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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. And he is applying on behalf of his Stanford Initiative for his own center. 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 their 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 at Stanford on M.E. featuring a series of presentations from 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 neuropsychologists, 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. He is not a cunning person, but his sunniness should not be taken for naivete, either. He knows the political lay of the land; he is strategic and wisely so. 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."
"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. The impediment he cites could be characterized as the most prominent and enduring blockade to discovery in M.E., the reason journalists get away with labeling the disease "baffling" and "mysterious" in 2017 when so much is already known.
"We are setting it up but we need funds and funds are not available. This has been going on for three decades now," he adds. "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 multiple 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. One might have expected lead investigator Avindra Nath to come to an international conference on the disease, held only once every two years and listened to M.E. specialists who have worked in the field for years. Their absence did not go unnoticed by several investigators, including Montoya.
"And not to invite us [to NINDS in Bethesda]? To talk to him?" 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--and, frankly, ignorant--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.