The last of three blogs on The Solve ME/CFS Initiative focuses on the SMCI’s core mission – funding research that makes a difference in chronic fatigue syndrome (ME/CFS).
Serendipity can play a major role in research and it may be doing so at the SMCI. Carol Head felt she got the complete package with Nahle: his strong research background and administrative and communication skills appear to have gotten him the job. Nahle has what appears to be an ideal resume for someone tasked with overseeing a research effort at a non-profit like the SMCI.
Whether Carol took it into account or not, Nahle’s specific research focus also makes him potentially a key asset. If energy production really is the problem in ME/CFS, then Nahle is well poised to research and understand it. Nahle’s past diabetes research actually focused on some of the same energetic issues (pyruvate dehydrogenase) that studies suggest are facing ME/CFS.
Nahle has taken the SMCI’s creative but slower moving research program and put it on steroids. Now instead of funding several larger projects every three or four years, the SMCI is funding four or five smaller projects and several research “initiatives” every year. The projects are smaller (10-20 people) and thus will provide less data, but they give Nahle the opportunity to chase or focus on rapidly emerging leads that show up in ME/CFS research.
The 2016 awards demonstrated a real nimbleness in doing that. Note a strong theme that emerges: determining how energy production problems are bollixing up the immune system in ME/CFS. Time will tell if Nahle has taken the right focus, but for now he appears to have made some timely funding choices.
The 2016 Melvin Ramsay Awards
Your Brain on Fire?
How can you not love, for instance, Nahle’s choice to fund Jarred Younger’s effort to use magnetic resonance spectroscopy – a tool we are seeing almost everywhere in ME/CFS – that’s been tweaked to add on a thermal element called thermometry (MRSt) Younger will use his MRSt machine to determine if neuroinflammation is present in ME/CFS patients’ brains, and if it is, where it is and how much of it is there.
Neuroinflammation, of course, has been of extreme interest in ME/CFS since a Japanese paper came out a couple of years ago showing it was present .Younger’s project – which is unique in that it uses a non-invasive technique (no radiation or dyes needed) – to assess the amount of neuroinflammation by measuring the temperature of the brain – was just crying out to be funded. Kudos to the SMCI for doing that.
As a bonus the project will collect data on several putative markers of neuroinflammation, including myo-inositol, glutathione, lactate, and choline which Younger and the SMCI will make available to the research community at large.
ME/CFS B-cells Breaking Under the Load? (Metabolic Analysis of B-Cell Maturation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome)
When we think of B-cells we automatically think of Rituximab, but Nahle also pointed out that many viruses including EBV hang out in B-cells and that B-cells are also, of course, key players in autoimmunity. It turns out that B-cells have to ramp up their metabolism immensely when they turn into antibody producing cells. Could energy production problems be messing with B-cells’ ability to get up to speed? This study, which will feature London ME/CFS and Chris Armstrong from Australia will apparently study the mitochondria of B-cells in ME/CFS patients as the cells mature into antibody producing machines.
A break in the action there – an inability to produce the energy needed at that vital time – could help explain why the B-cells are not working properly in ME/CFS (and why Rituximab is).
Natural Killer Cells Too Fatigued to Kill? (The Bioenergetic Health Index of NK Cells as a Diagnostic Tool for Chronic Fatigue Syndrome)
Reduced NK cell cytotoxicity has been found in ME/CFS for decades, but still no one knows why it’s there. Isabel Barao-Silvestre suggests that the NK cells in people with ME/CFS are just too pooped out to go out and kill the viruses and infections that plague ME/CFS patients. These punked out NK cells simply can’t keep up with the herpesvirus reactivations that plague some people with ME/CFS. Barao is using a hot new Seahorse technology to create a “Bioenergetic Health Index” of the different NK cells types in ME/CFS. That technology will track how well NK cells are turning fats and carbs into energy.
Finding problems with carb utilization in NK cells would back up findings from metabolomics studies and the Stanford mitochondrial study, and of course, lead to a new focus on finding way to give NK cells more energy.
HHV-6 Infections Whacking ME/CFS Patients Energy? (HHV-6 Mediated Mitochondrial Modulation and Its Association to ME/CFS)
After a long period in which HHV-6 infection hasn’t been addressed much in ME/CFS, the bug is showing life again. At the last IACFS/ME conference Nancy Klimas showed (unpublished) that indices of HHV-6 activation are correlated with symptom severity in ME/CFS. Now, working off of their lab’s findings showing that HHV-6 can affect mitochondrial functioning,
Bhupesh Prusty will determine just how this is happening and how often it’s happening in ME/CFS. If it turns out this ubiquitous pathogen – found in almost everyone – is sapping the cells’ energy – that would, of course, really be something.
A Genetic Predisposition To Autoimmunity?
Carmen Scheibenbogen and Madlen Lobel recently showed that autoantibodies in a subset of ME/CFS may be attacking two cellular receptors that Fluge and Mella have hypothesized may be in play in ME/CFS. This study will determine if ME/CFS patients have a genetic weakness that’s allowing that to happen. If it’s successful it could help tell us why Rituximab is working in some patients and why ME/CFS patients appear to have blood flow problems.
Taking the Initiative
Besides funding whole research projects, the SMCI is also funding what it calls “targeted initiatives” which display a similar focus on the interaction between metabolism, energy production and the immune system in ME/CFS.
The Metabolomics/Bioenergetics Initiative
In this initiative involving Dr. Hanson, Dr. Levine and Metabolon – the SMCI took the gut samples from Dr. Hanson’s already published gut microbiome study and gave them a metabolomics workout.
The gut, because it’s the origin of so many metabolites, is obviously a great place to do a metabolomics study. If I understand this initiative correctly, this study will help tell us what role the gut is playing in the metabolomic problems that present in ME/CFS. Nahle said the testing is done and the analysis – which will take several months – is underway.
Two other under-powered (not statistically significant) pilot projects in this effort will look at twins with and without ME/CFS, and so perform the first small metabolomics pilot study done before and after exercise. (Hopefully more such studies are on the way…)
The Cellular Aging Project: Immune Cell Senescence and Energetics
Feeling older than your years? Maybe your cells are aging more rapidly than they should.
Cell senescence is something new Zaher is bringing to the ME/CFS field. Cellular senescence refers to how quickly cells age biologically, and how cellular turnover affects their cellular energetics and functioning.
Apparently increased cell senescence; i.e. a more rapid turnover of cells than usual, can be triggered by a number of factors (telomere problems, cancer oncogene activation, oxidative stress and biological stressors), all of which, Nahle believes, could be present in ME/CFS causing dysautonomia, muscle weakening and neurological issues. This project, taking place at Washington University in St. Louis, will examine cell senescence in ME/CFS.
A Drug for ME/CFS? The SMCI’s Drug Screening Project
The SMCI’s Drug Screening Project taking place at none other than the renowned Memorial Sloan Kettering Cancer Center. The long term goal is to subject ME/CFS patients’ immune cells to thousands of drugs to see which ones will improve their cellular bioenergetics and ATP production. If cellular energy production is the big problem in ME/CFS, this project could go a long way in identifying drugs – probably drugs we’ve never suspected – that might be helpful in ME/CFS.
Metabolic Muscle Breakdown
A Cathleen K. Gleason PhD Fund project – Cathleen Gleeson’s ME/CFS story is a typically rough one. With her PhD in Counseling Psychology, Cathleen worked full-time at the University of Vermont until one fateful day in 1999 when she made a simple but life-changing mistake: she hugged a student with mono and got sick herself. She’s never recovered, and almost 20 years later remains disabled today.
Her husband, Dr. Maughn, a muscle disease specialist who is bursting with ideas, regularly attends the IACFS/ME conference. Their son and his wife last year created the Cathleen J Gleeson PhD fund at the SMCI to support ME/CFS research. It’s first project is a magnetic resonance spectroscopy (MRS) project to measure muscle metabolites in ME/CFS patients before and after fatiguing exercise. The first patient tested was a hit. Unusual metabolites associated with energy production suggested that he was experiencing a lot of oxidative stress – particularly after exercise. Talk about potentially getting to the heart of the exercise problem.
Registering for Action: The BioBank and Patient Registry
Currently at the Biobank Nahle listed three research projects – a biomarker discovery, an autoimmunity and a methylation study.
Finally – A National Registry for ME/CFS – Nahle had explained earlier that little is known about the “natural history” of ME/CFS – who get it, how it proceeds, the diseases associated with it, etc. He called the SMCI’s Patient Registry a mega project designed to bring ME/CFS up to speed on a critical area that ME/CFS needs to catch up on.
The SMCI scored a Robert Wood Johnson Foundation White Label PEER (Platform for Engaging Everyone Responsibly) award to help build an international patient registry to include demographic, genetic, clinical and even treatment outcome (!) data. People will be able to add their own data, including test results, and sign off on allowing researchers to contact them within a secure website. Researchers should be able to easily run surveys and find participants for their studies. It will be a grand ME/CFS registry that will hopefully greatly facilitate research efforts into this disease.
Research has been a strength of the SMCI for quite some time. Two years into his tenure at the SMCI, Nahle has built on that strength by bringing a new nimbleness to their research efforts. Instead of funding 4 or 5 large projects every year the SMCI is currently funding 9 projects, many of which focus on energy production, the immune system and infection. Nahle is putting a lot of his eggs into the immune-energy basket but it seems a risk worth taking.
Melvin Ramsay was among the first to posit that ME/CFS is a real biological disease. My guess is that he would be pleased by the awards offered under his name.
The organization’s ability to be one of four organizations to score a grant to produce an international patient registry could reap dividends by helping to explain the natural history of ME/CFS, and in spurring new research efforts that proceed more efficiently and cheaply.
Check out the SMCI Parts I and II