some issues in this blog failed.

Research

If Dr. Montoya’s termination stands, the fate of his Stanford Research Center and his continuing ME/CFS research are in doubt. It’s a good time, therefore, to assess Dr. Montoya’s research record and the possible loss to ME/CFS research that could ensue.

Dr. Montoya reported that, upon receiving a $5 million donation in 2008, he said, “Give me five years” and launched the first major Stanford effort on ME/CFS – the Stanford Initiative on Infection-Associated Chronic Diseases.

Montoya’s next publication (of which he was the lead or senior author) didn’t show up, however, until 2012, and that study, funded by Roche Pharmaceuticals (not his donor), was his long-awaited followup to the 2006 Valganciclovir study.

SCOPE, a publication by Stanford Medicine, reported in 2014 that Montoya was recruiting one of the largest ME/CFS cohorts ever: 200 ME/CFS patients and 400 healthy controls that he planned to follow over time and use in his studies. SCOPE provided news of a truly massive study – the largest study, in fact, that noted Stanford immunologist Mark Davis had ever taken on. Davis would use his new mass spectrometer to measure dozens of cytokines, 35 cell-surface proteins, 15 or so types of blood cells, and more than 47,000 genes and regulatory nucleic acids in 600 ME/CFS patients and healthy controls.

It was not until 2015 – 7 years after Montoya received his big donation – that he appeared as the senior author of an ME/CFS study. That study, which showed a striking abnormality in the right arcuate fasciculus of the brains of ME/CFS patients, received widespread attention in the media. Despite its scintillating results, though, over the next five years Montoya and his co-author, Zeineh, were unable to turn that pilot study into an NIH grant.

In 2017 a Montoya/Davis 600-person cytokine study indicated illness severity in ME/CFS was not associated with abnormally high cytokine levels (only one cytokine (TGF-b) was elevated) but rather with relative levels of cytokines. Montoya’s finding suggested the novel possibility that people with ME/CFS were abnormally sensitive to their own cytokines.

The study brought into question how efficiently Montoya was using his resources. The 192 patients and 392 healthy controls represented an unusually high number of healthy controls. A search through recent studies found that only one featured more healthy controls than patients and, in fact, the opposite was often the case (ME/CFS/healthy controls: 33/31; 39/25; 25/23; 251/153; 50.50; 200/70; 272/136; 14/11; 16/10; 10/10). One of the largest immune studies done in ME/CFS – the Hornig cytokine study – contained nearly equal numbers of patients and controls (298/348).

In a field with such little funding and such a small donor base, research programs must produce. Montoya’s output over the past 7 years has been meager, but in 2015 he reported that the program was about to start producing big time. He reported

“exciting evidence” of pathogens

that the final analysis of the big gene expression and immune study with Mark Davis was finishing up with a manuscript submission expected shortly

analysis of the big gene expression and immune study with Mark Davis was finishing up with a manuscript submission expected shortly that two manuscripts examining cardiovascular health and exercise in ME/CFS were in preparation for publication

manuscripts examining cardiovascular health and exercise in ME/CFS were in that two manuscripts from the Zinns on brain functioning were in review for publication

manuscripts from the Zinns on brain functioning were for publication and that the final analysis of a genetic and immune study from a Department of Defense (DOD) grant was underway and a manuscript was due to appear shortly.

Plus, four other studies were to begin soon:

gene expression Lyme Disease study with Mark Davis – to begin in late spring of 2015

with Mark Davis – to begin in late spring of 2015 A Severely Ill Patients study – to begin in the summer of 2015

study – to begin in the summer of 2015 An HPA axis Biomarkers study – to begin in the summer of 2015

study – to begin in the summer of 2015 A Universal Pathogen study that would look deeper into the body than anyone ever has before, surveying cerebral spinal fluid, lymph nodes, gut, bone marrow and natural killer cells.

Dr. Montoya’s 2016 Newsletter – the last newsletter The Stanford Chronic Fatigue Initiative put out – was much the same as the 2015 one. It reported that all the 2015 publications were still underway, it moved the start time of the new studies up a year or two, and stated that the new Lyme disease study was moving forward. Plus, a Brain and Tissue Bank was being set up.

Since then, of the 12 promised studies, Montoya has published three. Of the four new initiatives, one appears to have taken place. The exciting pathogen result never showed up. The final analysis of the DOD genetic and immune grant never ended up in a paper.

The immense 600-person trial that Montoya told SCOPE in 2014 was examining cell-surface proteins, 15 types of blood cells, and 47,000 genes and regulatory nucleic acids and gene expression appears to have turned into a 600-person cytokine study.

In 2016, Dr. Montoya’s research coordinator reported they were finalizing results of the gene expression part of that study, and the manuscript was going to be submitted “soon”. The report that the data was undergoing “heavy statistical analysis” strongly suggested something had badly gone awry which required special statistical tweaking to save the study. That attempt appears to have failed as, three years later, the study – which Dr. Montoya apparently used to repeatedly assert that ME/CFS is most akin to a systemic inflammatory disorder – has never been published.

Since Montoya received his initial $5 million donation in 2008, he has (besides the Roche valganciclovir trials) been the senior or head author of 4 physiologically based studies: the 2014 Zeineh brain imaging study, the 2017 cytokine study, the 2018 cytokine exercise study, and the 2018 Zinn brain imaging study. (He also recently published two epidemiological studies.) To my knowledge, the program has failed over the past ten years to receive any NIH grants.

An attempt to find out how many donations Dr. Montoya’s research center has received over the past ten years hit a wall. Despite the fact that the Center appears to be funded entirely by donations, Stanford Medicine refused to provide any figures regarding donations. The return on investment, however, appears to leave something to be desired.

Dr. Montoya, it should be remembered, has been juggling multiple roles: professor, doctor running a clinic, researcher in two subjects – toxoplasmosis and chronic fatigue syndrome, and a frequent contributor to ME/CFS efforts – he’s had a tremendous amount on his plate.

Research Loss? (Or Research Gain?)

If Dr. Montoya had received NIH grants, his loss would be severe. The money he’d managed to wrangle out of the NIH would disappear and not be replaced. The NIH, after all, has got oodles of money; funds are not the issue: finding researchers able to snag some of those funds – that’s our big issue.

Private donations, on the other hand, are different – the funding pie is small and limited. Private donations need to be used as efficiently as possible. Every research program that receives private donations has to be able to produce a record of results.

Dr. Montoya did produce results – just rather slowly and, in the end, not many of them, and not particularly far-reaching ones. Other researchers, I believe, are engaged in far more innovative and potentially far-reaching studies. If a consequence of his termination is more private donations flowing to more productive researchers, then the field will see a gain, I believe. Some of those research efforts include:

The Open Medicine Foundation funded the severe ME/CFS big data study, is furthering development of a possible diagnostic tool – the nanoneedle, uncovered the possibility of a plasma toxin, produced the Metabolic Hypothesis, uncovered red blood cell deformation problems, is assessing drugs, is investigating muscle physiology and metabolomics. We don’t know how any of these are going to turn out, but the Foundation is breaking ground in several new areas.

SolveME is pumping out interesting pilot studies like there’s no tomorrow. Its pilot studies have resulted in outside grant rewards including NIH grants.

Nancy Klimas has, with her extensive testing, supercomputers and modeling efforts, illuminated in detail what happens during exercise; has developed a two-drug combination; has begun a clinical trial – and has recently started pouring out papers.

Jarred Younger has discovered a new way to assess neuroinflammation, is determining whether immune cells are invading ME/CFS patients’ brains, has investigated numerous treatments, and may have found a better low dose naltrexone.

David Systrom’s invasive CPET testing is providing fundamental insights into the energy production problems in ME/CFS.

The one place the research field could be significantly hurt by Dr. Montoya’s termination is the loss, if the clinic closes, of his patient samples for studies. While Montoya did not produce many new studies, he was an important participant in several large studies led by others.

The Ron Davis Situation

Jose Montoya and Ron Davis, the great communicator and the great researcher, working together at one of the top research facilities in the world, seemed like a dream combination. In the end, it turned out to be nothing more than a dream. The two, in fact, were likely in conflict from the beginning.

Until Ron Davis arrived on the scene sometime around 2015, Jose Montoya was “it” for ME/CFS research at Stanford. Ron Davis’s entry to the scene, however, changed the landscape. With his immense reputation, his own lab, and the connections he’d developed over decades of research, Davis was able to quickly bring in Nobel Prize winning colleagues and other notable researchers to sit on the OMF’s Scientific Advisory Board.

Montoya, on the other hand, had reached deep into the University and established his own connections. He’d recruited hundreds of patients and healthy controls, had tons of samples and was working with Ron Davis’s friend, Mark Davis. He’d initiated a huge immune and gene expression study which Davis was surely interested in.

The situation seemed ripe for collaboration, but there appears to have been minimal collaborations between the two, and the evidence suggests that a split may have come relatively early.

Davis’s Working Group sessions included three doctors – Dr. Bateman, Dr. Kaufman and Dr. Chedda – but not Dr. Montoya. Similarly, two doctors, Dr. Bell and Dr. Peterson, now sit on the OMF’s Scientific Advisory Board, but not Dr. Montoya. As hundreds of people thronged to the OMF’s first Stanford Symposium, Dr. Montoya refused to attend and remained in his office. (He attended the second.)

That conflict between two researchers vying for funding was never better demonstrated than during the highly competitive battle to become one of the three NIH-funded ME/CFS research centers. The split showed up in spades when both submitted applications to become an ME/CFS research center – a situation which didn’t help either of them.

Not only did it look weird, but each had resources the other could have used. Montoya had the on-site clinic Davis needed to provide patients, plus he had research Davis could have potentially piggybacked on. Davis, on the other hand, had research cred like few others, connections all over the place and a large lab.

I asked Davis why didn’t he and Montoya work together on the NIH research centers application. His answer did not redound to Jose Montoya’s benefit.

Montoya, he said, was on his application. Months before it was due, Montoya had agreed to provide the clinical core for Davis’s application and write up that part of the application. Not long before the final application was due, however, Montoya pulled out, told Davis he was submitting his own application (and invited Davis to be on his application).

With a critical part of their application now gone, the Davis team scrambled. They were able to get Lucinda Bateman and the Bateman Horne Center (who were already featured on other applications) to be their clinical core. Particularly grating for them was the fact that given how large the application was, they believed Dr. Montoya must have been working on his application for months before he told them he was removing himself from theirs.

The Clinic

Montoya’s ME/CFS clinic on the Stanford campus filled a vital need, and numerous patients have described him as an unusually compassionate, caring physician. Patients also, however, have at times reported on limited testing and treatment options that were limited, and suggested that the clinic could and should be expanded to provide more options.

We don’t know what will happen with the clinic. Stanford has said they consider it an important feature and wish to continue it. Dr. Montoya’s loss, though, gives Stanford the opportunity to re-evaluate the clinic and expand its features to better serve the ME/CFS community.

A full-time director who’s not pressed with the many other obligations that Dr. Montoya had would be a big and much needed start.

Center of Excellence?

In the last year, Ron Davis did include Dr. Montoya on the Mark Davis grant and relations seemed to be improving. (Montoya did attend the second OMF symposium.) Now, however, there exists the possibility of starting over and creating a true Center of Excellence at Stanford – one which features a close integration between the Stanford ME/CFS clinic and Davis’s ME/CFS research center.

There’s no reason such a Center wouldn’t be successful. Stanford would fulfill a huge need and feature one of the few Centers of Excellence for a disease that’s getting more attention every year.

Check out the fantastic response to Dr. Komaroff’s JAMA article on ME/CFS.

Stanford should take note of a ME/CFS Center of Excellence that’s done quite well: Dr. Klimas has thrived in her clinic/research setting in Nova Southeastern University. Stanford might also check out one of its former researchers, Jarred Younger, who has created a spectacularly successful ME/CFS/FM program at University of Alabama at Birmingham. This is an up and coming field: all it needs is support.

Conclusion

The possibility that Stanford presents for advancements in ME/CFS care and research has never been achieved in part because the ME/CFS clinic and research center there were never fully integrated. The opportunity to do that now exists. Stanford should take this time to reassess its ME/CFS effort, improve its ME/CFS clinic, and fully integrate it with Ron Davis’s research effort. If that comes to pass, it would present a major advance for this community.

If, on the other hand, Stanford does not support the clinic and allows it to close, the loss of one of the few specialty ME/CFS clinics would be large – not just because of the patients who would be without a doctor – but because of the loss of patient samples for research studies. The loss of any ME/CFS expert is detrimental but we don’t know what will happen to Dr. Montoya. It’s possible he will open his own clinic.

In short, Dr. Montoya’s termination – as stunning and upsetting as it was and is on so many levels – provides the potential for a substantial loss to the ME/CFS community and a real opportunity as well to rethink and improve the ME/CFS effort at Stanford.