Documentary: Perspectives on ME/CFS
New video explores ME/CFS research at The Jackson Laboratory and digs into the issues that patients face on a daily basis. It also delves into the challenges faced by doctors and scientists alike.
For decades, no one has known what causes myalgic encephalomyelitis (ME, commonly called ME/CFS). As a result, this debilitating disease has been very difficult to diagnose and even harder to treat. Now a collaborative JAX research center led by Derya Unutmaz, M.D., is diving deep into the biology of ME/CFS patients to find a root cause, which may lie in their own immune systems. If successful, the work will provide patients with clear diagnoses and effective therapies.
Maybe it starts with a cold or case of the flu. It’s hard to know.
Patients with ME/CFS often report that their ordeal began with a bug or infection of some kind. But then their life gets disrupted. Severe, flu-like symptoms become constant, with muscle aches and trouble thinking clearly. Standing for any length of time is difficult, and exertion that they could previously handle without breaking a sweat, such as climbing a flight of stairs, becomes overwhelming and hard to recover from. Weeks turn to months, and still, the symptoms persist. Disease progression varies in severity, but the worst cases can leave patients bedridden or even unable to feed themselves.
But why? No one knows. And that’s a huge problem. There is no biomarker yet that positively identifies an ME/CFS patient. There’s also no ME/CFS specific treatment and no cure to help them. Indeed, doctors often misdiagnose patients or don’t diagnose them at all. They may prescribe exercise, a standard and helpful recommendation for patients with depression. For those with ME/CFS, however, exercise is intolerable, exacerbating rather than improving their condition. Or doctors may push patients to seek mental health treatment, again on the assumption that the symptoms are rooted in psychological, not physical, causes.
The research frontier at JAX
In part because of the misunderstandings and stigma, research into ME/CFS initially lagged. There were also some well-documented missteps and controversies that hindered discovery. More resources and effort are now being applied, however, and data are accumulating that at last points to a suspect: the immune system, perhaps in concert with microbiome dysfunction.
To thoroughly explore the possible connection, and are leading a systems-based research program at The Jackson Laboratory (JAX). Funded by a major grant from the National Institutes of Health (NIH), the JAX ME/CFS Collaborative Research Center (CRC) is pursuing both research and clinical projects to generate a comprehensive picture of ME/CFS at the molecular level. The goal is to understand the biology of ME/CFS in unprecedented detail.
Working with ME/CFS medical specialists, the researchers are rigorously analyzing samples from patients and healthy people to identify how they differ. They will look to define the disease mechanisms, with a focus on the microbiome as a possible immune trigger. Success will lead to consistent, confident disease diagnosis, and therapeutic targets for potential drug development.
“We need to be able to develop the tools and the methods that can be used in a clinical setting that allows physicians to say ‘yes, this is ME/CFS,’ or ‘no, this is something else,’” says Suzanne Vernon, Ph.D., the research director of the Bateman Horne Center (BHC), the core clinical collaborator for the CRC. “Because right now, they’ve got nothing.”
The patient’s biology
When looking for something that has been invisible for decades, it’s hard to know where to start. Hence the first C in CRC, “collaborative,” is a cornerstone of the effort. To acquire the insight needed to know where to look, then the data required for the search, it’s crucial to have a variety of perspectives and resources. The CRC has scientists from many different specialties, led by Unutmaz, a human immunologist, and Oh, a microbiome expert. But the CRC reaches well beyond the laboratory as well to engage clinicians, including those who work with the disease and the patients at the BHC, and patient activists whose voices were so often muted in the past. Importantly, three NIH-funded CRCs have now been established, with significant collaborations developing between JAX, Cornell University, and Columbia University.
“We’re sequencing thousands of species of bacteria. We’re determining hundreds of different populations of immune cells in the same person. We’re also analyzing their metabolism and determining hundreds of different metabolites in their blood. We’re trying to put the patient’s biology back together,” explains Unutmaz. Using an integrated analysis that requires an incredible amount of computation and technology, he and his group are combining these data with clinical data to look for hallmarks of the disease.
Unutmaz says they are already seeing profound differences in the immune systems of ME/CFS patients compared to controls. “We’re very excited about that,” he says. “In my mind, there’s no question that there’s an immunological basis for this disease.” Finding a biological basis for the disease, Unutmaz says, would enable a physician to diagnose ME/CFS by identifying the corresponding biomarker easily.
The clinical perspective
Lucinda Bateman, M.D., is the “Bateman” in the BHC’s name. She was drawn to the ME/CFS field when her older sister fell ill in 1987. At that time Bateman was training in Internal Medicine at Johns Hopkins University, but the stigma associated with the disease was still prevalent. After a decade of practicing primary care, she decided to focus on ME/CFS, and her practice expanded rapidly. Ultimately, in 2014, she spearheaded the formation of the BHC to address both the clinical needs of her patients and the clinical research so lacking elsewhere.
“The biggest barrier in the field has been a knowledge gap in the practice of medicine,” she says. “The science has moved slowly, mostly because it’s underfunded. But it is picking up speed. One of the reasons I’m so excited about working with Derya is I feel like our collaboration—so far and in the future—will be very substantial in terms of scientific results we can take back to get this illness mainstreamed into regular science.”
Also in the clinical equation are, of course, patients and patient advocates. Mary Dimmock became involved with ME/CFS advocacy when her son fell ill after contracting Giardia during a backpacking trip. He recovered from the initial infection, but his health continued to decline. A long, steep road followed, and Dimmock saw first-hand the misunderstanding and even hostility her son faced in the medical community. Her experience working at the pharmaceutical company Pfizer provided her with knowledge about research and disease, but it didn’t prepare her for what many ME/CFS patients face.
“I can appreciate that as a researcher, it may be easy to lose track of the urgency that patients feel. But for ME/CFS, there are no tests or medicines, and patients still struggle to get any help from their medical providers,” she says. “There’s an urgent need to deliver a diagnostic test and treatments as quickly as possible. Even treatments that provide only partial relief could make a huge difference in patients’ quality of life.”
A microscopic culprit?
The mystery underlying ME/CFS may have its roots in a larger puzzle about human life: the microbiome. We have long known we share our experiences with vast numbers of microbes (the latest estimate puts the number near 30 trillion, though precision is understandably elusive), but we’ve focused mainly on the relatively few pathogenic varieties until recently. Now we know that the entire microbiome plays a significant role in our health and in at least some diseases. Research is still in its early days, and precisely what happens and why it is still under investigation, but some initial results are highly intriguing. One new concept is that even if two people have the same species of bacteria in them, different strains of that species can have an impact on how they interact with the individual immune systems.
“What Derya and I have seen is that not only does immunogenicity differ by species, it can also differ by strain,” says CRC Associate Director Julia Oh. “And this is very significant for the disease because we think that ME/CFS patients may have different species composition, but they could also have different strains that could be what is underlying their disease in terms of immune interactions. And if we could get an idea from the initial patient cohorts of what some of the differences are between them and healthy controls, that would be awesome.”
Pushing microbiome research forward is one part of a highly innovative research program. Another is the computational component, which is vitally important for working with the massive amounts of data generated, involves novel tools developed by Managing the data for analysis will include machine learning and deep learning methods developed by Robinson, which will integrate the component data sets into a cohesive whole.
The new research tools and methods have the potential to shed light on ME/CFS’s mysterious pathology. “Technology is advancing very fast,” says Unutmaz. “Things we can do now weren’t even possible five or ten years ago.”
The excitement around this kind of innovation has everyone associated with the CRC optimistic about its future impact on ME/CFS understanding and treatment. “With all the data we generate, we hope to achieve two things,” says Unutmaz. “One is to generate new hypotheses about ME/CFS and determine the disease mechanism. The second is to come up with a variety of biomarkers to enable biology-based diagnosis of patients rather than having to rely on clinical symptoms. We have the opportunity to address the great unmet needs of both patients and physicians dealing with this disease.”
Could microbiome shed light on ME/CFS?
JAX microbiome researcher Julia Oh talks about how the microbiome could inform research into ME/CFS.