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Lipkin and Hornig go hunting for ME/CFS pathogens

by Simon McGrath

red bugFor me, the star attraction of Nancy Klimas’ recent CFS/GWI conference was always going to be Professor Mady Hornig and her talk.

Hornig might not be well known by ME/CFS patients – yet – but her boss is: Ian Lipkin, who so skillfully handled the XMRV ‘dediscovery’ study (which she worked on too). Despite disproving a link with XMRV, Professor Lipkin made clear his belief that ME/CFS was a serious disease that had not received the serious attention it deserved. Even more important – given his stellar record as a scientist – was his commitment to playing a serious role in trying to solve the illness. He’s asked Mady Hornig to lead their hunt for the cause of ME/CFS, so I was hoping for an update on how exactly they were going about the work and when results were likely. 

As well as that, we had a presentation of science that made my eyes pop, as Mady Hornig took us through some of her incredible work in other illnesses where brain and immune system take centre stage too. If she brings these kind of approaches to ME/CFS then I think we will benefit enormously – more on this next week.

First, though, to the world’s largest ever ME/CFS biomedical study: the hunt by Hornig, Lipkin and colleagues for a virus or other pathogen that may cause our illness.

Huge initial studies look for pathogens or tell-tale signs of infection

Work has already started with around 400 patients plus controls, including 200 patients + controls from the CFI pathogen study (Professor Hornig is Principal Investigator for CFI’s Pathogen Discovery and Pathogenesis). If that’s not enough, they are hoping to get funding for up to a further 400 patients and controls. Assuming my maths are right, that makes a mind-boggling maximum of 1,600 subjects: 800 patients and 800 controls. This is a big step up for ME/CFS research.

The major part of the study is looking for pathogens – viruses, bacteria or protozoans both known and unknown. But they are also looking for protein/immune abnormalites in patients, and they even plan to take a look at gene expression too to see if that throws up any clues.

The pathogen hunt has three steps:

  1. Screen for a panel of 18 specific pathogens already implicated in ME/CFS, such as EBV.
  2. If no such pathogens are detected, they move to the heavy-duty phase, basically sequencing all DNA/RNA in the blood, which should identify both known and unknown viruses. This technique has been successfully used by Ian Lipkin in the past to discover new viruses.
  3. To be thorough (and these people are nothing if not thorough) any ‘finds’ from the first two steps will be confirmed by a smaller-scale but more accurate technique.

Final bug hunt

Finally, once they have confirmed candidate pathogens – assuming they find ones that have a statistically significant link with ME/CFS – they will develop new tests specifically for these pathogens.

As a bonus, the heavy-duty sequencing techniques in stage 2 makes it fairly easily to look at gene expression too. Previous attempts to identify unusual patterns of gene expression in ME/CFS patients have found differences, but these have not stood up to the test of replication. Hopefully the much larger cohorts used here will produce more reliable findings, and show which genes go awry with with ME/CFS.

Protein signature for ME/CFS?

The team will also try to define ‘host profiles’, looking for a unique protein signature associated with the illness. If the study does find a robust CFS signature, it could be used for diagnosis – and a validated diagnostic test is almost the Holy Grail of ME/CFS research. The signature could also be used to measure treatment progress.

Yet more high-tech approaches

They are using a fancy technique called ‘multiplexed immunoassay’ to look at over 50 specific proteins that are markers of immune/inflammatory changes, or oxidative stress. Again, the idea is to home in on plausible candidates for disruption in ME/CFS. For a smaller sub-sample, they will look more widely for any abnormality in protein profiles using “Target proteomics Mass Spectroscopy” – Nature’s “2012 Method of the Year”, no less. This approach could throw up proteins no one has yet considered playing a role in ME/CFS, giving new clues to the causes of the illness.

Another good reason to look for protein signatures is to detect general signs of infection. One possible scenario raised by Hornig is that lots of different bugs can trigger ME/CFS, and if that’s the case then each individual pathogen might not show up as statistically significant. (This is to do with statistical power, but you really don’t want to know). Finding the fingerprints of infection or inflammation instead might prove a general link between infection and ME/CFS, even if no individual pathogens can be pinned down for sure.

First results due later this year

The first result for these studies will be submitted to journals in the next few months, with more papers submitted later in the year. By the time the year is out we should have a fairly good idea if there is a strong link between pathogens and ME/CFS.

Professor Hornig concluded by saying that they may not find an infectious agent, it may be an immune change. It could even be something else. But if you look at the scale and cutting-edge nature of their work then, even if it does turn out not to be a pathogen, these are very good people to have on the case.

Aiming to look for genetic factors

heading upstream to the source

Heading upstream to the source

In the Q&A section after her talk, someone asked if Mady Hornig and her team also plan to look for any genes that are associated with ME/CFS. It turns out they don’t have enough samples to look at the whole genome, so instead they would like to use a targeted approach that Hornig calls ‘swimming upstream’.

This involves identifying unusual patterns in proteins and/or gene expression using results from this study, then working backwards to identify which gene could be involved in producing these protein changes. It’s an approach the group has used successfully before, and requires a smaller sample size for robust results.  

A wider look at the whole genome might be also possible at a later date using meta-analysis. This would combine their data with data from other studies – giving sufficient ‘statistical power’ for robust results.

The studies I’ve covered above are hugely impressive, but what grabbed me even more was the rest of Mady Hornig’s presentation, where she discusses some of the extraordinary work she’s done on other hard-to-understand illnesses. She’s very keen on bringing similarly innovative approaches to ME/CFS (assuming the current work doesn’t solve the illness!) – as I describe in my next article, Mady Hornig: How do you solve a problem like CFS?.

 

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{ 65 comments… add one }

  • snowathlete June 18, 2013, 11:35 am

    I read this today: http://www.eurekalert.org/pub_releases/2013-06/slu-slu061713.php which basically is a 'new' technique where they sequence all the DNA and RNA in the blood (as Lipkin and co are doing) and then subtract the entire human genetic sequence from the genetic material of a blood sample and identify pathogens based on what remains.
    I assumed this was what Lipkin was doing with his next-gen sequencing, but it says at the bottom of this notice that its a new technique that St. Louis hope to patent. Does that mean that Lipkin isn't doing this human DNA subtraction as part of his technique, or is he doing so using some other method?

  • Andrew June 18, 2013, 12:55 pm

    FWIW, I sent emails to Lipkin and Hornig along with a link to one of Chia's research articles. I suggested they speak with Chia, or at least ask Klimas whether she thinks his tissue investigations are worth consideration. Hornig replied that she agrees with the importance of investigating whether microbes are in tissue other than blood, and she said she has regular contact with Klimas about this and other things.

  • Simon June 18, 2013, 12:59 pm
    snowathlete

    I read this today: http://www.eurekalert.org/pub_releases/2013-06/slu-slu061713.php which basically is a 'new' technique where they sequence all the DNA and RNA in the blood (as Lipkin and co are doing) and then subtract the entire human genetic sequence from the genetic material of a blood sample and identify pathogens based on what remains.
    I assumed this was what Lipkin was doing with his next-gen sequencing, but it says at the bottom of this notice that its a new technique that St. Louis hope to patent. Does that mean that Lipkin isn't doing this human DNA subtraction as part of his technique, or is he doing so using some other method?

    I'm a bit puzzled by this, as its exactly the approach described by Lipkin to discover unknown viruses in the past, and also my understanding of what they will do in this pathogen study. Maybe it's a twist on the technique, but don't think it's a brand new approach at all.

  • vli July 3, 2013, 5:33 am
    Simon

    I'm a bit puzzled by this, as its exactly the approach described by Lipkin to discover unknown viruses in the past, and also my understanding of what they will do in this pathogen study.

    Yes, can anyone shed any light on this too; I'm very confused.

  • Sea July 4, 2013, 4:30 pm

    We have discovered a technology that allows us to detect new viruses," said Adrian Di Bisceglie, M.D., chairman of the department of internal medicine at Saint Louis University. "We isolate DNA and RNA, amplify the amount of genetic material present in the blood, do ultra-deep sequencing and use an algorithm to search for matches for every known piece of genetic code, both human and for microbes.

    Key to the research team's success was the discovery of how to amplify the genetic material in the blood, says study researcher Xiaofeng Fan, M.D., associate professor of internal medicine at Saint Louis University.

    I would say the new technique is the amplification of genetic material which probably makes finding things either easier or more reliable with fewer samples

  • Nielk July 26, 2013, 11:35 am

    I just read this article today.

    Thank you Simon for a great article and for your replies to the variety of questions here.

    I have a very basic (probably silly) question. When they talk about finding EBV, do they mean and active EBV virus or are they talking about elevated IGG titers?

    I am always confused about this because if they do find the active virus then it could explain the symptoms and might rule out ME/CFS.

    My doctor, Dr. Enlander checks for antibodies for many pathogens like EBV, CMV, HHV6, M. Pneumonia, Coxsackie B, Parvovirus B19…etc I show high titers for all of these and he believes that it is part of my ME/CFS. When I show these results to my GP, he laughs at it and says we all have antibodies to many pathogens and it doesn't mean anything.

    What's up with this?

  • Simon July 26, 2013, 12:06 pm
    Nielk

    I just read this article today.

    Thank you Simon for a great article and for your replies to the variety of questions here.

    I have a very basic (probably silly) question. When they talk about finding EBV, do they mean and active EBV virus or are they talking about elevated IGG titers?

    I am always confused about this because if they do find the active virus then it could explain the symptoms and might rule out ME/CFS.

    My doctor, Dr. Enlander checks for antibodies for many pathogens like EBV, CMV, HHV6, M. Pneumonia, Coxsackie B, Parvovirus B19…etc I show high titers for all of these and he believes that it is part of my ME/CFS. When I show these results to my GP, he laughs at it and says we all have antibodies to many pathogens and it doesn't mean anything.

    What's up with this?

    Thanks, NeilK

    I'm pretty sure they are looking for pathogens directly in the blood (so EBV protein or DNA), rather than elevated IGG titres, either general or specific to EBV. And of course they will be comparing the rate of EBV in patients with those in their carefully matched controls. And I think the EBV resutls will be out later this year – may well have been submitted for publication already.

  • Firestormm August 14, 2013, 1:30 am

    Came across this earlier from Deckoff-Jones. Links to video presentation from Hornig. Don't know if you covered it before in the thread Simon but thought I would throw it out there anyway:

    CFS Patient Advocate IiME Conference 2013: Posted on 4 June 2013

    "Mady Horning gave a fine talk, echoing the one she gave in Florida in January. That talk can be accessed here. She spoke of the terrain and genetic defects leading to ME/CFS – what variables contribute to getting ME/CFS. In a follow-up question she was asked what we all want to know. What information can she give about the ongoing CFI Lipkin study? She said that 80% of the blood work is done, but that much additional work needs to be done on saliva, feces and urine. She said that they had identified several promising pathogen “candidates” including a “novel pathogen” – but the work was still early and no conclusions can be drawn. I have heard the term “novel pathogen” somewhere before."

  • JohnnyD August 14, 2013, 7:43 am

    An article from July 22? but folder indicates 2011?… and with some new and great quotes by Lipkin and Hornig that I don't recall.

    http://trialx.com/curetalk/2011/11/…equencing-and-proteomics-to-hunt-cfs-viruses/

  • Sasha August 14, 2013, 8:06 am
    JohnnyD

    An article from July 22? but folder indicates 2011?… and with some new and great quotes by Lipkin and Hornig that I don't recall.

    http://trialx.com/curetalk/2011/11/…equencing-and-proteomics-to-hunt-cfs-viruses/

    Good catch! And here's a good quote:

    Both Dr. Lipkin, who is a board certified neurologist, and Dr. Hornig, who is a board certified psychiatrist, stress that while they believe ME/CFS is a neuropsychiatric disorder because of the problems with concentration, memory and autonomic nervous system involvement, they do not consider it psychosomatic.
    “It’s very difficult in my mind to make this a psychological disorder,” said Dr. Hornig,“We do patients a disservice if we focus solely on secondary phenomena of being disabled or being unable to carry on life to your capacity – that shouldn’t ever be viewed as being the primary problem.”
  • Firestormm August 14, 2013, 11:16 am

    Just thought a prompt here about the alert Sasha had earlier about the CDC telephone conference involving Lipkin on 10 September might be appropriate to this thread. Don't know if he will update re: progress but I it might be mentioned.

  • Firestormm August 14, 2013, 11:21 am
    JohnnyD

    An article from July 22? but folder indicates 2011?… and with some new and great quotes by Lipkin and Hornig that I don't recall.

    http://trialx.com/curetalk/2011/11/…equencing-and-proteomics-to-hunt-cfs-viruses/

    Thanks Johnny :)

    Not a source I am familiar with. It's an extensive interview – and I did wonder if it came from somewhere else: but apparently not. What an excellent blog. I must have read it – know I did – but can't remember! Though you are correct it was November 2011 apparently.

  • JohnnyD August 14, 2013, 1:49 pm

    Thanks Firestormm, always nice to read it again in any case — especially with the CDC conference call coming up on September 10. Lipkins discussion title does not mince words: “Infection and Immunity in CFS”

  • Daffodil September 9, 2013, 3:29 am

    hello. on the x rx blog, it says that it was implied in january that dr. lipkin's lab may have found a "novel pathogen". i realize this was quite a while ago, but has anyone heard any more about this? i have been out of the loop

  • Sasha September 9, 2013, 3:43 am
    Daffodil

    hello. on the x rx blog, it says that it was implied in january that dr. lipkin's lab may have found a "novel pathogen". i realize this was quite a while ago, but has anyone heard any more about this? i have been out of the loop

    No more news.

    Have you seen this:

    http://forums.phoenixrising.me/inde…erence-call-including-unger-and-lipkin.24743/

    We're not expecting any big announcements (that would take publication and a press conference) but it might be interesting.