This blog came out of a trip last year to visit Dr. Kogelnik and learn about the Open Medicine Institute. Given the OMI’s location in beautiful Palo Alto, a hub of innovation and technology, if there ever was one, we begin with a look at ‘location’.
Location, Location, Location….Location Matters
Kogelnik loves that fact that the Open Medicine Institute is located in the biggest center of technological innovation in the country – Silicon Valley. A third of all venture capital investment in the US happens in Silicon Valley and more high-tech firms are started there every year than any place else. When you throw Abobe, Apple, Facebook, Google, Intel, etc., and some of the top medical research centers in the world (Stanford, UCSF) together things happen that don’t happen elsewhere. Kogelnik described an informality and willingness to experiment that isn’t found in many other places. OMI is about bringing that willingness into medicine as a whole… and to ME/CFS and neuroimmune diseases specifically.
Being located in Silicon Valley gives the OMI access to opportunities not found elsewhere
Technology, of course, is a huge driver in the medical field and getting on top of the latest breakthroughs can reap dividends. Kogelnik described, for instance, a successful trial of a new, more accurate way of measuring CD4 markers on T-cells he learned about at a social gathering. When he asked if the same techniques could be applied to natural killer cells the answer was yes, and, just like that, the possibility of a more effective way of testing NK cells – the big immune factor in ME/CFS – was born.
The OMI is eager to get on with this kind of nitty-gritty kind of work that could be vital to making progress in this disorder. Medical technology, or the lack of it, has been a big deal in ME/CFS. Dr. Chia believes poor enteroviral tests held up progress on that end in ME/CFS for over a decade. The Fletcher/Klimas team in Miami swears by the veracity of their cytokine tests which show more immune dysfunction than those done by other groups. How much time, money and energy has been lost by technology inadequate to understand ME/CFS?
As it moves forward the OMI will be assessing and validating HHV6, B-cell and NK cell assays that will hopefully allow researchers to dig deeper into ME/CFS than every before.
“I look at what’s impossible to do and say, okay, let’s find a way to do it” Dr. Ron Davis
When Kogelnik’s partner, Ron Davis, an eminent genome researcher and technologist whose son has a severe case of ME/CFS, doesn’t have a tool, his lab, which I took a short tour through, simply invents one. Given the immune issues in ME/CFS sequencing the HLA genes – the main participants in pathogen presentation to the immune system – are of great interest except that Kogelnik noted that you can’t order in depth HLA tests from a routine clinical lab; the technology is simply not there.
Except HLA genes just happen to be one of Davis’s major interests. Davis has been doing fine-tailed analysis of his sons labs for several years and now with the OMI’s million dollar genetic grant, Kogelnik and Davis’ll be looking at not just the HLA genes but scores of other immune and inflammation, and in some cases, the entire genome.
Data Junkie
Big Diseae Meet Big Data; the OMI can be viewed as a big data gathering and analysis project
When we say technology we”re not just talking test tubes and microscopes; the 21st century approach to disease requires being adept at using information technology and social networking as well. Kogelnik with his Ph.D in bioengineering, his post-graduate work in bio-informatics, and his creation of a software company, is well-placed to take advantage of the opportunities the information revolution is providing.
Kogelnik firmly believes the more data the better; in fact, you can envision the OMI as being simply a tool to gather and analyze more and more data. The integrated electronic database his physician network uses, his use of core blood draw areas to get disease control samples, and the online patient data system he’s developing are all attempts to get more and more data as efficiently as possible into his databases so he can bring bioinformatics tools to work on it.
Technology will provide the breakthroughs needed to understand ME/CFS but you also need patients to study and the kind of money needed to solve the problems ME/CFS is facing isn’t exactly falling off the trees. There are other ways to skin a cat, though. Sometimes efficiency is just as important as ‘big technology’
TREATMENT
Rituxan
Kogelnik felt the success of the early Rituximab trial shifted the conversation for chronic fatigue syndrome (ME/CFS) in a good direction but he’s cautious about the future of Rituximab in ME/CFS. Since researchers tend to pick patients they think will prove their theory early, small studies runs the risk of having inflated results. Dr. Peterson has warned about this as well. It’s hard to imagine that Dr. Peterson didn’t provide the Chronic Fatigue Initiative pathogen study with patients who were more likely to test positive for pathogens.
Dr. Kogelnik is using Rituximab in his practice. His patients are monitored very closely as they start off with vital signs being taken every 20 minutes. Don’t think I said this According to the Rituxan product label about a third of patients will get an infusion reaction and according to Kogelnik, Herxheimer type effects are fairly common but like with other treatments in this disorder, the people who get worse in the beginning often respond really well later.
An antiviral/rituximab combination is being used on a few patients. Kogelnik reported that some patients are experiencing the same type of dramatic recovery Fluge/Mella’s patients experienced. The fact that Kogelnik’s worried about patient selection suggest, however, that he’s not getting the kind of jaw-dropping results Fluge and Mella did.
A Heavy Weight
‘Boy, you’ve got to carry that weight, carry that weight a long time’ the Beatles
Kogelnik stressed, though, that it’s not all about pathogens. He believes ME/CFS is a stress-response disorder; if you remove the stressor – whatever it is – the immune and other systems rebounds. If it’s a pathogen you use antivirals; if it’s something else – you might focus on your gut, your diet, whatever. It’s all about reducing the load, what Dr. Kogelnik referred to as ‘weight’ on the immune system. Every factor, in some way, is just ‘weight’ and if you remove enough ‘weight’ the system functions will return.
Heart Breaking Stuff: A Cardiac Nurse, the Vo2 Max Test and Chronic Fatigue Syndrome
One of Kogelniks’s RN’s, Tracey came, from the other side of medicine where patients, by and large, can at least get the care they need and she wasn’t ready for the constant battles many ME/CFS patients have to engage in get their care covered.
Many of Dr. Kogelnik’s patient’s have seen scores of doctors; they’ve done their utmost best to get well and to see them get discredited and brushed off by the medical profession they put their trust in , sometimes left her in tears. She couldn’t believe in our modern society that many of the most disabled were left at home, unmonitored, to suffer. Tracey used to work in an intensive care unit (ICU) and she felt that many of Dr. Kogelnik’s patients were so sick they belonged in one.
A former ICU nurse was shocked at the degree of debility she saw in ME/CFS patients
Tracey oversees infusions and the VO2 max tests at the OMI. A former cardiovascular nurse who had seen the worst of the worst, Tracey said ME/CFS patients were completely different from the patients she’d seen in cardiovascular units before.
Her eyes opening wide, she said she was shocked by the changes between the first and second days of the two-day exercise test when she first saw patients having the tests…saying “I couldn’t believe these were the same patients. The Day I test results were already bad and the second day was much worse. It was like they were two different people”.
Thirty to forty percent of patients show abnormalities on the first exercise test – which means 60-70% do not and that its in the second test that many of the changes occur. Cardiovascular problems such as postural tachycardia syndrome (POTS) are common and cardiomyopathies are found as well.
Dr. Kogelnik emphasized how hard it was for some patients to assess their own degree of exercise intolerance. One person who was sure he was going to pass his exercise test with flying colors, found his oxygen threshold was blunted, his workload at anerobic threshold was a mere 20% of expected, and on the second day it dropped 80%.
Despite their sometimes incredible disability Kogelnik said ME/CFS patients demonstrated an ‘unbelievable’ dedication to getting through these often torturous tests. Often it was the sedentary but healthy controls they had to try and coax back.
Activity Management and Exercise
Activity management is a clear need and Dr. Kogelnik like Dr. Klimas, Dr. Peterson, Dr. Lerner and others uses heart rate monitors to keep patients activity levels within bounds. An exercise test is the best way to determine what your anerobic threshold is but there are some general guidelines you can use if you can’t get an exercise test done.
- If you can’t walk (or exercise) and talk comfortably -you’re doing too much
- like others Dr. Kogelnik believes watching your heart rate is the key to functioning better and improving your quality of life.
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A bike test is the best way to determine your anerobic threshold; if you can’t do that then follow the guidelines to the left
Keeping your heart rate below your anerobic threshold gives your body a chance to recover and avoids immune flares
- Plan rest periods throughout the day and take them whether you feel like you need them or not…
- Kogelnik rarely sees an anerobic threshold over 120 heartbeats per minute and it’s usually between 90-115 and is sometimes lower than that. That suggests a good starting place is to keep your heart beat rate between 90-115 bpm, and be aware that your safe heart rate level could be lower than that.
- Take your resting heart rate before you get up in the morning for five consecutive days
- Take your heart rate during a range of activities; see what it is during strenuous activities then cut it by 20-30% and don’t let your heart rate go above that..
- You may not like what your heart rate monitor tells you
- Use a shower chair to take a shower; it takes 25% more energy to stand up than to sit down
OMI is busy tying some of these heart rate monitors directly into OpenMedNet so that not only can patients track their heart and other clinical data online, but they can easily share it with their physicians and other researchers as they wish.
A Diabetes Link?
Dr. Kogelnik is finding that at a coarse measure perhaps 30-40% of his ME/CFS patients progress to diabetes – a much higher rate than in the population at large (about 14% for adults aged 47-59). Whether its due to sedentariness or some other aspect of ME/CFS is not clear but this metabolic shift is a big concern. With a larger OpenMedNet survey, OMI is hoping to better define these and other numbers over the coming year.
It shouldn’t be much of a surprise, however. People with ME/CFS are sedentary, cannot exercise, appear to have high rates of fatty acid oxidation and oxidative stress and perhaps inflammation. We’ll be looking into this further in future blogs.
Big Pharma Missing Thus Far At the Plate
The rituximab trials raised a huge amount of interest but several years later the biggest medical system in the world still can’t find a way to put on on. I asked Kogelnik why Pharma did not come calling after a rigorous if small placebo-controlled, double-blinded Rituximab trial succeeded in a disorder that affects about 1 million people in the US. How could this happen? He said that there is interest, but a typical drug study starts with a whole lot more scientific data than one small study and we are well on our way down that path with our proposed MERIT projects.
The Open Medicine Institute Video
Drug companies shy away from this disorder because a) they’re not sure a) if it’s a disease and how to characterize it and b) they and society at large don’t understand the huge morbidity and impact of the disease on patients and society. Add to that the huge impact if someone in this very ill, often very poorly characterized group died or got seriously ill during a trial and a pretty difficult disorder to make get any traction with.
Still, what drug companies want is a good infrastructure and good data and that is being built at the OMI and the patient registries and biobanks at the CFIDS Association, the Chronic Fatigue Initiative, the WPI and others.
RESEARCH
One Disease or Many?
Kogelnik noted we don’t know if this disease is one disease or twelve separate disease or if its a spectrum-type disorders and we’re not alone in that regard. Autism, fibromyalgia and many other disorders going through the same classification struggles.
Dr. Unger has talked about how crude definitions based on ‘phenotypes’; ie symptom presentation are. Given the many symptoms in ME/CFS it’s impossible to know which disorders ME/CFS or its subsets will end up being most closely related to. Given the incredibly low natural killer cell dysfunction found in both autism and ME/CFS, for instance, Dr. Kogelnik thinks it’s possible that the ‘same hit’ occurring at different times in a persons lifespan (very early in autism, later in ME/CFS) could contribute to both.
How many subsets are present in ME/CFS is anyone’s guess
With genomic advances driving a new era in science many organisms and disorders are finding new homes. Just as tumors are being defined based not on their location (phenotype) but on their molecular signatures, medical disorders are being subdivided into their molecular subtypes. Despite the fact that ME/CFS and fibromyalgia look so similar, when I asked Dr. Kogelnik if they were the same type of disorder, his response was ‘We’ll see”.
Finding out that answer will require understanding what’s going on in these disorders at a molecular level and that’s exactly what OMI-MERIT is committed to. Whatever chronic fatigue syndrome ‘is’ Dr. Kogelnik believes that neuroimmune diseases are probably four times as common as the current conservative estimates .
Autoimmune Disorder?
Dr. Kogelnik is cautious about the role autoimmunity plays in chronic fatigue syndrome. When I asked about the study suggesting that B-cell abnormalities were present he felt it had just scratched the surface of the autoimmune questions and suggested we be careful about defining ME/CFS as solely an autoimmune disorder until we better understand the mechanism. Kogelnik, like other doctors, has Valcyte responders and he noted that getting rid of viruses could be clearing up the autoimmune manifestations as well.
Instead of B-cells going bananas and attacking the body, he, like Dr. Lerner, believes B-cells are more likely to be a reservoir for pathogens such as Epstein-Barr Virus. Just as in HIV, ME/CFS patients immune systems are buckling under the strain; remove the stressor – the pathogen or whatever it is – and the immune system rebounds. Dr. Peterson has seen this same kind of unusual immune response; remove the pathogens and NK cell and other immune factors rebound.
Natural Killer Cells
Natural killer cell functioning is a huge area of interest in ME/CFS. With many of his patients NK cell functioning hovering in the teens and normal NK cell functioning levels in the general population are typically over 60, Kogelnik says he would give a good NK cell booster out like candy if one was available. Nutriceuticals are not going to be the answer here; they can give NK cells a 5% gain at best, he thought. An NK cell booster is going to take drugs; yet he knows of no work being done to produce one and he mused over the possibility that rituximab may be boosting NK cell functionality as has been shown in some cancer patients.
Still natural killer cells are a key interest and he would love to see what’s going on better with natural killer cells in other disorders. How interesting it would be to find low NK cell results in say, multiple sclerosis or perhaps in a disorder no one ever thought might be related to ME/CFS. But here’s where the open draw stations and OpenMedNet comes in. Kogelnik should be able to get scads of NK data from ME/CFS patients and NK data on other disease states from the open draw stations and online via OpenMedNet.
CDC Study
The study came about when the CDC, of all groups, put out a Request For Proposals (RFP) to ME/CFS researchers and offered to fund a study. Not since the Pharmacogenomics project was underway in the early 2,000’s had the CDC done such a thing. The catch was the response had to be laser-quick; researchers had a mere 30 days to get their data together and submit a detailed proposal.
The CDC study will look for subsets in different doctors practices
Kogelnik had been busy creating OpenMedNet an electronic data infrastructure for supporting clinics and doing research and he had already enrolled top ME/CFS physicians into the OMI network to collect and analyze data. Instead of paper files, they would collect digital data on everything…test results, treatments underway, diagnosis/prognosis, treatment effectiveness – in such a way that they could mine that data (depersonalized, of course) to understand how to treat ME/CFS better.
Enter Dr. Unger with her RFP. Dr. Kogelnik got in his proposal to do a global analysis all the doctors in his network – quickly – an impressive achievement according to Research Director of the CFIDS Association, Dr. Suzanne Vernon – and got it funded. Instead of the physicians examining their internal results the project went global; now the CDC would determine if the patients in different doctors practices were different and examine how ME/CFS physicians were diagnosing ME/CFS.
The project was successful enough that it’s morphed from a more symptom and demographic based study to one including extensive biological samples. With ME/CFS experts gathering scads of data you might say that the race for subsets is on. When Unger starting visiting the physician sites (when was the last time that happened?) she was impressed enough to state we must find a way to mine “physician intuition”. That lead to the CFIDS Association creating their ‘physician intuition’ survey to capture the decades of knowledge swimming in our best ME/CFS practitioners heads.
That process – an idea (a network of physicians feeding data into the same system) that grows (a ‘global CDC study comparing that data) and then grows again (adding biological data into the mix) and then sends out sprouts (a CAA physician intuition project) is the kind of process the OMI (and other organization) want to produce. It’s all about building a foundation that attracts ideas, projects and ultimately breakthroughs.
This is why the most forward thinking individuals in the field, the Kogelnik’s, the Vernon’s , the Klimas’s are so bent not just on creating good studies but on building foundations for success and opportunities for networking. This is why the Dr. Peterson’s are collaborating as furiously as they can.
A Cautionary Tale and a Focused Search For Biomakers
Kogelnik’s in full agreement with the adage ‘garbage in – garbage out” and he emphasized, in the context of gene expression studies, the need for ‘validated, replicable’ outcomes. Gene expression studies provide a cautionary tale here; with their ability to determine which genes were active or inactive gene expression studies were going to provide a window into the molecular heart of what was happening in this mysterious illness but study after study got differing results.
Kogelnik hopes a more focused gene expression study will lead to biomarkers for ME/CFS
One problem, Kogelnik thought, was too much signal/noise ratio. The data researchers were looking for was in there but it got washed out in the process. A better approach in retrospect might have been to focus specifically on what researchers know is already broken in this disorder such as natural killer cells. The correlation, he noted, between viral persistence and natural killer cells dysfunction was huge.
Kogelnik’s using the same finely tuned approach to search for biomarkers. He’s using reverse engineering; ie first he identifies patients who are responding to Rituximab and/or antivirals or other therapies and then compare them to patients who are not responding and their pre-drug sample. Doing broad data sweeps on responding vs non-responding patients should be able to tell which part of the system broke down in the first place. That will give him a ‘string’ he can start pulling on to determine where the core problem is. Kogelnik does have his eye on some potential biomarkers but he said it was too early yet to say what they were.
Conclusion
The Open Medicine Institute’s plate, with its OpenMedNet project and the OMI-Merit Initiative is full to the brim with projects. In his key note speech – “The Changing World of Medicine”- at the Invest in ME Conference Dr. Kogelnik asserted that breakthroughs in information technology, social media and biotechnology were providing not to be missed opportunities for less costly and more effective research. If they can leverage the energy and excitement around these areas, and they’re certainly in the right place to do that, they have a chance. That’s music to the ears for patients who have been waiting too long for the medical research community to give them a legitimate shot.
This is awesome!! But when will they start treating patients? I contacted them to be seen there but they weren’t accepted patients. I’ve lived in the heart of Silicon Valley and I’m a patient of Dr Montoya’s and I’ve had ME/CFS since 1998. We hear all this great stuff about the OMI but why can’t I call and make an appointment with a physician and receive treatment? Equal Access to healthcare now!
Thanks, Sean
YES!
How does one become a patient at the OMI? I’ve been a patient of Dr Montoya’s since 2006 and I’ve lived in the heart of Silicon Valley my entire life and I’ve had ME/CFS since 1998. So how much longer do we have to wait for the OMI to start treating patients? Where’s the link to contact them to set up an appointment with a physician? Here’s to Equal access to health care!!!!
Thanks,
Sean
I’m posting this for someone else who couldn’t
“How does one become a patient at the OMI? I’ve been a patient of Dr Montoya since 2006 and I’ve lived in the heart of Silicon Valley my entire life and I’ve had ME/CFS since 1998. So how much longer do we have to wait for the OMI to start treating patients? Where’s the link to contact them to set up an appointment with a physician? How does someone on Medicare and SSI get treatment at the OMI? Here’s to Equal access to health care!!!!
Thanks,
Sean
I don’t actually know the OMI contact for that but they do have offices and they are seeing patients..I saw them when I was there…
Yes, here’s to equal access to health care. I hope you can get in.
I saw Dr. Kogelnik last week, after a one month wait (it was supposed to be 2 weeks, but the initial appointment was canceled at the last minute).
I came down with post-viral fatigue type symptoms about 10 weeks ago and have been trying to get diagnosed and start treatment ASAP before things have a chance to set in. They checked me for POTS and took blood draws to get viral titres; I go back in a couple of weeks to discuss results.
Dr. Kogelnik spent about 45 minutes with me discussion my history and discussed some treatment ideas; he’s very patient and a good listener. However, my sense is that treatment options are going to somewhat reflect their research aims, e.g. he is not going to look for chronic Lyme in all his patients, even though that may be a factor in a good subset of ME/CFS suffers. Apparently I have mild POTS, and daily saline IVs for a week suggested.
If you want to see him, you will need a referral. Contact them here: http://openmedicineinstitute.org/contact-us/
Their e-mail is clinic@openmedicineinstitute.org
Thank you very much! :-))
Good article Cort. Thank you.
Thanks
Big Pharma isn’t going to be interested in losing money in the long haul! In other words, they’re not going to kill the goose that lays the golden eggs. The biggest golden egg is “inflammation”. But then, it is inevitable, eventually!
I don’t know how you do it, Cort, but another great article! I was able to really focus on everything you were writing about. You made it easy to understand ,and I have a sense of real hopefullness in reading what these researchers are doing, their investment and interest in CFS.
After all these decades the future finally looks so much brighter for all of us suffering every day with this illness.
What the nurse said was very touching and yet so true. So many of us still get the bugged- eyed look from doctors when we try to explain to their question about how much exercise are we doing,and our answer is that we cannot exercise because we have CFS. We can see the distain in their eyes as if we have done something wrong that we should feel embarassed about. (And that is not being paranoid. It is still happening with every new doctor I see)
Thank you, Cort. You are a light in the darkness.
We are still so much in the dark ages.. What this disease needs is validation and a name change; in short research. I think Kogelnik has found a way to elicit interest and get research going without a ton of money. We just have to keep pushing…
If we can get the CDC or someone else like that to validate the PEM in this disorder using the 2-day exercise test…I think we could blow the lid off this thing. In my opinion that’s numero uno for us.
Targeting NK cells in rheumatoid arthritis:
NKG2A is an inhibitory receptor present at the surface of a fraction of NK cells, NKT cells and T cells. NKG2A+ NK cells can infiltrate inflammatory sites, particularly in inflamed joints of patients with rheumatoid arthritis (RA). These cells have been shown to be able to recognize and kill chronically activated CD4+ cells, as well as other pro-inflammatory cell-types that mediate joint-destruction in RA patients. Targeting NKG2A could therefore be beneficial in patients suffering from RA or other chronic inflammatory diseases.
http://www.innate-pharma.com/en/product-pipeline/iph2201-nn8765-anti-nkg2a-mab-licensed-novo-nordisk/s
I hope that the OMI biobank will accept samples from patients who are bedbound/homebound and unable to leave their homes for a blood draw. There is no reason why the sickest patients cannot provide blood, urine, stool and cheek swab samples from home.
If OMI excludes the severest patients, Dr. Kogelnik will be missing out on an invaluable resource. Most studies have focused exclusively on mild/moderate patients. Perhaps that is why after 30+ years of research, we have ZERO biomarkers and ZERO FDA-approved treatments.
I contacted OMI weeks ago and they told me that they are a research only facility and that I would have to join a study. But after reading this article it clearly seems that the OMI is treating patients and not just having them as a participant in a research study. The OMI told me that they hoped I could join a study but they gave me no links and have not kept in contact with me. My concern is how they are selecting patients to be treated? How do they choose who gets treated there? Why isn’t Montoya able to refer patients to the OMI? The OMI is essential in that they publish their info but what’s the use if we can’t access it?
Sounds like all I need is a referral from Dr. Montoya, thanks again for the update on the OMI !! :-)) I will contact them again soon!
Sorry for the redundant comments I thought they we’re not posting and there’s no delete button. Thank you for the awesome article and for the contact support on the OMI :-))
Great article, thanks Cort.
Going through a particularly difficult period. Your article gave me hope. Many thanks, Cort!