ME/CFS Research: State of the Art, State of the Science

Written by Dr. Anthony Komaroff

On June 7, 2021, Drs. Lipkin and Komaroff published an article in Trends in Molecular Medicine on the state of ME/CFS research in the wake of COVID-19.

An illness like ME/CFS has been described in the medical literature for several hundred years.  Yet, when interest in the illness resurfaced in the mid-1980s, you could not find any mention of it in the major textbooks of medicine.

There were several reasons for this. First, past medical publications described the symptoms of the illness but did not report underlying biological abnormalities that might be causing those symptoms. Some doctors concluded that if no underlying biological abnormalities had been found, that the illness probably was not “real”. 

Furthermore, when doctors seeing patients with the symptoms of ME/CFS ordered the “standard” laboratory tests in the mid-1980s, the “standard” test results typically were normal. 

Unfortunately, upon receiving the normal test results some doctors told their patients that “there is nothing wrong with you.”  That was one possible conclusion.  Another possible conclusion that those doctors might have considered, but did not, was that they were ordering the wrong tests. Indeed, other tests available to them even in the mid-1980s did find abnormalities in many people with ME/CFS1.

Now, in the 21st century, we have state-of-the-art technologies for identifying underlying biological abnormalities that were unavailable (and even unimaginable) in the mid-1980s.  Most of the testing being performed by the Columbia Center for Solutions for ME/CFS employs these newer technologies.

These are some of the new technologies:

  • We now have much greater power to detect the presence of infectious agents—including previously undiscovered agents—using technologies like polymerase chain reaction (PCR). 
  • Diseases typically occur because the coordinated interaction of multiple different molecules has been disrupted. Most medical research previously measured only one or a few molecules in a blood sample. Today, we can measure literally thousands of molecules in a single sample. That means we can identify molecules that appear to be linked as part of a biological pathway. Once you identify pathways that are linked to a particular disease, the molecules in those pathways become candidates to serve as possible diagnostic tests, and also can become the basis for designing new treatments.  The Center is measuring thousands of different molecules in people with ME/CFS and in healthy control subjects.
  • The molecules the Center is measuring are not just the molecules made by our body. They also include molecules made by the microbes that live on and in our body. One of the great discoveries of the past 20 years has been the recognition that the genes of the microbes that live within us (our microbiome) produce molecules that affect our health. The Center is measuring those microbes, and the molecules they produce.
  • We can measure the structure of all the human genes as well as the microbial genes. That’s important because the purpose of a gene is to make a particular protein, and the structure of the gene determines the structure of the protein. It is the proteins that ultimately make our bodies work—that allow us to move, to see, to think. If there’s something wrong with the structure of a person’s gene, the result can be the production of a defective protein.
  • We also can measure whether a particular gene is activated to make the protein it is supposed to make. That’s important because even if the structure of a gene is perfectly fine, if the gene is not activated when it should be, it can have adverse effects on health.

That’s the remarkable state-of-the-art in biological technologies that can be deployed to study disease in 2021.  What’s the state-of-the-science, regarding ME/CFS?  I and Dr. Ian Lipkin, Director of the Center, have just published an article summarizing the state-of-the science. It was published online in late June 2021, in the journal Trends in Molecular Medicine2. As summarized in more detail in that article, we note that people with ME/CFS have:

  • Larger numbers of inflammation-causing bacteria, and smaller numbers of inflammation-fighting bacteria, in their gut, changes that correlate with symptoms;
  • Higher numbers of activated immune cells called T cells, as if the cells are fighting a battle against something;
  • Depressed function of another type of virus-fighting cell called natural killer (NK) cells;
  • Higher levels of certain chemicals (cytokines) that the immune system uses to fight battles;
  • Various autoantibodies—evidence of an autoimmune process in which the body’s immune system attacks not some foreign invader but attacks parts of the body, itself;
  • An impaired ability to make energy molecules (ATP);
  • Various abnormalities in the brain and autonomic nervous system

Finally, our recent article discusses how the growing knowledge about ME/CFS may affect our understanding of the lingering illness that can occur in people who develop COVID-19—postacute COVID-19 syndrome, or “long COVID”—and vice versa. We also propose a research agenda for both ME/CFS and postacute COVID-19 syndrome. We need to know whether the underlying biological abnormalities of ME/CFS are similar or identical to those in postacute COVID-19 syndrome.  Although we don’t yet know how many people will develop postacute COVID-19 syndrome, it is plausible that the number in the U.S. soon will match the number who already suffer from ME/CFS—as many as 2.5 million people3.

In summary, the recent article summarizes in some detail what is known about the underlying biology of ME/CFS. It also highlights the fact that understanding a disease sometimes awaits the development of new scientific technologies. The article also emphasizes why physicians should never dismiss an illness just because they don’t understand it. With dedication, new tools and an open mind, the answers are coming.

1Bates DW, Buchwald D, Lee J…Komaroff AL. Clinical laboratory test findings in patients with chronic fatigue syndrome.  Arch Intern Med 1995;155:97-103.

2Komaroff AL, Lipkin WI. Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome. Trends Mol Med 2021, published online June, 2021

3Komaroff AL, Bateman L. Will COVID-19 lead to myalgic encephalomyelitis/chronic fatigue syndrome?  Front Med 2021;7:606824. doi: 10.3389/fmed.2020.606824

Dr. Anthony Komaroff

Anthony Komaroff, MD

Editor in Chief, Harvard Health Letter

Anthony Komaroff is the Steven P. Simcox/Patrick A. Clifford/James H. Higby Professor of Medicine at Harvard Medical School, senior physician at Brigham and Women’s Hospital in Boston, and editor in chief of the Harvard Health Letter. He was director of the Division of General Medicine and Primary Care at Brigham and Women’s Hospital for 15 years, and is the founding editor of Journal Watch, a summary medical information newsletter for physicians published by the Massachusetts Medical Society/New England Journal of Medicine.

One thought on “ME/CFS Research: State of the Art, State of the Science

  1. Truly appreciate the summary update Dr Kamaroff. I keep trying to tell people that this is the process that’s science needs to follow in order to discover the causes of the disease. There’s a lot of impatience in the ME/CFS community, which is understandable, but what I don’t think a lot of them realize is that there are decades of neglect in play here that won’t be made up in one day.


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