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The End ME/CFS Project: History Taking Root

ClarkEllis submitted a new blog post:

The End ME/CFS Project: History Taking Root

Clark Ellis spoke with Dr. Ronald W. Davis and Linda Tannenbaum about the End ME/CFS Project ...


The history books record that in the nineteenth century Louis Pasteur formulated a “germ theory” of microbes as the causative agents of disease, and thus revolutionized medicine. His findings, along with his contemporary, John Snow (who linked cholera to infected water supply), changed the way we thought about disease causation, putting the previously popular miasma theory to bed.

In 1983 Robert Gallo and Luc Montagnier independently discovered the causative agent of AIDS, the retrovirus later named HIV (human immunodeficiency virus) and created another paradigm shift which legitimized the illness.

The person who cracks myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) is going to go down in history, and history will view the disease armed with the knowledge of what this disease truly is. The broken ideas that it displaces will go right onto the historical scrap heap, along with their associates.

History Taking Root

A few of the Great Minds involved

A new research consortium was recently launched by the Open Medicine Foundation (OMF) supported by several of the world’s top scientific minds. Under the guidance of world-renowned geneticist Ronald W. Davis, PhD, the End ME/CFS Project is a movement aimed at blasting ME/CFS research into the mainstream. Its stated goal is to “understand the disease at a molecular level, finding diagnostic markers, effective treatments, cure and prevention.”

An impressive scientific advisory board has been formed, which in addition to Dr. Davis, includes three Nobel Prize Laureates — James D. Watson, famous as one of the co-discoverers of the structure of DNA; Mario Capecchi, famous as one of the co-creators of the method to create knockout mice; and Paul Berg, famous for his pioneering development of recombinant DNA techniques.

As if that weren't enough, there are several other distinguished scientists on board from a variety of backgrounds, including immunology, neurobiology, physiology, inflammation and the brain. Andreas M. Kogelnik, MD, PhD, is a well-known ME/CFS medical expert and founder of the Open Medicine Institute.

The makeup of the board clearly demonstrates that this project is different from the others. Attracting the participation and expertise of these figures is in itself an impressive feat, but there are plans afoot for a $5 million a year biological research programme.

The scientific revolution that we so desperately need in ME/CFS research may already be taking root, and Dr. Davis and his team are in with a very good shot of making history in this disease.

Dr. Davis is Professor of Biochemistry and Genetics at Stanford University and has directed the Stanford Genome Technology Center for the past two decades. He has won multiple awards in recognition of his pioneering genetics innovations — technologies that were instrumental in creating the foundation of the Human Genome Project, in which he was a key player.

Among his biotechnological innovations were the development and standardization of the very first microarrays — tools that are now routinely used across the scientific community but which kicked off a genetics revolution when they were introduced.

He is extremely well-published and is widely cited by other researchers. He is respected and renowned for his innovative, methodical and rigorous approach to problem solving and has a reputation for coming in and having a revolutionary impact. He’s a game-changer. A solutionist. A winner.

With Dr. Davis involved, it is only a matter of time before ME/CFS is in vogue and on its way to being resolved. And great minds like Dr. Davis are like magnets. They attract other great minds.

The Scientific Advisory Board

I spoke with Dr. Davis and he told me about the experts who are involved in the project.

“I've had the chance to meet lots of good people, and having these people involved is tremendously helpful.

“What I look at is the intellect to arrogance ratio. I want people who are very smart and very humble; then they will reveal things, they share ideas. And because of the fact they are really smart, they come up with really novel ideas. That’s the basis of how I pick people to be on the scientific board.”

What’s The Setup?

The End ME/CFS Project is based on the same models that proved successful in previous large projects that Dr. Davis and other members of the Scientific Advisory Board were involved in, namely, The Human Genome Project and The Consortium on Inflammation and Host Response to Injury in Humans.

I asked how it is all set up.

“We plan to be the coordination centre, using the clinicians that will be involved and procuring samples from their patients, sending to a central place for the analysis. That means the samples need to be stabilized, which will take some lab work. But the plan is not to set up a lab that can do everything — although we can do a lot — rather we want to go to the very best labs, or close to the best labs, and ask them to run the actual experiments, carry out the analysis.

“The concept of a single lab that does everything is a little outdated, given the complexity of things. The best way to do this is to utilise the best people and the best facilities, no matter where they are.

“I’d love to have everybody involved in ME/CFS work get involved into such a consortium. I think this is a complex problem and I'm not sure setting it up as a competitive exercise is the best way to solve the problem. I think that can be deleterious to the outcome and you could get the same answer cheaper and faster by having a network of people being cooperative, where everybody shares in the ownership and the credit.

“At the same time this would not exclude people trying things on their own, they have an idea, and they want to pursue it alone, that’s fine. Myself, I'm not out there trying to get credit for this, I've had enough success in science that I don’t need to take any credit for this and that’s why I set up to do this because I just want to make sure it is successful."

Focusing on Severe Patients

Dr. Davis' son Whitney suffers from severe ME/CFS

Dr. Davis has a son with severe ME/CFS, so he has a clear picture of how serious this disease is. I asked him about the projects initial focus on severe patients like his son.

“My son’s not really able to communicate now, but before he got that sick we talked about revealing things about him, and would that be okay? And he said if it helps solve the problem then by all means — do anything you want. This is a horrible disease and we have to do anything we can about it.

“One of the problems with this disease is that often you fail to pick up that they’re sick, even when they are pretty severely ill. As long as the person can stand up they might look pretty normal.

“My son was the same way, but if you looked more carefully there was the fact that he would stand up for a couple of minutes and get so exhausted that he had to go to bed. It's only now that he’s so severe and he’s lost a lot of weight, that he obviously looks quite ill. And he is quite ill.

“It is a very debilitating disease. We’d like to sort out what’s going on. Initially I’d like to focus on severe patients and do what we can with them.

“We're going to start by launching a simple project — from the lab point of view — looking at severe patients. Hopefully the more severely ill patients will display a much bigger signal of what’s wrong. As a result we won’t need as many patients, but logistically it's difficult as we have to go to them. They are bed-bound, and nobody has done bed-bound patients, largely because they don’t come into the clinic."

Research Programme

With such a talented scientific board, coming up with lots of novel ideas, I asked where do they begin to look? What’s the first objective?

“We hope to find a biomarker. In the past, people have hoped for one thing — a metabolite, a certain enzyme activity or protein — but in the modern era of genomics we can measure lots of seemingly unrelated things, to try and identify a working biomarker.

“We want to look at a variety of things and pick out a highly reliable set of markers. We would like those markers to be easily done and not too expensive to run. We want something where a doctor can prescribe the test and get the results back, no problems. The cheaper and easier it is to do the more likely someone will try it out. We are conscious of the cost of some of these things. We need a biomarker no matter what it costs, but I would like to get a biomarker that’s cheap.

“As well as a biomarker allowing you to diagnose better, it is tied up in the disease structure; that’s where you can begin to explore what you might be able to do about the disease. If we can find something that may not cure the disease, but make it much better, that’s a good start; and sometimes treatments give you further clues as to what's going on.

“If successful, we'll expand that into house-bound patients, who perhaps can walk around, but are still very ill. A possible problem with bed-bound patients is that we may get a lot of confusing signals as a result of being bed-bound. If things are promising then we'll move into a larger collection of people with the disease, who are trying to live something closer to a normal life."

Technologies and Research Focuses

With Dr. Davis’ proven track record over many years, of innovating new technologies and then developing them into robust tools that result in significant advancements, I asked what technologies might be employed, and what things the project might look at.

“There is obviously the opportunity to do extensive sequencing of patient DNA, to look for genetic components to the disease. There is also ability to look at methylation, epigenetic changes that might account for some of the disease. We can look at gene expression levels — we’ll probably do that by both sequencing and array hybridization because they have different dynamic range characteristics.

“And we have the ability to sequence gut microbes, try to identify what’s in the gut, and also to look at the genes of those organisms. You might recognise certain toxins for instance, but discover them in organisms that you didn't expect to produce such a toxin; so just identifying the organism plating may be inadequate.

“We can do RNA sequencing looking for things in the blood, or any other easily accessible biomaterial, like saliva or spinal fluid.

“We need to look at immune cells a lot as there’s a lot of immunology involved here. I'm a little bit focused on pursing individual cells, with some new technologies — we've just got to develop those technologists to get the costs down. The thinking is that if we can profile individual cells without having to do the traditional cell separation, then we may find very many unusual cell types that are present in this disease that nobody knows about. So we've got to be able to do that in a cost effective fashion; maybe they need to be perfected a bit, otherwise we do more classical cell separation and profiling. Because we need to characterize the immune cells in terms of surface markers as well as proteins — with the proteomic aspect to this — we’ll utilize mass spectrometry but also antibody arrays.

“We also have a new technology to measure cell density looking at magnetic suspension — that hasn't been applied fully yet but we do see some differences in patients with ME/CFS compared to normal in some initial testing, so we need to follow that up. It’s a new technology looking at magnetic fields. It’s interesting because it’s very inexpensive and very fast. And it’s just new enough that we don’t know if it’s going to pan out, but we need to take on some new technologies that might allow us to see things that otherwise we’re blind to — things that no one has looked at before.

The Last Major Disease

"It could be affecting more people than we realise. There are lots of people out there who are undiagnosed and a biomarker might also allow us to recognise milder versions of the disease.”

According to a recent report by the Institute of Medicine, the disease affects between 836,000 and 2.5 million Americans, and Dr. Davis thinks this could be the tip of the iceberg.

"This is a major disease even at those levels; more common than multiple sclerosis, and AIDS. It’s likely to be present in one per cent of the population globally. If someone wants to try and make a difference in the world, this is where you can do that.

“I consider it to be the last major disease in the world that we don’t understand yet. It’s largely been hidden by the fact that until recently it hasn't been recognised as a disease. It should be viewed as a career builder — but that’s going to require a high IQ, to recognise that reality — if you want to get involved at the ground floor in a disease that we don’t yet know the origin and what’s going on ... this is the last disease, the last opportunity.

“Some people find that kind of exciting.”

5 Million Dollars a Year – More Talent

I offered this speculation to Dr. Davis — As a patient you want the NIH to say, ‘we’ll take this seriously; here’s loads of money for research,’ but that’s pretty unrealistic I guess. It sounds like you don’t need that necessarily — you just need enough support?'

“In the Human Genome project, we didn't just dump money out there, and say ‘come and get it’ — we went round the country looking for the best people. That started with some really top-notch researchers, and that laid the groundwork for more good people to get involved, and that was the final strategy that made that project successful.

“What we need is support for sustained growth.

“If someone wanted to try and make a difference in the world, this is a great way, doing it in a kind of logical way; try to get some of the very best people involved in doing the research. Like the Gates Foundation has done for underdeveloped countries. I think he deserves a lot of credit for trying to do something really good for the world. It shows real imagination and invention, in addition to what he did to get Microsoft started.

Dr. Davis and Ms. Tannenbaum make a formidable team

“The main sources of funding are the NIH and private funding. I met Linda and I said, ‘I'm a good researcher but have no idea how to fundraise.’ Linda said, 'I'm a good fundraiser but have no idea how to research.'

“That’s really the concept: that people should be using their expertise to solve this problem together, rather than trying to do everything themselves.”

I was highly impressed by Dr. Davis when I interviewed him. I've spoken with quite a few ME/CFS researchers over the last few years and I frequently find dedication and ability. None, however, have left me as impressed as Dr. Davis.

So imagine my delight when I speak with Linda Tannenbaum, the other half of this operation, and I find that she is equally brilliant at what she does. Creative, organized, experienced, determined, smart, and astute — all these words belong.

I asked Ms. Tannenbaum how the foundation will fund all this quality research.

“I have hired a fundraising consulting company to give us the best chance to raise funds. There are multiple people and groups around the world that are fundraising for the OMF. There are people in Sweden making and selling bracelets and pins, there are people in Slovakia starting a global crowdfund, UK and Australia working together to set up a challenge of some sort, walks and dinner parties are being set up in the US along with corporate matching programs taking us under their wing ... all to help keep this research going.

“People writing articles and mentioning OMF in their documentaries. People thanking us every day on Facebook and when writing notes to us as they sign up for newsletters. This momentum is exciting, thrilling and shows how we must keep going and find a cure.

“Any help we get from the patient community goes to keeping it going, to making the End ME/CFS Project a success. That plays an important part and we value, and want to acknowledge, everyone who helps.

“But the project isn't just about crowdfunding in the patient community. We are pursuing private funding opportunities in addition to government funding; exploring all avenues within NIH.”

And we’re in good hands — Ms. Tannenbaum left a successful independent clinical laboratory that she set up and ran for more than 21 years, in order to dedicate herself to this project full-time, and with her experience and tenacity, we have every reason to think that her efforts will pay off and bring an end to ME/CFS.

To find out more about the OMF and their End ME/CFS Project, visit the website: www.openmedicinefoundation.org and for more information on their initial study of severe patients, check out their Severely Ill Big Data Study. If you want to donate to the OMF's outstanding work then you can do so via their donation page.

Phoenix Rising is a registered 501 c.(3) non profit. We support ME/CFS and NEID patients through rigorous reporting, reliable information, effective advocacy and the provision of online services which empower patients and help them to cope with their isolation.

There are many ways you can help Phoenix Rising to continue its work. If you feel able to offer your time and talent, we could really use some more authors, proof-readers, fundraisers, technicians etc. We’d also love to expand our Board of Directors. So, if you think you can help in any way then please contact Mark through the Forums.

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Donation done. Made it in honor of ME/cfs patients surviving everywhere : Keep On !!
Cause we all deserve recognition for the huge effort needed to live with this plague.
Yes, I hope so as well, as it seems to be involved in at least a subset of patients.
From an old facebook post, apparently they did explore a possible mold connection, and I'm assuming, ruled it out.
I do not believe they have ruled out mold and are still looking at all pathogens. My doctor told me that there are many paths that get us to the same endpoint of ME/CFS like many trains that meet at the same train station. I suspect the Severely Ill Patient Study will look at everything humanly possible.
I hope they decide to examine mold toxins.
Yes, I hope so as well, as it seems to be involved in at least a subset of patients.
I do not believe they have ruled out mold and are still looking at all pathogens. My doctor told me that there are many paths that get us to the same endpoint of ME/CFS like many trains that meet at the same train station. I suspect the Severely Ill Patient Study will look at everything humanly possible.
Nothing is off the table, that's for sure. And they will explore every and all avenues if needs be. Many of the technologies being talked about are able to look at a wide range of things too, so if mold is a problem that ought to be picked up by their studies I should think.
I do not believe they have ruled out mold and are still looking at all pathogens. My doctor told me that there are many paths that get us to the same endpoint of ME/CFS like many trains that meet at the same train station. I suspect the Severely Ill Patient Study will look at everything humanly possible.
I agree completely. I was just saying it seemed like they had ruled mold in Whitney's case.
I agree completely. I was just saying it seemed like they had ruled mold in Whitney's case.
Sorry I totally misunderstood and thought you meant they ruled out mold in general as a causative factor in CFS. I didn't realize you were talking about Whitney's case.
Reasons to donate to End ME/CFS Project's Severely Ill 'Big Data' study

ME Awareness Day seems a good time focus on End ME/CFS' Project's main study, which harnesses some extraordinary science to try to nail some affordable and useable biomarkers:
Although many of the symptoms are neurological, neurological diseases often produce molecular biomarker(s) that may be found in the blood, saliva, sweat, urine and feces. Identifying biomarker(s) in these easily assayed fluids can be convenient, inexpensive and can be conducted on bedbound patients. Such an easy and distinguishing test is more likely to be diagnostically useful in the clinical setting
The big problem is not knowing what the best biomarker will be - people have tried without success yet for decades (Lipkin & Hornig may be closing in with a cytokine panel) - so their answer is to look at what seems like everything. They are throwing the kitchen sink at the problem, albeit a very high tech one.

One strong possiblility is that a characteristic set of biomarkers will succeed where single biomarkers have failed, and looking at dozens of biomarkers at the same time in the same patients. The work may even identify unique clusters of patients, perhaps with different underlying disease mechanisms than can be targeted with different treatments.

Here's a run down of some of the many things the study will look at. Nothing on this scale has ever been done before in ME/CFS.

  • Whole genome analysis (yup sequencing the entire genome). looking for what might be different in mecfs patients. For good measure they are doing this in saliva as well as blood (presumably as saliva is easier to collect from the housebound: 'spit and mail', if the results are good enough)
  • Epigenetics, looking for unusual DNA methylation patterns (a form of long-term gene regulation)
  • Mitochondrial genome analysis
  • Gut microbiome (via analysis of DNA in faeces)
Which would be a lot in itself, but there's plenty more too:
  • Metabalomics in blood, saliva and urine. This looks at metabolites, 'chemical clues in the blood', small molecules like tryptophan and serotonin that gives a window on what's go on, or wrong, with the body's metabolism.
  • Pathogen hunt in blood, saliva, faeces and urine.
  • Isolating and identifying all the different types of immune cells, including Natural Killer subtypes
  • Cytokine levels
  • Gene expression and activity levels of Natural Killer cells, and obvious target given the repeated findings of reduced NK activity levels in patients. Actually, they plan to look at gene expression for other immune cells too.
Zooming in on the immune system
This is where they go way off-piste.
  • "Immune repetoire": you know how we can make oodles of different antibodies, which is what gives us the power to fight off so many infections? It's the same story with T cell receptors, and the immune repetoire basically catalogues all the different antibody and T cell receptors in circulation - which is a big number. This could, for instance, indentify past infections (by identifyng the antibodies that bind particular pathogens). It's a bit mind-blowing, really.
  • Sequencing HLA genes. HLA proteins present antigen to T cells and play a critical role in the immune system. HLA mutations have been implicated in both vulnerability to particular pathogens and to autoimmune disease, both potentiall relevant in ME/CFS. (One HLA variant protects against HIV infection but is a risk factor for the autoimmune disease ankylosing spondylitis). More about the role of HLA in the immune system. For boring technical reasons HLA genes are very hard to sequence so are usually ommitted from genome analyses and they need to be analysed separately.
  • Sequencing Natural Killer cell Immunoglobulin Receptor genes, 'killer receptor'. Like HLA genes, these can have a key role too, but I won't go into the details.

More unusual stuff
  • Real time analysis of sweat by wearable electronics (iSweat device??), including salt levelsl and cytokines. I had no idea this was possible.
  • Analysing levels of copper and other metals in blood and urine
    I hope they decide to examine mold toxins.
    Yup, that's in too (mycotoxins is the jargon for this): they are looking in blood, saliva, urine and poop.
Actually, even that's not all of it but it gives you a good idea of the scale and ambition of this project.

What you get for the money
This comprehensive approach costs $25,000 a patient, so the initial $1 million goal will cover 40 patients. Luckily the team already have good data on controls (presumably from earlier work using the same high-tech kit) which means donors' money will go further.

There's more: the team will release the Big Data set to the research community, allowing other scientists to make further discoveries using this unprecedented combination of molecular and clinical data.

What are you waiting for :)? » ME/CFS Severely Ill, Big Data Study

Feed the boffins! :nerd::nerd::nerd::nerd::nerd:

Thanks to Linda Tannenbaum for answering some questions on this yesterday - and of course to Clark Ellis for his blog.
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This is a terrific video - can somebody put a comment on with a link to the END ME/CFS project and asking people to donate? Needs a google account.
Palo Alto Weekly said:
Some prominent Palo Altans are stepping forward to try to help Davis further his research. Yoriko Kishimoto, former mayor and director at Midpeninsula Regional Open Space, current Mayor Karen Holman, and former City Councilwoman and retired Judge LaDoris Cordell wrote a letter to rally attendees of an upcoming, July 16 event to raise $1 million of the $25 million Davis and his team need for research.

"This is a serious request on a serious topic — a call for help from our Palo Alto community but also a chance to break through a major medical research frontier," the trio wrote.
Let's hope they raise that $1m!
OMF's ME/CFS Severely Ill-Big Data Study Explained by Stanford's Brian Piening, Phd

Uses methodology published in Cell in 2012:
Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes: Cell

Graphical abstract:

Basically looks at each person's unique biomolecule profile and, as Brian Piening explains, the hope is that part of this unique profile is related to disease status, and common features will be found between people with the same disease (mecfs in this case). That would reveal clues to chase down.
Excited to see that Ron Davis is the first in the line-up to take part in the Invest in ME Conference 2016 (IIMEC11) & Biomedical Researchers into ME Colloquium (BRMEC6) - http://investinme.eu/IIMEC11-news.shtml

Linda Tannenbaum's pre-conference dinner speech is on the 2013 IIMEC8 DVD - http://investinme.eu/IIMEC8.shtml#dvd and there's a transcript on Christopher Cairns Patient Advocate blog - http://cfspatientadvocate.blogspot.com.es/2013/05/linda-tannenbaum-at-investinme-2013.html

Great article Clark - thank you.