“The immune system has to think on its feet” Mark Davis

broken-eggsIt’s the classic question: the chicken or the egg? What determines your health more – your genes or your environment? A major study by renowned Stanford immunologist Mark Davis suggests that at least with regard to the immune system – it’s probably mostly the egg.  The infections you’re exposed to, the foods you eat, the toxins you bump into, impact your immune system more than the genes you’re born with.

Cell. 2015 Jan 15;160(1-2):37-47. doi: 10.1016/j.cell.2014.12.020. Variation in the human immune system is largely driven by non-heritable influences. Brodin P1, Jojic V2, Gao T2, Bhattacharya S3, Angel CJ4, Furman D4, Shen-Orr S5, Dekker CL6, Swan GE7, Butte AJ8, Maecker HT9, Davis MM10.

Davis and his team measured more than 200 immune-system components in 210 pairs of twins. They found that three-quarters of the time, nonheritable influences (previous pathogen or toxin exposure,  vaccinations, diet, dental hygiene) determined more that 50% of the immune changes between the twins. Startlingly, almost 60% of the immune changes found between the twins were determined almost entirely by the different factors they’d bumped into in their environments. .

To put it simply, with regards to the immune system what you do and what you interact with matters more than who you are. In the nature vs nuture argument, the winner is nuture.

Age Matters

That pattern strengthens with time. The longer you’re on the planet, the more distance your immune system puts between its genetic roots and the way it functions.  In retrospect, this only makes sense. No other system in the body places such a premium on adaptability. Not only are pathogens all around us but they can evolve at a tremendous rate. If our immune systems can’t counter that diversity by adapting we’re dead ducks.

The larger than expected role the environment plays in shaping our immune response was unexpected. What was really shocking, though, was how large a role one familiar group of viruses plays.

Herpesviruses Are Major Agents of Change

The biggest agents of immune system change were pathogens. One herpesvirus, in particular, demonstrated a remarkable capacity to re-engineer the functioning of much of our immune systems.  Davis found that twins exposed to cytomegalovirus had vastly different immune systems than twins who had not been exposed to it.


Herpesviruses appear to be important drivers of immune system change in humans

Note that both twins were healthy; the twins with CMV were clearly successfully controlling the virus. Their immune systems, though, had shifted dramatically, in order to keep it under control. Almost 60% of the immune factors measured in the infected twins were different as a result of  their exposure to CMV. The study demonstrates the power that even latent viral infections can have.

It also brings to mind the immense changes in immune networking Dr. Broderick and Klimas at the Center for Neuroimmune Medicine have found in ME/CFS patients. Broderick’s proposed that the more complex immune networks he’s found in ME/CFS patients could be driven by a infection. That jibes well with the more complex immune systems found in Davis’s CMV exposed twins as well.

“We suggest that repeated environmental influences like herpes viruses and other pathogens, vaccinations, and nutritional factors cause shifts in immune cell frequencies and other parameters and, with time, outweigh most heritable factors.”

The herpes virus most commonly associated with chronic fatigue syndrome, Epstein-Barr virus, wasn’t  highlighted in the study. That’s not surprising given the fact that almost everybody has been exposed to it. Time of exposure may be a more relevant factor regarding EBV, however.  Being exposed to EBV during childhood usually results in few or no symptoms, but being exposed to EBV during adolescence often causes a protracted case of infectious mononucleosis. The Davis findings suggest a major and perhaps prolonged shift in immune functioning could occur during that period.

That’s intriguing given the anecdotal reports suggesting high rates of past infectious mononucleosis episodes may be present in the ME/CFS community. If that’s true, it’s possible that the immune shifts occurring during that time  increase the risk of ME/CFS either then or later in life. Some researchers believe late exposure to EBV sets the stage for the appearance of autoimmune disorders decades later.

Simply being exposed to CMV produced large immune system shifts

Simply being exposed to CMV produced large immune system shifts

Davis’s findings  may also fit well with those of the recent Chronic Fatigue Initiative Lipkin/Hornig ME/CF study. That study found a strong immune signature in early duration but not later duration ME/CFS patients. It appeared that a common factor such as an infection produced profound and similar changes in ME/CFS patient’s immune system functioning early in the course of the disorder. Whatever the factor or factors were, they brought the immune systems of people with ME/CFS into alignment for a period.

As time went on, though, and new challenges showed up, that distinctive immune signature wanned. One person came down with the flu, another received a vaccination, another changed their diet. As each challenge produced new riffs in immune system functioning, the strong connections in the group faded.


Some caveats are present. Davis studied the immune makeup and genetics of healthy twins. It’s possible that some of the adaptive machinery of the immune system has broken down in immune-mediated illnesses leaving genes to play more of a role than they would otherwise.  We know that genes do play a significant role in autoimmune illnesses.

The few heritability studies done in chronic fatigue syndrome, and/or fibromyalgia suggest that higher degrees of heritability may be present in ME/CFS and FM than in most diseases.

Davis’s findings don’t suggest genetic makeup doesn’t play a role; it’s an important component – just not as important as once thought, and it’s importance wanes over time.

Innovator, Disrupter and ME/CFS Researcher

“For the mice in the audience, I have wonderful news!” Mark Davis

Davis is quite comfortable in his role as the disrupter of received wisdom. Mouse models have guided immunological research for decades but in a 2012 editorial Davis excoriated the immunological world for using out-dated models that poorly reflect human immune functioning. The technology is now available for human immune modeling to step forward.

It was just a couple of years ago that he was asked to create an Institute that would bring together three isolated communities. The immunology,  infectious disease and transplant communities have a heck of a lot in common – but which rarely talk to each other.

Mark Davis Phd on the Center for Immunity and Infection

His ultimate goal at what became the Institute for Immunity, Transplantation and Infection  is to be able to produce simple tests that portray the health of the immune system and guide doctors decisions. Davis hopes to develop tests that can pick people out before they get autoimmune disorders, or cancer or perhaps ME/CFS – and develop protocols to help stop them from getting those diseases.

First, though, he’s going to have to figure out what a healthy immune system looks like – a surprisingly difficult task.

“If a patient were to ask me, ‘How’s my immune system doing today?’ I would have no idea how to answer that, and I’m an immunologist. None of us can answer that. Right now we’re still doing the same tests I did when I was a medical student in the late 1960s” Gary Fathman, MD. Associate director of the Institute for Immunology, Transplantation and Infection at Stanford.

For all the money spent on it, the ever so complex immune system is still mostly a black box. Researchers aren’t even clear what impacts immune drugs are having on it.

“Despite billions spent on immune stimulants in supermarkets and drugstores last year, we don’t know what — if anything — those really do, or what “immune stimulant” even means.” Mark Davis PhD

Center Immune Infection and Transplantation

Davis’s center brings together immunologists, infectious disease specialists, transplant specialists and more.

Understanding what a healthy immune system looks like – in order to give researchers a baseline to understand what an unhealthy immune system does, is huge goal, but it’s ignited a lot of interest – and money.  Since the Institute has has been launched Davis has received over $80 million dollars in public and private funding. That doesn’t include the $50 million the Gates Foundation gave him last January to create the Stanford Human Systems Immunology Center to produce better vaccines within five years.

He’s engaging one of the most sophisticated immune monitoring efforts in the world to do it. One of only five machines like it in the world (in 2012) shatters cells and tags the proteins found in it.  Another can tweak a cell or any number of cells with a pathogen or other stressor and determine how it responds.  All told he’s collecting about 40,000 data points on each blood sample.

As of 2012, the Center was running studies on biomarkers of aging, Alzheimer’s, autoimmune disease, cancer, chronic pain, rejection in organ transplantation and viral infection — both acute (influenza) and chronic (HIV). The biggest one running now, though, is a 600 person ME/CFS study. It will take them a year to run all the blood samples in the study.

It’s great having a heavy hitter like Mark Davis engaged in ME/CFS research, but he’s gone further. He’s one of eight distinguished researchers to sit on the Open Medicine Foundation’s scientific advisory board with Ron Davis. He’s a also major collaborator in the End ME/CFS Project.

Mark Davis and other members of the OMF’s scientific advisory board – including two Nobel laureates – are an example of the unique clout Ron Davis has brought to the ME/CFS field. That clout is opening and will continue to open doors that have not been open to us before.  We’re very lucky to have them both.

  • Coming up soon: The End ME/CFS Project’s First Project!

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