The Open Medicine Foundation released two videos of Ron Davis talking about their work over the past couple of weeks. I got a chance to talk to Davis twice since then and to flesh out a bit more what he’s doing right now.
As most people probably know, the Davis group’s working hypothesis right now is that problems with glycolysis – the process producing many of the raw materials the mitochondria use for energy – is impaired in chronic fatigue syndrome (ME/CFS). Their data is leading them to suspect an enzyme called pyruvate kinase is this issue. The Fluge/Mella group has come to a similar conclusion, but they’re more focused on a different enzyme called pyruvate dehydrogenase.
Both are coming to the conclusions in an indirect sort of way. Fluge and Mella’s amino acid metabolism results suggested problems with glycolysis were present. Davis’ experiments and metabolomics results suggest the same. Davis noted, though, that neither is directly measuring the performance of the enzymes that break down pyruvate.
Tools of the Trade
“He’s not just a one-hit wonder. He’s a frequent provider of disruptive core technologies.” George Church, Professor of Genetics, Harvard
Davis’s forte is creating new technologies. Named one of the great inventors of the century by the Atlantic, he created many of the tools that made the Human Genome Project possible. George Church, a Harvard professor, called him a “frequent provider of disruptive core technologies”.
It’s no surprise, then, that Davis has been creating new tools to help him better understand the energy depletion process he believes lies at the core of ME/CFS. Davis is guided by two ancillary goals as he does this: to make the tools as cheaply as possible to avoid the problems with funding that come with ME/CFS, and to produce “fast assays” he can use to test as many potential treatments as quickly as possible.
Indirect Measurement of ATP
Davis has produced an assay which involves bombarding cells with sodium chloride. Because too much sodium chloride is toxic to cells, they have to pump it out again. They’re easily able to do that but that process requires energy, lots of it. Davis’ working hypothesis is that cells that die when placed in sodium chloride probably die because of their inability to produce enough ATP to get rid of the salt.
Science can be messy though. The sodium chloride is triggering inflammation in the ME/CFS patients’ cells but not the healthy controls’ cells. That raises the question whether inflammation is the problem or reduced ATP production or both? It’s an unexpected twist that has to be explored. Davis noted that these kinds of twists and turns are normal in science.
“We teach the engineers medicine and they teach us electronic circuitry. It’s a whole bunch of people learning all the time. We feel like there’s nothing we can’t do.” Ron Davis
Electrical engineers are providing the next step by measuring electrical impedance (the amount of electrical resistance) in ME/CFS patients’ cells.
This tool was produced using nano fabrication. About the size of a dime, it needs a 1/10th of a drop of blood to function. In order to account for cell movement, 2500 electrodes placed 100 nm apart measure the electrical current in the cell. How big is a nanometer? It takes an electron microscope to distinguish a nanometer and those little electrodes – you can’t see them either.
These electrodes aren’t only small – they’re blazingly fast – making 200 measurements per second. By using a 3-D inkjet printer – the next step – Davis will be able to print out this tool at an amazingly cheap cost – just $.10 a sample.
Davis said electrical impedance is increased in cancerous cells and cells infected with bacteria, probably because the cells are dying. ME/CFS patients’ cells are not in such bad shape at rest, but when Davis puts them under salt stress their electrical impedance increases as well. Cells from healthy controls, on the other hand, show normal levels of electrical impedance under salt stress.
Davis’s recent finding of reduced electrical impedance levels in a chronic fatigue syndrome patient (ME/CFS) who is still working and is pretty functional suggested that he may be getting at a core part of the disease. Next Davis will look at a range of subjects including a student who had ME/CFS and is now recovered. If the cells from the recovered student – who can now run 10 miles at a time – also have increased impedance, Davis may have uncovered a hidden weakness that predisposes people to ME/CFS. He will also start doing the test in people with different kinds of fatigue including people with overtraining syndrome.
Levitating Cells To Understand ME/CFS
Davis is also using magnetism to levitate cells in glass capillary tubes. The cells float to the top or drop to the bottom depending on how dense they are.
He’s been doing this with his son Whitney’s cells for quite some time. Whitney’s cells have always proved to be quite light; they float right to the top of the tube. Davis isn’t sure why this is, but he suspects that it could be because the glucose in Whitney’s cells is getting consumed and being turned to fat – a lighter substance.
Cancer cells also display this characteristic. Again, Davis believes that as cells begin to die their density may drop.
This is another astoundingly cheap (5 cents/sample) test; the tool simply needs an IPhone to do its work. It takes about 10 to 20 minutes and could easily be done in a doctor’s office.
Finding the Culprit – the Serum Studies
“If it is in the serum, we probably can find it and that is what we’re trying to do now, which is find the component or components – most likely plural – that is causing this effect… Now this a good hypothesis, and we are now testing it.” Ron Davis
Davis can potentially get at what in ME/CFS patients’ serum is causing ME/CFS or healthy cells to be so lethargic in a couple of ways. He can add things to or filter out substances from the serum and see if the cells return to normal; i.e. have normal electrical impedance levels.
Thus far Davis have found two substances, pyruvate and ATP, which allow their cells to act normally. Unfortunately neither of these are possible candidates for treatment. In fact both could make patients ill or even kill them.
Pyruvate could be providing the energy the cell needs or it could simply be blocking whatever is blocking the pathway now. Because pyruvate is not very soluble, it would be hard to take enough do any good, and in doing so might cause other problems such as bacterial overgrowth or increased lactate production.
As Davis learns more he’ll model the effects of pyruvate on ME/CFS patients in order to learn what it might be doing. He believes, though, more effective substances will come along.
ATP plays the role of a signaling molecule outside of the cell and could make people quite sick or even kill them if they were to take it in sufficient quantities.
As Davis finds substances which increase the energy status of ME/CFS patients cells he’ll test these other substance in people with other fatiguing illnesses such as overtraining syndrome to see if they react as well.
As noted earlier Davis’s tools are being produced in service of a goal to rapidly assess the effectiveness of scores of drugs or compounds in chronic fatigue syndrome (ME/CFS) patients cells.
His literature search has given him a set of factors that could be elevated or depressed in ME/CFS patients’ cells. Another search has given him a list of drugs that could impact those factors. Plus he has samples of virtually every FDA approved drug in existence that he can test in ME/CFS cells.
Currently he’s examining the effects of 96 drugs on the cells. He’s hobbled a bit right now in his inability to test large numbers of cells and substances at once using the instruments he’s developed. Fixing that problem is the next step.
A Strategic Approach
Davis’ strategic approach (so far as I understand it) to understanding and finding ways to impact the energy problem in ME/CFS patients’ cells has been the following:
(1) First he found a way to assess our cells ability to generate energy by putting them under salt stress (the sodium chloride test)
(2) He then created a tool or tools (electrical impedance, magnetic levitation) which he can use to measure their energy status or health (electrical impedance, magnetic floatation).
(3) With these two tools he can put cells under stress, add possible treatments to them and see if they respond.
(3) After tests suggested that something in ME/CFS patients’ blood was inhibiting their cellular energy production, Davis began filtering their blood to see if he could remove the substance. He found that he could and that a large molecule or protein was likely responsible for blocking the cells’ energy.
(4) Using what he’s learned about the energy production problems Davis began to add substances to the serum to see what would allow the ME/CFS cells to tolerate the salt stress. He’s found two substances so far. He’s also begun to test those substances in a wide variety of patients and people with other fatiguing illnesses to determine if the same issues are present in them.
(5) Davis also used the scientific literature to come up with a list of drugs that might help. He’s testing about a hundred of them in the serum now.
(6) A next step is to be able to create the ability to quickly test many numbers of cells and substances at once.
(7) Drugs or substances that pass the test will give him clues about what’s going on and will provide the foundation for further tests. A variety of problems may be found.
A Drug Target
Ultimately Davis is looking for a drug or other substance that can turn ME/CFS patients’ cells back on. (Davis is on board with Naviaux’s idea that something is keeping the cells in a hypometabolic state.)
His finding that a large molecule or protein is probably responsible, and is hopeful because that kind of molecule is a perfect target for a drug. That drug – which no one probably has ever connected with ME/CFS before – could be sitting on a drug company’s shelves, somewhere.
Davis noted that drug companies have produced thousands of compounds that never made it to market. The market may have been too small to justify the cost of expensive trials or the side effects may have been a problem or the drug just didn’t work in that patient population. A significant number of drugs have already gone through Phase I (safety testing in humans) and Phase II (efficacy and further safety testing in humans) trials.
AZT is a glaring example of a drug that was sidelined for years but which laboratory tests (much like Davis’) using a similar procedure suggested could be helpful for HIV-AIDS. HIV researchers put AZT in HIV-infected cells to see if the virus went away. Davis is putting compounds in cells to see if the cells act normally when put under stress. It’s the same basic procedure.
Davis suggested that an effective drug for ME/CFS might just end up being a complete surprise – a drug that no one has ever considered might work. He doesn’t, by the way, think that people with long-term cases of ME/CFS are lost. While changes in the illness may occur over time, he believes that if their systems have been reset once they can be reset again and recovery should theoretically be possible.
Davis also doesn’t believe that the protective mechanism that Naviaux (and he) believes is keeping the cell in a hypometabolic state is protective any longer; he thinks a switch got flipped on that should have gotten flipped off and never did.
In fact, if Davis and Naviaux are correct, then the right drug might not just temporarily correct ME/CFS but could solve it permanently simply by getting the body back on the right track again. In this scenario you don’t take a drug again and again and again. You take it once or enough to reset the system so that it proceeds normally.
In the recent video Davis also presented the hypothesis or possibility that trying to push through ME/CFS symptoms has kept Naviaux’s alarm system on. Davis didn’t elucidate more on this hypothesis, but you could envision a scenario where Naviaux’s danger response gets invoked as ME/CFS patients try and push through their illness. The danger response’s response, of course, is to then inhibit the energy production of the cells.
Picture this happening time and time again – each time the danger response clamping down on the cell’s energy levels more and more. Picture it happening so many times that the danger response has so inhibited energy production that a person becomes bedbound. That, at least, is my interpretation of what Davis suggested could be happening.
NIH Research Center?
Like all ME/CFS researchers, Davis needs money and he’s going to apply for an NIH funded ME/CFS research center grant. Each ME/CFS research center will get about 1.2 million dollars to play with. The university the centers are attached to will, if I got it right, also get about $800,000 a year in indirect costs. If those numbers are right (about $2 million/center) we’re looking at three NIH funded research centers coming into being over the next year.
Two hundred thousand of that $1.2 million will go to a collaborative project all the research centers will work on. Some money will get eaten up by the stiff reporting requirements.
Some will also get eaten up by the collaborative nature of the grant. The NIH wants the research centers to collaborate with outside institutions, but that’s going to come at a cost. Each research center will be responsible for the indirect costs (@40%) it has to pay to the university the researcher it’s collaborating with is associated with. (If an outside researcher is paid $300,000 for a project, the University will get an additional $120,000 or something like that. That money will get paid out of the $1 million dollar grant for the Research Center.
With that we’re down to $850,000 or something like that a year that each research center will have to use on its own projects.
Davis’ grant application will contain a long list of researchers he will be collaborating/consulting with. (Indirect costs do not need to be paid to consultants/volunteers). It’s a pretty heady mix of collaborators/consultants. (notice Davis’s propensity below to attract researchers who have their own labs.)
If the grant is awarded purely on the strength of the team each researcher can enroll, Davis may very well come out on top. He’s drawing from Stanford, University of Utah, Harvard and other universities. He’ll get his patients from Dr. Montoya, Dr. Bateman and Dr. Levine.
- Mike Snyder, PhD, Chair of Genetics Dept, head of the Snyder Genetics Lab at Stanford, Director – Stanford Center for Genomics and Personalized Medicine
- Craig Heller PhD, Biology Prof, co-director of the Stanford Down Syndrome Research Center and director of the Craig Heller Lab
- Mark Davis, PhD, Chair of Immunology Dept, head of the Mark M Davis Lab at Stanford
- Catherine Blish, PhD, Asst Prof, Immunology, NK cell expert and head of The Blish Lab at Stanford
- Laurel Crosby, PhD, Research Assoc, Stanford
- Raeka Aiyar, PhD, Molecular Biologist and Communications Director, Stanford Genome Technology Center
- Jennifer Frankovich, PhD, PANS Program Director, Stanford Children’s Hospital
- Rahim Esfandyarpour, PhD, Research Engineer, Stanford
- Fereshteh Jahaniani, PhD, Geneticist, Research Associate, Stanford
- Peidong Shen, PhD, Chemist, Research Associate, Stanford
- Jose Montoya, MD – Director of Stanford Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Initiative
- Baldomero Olivera, PhD, Director of Olivera Lab at University of Utah
- Mario Capecchi, PhD, Molecular Geneticist, Director of Capecchi Lab at U Utah, 2007 Nobel Laureate
- Alan Light (PhD) and Kathleen Light, (PhD), U Utah
- Lucinda Bateman, MD – Bateman Horne Center – Salt Lake City, Utah
- Suzanne Vernon, PhD – Bateman Horne Center – former Research Director of CAA, CDC ME/CFS researcher
- Wenzhong Xiao, PhD, Physical Chemist and Bioinformatisist, Director, Inflammation & Metabolism Computational Center, Harvard professor
- Ron Tompkins – Professor of Surgery, Harvard
- Curt Scharfe, PhD, Geneticist, mitochondrial expert, professor at Yale
- Robert Phair, PhD, Biochemist, retired from Professorship at Johns Hopkins, now CEO of Integrative Bioinformatics
- Mohsen Gorgani, PhD, Biochemist, retired
- Susan Levine, MD – New York
It’s a lot of people – easily enough people for a $5 million a year grant – which is exactly what Davis hopes to see over time. Davis hopes that the level of the funding award increases soon. He pointed to the fact that Vickie Whittemore (whom he and others praised) said one of the difficulties raising money was that by the time the effort got started the NIH Institutes had allocated their funding for the next three years. That meant the Institutes had to raid other diseases to get their funds.
That suggested that by the time the Trans NIH Working Group got its program together and jumped through a few hoops, the $2 billion dollar increase the NIH got had already been allocated.
Thinking Outside of the Box
“I wanted the most out of the box thinkers I’ve ever met. I made a list, called them and they all said yes.” Ron Davis on the OMF’s Scientific Advisory Board
Davis is a fan of thinking outside the box. Our thinking is often limited, whether we know it or not, to certain options and possibilities. Because thirty years hasn’t gotten us to where we want to be in ME/CFS, Davis suggests it’s probably time to think differently – to have the courage really – to look outside of the box and entertain new possibilities.
That brought to mind the parable of the man searching for his keys.
A police officer sees a drunken man intently searching the ground near a lamppost and asks him the goal of his quest. The inebriate replies that he is looking for his car keys, and the officer helps for a few minutes without success. Then he asks whether the man is certain that he dropped the keys near the lamppost.
“No,” is the reply, “I lost the keys somewhere across the street.” “Why look here?” asks the surprised and irritated officer. “The light is much better here,” the intoxicated man responds with aplomb.
One example of thinking outside of the box is to think of fatigue differently. Fatigue has understandably come to be something of a bad term in the ME/CFS community, but fatigue is a very common outcome of chronic diseases. Plus, because fatigue is potentially able to affect every cell and organ in the body, it’s possible that in some ways it could underlie many diseases. Davis asked Francis Collins, the director of the NIH, how he would feel if ME/CFS turned out to be the answer to many diseases and Collins missed the opportunity to study it.
Davis wonders if the fatigue in chronic fatigue syndrome (ME/CFS) could be of a special kind. In other diseases, patients may have a type of fatigue that doesn’t allow them to exert themselves – hence they have limited post exertional malaise. ME/CFS patients, on the other hand, may have a type of fatigue which allows them to over exert themselves – hence the extreme problems with PEM. (So far as I can tell the term PEM didn’t exist before ME/CFS came on the scene).
Davis isn’t saying that this is true – it’s just an idea. It’s a way of thinking outside of the box. Another example of this concerns the Institute at the NIH ME/CFS belongs in. We’ve long thought that ME/CFS should belong in either the immune (NIAID) or nervous system (NINDS) Institutes, but if the metabolic abnormalities hold up it’s possible ME/CFS might fit better in the (NIDDK) National Institute of Diabetes, Digestive and Kidney Diseases.
A New Field Emerges? The “Haplogenetic” Study
Another example of thinking outside the box is the Open Medicine Foundation’s (OMF) genetics/metabolomics study that’s being done in collaboration with Dr. Naviaux. The study will explore a novel hypothesis Davis has come up with that Davis’ partner, Janet Dafoe, has termed “haplogenetics”. It involves a situation called heterozygosity which occurs when one copy of a gene (we all carry two copies) doesn’t work resulting in that gene producing only 1/2 the normal amount of protein that it usually does.
Ordinarily that’s enough, but Davis wonders if increased levels of heterozygosity could result in a hypometabolic disease like ME/CFS. If, for instance, NAD, a coenzyme vital to the energy production process, is low across the board, it would affect many metabolic pathways. Other heterozygous genes could help explain the heterogeneity present in the disease.
Researchers Ready to Engage – If the Funding is There
From day one,of course, Davis has been working on getting outside researchers involved. When I asked him what the reception has been like, he said that everyone he’s asked has been interested; there’s something to exploring the unknown that’s tremendously exciting to good researchers. Throw in the possibility that they may be uncovering basic biochemical pathways in the body and you have some real interest.
Plus Davis has done this before with the Human Genome Project and the sepsis project. He’s good at tackling big questions and creating collaborative environments that give creative minds the room the grow.
The OMF’s Severe ME/CFS project is funded, but Davis’ possibly most exciting work is still being done on a wing and a prayer. He’s jury-rigged a project that is almost entirely dependent on volunteers. He’s got some great volunteers – electrical engineers, geneticists, immunologists, etc. – but you can only do so much volunteering your time.
His program, like others, is crying out for dedicated funding. In the Q&A video Davis said that in order to do what he did with the Human Genome Project, to really attack the problem with skilled researchers he needs $5 million/year for multiple years.
It’s not a lot of money. Surely people exist in Silicon Valley or elsewhere with relatives or sons or daughters with ME/CFS who could contribute $1,000,000 a year for five years or ten who could contribute $500,000 a year.
When I look at what Davis is doing with his limited funds, I wonder what more he could be doing with a dedicated team devoted 24/7 to figuring out what the heck is going on. I wonder what we are missing by not giving those fertile minds the opportunity to do that. That’s a question every potential donor with deep pockets might think about.
I propose that one person step forward and state that they will commit to providing Davis a million a year for five years. Then perhaps four more people will step forward and do the same – and we will see what happens. At $5 million a year you’re not working around the edges anymore, you’re not cutting corners – you now really have a chance to make a difference. That’s exciting stuff.