Accelerating Research on ME/CFS

 National Institutes of Health
April 4 & 5 2019

Summary of select presentations
by Dr. Eleanor Stein

This 2-day NIH symposium on ME/CFS research is one of the most exciting I have listened to. There were the usual suspects progressing their research and a host of researchers new to the field. The new researchers are attracted to ME/CFS because they believe the disease is serious, real and biomedical – a legitimate disease to study. Many of the new researchers have very impressive track records in other fields and are bringing this expertise to ME/CFS. They are attracted to the challenge of understanding and treating a condition that has been orphaned by medicine. The recordings of the 2-day Symposium are freely available on the NIH website.

Increased funding and Financial Support for ME/CFS

More good news is that the financial support from the National Institutes of Health in the US for ME/CFS has increased significantly. There are now 3 NIH-funded research centers along with infrastructure to gather data and foster collaboration. In addition, the NIH is undertaking an intramural study (designed and completed at the NIH). They will study a small number of carefully selected patients and healthy controls and test everything imaginable looking for hints about what to explore further. Participants travel to the NIH twice for 2 weeks at a time!

As we in Canada apply again for a catalyst grant for ME/CFS funded by the Canadian Institutes of Health Research (CIHR) we have the opportunity to benefit from this American infrastructure. It’s a win-win.

I will summarize the research studies which I find the most exciting and for which I understand the implications with apologies to those I have left out. The researchers’ names and affiliations are in green making it easier for you to skim to those of most interest to you. Some of these lines of research have been featured in previous posts. It is important to note that the researchers mentioned in this summary are the team leaders (the grant holders). Each of these researchers has a large team of collaborators, students and technicians who actually carry out the research.

What is ME/CFS?

For people wanting to get an evidence-based introduction to ME/CFS, I recommend the first talk of the NIH recording called “ME/CFS 101” by Dr. Cindy Bateman from the Bateman Horne Center in Salt Lake City. Dr. Bateman is one of the best clinicians in the field and contributes patients to many research studies. For those wanting a more in-depth understanding, I recommend a recently recorded 6-part ME/CFS information series on Dr. Bateman’s website. 

ME/CFS Research: BIG DATA (combining data looking at many different things)

Dr. Ian Lipkin from the Center for Infection and immunity at the Columbia University Mailman School of Public Health presented an update of his research on ME/CFS which is now ongoing since 2011. After struggling for funding for ME/CFS research for years, Dr. Lipkin’s lab is now one of the three NIH-funded research centers. He has a growing number of bodily fluid samples including blood, feces and saliva from both patients and healthy controls. He reiterated that he has not found evidence of any active infection being more common in the patient group compared to the healthy controls.

In the meantime, to prove he is deserving of the title “virus hunter” he is testing a chip to diagnoses tick-borne diseases such as Lyme Disease and co-infections. And he believes he has found the cause of acute flaccid myelitis in children (enterovirus types A & D). Lipkin’s team has developed a chip to test for all known bacteria including markers for antibiotic resistance. In other words, he’s pretty good at finding bugs.

Dr. Lipkin’s most recent research in ME/CFS is looking at the microbiome (gut bugs). The team found an increase in inflammatory species and a decrease in bacteria that produce butyrate. Butyrate is a short-chain fatty acid, critical to the health of the intestinal cells. When we eat fibre, the bacteria in our bowels convert it to butyrate. Saliva studies show an increase in species associated with oral and GI disease.

Ron Davis, Professor of Biochemistry and Genetics at Stanford University School of Medicine has probably done more recently than any other single person to advance the research of ME/CFS. Dr. Davis has leveraged his considerable networks to encourage many very prominent scientists to join research funded by the Open Medicine Foundation. Their studies including the “big data study” and the “severely ill study” are described on the Open Medicine Foundation website. Where other people see barriers, Dr. Davis and his growing network of collaborators see opportunities to invent new devices and tests. And in the ethic of open medicine, their goal is to develop accessible and inexpensive tests and treatments.

One very provocative, just accepted for publication, finding from this group is a nano-needle probe that measures the bioimpedance of cells in real-time. Molecules such as salt, metabolites and drugs could be added to the solution as a way of testing the reaction of the blood of individuals with ME/CFS. So far there is 100% separation between the responses of cells of patients with ME/CFS and those of healthy controls when salt is added to the drop of blood.

What is even more interesting is that when cells from healthy controls with normal nano-needle impedance are bathed in serum (the liquid portion of blood) from patients with ME/CFS, the cells begin to respond abnormally. This suggests that there is something in the liquid portion of blood that can transmit the dysfunction of ME/CFS to healthy cells.

The search is on to figure out what is being transmitted. Davis reports that the transmissible molecules are not metabolites or cytokines. They hypothesize that the transmitted message may be a dangerous signal from the mitochondria possibly in the form of an exosome. Exosomes are small vesicles extruded by cells into the blood containing information about the origin and health of the cells. They are one form of communication between cells. There is a lot of hope that exosomes may provide information about the brain – an area otherwise hard to access.

Nancy Klimas is the Director, Institute for Neuro-Immune Medicine, Nova Southeastern University. Dr. Klimas has amassed a team of 60 scientists studying Gulf War Illness and ME/CFS at Nova Southeastern University in Fort Lauderdale. They use a multidisciplinary, systems biology approach. They have reported that compared with healthy controls, individuals with ME/CFS have decreased metabolism, decreased signalling (between body parts and cell types) and decreased connections between cells and systems.

Their data suggests people with ME/CFS have moved out of healthy homeostasis (range of the function), and are stuck in disease homeostasis. Think of being stuck in a sand trap on a golf course and being unable to get back onto the green. Some efforts actually bury the ball deeper in the sand. Klimas’ team is using computer modelling to identify strategies for getting people out of the chronic disease sand trap and back to healthy homeostasis (a reboot). They have had some success with a mouse model of Gulf War Illness and are currently trying a treatment that impacts cortisol production to reboot ME/CFS.

Interestingly one of Dr. Davis’ team, Dr. Robert Phair, is proposing a similar hypothesis. Phair describes a pathological steady state called a “metabolic trap” in which people get stuck. They have identified a model involving the serotonin pathway and are working on a cell (in vitro) model to test it further.

Mitochondria and Metabolism 

Dr. Robert Naviaux’s lab is part of the Mitochondrial and Metabolic Disease Center at the University of California at San Diego. For more on Dr. Naviaux’s research see my newsletters from May and October 2016 and December 2018. In his talk at the NIH, Dr. Naviaux explains his hypothesis that ME/CFS, FM and ES among many other chronic conditions are caused by a block of the healing cycle. Dr. Naviaux stresses that trying to treat or reverse an illness trigger (such as a physical trauma in FM, infection in ME/CFS or chemical exposure in ES) will be unsuccessful.

Naviaux’s research is a search for interventions that will help cells get unstuck and move through the healing cycle. The first stage of healing is inflammation. The second stage is proliferation (growing new cells to replace damaged ones) and their third stage is remodelling and restoring communication (in which the new cells learn their jobs).

Maureen Hanson is Liberty Hyde Bailey Professor in the Department of Molecular Biology & Genetics at Cornell University, one of the three NIH-funded research centers. Dr. Hanson’s group’s work was eloquently presented by team member Alex Mandarano. She gave a wonderful explanation of a new instrument that is breaking open mitochondrial research. With the Agilent Seahorse XF Cell Mito Stress Test, researchers are gathering a huge amount of precise information about oxidative metabolism and glycolysis in real-time in all kinds of cells. It turns out that in ME/CFS different cell types respond differently.

The team is also using sophisticated fluorescent staining of the mitochondria to view them microscopically and measure mitochondrial mass and membrane potential. The CD8 (cytotoxic T cells) of ME/CFS patients function normally at rest but metabolism fails to increase as needed when the cells are activated. The CD8 cells of ME/CFS patients have a lower membrane potential than those of healthy controls. Their conclusion is that the immune cells in ME/CFS overall are hypometabolic. This is supportive of Dr. Naviaux’s work of dauer or hibernation and is not supportive of an autoimmune mechanism of ME/CFS. In autoimmunity, the metabolism of immune cells is generally overactive.

Bhupresh Prusty is a Group Leader in the Department of Microbiology at the Julius Maximilian University of Wuerzburg Germany. Dr. Prusty is the recipient of a Ramsay award from the Solve ME/CFS Initiative (https://solvecfs.org/). He has been researching the provocative finding that some of the dysfunction on ME/CFS may be transmissible through the serum. He has found that when human herpes viruses such as HHV6A infect cells the mitochondria fragment becomes less able to produce ATP. They are able to visualize this using fluorescent staining and high-powered microscopy.

Prusty reports that 40% of the ME/CFS cells they have tested have a signal for a small non-coding RNA from HHV6 – even in the absence of positive serology or PCR. This small molecule is evidence of active infection and is not found in cells in which the virus is latent. When they added serum from patients with ME/CFS to healthy cells they saw the fragmentation of mitochondria very similar to the fragmentation caused by fluid in which HHV6A virus had been grown. The search is on for what is being transmitted.

Furthermore, the group has shown that the mitochondrial changes are reversible. After the mitochondria have fragmented in the presence of serum from ME/CFS patients, if the cells are washed and the serum is replaced with healthy serum, the mitochondria recover within a day. This has huge implications for in vitro research (in a petri dish). In most studies to date, cells from patients with ME/CFS are grown in artificial media rather than serum from the donor individual. This may have resulted in many false-negative findings over the years.

Please note that this research does not mean that ME/CFS can be caught or transmitted in blood like an infectious disease. The molecules being transmitted in serum are not self-replicating. They may be danger signals from the mitochondria which promote cells receiving the message to also emit a danger response.

Autonomic Function and Exercise 

Dr. Peter Rowe, Director of the Children’s Center Chronic Fatigue Clinic at John’s Hopkins Hospital reported on a new tool to measure brain blood flow. Using this tool, he is able to show that by the end of a tilt table test patients with ME/CFS have a 25% decrease in brain blood flow on average even when their blood pressure and heart rate remain normal. Based on these results, Rowe warns against interpreting a normal BP and HR as evidence that there is no autonomic problem.

Both Dr. Rowe and Dr. Cindy Bateman recommend the 10 minutes NASA Lean Test as a low-tech way to identify people with orthostatic intolerance (OI), one common type of autonomic dysfunction in MECFS. Detailed instructions for physicians and patients about how to undertake and interpret the test can be found here. 

Autonomic symptoms are often treatable and the treatments can help people feel much better. Searching for Dr. Peter Rowe on Youtube leads you to many of his talks including some very recent ones given at the Elhers Danlos Society. For more on Elhers Danlos Syndrome see my January 2017 newsletter.

Dr. Bateman reminds us that the symptoms of acute and chronic orthostatic intolerance differ. People with chronic OI have adapted to their state and manifest symptoms such as nausea, fatigue and cognitive dysfunction much of the time; more severe when upright.

Dr. Bateman’s tips for managing OI include: 1. loading with fluid and salt (+ Florinef if needed), 2. compression garments (+ midodrine if needed), 3. Beta-blockers if the heart rate is too fast, 4. pyridostigmine for people with POTS if none of the above have worked and 5. some kind of exercise of the muscles of the lower body even this can only be done horizontally in bed. The muscles are pumps and keep blood flowing. See Session #3 of my manual “Let your light shine through” for more on these strategies.

David Systrom is a physician at Brigham and Women’s Hospital and an assistant professor of medicine at Harvard Medical School. His area of expertise is the Invasive Cardio Pulmonary Exercise Test (iCPET). In addition to the usual measures from a CPET such as how much O2 and CO2 are exchanged and how much work is produced during exercise, the iCPET measures right atrial filling pressure and pulmonary wedge pressure (how much blood is entering each side of the heart with each beat) and how much oxygen is extracted by the tissues. Systrom’s team has found that patients with ME/CFS have significantly decreased filling pressure, especially at higher workloads. This means that the heart doesn’t have enough blood entering it to function optimally. When they gave patients an intravenous saline solution the deficits improved markedly.

There is also impaired oxygen extraction in ME/CFS. This is called peripheral left to right shunting. It could be that the blood moves through arterio-venous shunts without getting to the tissues. Or it may be that in ME/CFS the blood is getting to the tissues but oxygen isn’t being used due to the lower metabolic rate. Systrom notes that many of the patients with cardiac preload abnormalities also have evidence of small-fibre polyneuropathy (SFPN) using Dr. Oaklander’s biopsy method (see more on this later in this newsletter). If there are far fewer nerve fibres wrapped around the smallest arterioles and venules, control of blood flow may suffer.

Betsy Keller is a professor in the Department of Exercise & Sport Sciences at Ithaca College in New York. She has been doing 2-day CPET tests since 2005 and has published data confirming that of Stevens and Van Ness who originated the test. She is now reporting data on a finding called “Chronotropic Incompetence”. During the 2-day CPET protocols, she (and others) have noticed about 60% of individuals with ME/CFS are unable to achieve their age-predicted maximum heart rate. These same individuals have lower than expected ventilation (how much air is moving in and out with each breath) and a failure to increase the systolic blood pressure (SBP) with exercise. Dr. Keller believes all of this is evidence of insufficient blood flow and oxygen delivery as a result of autonomic dysfunction.

Dr. Anne Louise Oaklander, director of the Neurodiagnostic Skin Biopsy Laboratory at the Massachusetts General Hospital. Dr. Oaklander is an expert on diagnosing small-fibre polyneuropathy (SFPN) using skin biopsy. Patients with SFPN have significant decreases in the number of small nerve fibres in the skin. My January 2015 newsletter discusses the evidence for SFPN in about 40% of patients with FM.  Dr. Oaklander recommends a skin biopsy for SFPN in any FM patient with autonomic dysfunction or tingling. This test is not currently available in Alberta. To hear more from Dr. Oaklander about the connection between SFPN and fibromyalgia click here.

What Causes Neuroinflammation?

There were several speakers discussing the evidence for neuroinflammation in ME/CFS. One of these is Dr. Jarred Younger, Director of the Neuroinflammation, Pain and Fatigue Laboratory at the University of Alabama at Birmingham. Dr. Younger has been using Magnetic Resonance Spectroscopy – a method that measures the abundance of different types of molecules in the brain. They have confirmed previous findings by Dr. Natelson’s group that lactate levels in the brain are significantly (4X) higher than in the healthy controls. This finding, among others, supports impaired aerobic metabolism in the brain leading to more glycolysis and production of lactic acid and the presence of neuroinflammation in ME/CFS. Prime candidates to cause the neuroinflammation to include: infection, autoimmunity, gut bacteria, lack of energy production and a leaky blood-brain barrier. The finding of neuroinflammation has been correlated with symptoms of ME/CFS such as cognitive dysfunction in ME/CFS, fatigue and generally poor level of function.

New Research Gives Hope for ME/CFS Patients

What is the take-home message from this research? When cells are exposed to the danger of different types the mitochondria sense the danger and respond by reducing energy production. This is protective for the cell but has adverse consequences for that cell and surrounding cells. If enough cells move into this low metabolic state, eventually whole systems and even the entire organism are impacted and have to downgrade activity expectations. It seems that the cells’ response to danger may be transmitted to surrounding cells through the serum in a way that is not yet understood. Many of the symptoms of ME/CFS could be explained by a hypometabolic model.

It is frustrating that we can measure so many significant abnormalities in ME/CFS but do not yet know the upstream causes. For example, there is agreement that there is neuroinflammation but no agreement on why. There is clear evidence of autonomic dysfunction but we don’t know why. The hypothesis of metabolic traps and blocks in the healing cycle may explain why patients get stuck in illness homeostasis but we don’t yet understand what causes some people to get stuck and others not when they are exposed to similar stressors.

The advent of big data, computational biology and nanotechnology is leading to significant advances. The influx of so many top scientists is pushing the field ahead like never before. Many ME/CFS researchers have skin in the game – they got involved because of friends or family who have ME/CFS. They are highly motivated to find practical solutions quickly.

Even if you are severely ill there is hope.

Author: Eleanor (Ellie) Stein MD FRCP(C)

I am a psychiatrist with a small private practice in Calgary and am an assistant clinical professor in the faculty of medicine at the University of Calgary. Since 2000, I have worked with over 1000 patients, all with ME/CFS, FM and ES. My passion for this field comes from my own struggle with these diseases, my desire to improve my health and then pass on what I learn. My goal is for every patient in Canada to have access to respectful, effective health care within the publicly funded system.

Ready to take back your health?

Check out more resources to help combat ME/CFS, FM and ES