In May the Open Medicine Foundation announced they’d committed a major chunk of change – $1.8 million – to fund an ME/CFS Collaborative Research Center at Harvard Medical School affiliated hospitals. With the addition of the Harvard Center, chronic fatigue syndrome (ME/CFS) research centers are now found at two of the top four medical research universities in the U.S. (Harvard #1, Stanford #3). (With Peter Rowe at Johns Hopkins and Ian Lipkin at Columbia we have active research efforts/research centers in four of the top eleven medical research universities.)
The advent of a new research center at Harvard, of all places, further demonstrates Ron Davis’s reach at the top universities in the country. The new center will be lead by OMF Scientific Advisory Board members Ronald G. Tompkins, MD, ScD, and Wenzhong Xiao, PhD. Both have been involved in Davis’s ME/CFS work from the beginning and both are longtime collaborators.
A Focus on Muscles
For the time ever in chronic fatigue syndrome (ME/CFS) a concentrated effort to assess the molecular dynamics of what must be a core part of ME/CFS – the muscles – is underway. Ron Davis and other researchers are collecting mountains of data on the immune cells in the blood, but few researchers have assessed where the rubber meets the road with regards to exercise problems in ME/CFS. With Workwell’s two day exercise and David Systrom’s invasive exercise studies suggesting that profound problems exist with the delivery and utilization of oxygen at the muscle level this muscle study fulfills a crucial need in ME/CFS research and couldn’t have come at a better time. It’ll be fascinating to see how the blood and muscle results intertwine to tell us more about ME/CFS.
The New center will also establish a Clinical Trials Network that will utilize the facilities at Mass General Hospital to provide a foundation for the multi-center clinical studies we all hope will at some point break the back on this disease. Given the difficulties getting clinical trials underway in this disease nowhere is an effective and efficient clinical trials infrastructure more needed.
Extraordinary Research Team
Not surprisingly given their address – Harvard – the two researchers leading the new Harvard ME/CFS Collaborative Center have extraordinary resumes.
Ron Tompkins is Professor of Surgery at the Harvard Medical School and the Chief of Trauma, Burns and Surgical Critical Care Service at Massachusetts General Hospital. He’s also the founding director of the Center for Surgery, Science and Bioengineering and the Center for Engineering and Medicine. Tompkins was the lead investigator of an NIH “Glue” grant on Inflammation and Host Responses to Injury. The massive grant – the 10th largest extramural grant ever awarded by the NIH- lasted an incredible 13 years. Tompkin’s has published more than 450 scientific papers.
Wenzhong Xiao is the director of the Immuno-Metabolic Computational Center at Mass General Hospital and is an Asst. Professor of Surgery at Harvard Medical School. His bio states he is “internationally recognized in the field of Computational Genomics in Surgery and Medicine”. Xiao directed the computational arm of Tompkin’s massive Glue Grant study. A former study of Ron Davis’s, Xiao’s bio states he’s collaborated with Davis to create “new bioinformatic and statistical tools for data analysis”. Xiao also directs the Computational Genomics Lab at Davis’s Stanford Genome Technology Center.
We’re clearly lucky to have two such distinguished researchers working on chronic fatigue syndrome (ME/CFS).
The Glue Grant Project
The massive study which utilized 22 academic centers and involved dozens of researchers used (and developed) cutting edge molecular biology techniques to attempt to learn how inflammation – a protective process when kept under control – can spin out of control and cause immense damage. It’s a central question – why one person is able to recover from a serious injury while another dies of inflammation (sepsis) is not so different from the question of why ME/CFS patients remain ill.
It’s an important and long unanswered question. Despite billions of dollars and over 100 clinical trials, not a single drug has been produced that can successfully treat sepsis. Tompkins, Xiao, Ron Davis and others took a deep dive into molecular biology in an attempt to understand it.
The Glue Grant project proved to be a fertile ground of creativity. It pioneered a multi-systemic approach to severe trauma and burn patients which involved the integration of large-scale cellular and physiologic, proteomic, genomic and gene expression data. The massive amounts of data (petabytes – millions of gigabytes) obtained required the development of new analytic procedures by Wenzhong Xiao and his computational team. Another group of researchers spread across multiple laboratories developed experimental models of tissue injury, blood loss, and endotoxemia. Another group developed new ways to assess biological data including new microarrays which contained >6.9 million features. In all the new techniques pioneered by the team over the course of the study were published in 19 papers.
The Glue Grant ended up transforming how the medical profession views trauma. By 2015 the medical profession’s paradigm of sepsis – that a deficient initial systemic inflammatory response which left behind unresolved infections/ damaged cells and then created problems when a later anti-inflammatory response kicked in- was overturned. Plus the mouse model investigators had relied on for decades to understand sepsis was shown to be almost completely faulty. A central conclusion of the Glue Grant project was that to understand sepsis in humans you’re going to have to study humans – which is just what this project did.
The criteria for entry into the trauma study were stark; patients had to experience “blunt trauma”, display significant metabolic alterations (acidosis) and require a blood transfusion to treat severe anemia because of blood loss. To ensure that the participants received a standardized level of optimal care, the study mostly took patients from four elite trauma centers in the U.S. By 2015 complete data from over 2,800 critically injured or burned patients had been included.
In 2015 Tompkins produced a review article describing one aspect of the project called “Genomics of Injury: The Glue Grant Experience“. In it,Tompkins stated that he believed the trauma and burn findings would apply to severe infection as well. Glue grant studies indicated that generating an inflammatory response and flu-like symptoms in healthy controls using a single dose of an endotoxin (bacterial toxin) replicated almost 50% of the gene expression found in severe burns and trauma. Given that that was a mild hit to the immune system, it was no surprise to find that Tompkins called the gene expression response in sepsis, ARDS (acute respiratory distress syndrome) and infections “almost identical” to that seen in the trauma patients.
Takeaways from the project included the occurrence of a “genomic storm” which altered the expression of about 80% of the patients’ white blood cell genes. As probably occurs in sudden onset ME/CFS patients, the vast majority of the gene changes occur in the first 24 hours. During that period the gene expression of cells associated with our innate immune system – the rapid response arm of the immune system – dramatically increased. Meanwhile the gene expression of cells associated with the adaptive immune response such as T and B-cells dramatically decreased – probably to avoid triggering an autoimmune response to the many new molecules found in the blood.
In a huge surprise, the suspected reason for the decline into sepsis and often death – a cytokine storm – was not present. Even with the massive and unprecedented changes in gene expression seen in these patients’ white blood cells, the cytokine levels of the recovering vs. declining patients were almost indistinguishable from each other. Cytokines were not driving the illness process.
Most of the gene expression in the two patient cohorts (recovered vs. still ill) were similar as well, but major differences did show up, interestingly, not in the hugely up regulated innate immune genes but in the down regulated adaptive immune genes. Adaptive immune gene expression suppression (HLA-DQ, HLA-DA; interferon genes IFIT 1,2,3,5) was much more dramatic in the still ill patients. About half of the overly down regulated genes were downstream of interferon – a result that no one suspected – but which has created new opportunities for treatment.
In another surprise, no late anti-inflammatory response showed up. Instead, the changes in gene expression associated with poor recoveries began very early and were sustained throughout the study period, suggesting that, as is suspected with ME/CFS and FM, people who failed to recover from the trauma were in some way primed to stay sick once it occurred.
It’s hard not to think that a touch of serendipity has struck ME/CFS. Whitney Dafoe’s severe illness brought his father Ron Davis into the picture and, in turn, Davis brought in Ron Tompkins and Wenzhong Xiao – two researchers who’ve spent more than a decade studying how inflammation – long believed to be a key part of ME/CFS – can turn into chronic illness.
The Ron Tompkins Interview
After hearing that a Harvard ME/CFS center might be in the works, I spoke to Tompkins at the Montreal ME/CFS Conference. He was excited about the possibility of running an ME/CFS research center, and in particular, having one at Harvard – a presence that can only boost the prestige of this field.
After the Center was announced, I asked Tompkins questions that were related mostly to a recent paper he had co-authored which described the systemic metabolic and mitochondrial changes that occurred after burns.
In one study you found that burn activated the mTORC1 protein complex and hypoxia-inducible factor (HIF)-1α. In parallel with activation of these two factors came all sorts of mitochondrial issues including morphological alterations (i.e., enlargement, partial loss of cristae structure) and impairment of the respiratory supercomplex. Are these the kind of things you’ll be looking for in your biopsy studies?
Burn injury and massive blunt trauma are very severe forms of stress that require a human to respond. Serious viral or other infections are other forms of severe stress. Most patients ultimately recover to a condition that is near to their normal homeostatic state. Some patients do not ever make it back to that same “normal” condition. We do not understand why this happens. The abnormalities mentioned above regarding mTORC protein complex, HIF activation and mitochondrial abnormalities are likely also seen in ME/CFS. There are differences, however, and we need to better understand those differences.
We will be evaluating these and many other ways that mitochondria respond to severe stress but might not recover completely after that initial stress resolves and what persistent abnormalities might be found in ME/CFS.
The 2016 Lancet paper you worked on demonstrated that a metabolic shift occurs after severe burns which affects the entire body – not just the burned area. It’s as if this trauma – which you note produces an almost unparalleled stress response – resets how the body functions for years. One of the things believed to happen is that the muscles become a nitrogen source for the rest of the body. Some studies, if I remember correctly, suggest that problems utilizing fats for aerobic energy production might be similar to the process occurring in ME/CFS. If that process is occurring, would you be able to tell that from your studies?
Serious stress from massive blunt trauma and serious burns results in severe inflammation that places patients in a new steady-state. Immediately after the injury, the inflammation causes phosphorylation of the enzyme pyruvate dehydrogenase and impairs its function and that of citrate synthetase. This blocks three carbon molecules from entering the TCA cycle. This impairs ATP generation from the “burning of glucose” in the peripheral tissues (e.g. skeletal muscle and skin). Simultaneously, peripheral triglyceride is broken down and fatty acid flux increases by many fold. Peripheral tissues dramatically prefer to “burn” or oxidize fats in order to generate ATP – a switch to beta oxidation. Elements of these same effects are seen in ME/CFS, but we need to understand the extent and relevance of these well-known phenomena.
In both sepsis and burn a metabolic shift from aerobic energy production in the mitochondria to ATP synthesis by anaerobic glycolysis occurs. The strange thing is that it occurs in the presence of abundant oxygen. This process, known as the Warburg effect or aerobic glycolysis, can be induced by inflammation. Do we know why the body would at times prefer a less efficient, less effective and more toxic way to generate energy (glycolysis) when a more efficient process (oxidative phosphorylation) is available?
This is a very interesting point. I can best explain it by teleological arguments. I’d be happy to discuss with you when we next meet. It’s more of a conversation. The points you are making are extremely insightful and I would hope to provide multiple publications to begin to explain this very interesting story to follow.
This process is initiated by a master transcription factor called hypoxia-inducible factor (HIF)-1α which upregulates the activity of genes involved in glycolysis (glucose transporter-1 (Glut1) and pyruvate dehydrogenase kinase-1 (PDK1) genes. Could a similar process be occurring in ME/CFS? Will you be looking for upregulation of these genes in your studies? Or is it more likely that the shift to glycolysis in ME/CFS is occurring because of low oxygen levels?
Yes. The HIF process might not be the only mechanism, but we need to start there. The good news is that this is a general and very important process, so that understanding how this works and how to modulate it is very important, not only for ME/CFS, but also for other important diseases and disorders. This level of importance can make progress in ME/CFS move forward faster as its mechanisms are likely shared by many other very poorly understood conditions. These responses do not necessarily require tissue hypoxia.
Some studies suggest that problems with the blood vessels could result in reduced oxygen or hypoxic conditions in the muscles in ME/CFS patients. That, in turn, would lead to a reliance on glycolysis, reduced energy and increased levels of lactate. If the muscles are getting less oxygen in ME/CFS, would this show up in your muscle studies?
This is a very complex matter. There are no appropriate data to actually understand the oxygen tension in skeletal muscle in ME/CFS, but there is a great deal of presumption. Actual tissue hypoxia requires a great deal more direct evaluation before I can respond to your questions appropriately. I am quite familiar with hypovolemic conditions after serious injury and I am aware of the reduced blood volumes in ME/CFS but I am uncomfortable making any predictions of fact regarding ME/CFS until the condition is properly determined without ambiguity.
With regards to establishing an ME/CFS clinical trials network, how can the Harvard Center help with that? What kind of resources does it bring to bear? Would this network begin by testing substances that Ron Davis’s work at Stanford suggests might be useful?
The Harvard Center intends to support systematic multi-center study groups who agree upon definitions, allow audits of their investigational infrastructure, and comply with terms and conditions agreed upon by the consortium. So many clinical studies to date in ME/CFS are single site studies either with or without confirmation with studies done in other sites. Large-scale consortium results add an additional dimension to the relevance of the conclusions of interventional or observational studies. This is true in any field, not just ME/CFS. It is harder and more expensive, but required to move a field forward with understanding.
The Harvard Center is fully open to any investigators wishing to participate. We would hope to eventually be funded at a level to accomplish this condition. We intend to collaborate with the Stanford ME/CFS Collaborative Center and take forward those promising tools and techniques developed by Ron Davis and his colleagues. We also intend to provide patient tissues and materials that will propel studies at the Stanford ME/CFS Collaborative Center. We also intend to collaborate with the three NIH funded ME/CFS Collaborative Centers in a similar manner as well as the expected new Collaborative Center in Canada.
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