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The Other MEGA Chronic Fatigue Syndrome (ME/CFS) Project: Dr. Hornig Talks

June 29, 2016

Three MEGA chronic fatigue syndrome (ME/CFS) projects (The OMF’s Severe ME/CFS Big Data project, NIH’s Clinical Center Study, The UK’s Grand Challenge) were recently discussed on Health Rising, but another “mega” project exists.

They all have some similarities. Like the others, the mega project underway at the Center for Infection and Immunity (CII)  is attempting to get at the molecular roots of chronic fatigue syndrome (ME/CFS). Like the others it’ll be searching through vast amounts of data in an attempt to uncover the unique biological signature(s)

personalized medicine

The CII hopes to develop a molecular signature of ME/CFS

Like the Open Medicine Foundation and NIH Clinical Center projects, some of the technology has been developed in-house. We’re blessed with the attention of some of the most innovative researchers in the world.

Let’s take advantage of a recent talk by Simmaron Researcch Foundation Scientific Board member Mady Hornig in Sweden and check out the CII’s big plans for ME/CFS. (A transcript of the talk is provided  on the striking, new Microbe Discovery website).

We learned recently that the internationally renowned Ian Lipkin is all in for chronic fatigue syndrome (ME/CFS); that his bucket list includes just two diseases: ours and autism.  Mady Hornig certainly didn’t skimp on her vision for ME/CFS at the talk either; she wants to create a Center of Excellence for ME/CFS at the CII, and hopes that the large array of studies the Center is engaged in will lay the foundation for that.

You can’t have research centers without funding, though. The NIH has been very responsive recently, and the big Clinical Center study is very exciting, but extramural funding is where it’s at and little money thus far has flowed to outside researchers. Last year Ian Lipkin and Mady Hornig in one of the weirdest grant awards ever received money for sampling but no money for analysis (?) –  and then had to drop in 500 K in to complete their sampling. It’s no wonder then that Mady Hornig (six months ago) referred to a “crisis” in funding. This, of course, is a crisis that’s been present for over 20 years.

Times are changing, though, and hopefully we’ll get some good news soon about the Trans NIH Working Group’s”strategy to reinvent ME/CFS at the NIH.

Even with this dearth of federal funding the CII, with the help of the Chronic Fatigue Initiative (funding metabolomics, proteomics, immune signatures, pathogen discovery projects), the Microbe Discovery Project, the (microbiome), the Stanford program (pathogens), the Simmaron Research Foundation (spinal fluid) and others, has put together a megaproject – a diverse, multidimensional attack focused on getting at the molecular underbelly of ME/CFS.

Check out the different stabs at ME/CFS the group is taking.

pathogens chronic fatigue syndrome

Dr. Montoya said last year to prepare for some exciting results in the pathogen study.

The Pathogen Slant  – in a very large study, the CII using PCR, Mass Tag PCR  (developed in Lipkin’s laboratory) and high throughput will scan for 1.7 million agents in, if I’m reading it right, 800 patients and controls. In his Spring 2015 and 2016 newsletters, Dr. Montoya said to expect some exciting results. They’re looking at viruses, bacteria, and for the first time ever in ME/CFS, fungi.

The Gut Plus Slant – (n=100) -The CII expects their microbiome analysis of the bacteria and fungi in gut will tell them a lot about immune functioning. It turns out that no less than 60% of our immune cells travel through and get altered by bacterial metabolites in the gut before they make it to the blood. They’re also looking at the throat area to see what this common collection point for pathogens might tell them. The CII has finished their first analyses of their initial gut study: the results were apparently good enough for the team to expand their study and begin taking multiple samples from the same patient over time.

It’s this kind of rigorous, dogged, longitudinal approach to ME/CFS – which no one by the way as ever done before – that they hope will put them first in line for a Center of Excellence. I don’t think anyone, ever, has watched the immune and microbiome systems over the length of time (12-18 months) the CII is. It would be very hard, indeed, to discount any pattern that consistently showed up over that period of time.

Plus, they’re building quite a biobank of samples at the same time. The CII will surely be at the top of the NIH’s list of potential ME/CFS research consortiums.

The Autoimmune Slant – Autoantibodies could conceivably be behind everything that happens in ME/CFS. The CII will be looking for autoantibodies to human cells and  pathogens including viruses, bacteria and fungi. This will allow them to dig up evidence of past infections that may have triggered ME/CFS. Their search will also include those adrenergic autoantibodies recently found in POTS patients that dysregulate their heart rates.


Genetic, immune and pathogen data could come together to form a model for ME/CFS

The RNA Seq / miRNA – Gene expression Slant – Gene expression tells  us which genes are doing what. This study will determine what’s happening with the immune genes in ME/CFS. Right now we might guess they’ll see increased immune gene expression early in the disease and reduced gene expression.

Since studies have shown that unique patterns of gene expression or genetics predispose people to prolonged courses of illness after an infection, this study is ripe with promise.  (If I’m reading this right a paper should be out in the not too distant future.)

The CII could end up identifying:

  1.  pathogens that kick off the illness
  2. a pattern of gene expression that makes ME/CFS patients particularly vulnerable to that pathogen and
  3. the autoimmune reaction that grew out of an inadequate immune response that failed to quickly dispatch the pathogen.

Itraq / MRM Metabolomics ( amino acids, kynurenine, serotonin) Slant – The CII is particularly interested in how metabolomics (the search for metabolites in the blood) may be able to tell them what’s happening in gut.

tryptophan-kynurenine pathway

Some results suggest the kynurenine pathway has gotten turned on in ME/CFS

The L-tryptophan and the kynurenine pathway is a particular focus.  L-tryptophan should metabolize into serotonin, a feel good chemical involved in sleep, sex drive, vigilance and mood regulation. L-tryptophan, however, can also be captured by the kynurenine pathway which metabolizes it into some nasty products (bye-bye good feelings). The kynurenine pathway has popped up in an array of neurological and neuropsychiatric diseases.

Dr. Hornig noted their metabolomic analyses suggest the kynurenine pathway is alive and well in some ME/CFS patients. In a prior talk, she reported that their early data suggests that a subset of people with ME/CFS with low serotonin have increased immune activation ( IL-1 beta, TNF alpha, IL-12p40, and L-17F) as well.

Interestingly, interferon gamma (IFN-y) (see below) – an antiviral and proinflammatory activating cytokine, and TNF-a – a powerful pro-inflammatory cytokine, both of which may have become activated early in the disease, both push tryptophan metabolism into the kynurenine pathway.

Dr. Hornig said they were “very keen” to understand tryptophan’s role in ME/CFS.

Cytokine and Immune Arrays Slant  – They are or will be examining a wide array of cytokine levels over time to pluck out the most consistent contributors to ME/CFS.  Many people are interested in the role the autonomic nervous system plays in ME/CFS but the Lipkin/Hornig group may be the first to examine the role the immune system plays in causing  the ANS  issues and/or problems with orthostatic intolerance.                                                                                                                                                                                                                                                                               Allergy related cytokines (IL-4, IL-13, IL-17A, IL-10, Eotaxin) that can affect histamine production and alter blood pressure have popped up in their studies (and eotaxin has popped in other studies). Histamine, of course, can have devastating effects of blood pressure and circulation.  Dr. Hornig believes some of the “systemic fatigue” in chronic fatigue syndrome could originate here.


Similar results in spinal fluid and blood tests would provide a powerful validation for immune dysregulation in ME/CFS

The Spinal Fluid Slant – The Simmaron/CII study was not only the first study ever to document similar immune changes in the blood and spinal fluid, but it also introduced two new subsets; Dr. Peterson’s typical / atypical patietnts.  Dr. Lipkin was so high on expanding the spinal fluid study that he flew out to Lake Tahoe for the first time in 20 years to rally support for it.

An expanded Simmaron/CII spinal fluid study with more participants and more testing is underway. Should testing reveal similar findings in the spinal fluid and the blood again, a powerful message would be sent that ME/CFS is a immune disease.


People with shorter duration illnesses could possibly benefit from  antibodies to IL-17A or interferon gamma that could  reduce their hyperactive response to these cytokines. Many commercial antibodies, in fact, are now available. If Hornig/Lipkin can validate upregulated IL-17A or interferon gamma is present those treatments could become available to people with ME/CFS.

For the longer duration patients Dr. Hornig suggested that increasing the immune response by using Ampligen or [ an IL-1 receptor antagonist could be helpful.


The immune system doesn’t just poop out in the longer duration patients – it kind of goes bananas. An immune networking comparison in short vs longer duration patients suggested  a very focused and active immune network existed in short duration patients. In the longer duration patients, though, a much more complex immune network featuring many down-regulated immune pathways was present. It’s the stark a portrayal of these two subsets that I’ve seen.

surprise results

These big data studies may result in some surprises popping out.

Biomarker? – Despite the fact that interferon gamma levels were not particularly high they were incredibly predictive of short duration patients. That suggested, as Jarred Younger’s and Gordon Broderick’s work has suggested, that context is the key. It’s possible that increased IFN-y in the context of ME/CFS has unexpectedly strong effects.

Remember This – A big surprise in the longer duration patients spinal fluid was the almost complete disappearance of IL-6, a cytokine needed for memory storage and retrieval.  The IL-1 receptor- antagonist (IL-1ra) was very low as well. That was an intriguing finding given that (a) the network analysis suggested that IL-1ra was a key down-regulating element in ME/CFS and (b) drugs such as Anakinra could boost it back up – and presumably stop the central nervous system down-regulation.


The Center for Infection and Immunity, led by Dr. Lipkin and Dr. Hornig, is engaged – largely thanks to the Chronic Fatigue Initiative as well as the Simmaron Research Foundation – in the third mega study of ME/CFS under way. Among the unique elements of this project are it’s continuing spinal fluid component, it’s strong focus on the gut and the kynurenine pathway, and it’s long term longitudinal study that could prove pivotal in validating ME/CFS as a disease.

The CII’s strong blood immune and spinal fluid studies last year probably helped the NIH agree to reinvigorate ME/CFS research. Hopefully, that’s just beginning of the role the Center will play in deciphering ME/CFS. Boasting one of the most extensive research efforts on ME/CFS, it surely it’s a strong candidate to be one of the ME/CFS research consortiums we hope will get funding.

Next Up – the Center for Infection and Immunity Replies to the NIH’S Request for Information on the next steps for ME/CFS


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  • Catherine

    June 29, 2016 at 5:12 pm - Reply

    This is wonderful news!!n There are aspects of each one of these research efforts that make a lot of sense to me:
    1.My disability status was based on very poor short term memory retrieval and multi-tasking – though my prior career (pre fibro/CFS) was a state level program developer. 2. Delayed allergy response that always loops into an EBV flare that lasts for a month or more; 3. Genetics – pretty sure my dad also had fibro/EBV….v. healthy until early 50″s then achey, sleeping alot – he always denied depression – now I suspect fibro//EBV. I am so heartened to hear these significant research efforts are underway. There are too many lives being significantly altered and shortened by these “invisible” health conditions. I truly believe there may be or more answers to these illnesses and their treatment. THANKS!

    • Cort Johnson

      July 1, 2016 at 5:26 pm - Reply

      You should be in a study Catherine! I think they could learn a lot from you.

  • lizzie

    June 29, 2016 at 6:05 pm - Reply

    great article!! thanks!!

  • Ryan

    June 29, 2016 at 7:08 pm - Reply

    Thanks for all the info Cort. I appreciate all the work you do. It seems like it’s the same old research though. These studies have been going on for a long time. There’s always big promises and then a request for money. Sorry for the discouragement. I’m so depressed at being so sick that I don’t know that I can go on anymore. I’m tired of getting my hopes up over and over. The depression may be feeding my perception. I’ve been sick too long and too many patients are dying.

    • Cort Johnson

      June 29, 2016 at 7:26 pm - Reply

      Hang in there Ryan. I don’t think anyone thinks ME/CFS is going to be solved tomorrow or even the next day but these studies are going places researchers have never gone before.

      In the meantime I hope you can find some joy or contentment even in the midst of illness; no easy task I know but it is the one in front I think for all of us. Good luck!

    • jsuzor

      July 3, 2016 at 4:16 am - Reply

      Ryan, there is a nice support group that you might like on Facebook. I can’t think of the exact name at the moment, but it has the words Fellow Travelers…Someone here may know of it. I can look up the rest of the name if you would like me to. Maybe someone else can suggest online support groups for coping. Take Care, from someone who has felt exactly the way you are feeling.

    • Lynne

      July 5, 2016 at 4:43 pm - Reply

      Hey Ryan: I just wanted to say I’m sorry you are suffering so; I’m having one of those days today myself. But just hang on as those very depressed fed-up spells do lift at least for me. In coping recently, “take heart. Have courage” came to me. Then while reading a book, this quote grabbed me: “When life is more terrible than death, it is then the truest valor to dare to live.” By Sir Thomas Browne. There are days I can grab hold of those words to give me courage and days like today when I can’t quite get there. BUT even on days like today, it’s enough to hang onto something–anything (anger or calling someone or forcing yourself to watch a stupid funny tv show) until the worst of the depression lifts to something more bearable. Please hang in there and I will too, ok?

  • Julie

    June 29, 2016 at 8:42 pm - Reply

    This truly is wonderful news. Thank you so much, Cort, for these excellent updates. I believe only comprehensive studies will discover the critically important biomarkers we need to finally have legitimacy in the medical bureaucracy.

    • Cort Johnson

      June 29, 2016 at 8:51 pm - Reply

      Thanks Julie, and thanks to the Simmaron Research Foundation for their support which allows me to do that.

  • gg

    June 30, 2016 at 3:56 am - Reply

    Available as PDF?

    • Cort Johnson

      July 1, 2016 at 5:28 pm - Reply

      No – but email me and I will send you a word doc (wiithout pictures :))

  • Sasha

    June 30, 2016 at 3:33 pm - Reply

    Thanks, Cort – another very interesting article!

    You said, “Many people are interested in the role the autonomic nervous system plays in ME/CFS but the Lipkin/Hornig group may be the first to examine the role the immune system plays in causing the ANS issues and/or problems with orthostatic intolerance.”

    But didn’t Nancy Klimas say something a few years back about the ANS tanking first in response to an exertional (and/or orthostatic challenge) and taking the immune system with it?

    I’ve never seen that published but I thought it was based on research findings that she’d produced. Do you know anything about what happened there? It’s frustrating to think that there’s useful research that’s going unpublished!

    • Cort Johnson

      June 30, 2016 at 4:04 pm - Reply

      I remember that well! I haven’t heard anything about that and I hope we do…I don’t think its made it out to publication. Dr. Klimas did, however, illuminate neuropeptide P which is a bridge, if I remember correctly between the ANS and the immune system..

  • A Moss

    June 30, 2016 at 5:43 pm - Reply

    This is such a great articulation and explanation! It is so great seeing this explained this way. I think it is phenomenal what CII have brought to the ME/CFS field and bet they are doing far more behind the scenes that we don’t get to see. I read somewhere they may have some new papers out soon is that correct? I have been waiting for so long for more work from CII to come out. It is almost ironic all these ‘megas’ going on lately and big data but CII have been onto this for a while and we need replication as well as investigation. Go CII! They seem to be working with so many different people. Thanks again Cort for another brilliant read!

  • Simon McGrath

    July 1, 2016 at 5:09 pm - Reply

    Another great article, Cort, thank you. I hadn’t realised the spinal fluid study was going to be exapanded – that’s great news. I’m hoping we’ll see some papers coming out of this work soon; it’s all so tantalsing.

    • Cort Johnson

      July 1, 2016 at 5:28 pm - Reply

      I agree Simon it is very tantalsing 🙂

  • randy nayfack

    July 1, 2016 at 9:42 pm - Reply

    Great job Cort!! You are so amazing! With you at the helm, we should be out of bed in no time!!

  • David Downer

    August 1, 2016 at 11:26 am - Reply

    Thank you so much Cort for this great news.

  • Nansy Mathews, CRNP

    August 1, 2016 at 1:44 pm - Reply

    Thank you, Cort, for this excellent update and synopsis. You do a wonderful job of stating complex findings in a way that makes it possible for all of us to understand. I used to be a research N.P., but I find it difficult to understand much of the bench research without the “Cort”filter.

    • Cort Johnson

      August 7, 2016 at 12:13 am - Reply

      Thanks Nansy – glad to be a filter for you 🙂

  • Mavis Dixon

    September 30, 2016 at 10:57 pm - Reply

    Thank you! I’ve shared this with people who are looking for hope and science – and this is a lovely blend of both!