Reprinted with the kind permission of Cort Johnson and Health Rising
By Cort Johnson
Those ten NIH research center proposals contained a hidden gift. Of the ten grant applications, seven failed, leaving at least 21 potential individual research grant applications that could be sent to the NIH. That is potentially a major boost to a field that averages about 15 grant applications a year.
Apparently Ron Davis didn’t get that message. He’s already put in one grant application to support Mark Davis’s project and plans to get two (R21 for nano-needle + ?) more in by February. At some point, Ron Davis is actually going to get funded by the NIH for his chronic fatigue syndrome (ME/CFS) study.
Patient Community Shows up for Stanford Collaborative Research Center
Ron Davis worried that his inability to garner an NIH research center grant would turn donors away. He was so worried and upset at some of the reviewers’ weird comments on his application that he went so far as to publish some of them.
As it turns out he needn’t have worried about the patient community. They responded to the Open Medicine Foundation’s (OMF’s) “Giving Tuesday” request with a blistering $452,000 in donations. The OMF responded to that a couple of weeks later by providing a $1.2 million dollar grant to Davis et. al. for their Stanford Collaborative Research Center.
Thanks to the patient community’s support, Davis and company will actually have more money to spend next year than each of the NIH’s Collaborative Research Centers, which are hobbled by high reporting requirements.
Davis would surely like to have an NIH-funded research center, and the guaranteed multi-year funding and collaborative opportunities that come with it, but his work will continue.
That’s good news because Davis is engaged in three of the most interesting research projects going.
Activating the T-cell Activation Study
First, the OMF will fund an expansion of Mark Davis’s findings that T-cells are being clonally activated at a high rates in ME/CFS. Davis’s initial T-cell findings suggest that these master immune regulators are being tweaked by something. Here’s what Dr. Koroshetz said about that project:
Mark has really pioneered the way to go — from how the immune system senses either an external or internal antigen — and then actually how that response is generated.”
And it’s very groundbreaking work in that he can go from not knowing what the body is responding to, to actually doing detective work and tracking back to find where the original response was. For example, in a large cohort of chronic fatigue patients, he has now found a number of new antigens that correlate with disease. And he hasn’t published this yet, and he’s not ready to tell us because he needs to be 100 percent certain of what these antigens are, but I think the approach itself is really groundbreaking.
If Davis can determine what that something is – which is not easy at all – any time Ron Davis calls something “non-trivial”, it means it’s not easy to do – he could conceivably get at the heart of what is causing the immune problems in ME/CFS – and who knows, perhaps even ME/CFS itself. This study will use emerging technologies produced by Mark Davis’s lab, the product of which recently appeared in a publication in Nature – one of the most sought after journals in the world.
This study will also utilize advances in understanding the HLA genes produced by Davis’s Stanford Genome Lab. HLA genes enable immune cells to present pieces of viruses to the immune system so that it can react to them. Mapping these highly variable genetic segments was long thought to be impossible but Davis’s Stanford Genomics Center Lab cracked that nut a couple of years ago. The two Davises and others spun a company called Sirona Genetics out of their findings. That company was acquired by another company, Immucor, in 2016.
The Big Data Study Goes Mainstream
The OMF is extending the same kind of data collection and analysis applied to the severely ill patients to the less severely ill and their families. Importantly, the study will use family members who are not ill as healthy controls. Family members are the best kind of healthy controls because they have similar genetics, environment and diet. Anything that pops up, then, will probably not be due to these factors – making the results more meaningful. Mike Snyder’s lab is overseeing this project.
Threading the Nano-Needle
The nano-needle is an exciting bit of new technology but as Davis reminded us in a new video, it is new technology – and that means issues are going to crop up. Basically, Davis stated, there’s going to be “one problem after another”. The nano-needle is in the “one problem after another phase”.
A perplexing blood preparation issue, for instance, caused them to step back. It turns out that freezing blood, keeping it cool on ice, etc. doesn’t work with the nano-needle. The sample preparation that works for the nano-needle, ironically, is the easiest one: keeping the sample at room temperature.
On the bright side, they’ve got 21 samples tested. So far, every ME/CFS patient and no healthy controls have tested “positive” i.e.; their cells appear to be unable to handle the increased stress produced when salt is added to the mix. This very, very consistent finding has resulted in a rarely seen probability factor (p<.00003) which indicates that the needle, so far, is picking up something quite unique to ME/CFS. Davis noted that although the sample size is small, with their billion data points each, each sample reading is very robust.
The nano-needle is a case of technology outstripping our understanding. It’s showing something dramatically different is occurring in ME/CFS patients’ cells but they’re not sure what it is. They are pretty sure that the cells are not dying but they are clearly changing in some other way.
Next up, they will run other disease samples (multiple sclerosis, diabetes, FM, Lyme disease, autoimmune diseases) to see what kind of signature they produce.
Freeing the Data
There’s been a good amount of talk about freeing the ME/CFS data and going open source. Except for perhaps some CDC data, I’m not aware of open source data on ME/CFS. Given the highly competitive research field and the worries about being scooped, researchers have legitimate concerns about providing their hard-won data to others.
A year or so ago, Davis said he was committed to providing the group’s data to other researchers in hopes that it could help inform others work on ME/CFS. That hasn’t happened yet and I asked him why.
Davis said that, like so many other things in science, providing the data turned out to be much more complicated than he’d thought it would. The problem was Stanford. If you look at Davis’s Stanford Chronic Fatigue Syndrome Research Center website, it’s situated inside the Stanford Genome Technology Center’s website. For maximum credibility that’s right where you want it but Stanford told them there was no way in the world they were going to be able present the data on the Stanford website.
Stanford, it turns out, is very protective of its firewall. It doesn’t think kindly of anyone outside of the University being able to penetrate it. Plus, Stanford only wanted researchers to access it. Eventually – it took a year to work everything out – the Davis team housed the data on a server outside of Stanford and it should be accessible – via application for researchers – soon.
The open source platform took longer than expected but it could be a big win. It’s clear that Davis prizes collaboration. He knows he’s not going to solve this disease by himself – at least not in an appropriate timeframe. That’s why he’s putting so much effort into making his data public. It’s why he put together the Symposium last year. The SMCI, to their credit, produced a similar gathering a couple of months ago. The NIH, to their credit, is requiring that their research centers share data and collaborate as well.
The Severely Ill Big Data Project
The sample size of the Severely Ill Big Data project is not large but the amount of data that’s been gathered on each patient is huge. No other study has examined any cohort of patients with the depth that Davis has. Of course, no one has looked at really severely ill patients with any detail at all before.
The severely ill patient data will help tell us what’s going on the severely ill now – and should reap dividends for years as other deep-dive projects (the NIH’s Intramural study comes to mind) featuring healthier ME/CFS patients get finished up and the two groups can be compared.
Analyzing that much data is taking time but the addition of a bioinformatics researcher is helping. Thus far, the genetics portion of the study is finding a lot of polymorphisms e.g. unusual genetic variations in the severely ill patients, particularly in the “KIR locus” which is involved in infection.
The study is too small in and of itself to validate these findings, but with Davis working on other genetic studies with larger cohorts, and with Dr. Klimas hooked into Patients Like Me and doing her own genetic study (See the Great Chronic Fatigue Syndrome (ME/CFS) Gene Project https://www.healthrising.org/blog/2016/09/16/great-chronic-fatigue-syndrome-mecfs-gene-project/), we have some bigger genetic studies underway.
Surprisingly, no infections have been found – yet. While studies have had difficulty finding pathogens in the broad ME/CFS community, Davis thought he would surely find infections in these very ill patients – but not yet. Davis isn’t through; he’s going to use some new technologies to look again for bugs. He’s confident that if an infection is present in the body, it will show up in the blood at some point.
Thus far, the data also suggests that multiple pathways to becoming severely ill exist: no core abnormality has of yet been found in all of them.
The Weird Blood Project
I asked Davis about the next year – I said he’d be focusing on the big three projects, right when Janet cut in – Ron is always investigating; you never know what might turn up. “The Weird Blood Project” (my name for it) is a perfect example of that.
The idea that red blood cells issues might be causing problems is not new. The red blood cells, after all, deliver oxygen to the mitochondria in our cells. If something has gone wrong with them, then energy production would drop.
Could unusually formed red blood cells be having trouble getting to the tissues?
In 1993, Simpson found alterations in red blood cell shape after exercise which he thought could result in reduced oxygen transfer to the tissues. In 1999, David Berg proposed that low level increases in coagulation were rampant in ME/CFS. (At an LDN conference, Dr. Holtorf stated that he finds heparin to be quite effective at times.) In a small (n=20) 2010 study, though, Brenu found no changes in red blood cell aggregation or deformability or fibrinogen levels between ME/CFS patients and healthy controls.
Recently, Anand Ramasubramanian, Ph.D., a bioengineering specialist from San Jose State University (my alma mater ?? ) has with Davis begun taking another look at the red blood cells in ME/CFS. Ramasubramanian, who is a blood flow expert and inventor, learned about Davis’s ME/CFS studies from one of his team members. Both groups were interested in the biomechanics of cells, making their collaboration a natural fit. Dr. Amit Saha is leading the effort at SJSU.
Saha is looking at the rate at which the red blood cells from Ron Davis’s patient population flow from a larger test tube to a smaller one; i.e. from a blood vessel to a capillary. The results are still quite preliminary, but thus far he’s finding significant reductions in how quickly the ME/CFS patients’ red blood cells flow into the smaller tube. Ramasubramanian said the early results “are intriguing to say the least”.
Why ME/CFS patients’ red blood cells are getting bunched up in the capillary tube isn’t clear. They could be too stiff and are having trouble deforming. They could be an odd shape, or something else may be going on. Ramasubramanian said they were starting to do microscopy on the blood vessel to see if they were structurally different in some way. He expected to have answers in a couple of months and to be writing a research grant proposal to study the issue in more depth.
About that Symposium – I asked Davis if there would be another one next year. He said he hoped so. Whether it is or not is largely dependent on funding. I got the feeling that this is something Davis wants to continue with and if it doesn’t happen next summer, it will happen the next.
Dr. David Kaufman MD, a former HIV specialist who turned his talents to ME/CFS about five or so years ago, has been sitting in on the group’s weekly meetings. Kaufman, who’s gotten some great reviews, left the Open Medicine Institute a couple of months ago and formed his own clinic.
More from Ron
Check out a beside chat with Ron Davis – the first in a series of bedside chats with researchers – begun by Janet Dafoe
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