Jose Montoya and the Stanford Experience, Part Two (of Three)

Jose Montoya, Professor in the Department of Medicine and Division of Infectious Disease and Geographic Medicine, Stanford University School of Medicine

Jose Montoya, Professor in the Department of Medicine and Division of Infectious Disease and Geographic Medicine, Stanford University School of Medicine

 

By

Hillary Johnson

Copyright 2017, All Rights Reserved

 

 

3. A Big Umbrella

 

After several years of medical training in his native Cali, Columbia and at Tulane University in New Orleans, Jose Montoya arrived in Palo Alto, California in 1991 to begin a three year fellowship in infectious diseases.  He completed his fellowship under the mentorship of Jack Remington, who is today a professor of medicine emeritus at Stanford.  

During one of Montoya's fellowship years, however, he was mentored by Thomas Merigan, the chief of infectious diseases at Stanford.  Merigan was a nationally-known scientist at the forefront of AIDS.  By 1987, he was conducting one of the largest and most expensive treatment trials ever in AIDS, experimenting with AZT and interleukin-2.  Merigan's status was such that in 1988, the National Institutes of Health chose Stanford along with six other universities to become Centers for AIDS research. Each center, including the one that would be headed by Merigan, was promised generous NIH support for at least five years.  

Although the influential and outspoken Merigan caused great harm to the discovery process around M.E. and equally harmed uncounted individuals with M.E. in those years, he--perhaps ironically--intuited something unique in his star pupil Montoya.  Early on in their relationship, the infectious disease chief told Montoya, "You have a special brain, a special mind, Jose, to discover things that have not connected and yet you will connect. I can see you in the years ahead discovering things that have not been discovered before."  

Merigan couldn't possibly have imagined it then, but Montoya would turn out to be an internationally known specialist in a malady Merigan had believed for years was sheer nonsense.  In fact, Montoya single-handedly turned Stanford's medical school around on M.E., revealing a significantly contrary worldview between himself and his colleagues.

The process didn't begin until twelve years later in 2004 when Montoya met his first M.E. patient.  Montoya was unaware at the time that seeing such a patient was not allowed at Stanford by Merigan's fiat.

After seeing four patients in 2004 and helping them considerably with long-term Valcyte therapy, Montoya's commitment to the malady was bedrock. He knew enough about academia by then to comprehend what might be required to overcome years of deeply held bias among his colleagues.  The harsh reality of academic medicine, its adherence to the 1940s dictum, "When you hear hoof beats think of horses, not zebras," had resulted in a hardline negative stance on a gravely important disease few in academia actually knew anything about.  Years of dismissal of M.E. at Stanford was going to require that Montoya lay out, patiently and meticulously, a line of evidence to persuade the naysayers they were wrong.

“You can imagine," Montoya says, "if I had gone to the bone marrow from day one working on this, or I had gone to the spinal fluid from day one.  They would have said, ‘What are you doing?’ Versus the easiest thing, which was to just get the blood.  And then they start to say, ‘Wow,’ and ‘Oh wow,’ and eventually it was just one ‘Wow’ after another."

Montoya suspected a pathogen, specifically a virus, was causing the disease after seeing his first patient in 2004.  Nothing he has seen or read since has caused him to deviate from that hypothesis.  And yet, transmission, viral etiology--although theorized by many clinicians and researchers who study M.E.--is rarely if ever broached in public settings, even at IACFS conferences where one would expect researchers to discuss the subject in depth. It's the 800 pound gorilla in the room, the third rail of M.E. science. It's almost de riguere to discuss genetic susceptibilities instead, avoiding the fact that most people with the disease are not related by blood and that the not atypical phenomenon of transmission in families is more likely to occur as a result of close or intimate contact. 

Surely, it was not a dialogue Montoya could have with his Stanford colleagues in the mid-2000s. He had to get them past the shock that he was even seeing patients and that he believed the patients were suffering from a disease. A year after he published his first paper on Valcyte therapy, Montoya admitted nonetheless that he was bringing patients into the Stanford infectious disease clinic "...through the back door." 

Since receiving $5 million from an anonymous donor in the mid-2000s, Montoya currently has created at Stanford a robust "ME/CFS Initiative" with multiple collaborators. He also has co-authored studies with NYC's Ian Lipkin at Columbia in the realm of cytokines and he will be among the investigators named on Columbia's grant submission to the NIH on May 2 for funding to create Centers for Research.  He will also be named on the Open Medicine Foundation grant application to the NIH.  Thus, it seems possible that Montoya will be participating in more than one center.  No fewer than nine groups are applying for a center; no one yet knows how many there will be.  Competition is fierce. In future NIH bureaucrats will find it difficult to justify their failure to fund on the tread worn complaint that too few researchers are applying for grants or that not enough scientists are interested or qualified.

The distance Montoya has come since 2004 was on full display in 2014 when he served as host of a day-long conference on M.E. featuring a series of presentations from Stanford colleagues.  The only false note was a presentation by cardiologists who reported they were unable to find any heart abnormalities in M.E. patients.  On questioning from a patient in the audience, it turned out the cardiologists had chosen as their subjects people who could perform on exercise equipment for lengthy periods without difficulty.  Needless to say, the cardiology piece has moved forward and Stanford is looking at heart endothelial cell function.  A team of neruopsychologists, Marcie and Mark Zinn, now at DePaul in Chicago, presented their work on encephalopathy in M.E.    

"You have to find the best people for each of the pieces," Montoya says.  "If you pretend to be the expert on everything that you are working with, it's doomed to failure--or if not failure, it goes lower.  The best thing is to have a vision, a big umbrella with an overarching vision, and then all the other pieces working with that.  You cannot condescend or patronize, because everyone has the expertise and everyone is moving.  And your vision can change.  But if you said 'My ultimate dream is to eradicate M.E. from the surface of the earth,' nobody would argue with you.  And then if you move closer to earth, and you say 'My ultimate goal is to find a cure for M.E.,' nobody would argue.  If you go even smaller--'My ultimate goal is to find an effective treatment for M.E., not even necessarily a cure.' So--if you have that crafted--then it's easy to align people around you.  But if you say, 'My ultimate goal is to find an immune abnormality,' then you exclude the geneticist, you exclude the pathogen discovery. 

"So I have created this at Stanford.  This is a huge umbrella that makes sense, is very consistent, where all the experts can fit in."

***

My first glimpse of Jose Montoya occurred in 2007 at an IACFS conference in Ft. Lauderdale.  He seemed surrounded by an entourage at all times, a person of importance, but at the same time, a newbie.  I suspect now that he was holding back.  His talk on M.E. took place in a medium-sized room filled with occupied chairs and more patients standing along the sides and rear of the room.  They knew Montoya was treating sufferers with antivirals.  His first paper on the subject had appeared the year before and seemed to offer the first real hope since ampligen--a worthy drug that the FDA has been loathe to approve for thirty years. Valcyte, on the other hand, was readily available. The proverbial pin drop could have been heard while Montoya spoke.  There seemed little question that he was someone who was going to try hard, very hard, to make a difference.

Ten years later, he has created an atmosphere at Stanford where he can propose to look for pathogens in the bone marrow, in spinal fluid, and in cell compartments without causing his co-investigators to flinch. 

His ideas come to him in moments of rare solitude and quiet.

"Again, this comes at dark, all night, alone," Montoya says.  "If you give me an immune cell that may be compromised in M.E., what comes to your mind?"

"NK cells?" I respond.

"NK cells," he affirms.  "Everybody mentions NK cells.  And nobody has ever thought about looking for the pathogen in the NK cell.   It's like, you have a pathogen that has a target where the NK cell gets in and either destroys it. Or, if (NK cells) don't go through the floor they will be dysfunctional.  Well--what about looking in the NK cells?  I have a collaboration that I'm very excited about."

Patients have been telling us all along. All along they’ve been giving us the clues. We just haven’t had enough ears for those clues to be translated into research.
— Jose Montoya

"When one does research into biological specimens, the lower hanging fruit, the specimen that is easiest to collect, is the blood," he continues.  "It's easy to go for the blood, but it's harder to reach deeper compartments.  So I think that a potential factor [to explain] why we are NOT were we should be has to do with failing to go after certain compartments. A lot has been said bout NK cells potentially not working in this disease and I think it's a good story.  So I've been surprised that this lead has not been followed in a more rigorous way. A question that has to be answered--is there an infectious agent that hides in the NK cell? 

"There is no precedent for that in biology, but there has been no research, either."

Montoya broached the idea of looking for the pathogen in the bone marrow at the IACFS conference in Ft. Lauderdale last fall during a presentation on circulating cytokines and their relationship with disease severity. (His conclusion was that of 17 cytokines correlating with severity, 13 are inflammatory in nature and likely to be associated with M.E. symptoms.) 

Later, in conversation, Montoya points out that bone marrow is the body's factory for immune cells.  M.E. is clearly a disease of immune system dysregulation as well as inflammation, given the symptoms of the malady, he adds.

"Patients have been telling us all along.  All along they've been giving us the clues," he continues.  "We just haven't had enough ears for those clues to be translated into research.  Our work and the work of others is finding there is an inflammation that fits very well with symptoms and also suggests the key to the secret of the disease may be in the bone marrow, because that's where the immune cells are made--that's the factory for the immune system."

Unfortunately, as enticing as bone marrow research may sound in Montoya's description, the work has yet to begin, though he says he has a collaborator. 

"We are setting it up but we need funds and funds are not available.  This has been going on for three decades now.  You cannot not do research based on your ideas, based on academic freedom that was once there in medicine.  It's very sad.  You do the work that is not necessarily what you want to do but the work that is paid for.  We [cannot] do what we think is the job we should do, the ideas we should follow.  We are under limitations, even if we have great ideas."  As for the bone marrow investigation, Montoya adds, "We need funds to pay the people involved.  We have everything set up but are waiting for the funding.  You cannot bring people into work on this disease and not cover their salaries and not cover their work."

Montoya is excited the NIH is making funds available for research centers.  The total amount will be $29 million for the first year to be distributed among every center, but a significant portion of the money will go to administrative costs and not directly for scientific research.

"Certainly, [the NIH offer] is making us all talk to each other and look to each other.  It's not anymore Cornell, Stanford and Columbia.  It's a lot of other groups," Montoya says, a reference to the six other research collectives who are applying for grants.

Nevertheless, although he expresses his pleasure that the NIH has made the overture, he adds, "In my view, it's way lower that what they should have given to this disease given the fact that nothing or very little has been done for thirty-five years." 

And while patients feel uplifted by the government's apparent commitment to sorting out M.E.--as evidenced by the National Institute for Neurological Disease and Stroke study of 40 patients led by Dr. Avindra Nath, a specialist in brain infections, and lip service in press releases by NIH director Francis Collins--Montoya cautions that it's not that the entire federal health bureaucracy has turned around on the subject of M.E., it's that a handful of people in agencies such as NIH have turned around.  The struggle continues.

The fact that no one from NINDS other than Vicki Whittemore, a grant officer, attended the IACFS conference last fall, for instance, a two-day commitment that would have brought NINDS investigators up to speed on the latest findings in M.E., was telling.  Their absence did not go unnoticed by several investigators, including Montoya.

"And not to invite us [to NINDS in Bethesda]?" Montoya asks incredulously when I bring up the subject .  "Not to ask, 'What have you guys done, what have you found?'" 

His impatience, given his years-long commitment to patients and to M.E. science, is easily grasped.  (This is especially true considering one the first speakers invited by NINDS to talk to investigators there was M.E.-denialist and hater Canadian Edward Shorter, someone so vehement in his decades-long opinion about the false nature of M.E. he sounds increasingly as if he has a screw loose.  That decision still stuns. The hysterical Edward Shorter vs. Jose Montoya? Really, Dr. Nath???)

"[The government] is moving in a positive direction but we need to be aware that the whole system is still bathed by that thinking," Montoya says.  "And what I don't like is that nothing is coming in terms of the hundreds of millions of dollars that are needed for this disease.

"Ideally, in my dream, there would be some calculator where we could calculate how much money should have been given every year if this had been recognized as a real disease, and that could be compounded by today's dollars.  And so that, for thirty-five years they have given us, nothing, literally, for M.E. How much money would have to be given in today's dollars?  And then," Montoya continues his dream fantasy, "They would say, 'Here--here are X million dollars per year that can only be spent on M.E--you cannot spend that money on other diseases."

"And second," the doctor continues, " a formal apology to the patients by every medical society--the American Medical Association, the infectious disease societies, the National Institutes of Health, the Centers for Disease Control--a formal apology."

What a beautiful dream.

 

 

Next:  Jose Montoya, Part III

Stanford then and now: An Interview with Stanford's Jose Montoya, with detours into the fractious HIstory of m.e. at one of the world's top medical centers

Stanford University's historical mistreatment of patients with M.E. is infused with irony given that the prestigious medical center is today a hive of activity and intellectual engagement on behalf of the disease.  In fact, there is probably no other major university with as many movers and shakers who have stepped into the fray of the the small but competitive M.E. field.  

In stark contrast, in the late 1980s the medical school sent an unambiguous letter to hundreds of doctors in the Bay Area letting them know that Stanford would not accept M.E. patients (as well as chronic Lyme disease patients) into their infectious disease clinic.  The policy existed well into the 2000s.  One specialist at Stanford, Jose Montoya, quietly rebelled, however, eventually bringing M.E. sufferers into the infectious disease clinic surreptitiously, or "through the back door," as Montoya once described his effort during a packed address at an IACFS conference in 2007 in Ft. Lauderdale. 

Montoya, who was expert in employing antiviral drugs for lengthy periods to help transplant patients and cancer patients survive, began demonstrating through controlled trials that he could create partial or full remissions in M.E. sufferers by using the same drugs for six months or more.  By doing so, he revolutionized the climate at Stanford, winning praise recently even from Thomas Merigan, once the chief of infectious disease at Stanford, now now-emeritus professor. It was Merigan who decided in the late 1980s that M.E. patients would not be seen in Stanford clinics.  At the time, Merigan waved the M.E. epidemic away with the words, "People need a way to express their anxiety" on prime time television, defusing public concern about the spread of the disease. 

Today, Montoya's careful methods, combined with his respectful but persistent efforts to engage his colleagues at Stanford in collaborative projects to explore hypotheses about the disease, has altered the Stanford ecosystem in the realm of M.E.

In the story that follows, Montoya talks about his encounter with his first M.E. patient.  He also discusses what he thinks about during long, middle-of-the-night bus trips through the Colorado Rockies.  A hint: his ideas about the origins of the explosion of cases in the 1980s and the M.E. epidemic's relationship to the AIDS epidemic.

Stanford's contentious relationship with the disease that rocked the urban centers of California, north and south, in the 1980s is reviewed, as well.

 

 

Numerology, Part Three: What did they know and when did they know it?

A year of breakthrough discoveries in brain abnormalities in M.E

The year 1989--twenty-eight-years ago--was a remarkable one for the discovery process in myalgic encephalomyelitis.  Academic interest in the disease had not yet been muted by NIH investigator Stephen Straus' poorly-conceived and executed research suggesting mental illness predisposed people to M.E., though Straus' paper was published in a psychiatric journal that year. 

On another coast and seemingly a world away, California reearchers were studying the impact of the disease on the brain. Using imaging technologies that surpassed the MRI scan for sensitivity and specificity, their findings pointed overwhelmingly to outstanding patterns of brain damage.  They observed low blood flow, reduced metabolic activity and reduced oxygen to the brain in a majority of patients tested.  The first report on low blood-flow to the brain was presented at a scientific conference Cambridge, England in 1990.  

Evidence to explain in some part what is today called "post exertional malaise" was discovered in 1989, too.  The Institute of Medicine's 2015 report on M.E. suggested the disease be named for this symptom alone. 

By 1989, M.E.'s stark impact on brain integrity was increasingly apparent.  As a neurologist colleague of clinician Paul Cheney told him at the time, "All bad diseases get to the brain eventually."

 

Francis Collins: Should M.E. Sufferers Care Whether He Leads the NIH? Part Two

Part One of this two-part series on NIH Director Francis Collins examined his current tenuous status with the Trump Administration, his appeal to the far-right wing of the Republican party, as well as his "Christian apologetic" ethos on God, creationism and evolution. Part Two assesses Collins' leadership in the struggle to recognize M.E. as a serious disease and fund it appropriately.  In this author's view, Collins has failed on both counts, although the leadership at Solve ME/CFS Initiative takes a kinder, certainly more politic, view.  Also addressed: the need for a formal apology from the U.S. government to M.E. patients and Trump's interest in vaccine safety.  Will commitment to studying relationships between vaccines and autism be Trump's litmus test for winning the top jobs at both CDC and NIH? 

NIH Director Francis Collins: a Trump Fave or A PlaceHolder? And Does it Matter? Part One

Francis Collins has been director of the National Institutes of Health since 2009.  At the eleventh hour, the Trump transition team asked Collins to stay on for the time being at NIH rather than accept his resignation--as is typical when a new president assumes power.  Has Collins' born-again bona fides made him especially attractive to the right wing of the Republican Party and will he serve another four years--or is he a placeholder who will step down eventually, given that several other candidates appear to be under consideration?  And does Collins' fate matter to M.E. sufferers?  Consider the possibilities in this two-part report on the politics of science and leadership at the nation's premiere research institution, and the often opaque Trump agenda.

Numerology, Part Two

Numerology, Part Two continues to list some of the most dramatic turning points during the early years of the M.E. epidemic, a period when the medical establishment began to split into camps.  One faction was following the pedantic Stephen Straus of NIH, who was working to shore up his psychoneurotic theory of the disease in the medical literature.  Scientists outside the manicured NIH campus were struggling to demonstrate just how serious M.E. could be and raising alarms about its transmissible nature.  The fight, a.k.a., "medicine's holy war," was shaping up to be far from fair.

Numerology, Part One

How many years have passed and how many people have fallen ill since the world-wide M.E. epidemic began--and when did it begin?  If one searches for all the documented cluster outbreaks that were confined to institutions or even small towns, one can find accounts of the disease going back to the 1930s, possibly earlier.  But history suggests something occurred in the 1970s and early 1980s to change the dynamic.  M.E. began to rage through the population at large, unconstrained by walls and geography.  Eye View Exclusive presents a five-part series called "Numerology." The series notes the high-water marks of the early days of this pandemic spread.  It also measures in specifics the years lost to millions who contracted the disease while individuals struggled to press an intractable government into action.  Herewith, Part One...

Carol Head: Leader for a New Era, Part Two

Carol Head: Leader for a New Era, Part Two

"A Devastating tragedy unworthy of the American people."  Vanderbilt University ethicist, doctor and chairwoman of the Institute of Medicine's committee on M.E., Ellen Wright Clayton, did not mince words about the epidemic and the failed response of the American medical establishment to the disease and its victims.  Part Two of Hillary Johnson's series on Carol Head, president of the largest and oldest patient organization in the U.S., describes Head's return to patient advocacy after years of exclusive devotion to research.  The 2015 Intsitute of Medicine and the late-2014 "Pathways 2 Prevention" reports on M.E., both sponsored by the Department of Health and Human Services, jolted everyone with strong language seeking increased research funding, medical education and more humane treatment of sufferers.  Head decided the time was ripe.  She accompanied the actress Morgan Fairchild, a former PWME and activist, and I.O.M. report author Ellen Clayton to a meeting with Anthony Fauci, long-time head of the National Institute of Allergy and Infectious Disease, seeking a permanent home for the disease at NIAID.  Read Part Two for the full story.