I listened miserably to the sounds of silence broken by my occasional exclamations: “really?”, “no kidding”, “fascinating!”. During my two long sessions with Dr. Klimas, the recorder app on my phone had decided to record only my questions – leaving silence for her replies. The few item my memory gleaned from the interview included: Dr. Klimas is investigating mold and seeing lots of mycotoxins in her patients. Sleep apnea is turning out to be surprisingly common as well, and, mentioning a recent gut finding, she said to keep a close eye on other central nervous system diseases such as Parkinson’s Disease. Findings there will help inform chronic fatigue syndrome (ME/CFS) and could even lead to treatment possibilities.
The big surprise was the news that Dr. Gordon Broderick, the originator of the computational modeling approach to ME/CFS, was now leading his own effort at the University of Rochester in New York. Travis Craddock is now in charge of Dr. Klimas’s computational biology effort at Nova – an effort that stirred so much enthusiasm in Parkinson’s disease that they tried to persuade her to devote her time and her team to that disease. Thankfully, Dr. Klimas said no, and she, Craddock and Broderick continue to work together on ME/CFS and GWI.
My interviews in shambles, there was still a lot to report from Dr. Klimas who has gone from strength to strength in her move from University of Miami to Nova Southeastern University seven or eight years ago.
Building on Success
There’s nothing like success to breed success. In 2012, not so long after she arrived at Nova Southeastern University, Dr. Mariana Morris, Nancy Klimas and Gordon Broderick received a $4 million Consortium Award for the Gulf War Illness Research Program (GWIRP). The goal of Consortium awards is, as their name suggests, large awards that bring together a range of researchers to battle complex problems.
Gulf War Illness is a puzzling condition brought on by exposure to toxic elements from oil well fires, munitions, etc., vaccinations, heat, and the stress of war during the first Gulf War. It took one relatively short but intense exposure to this toxic brew of factors to irretrievably push many of these fit and mostly young warriors into a chronic illness state. Remarkably, from a quarter to a third of the servicemen and women participating in the first Gulf War have remained ill three decades later.
The really interesting thing is that despite their different trigger, they’ve looked exactly like people with chronic fatigue syndrome (ME/CFS). Their symptoms – including post-exertional malaise – are almost identical to ME/CFS. Some of them are extremely ill as well – just as some people with ME/CFS are.
Dr. Klimas’s studies have revealed, however, that despite their surface similarities, underneath the hood the two diseases are quite different. Immune networking studies indicated that the GWI patients’ immune systems have leapt to their defense and exhibit a kind of hyperactive, hyper-connected state, while the ME/CFS patients’ immune systems headed in the opposite direction; they’re characterized by eroded/impaired immune networks – they look depleted, overwhelmed and exhausted.
Klimas knew the two diseases looked the same but were actually different because the technology she used to understand ME/CFS was the same technology the first Gulf War Consortium funded helped her to develop for GWI. Now that she’s gotten another huge GW grant, we can anticipate the same result happening: she will get better at understanding GWI – and ME/CFS.
A Strategic Approach to a Disease
The feds are taking a different approach to GWI. It’s a strategic approach that’s designed to lead to clinical trials. It started in 2012. Check out what a strategic approach to a disease looks like.
Beginning in 2012, Marianna Morris, Dr. Klimas and Gordon Broderick used the a Consortium Award from the Congressionally Directed Medical Research Programs (CDMRP) to develop an animal model and to use exercise, massive data gathering efforts and computational biology to attempt to understand the processes at work in GWI and identify potential treatment targets. (Solve ME is trying get ME/CFS eligible for funding from the CDMRP).
At the same time, another winner of the 2012 Consortium Award – a the Boston group lead by Dr. Kimberly Sullivan – used the award to uncover a neuroinflammatory component and further immune disruptions in GWI illness patients. It’s been looking at a subject near and dear to ME/CFS – neuroinflammation and the microglia. Dr. Sullivan believes that continuous activation of the microglia in the brains of people with GWI is leading to a state of chronic “sickness” behavior: i.e. unrelenting states of fatigue, pain, cognitive problems, flu-like symptoms, etc. The same hypothesis has been proposed for ME/CFS.
She’s now examining markers in the blood and brain fluid (cerebrospinal fluid), doing extensive brain imaging, and studying brain cells under special microscopes.
Flexibility was built into these programs from the start.
“It is the responsibility of this Consortium to be responsive to new knowledge quickly, and not restrict the research efforts of this Consortium to the studies highlighted in this proposal. Thus, this Consortium will have a process in place to provide new research ideas with appropriate review”.
Sullivan’s 2017 Consortium award added an important piece of the infrastructure puzzle to GWI: the massive BBRAIN (Boston Biorepository, Recruitment, and Integrative Network) repository that will house just about every biological specimen you can imagine (whole blood for DNA and RNA analyses, plasma, sera, PBMCs, saliva, urine, fecal samples) as well as clinical data (cognitive data, health symptom and demographic surveys) from 500 GW Veterans. BBRAIN will also collaborate with other disease biobanks including at least one that includes people with ME/CFS.
Then, in September 2018, Dr. Klimas received a $5.3 million GWIRP Clinical Consortium Award designed to combine the expertise and knowledge gained from the two previous consortia and begin trying out a variety of treatments for GWI.
The specific goal at the start of these efforts was to “create a short list of attractive Food and Drug Administration-approved drugs that could be tested rapidly in clinical trials without requiring a drug development effort.” That effort was buttressed by the development of a “streamlined infrastructure for conducting Phase I and II clinical trials” Meanwhile, the BBRAIN repository provided an infrastructure component which allowed for a more efficient exploration of the mechanisms behind GWI, the identification of biomarkers, etc.
Basically, we have a massive and strategically coordinated effort to understand GWI and bring relief to long suffering veterans.
And here we are: using the latest Consortium funds, over the next four years, Dr. Klimas will produce no less than five Phase I or Phase II clinical trials in GWI.
They will all target similar issues to those found in ME/CFS – energy production, inflammation, and immune function – and all could ultimately apply to ME/CFS. Even though the niceties of the two diseases may be different, the core problems – neuroinflammation and HPA axis disruption – may be the same and may require similar approaches.
In short, a strategic program was created seven years ago with the intention that it would rapidly progress to clinical trials – and it has. That’s a far cry from what’s happening in ME/CFS where research is funded haphazardly – no strategic is in plan in place and no funding is available for clinical trials. (In fact, the past program announcement did not allow funding for clinical trials.)
The GWI saga demonstrates the difference between an organization (the Dept. of Defense) that has proceeded with a strategically oriented approach focused on producing data-driven clinical trials, and an organization, (the NIH), with a muddled, laissez-faire approach to ME/CFS which does not include clinical trials.
Dr. Klimas’s ME/CFS Program
At the Emerge Conference, Travis Craddock, the leader of Dr Klimas’s computational modeling effort (Gordon Broderick is now at the University of Rochester), highlighted how large Dr. Klimas’s INIM effort is. It’s made up of five cores, of which the one he leads (the clinical systems biology core) has no less than 9 members. INIM is clearly our first true ME/CFS Center of Excellence; it’s got a research and clinical team (two clinical offices, in fact) and is involved in educational efforts on the Nova Southeastern University Campus in Ft. Lauderdale, Florida.
As Broderick, Craddock and colleagues created their computational models, they tested them to see if they could reproduce known physiological processes. It’s not been easy. The female hormonal system, for instance, was so complex that it required four models simply to describe it. Once they have a model which seems to work, they perturb it to see if they can reproduce how a person might come down with ME/CFS in response to a triggering factor such as an infection, etc.
It’s worth repeating just how much data Dr. Klimas is able to throw into her computer modeling efforts. She has massive amounts of sex hormones, immune cell, cytokines, gene expression, DNA methylation, etc. data that’s been gathered 9 times before, during and after maximal exercise tests. All that is thrown into a supercomputer where it’s integrated into physiological models the team has created.
According to what I think I got from Craddock’s incredibly complex EMERGE presentation (which I can no longer find), the models suggest that the main areas of immune system interest in ME/CFS include B and T-cell receptors, TNF-a and transforming growth factor beta (TGF-b). TNF-a levels correlated most with severity scores, while TGF-b seems to be associated with pain.
Gordon Broderick’s ME/CFS models very early on indicated that a strong enough stressor such as a high chemical or viral load could, under the right conditions, so destabilize a person’s system as to drop it into a suboptimal homeostatic state from which escape, even after the original stressor has been removed, was difficult or impossible. Walls had basically had been erected to keep the system in place.
The silver lining was that escape from that alternative homeostatic state was possible: the system just needed a big push to get it over the wall, so to speak, and let it slide back to normality – where, hopefully, it would stay put. Klimas’s goal has been to find the right combination of treatments to push the system back to normality. She’s been focusing on already available drugs and supplements to get the fastest relief possible to the ME/CFS and GWI communities.
A recently published paper, authored by members of Broderick’s team at the University of Rochester and Dr. Klimas’s team at Nova Southeastern University, asserted two things:
- ME/CFS is likely so heterogeneous that one treatment cannot be expected to apply to all patients;
- ME/CFS is most likely addressed by combination therapies tailored to specific patients.
“The current literature on the treatment of ME/CFS leans strongly toward a single conclusion: that there is no single solution. The assumption that a single drug can successfully treat ME/CFS is likely incorrect. The multifaceted, complex nature of ME/CFS may instead be more effectively treated with combination therapies, tailored to the specific causes and symptoms present in each individual patient.” Richman et. al. 2019
The breakthroughs in ME/CFS treatment, they believe, will most likely come from systems biology efforts which use a variety of “omics” data (genomics, metabolomics, proteomics, etc.) to identify the biological drivers behind the multisystemic problems found in ME/CFS. A personalized medicine approach will complement those findings. Subtyping or subsetting ME/CFS patients will be critical.
Once Klimas’s and Broderick’s team were able to produce a model which could replicate what’s happening in ME/CFS (i.e. demonstrate a infectious trigger could under the right conditions result in a steady-state condition like ME/CFS), then they were ready to perturb the virtual ME/CFS or GWI patients’ systems with treatments.
For instance, in a system characterized by the high Th1 cytokine and cortisol levels and low testosterone levels in GWI, the model indicated that a cytokine inhibitor Enbrel (etanercept) would drive the inflammation down but would not return the system to normal. Adding a glucocorticoid inhibitor (mifepristone) at a later stage, the model indicated, could return the system back to normal.
The team has uncovered other models of “stuckness” they believe are present in ME/CFS. The high Th1 cytokine/cortisol/low testosterone model applies to women not men and the Enbrel/mifepristone treatment regimen is not being proposed for men.
Gulf War Illness Studies
Two GWI studies (and one ME/CFS study) will focus on etanercept (Enbrel) and mifepristone, introduced in a staggered fashion. Two more GWI studies will focus on supplements that the group’s computer modeling suggested hit “all the right points”. One will assess the effectiveness of CoQ10 or glutathione, and then combine the best match with intranasal insulin. Another will examine the effects of a nutriceutical Bacopa, which has been shown to impact inflammation, immune function, and energy production. (Tumeric is another nutriceutical which the model predicted would hit many of the right points, but which has absorption issues.)
Focus on Bacopa
Our results strongly suggest that bacopa and its constituents are promising candidates for the development of novel therapeutics that target neuroinflammation, and have the potential for treating a wide range of CNS disorders. Nemetcheck et. Al.
Bacopa monnieri or Bacopa is a fascinating herb which, like many, is reported to have miraculous qualities :). Also called “Brahmi” or the “herb of grace”, it’s been used in Ayurvedic medicine to treat epilepsy, asthma, inflammation, ulcers, etc. and improve cognition for centuries. In Ayurevedic medicine, it’s considered a “medhya rasayana” or herb that sharpens the mind and intellect. One website reported that it was used by Hindis to help them memorize long texts.
Also known as “water hyssop”, this pretty little water-loving plant is also found in Australia, and the United States. Many studies suggest Bacopa can cool the flames of inflammation in the body but Dr. Klimas wants to calm the fires of the central nervous system. A recent study suggests that Bacopa might do the trick. This 2017 study assessed whether a tea, infusion, and an alkaloid extract of bacopa were able to affect microglial activity in vitro – that is, in the lab. It found that the infusion extract and the highest concentration of the alkaloid extract were able to stop microglial cells from producing two powerful pro-inflammatory cytokines – TNF-a and IL6, as well as caspases 1 and 3.
Increased levels of both cytokines are associated with a variety of central nervous system disorders. Interestingly, the factor thought responsible for Bacopa’s anti-inflammatory effects, Bacoside A, actually increased inflammation. Note that this was a lab study – not a human trial – but it does suggest the potential may be there for Bacopa to cool the flames of the central nervous system. It is also being investigated as an anti-pain herb.
Lots of testing, including going back on the bike, will be used to assess the treatment’s effects. The results will then be fed back into the modeling program. Even if the clinical trials fail, they will provide important data that will help the researchers refine their models further – and come up with better treatment candidates in the future.
The ME/CFS Field
The NIH does have a loose strategic plan for ME/CFS which includes funding several small research centers, an in-depth intramural study, and a central database – and seeing what pops up. The ME/CFS field also contains, in seed form, some of the innovative elements that are speeding up GWI illness research and treatment. Solve ME’s Patient Repository will, when it’s up and running, contain some of the features of BBRAIN. Ron Tompkins is committed to building streamlined infrastructure for the assessment of treatments at the Open Medicine Foundation’s ME/CFS Collaborative Research Center at Harvard. At Stanford, Ron Davis is dumping all his information into a publicly available database for researchers and the new Harvard ME/CFS group will do the same
All of these activities, to my knowledge, however, are privately funded and thus bear the marks of that: more funding is needed and most will probably take quite a bit of time to come to fruition (if they do). Whether the disparate and often not so cooperative elements of the ME/CFS research field will work together is unclear.
There’s no doubt that ME/CFS is more complex than GWI – an illness that was initiated by an at least somewhat homogenous set of stressors over a short period – but note how quickly the Consortia have moved from understanding GWI on a mechanistic basis to funding clinical trials. The trials may or may not be successful but even an unsuccessful trial should reap dividends as the researchers use the results to further improve their models.
Dr. Klimas has said for several years now that she’s ready to progress to Phase I clinical trials in ME/CFS now – and would have – if not for the funding barriers erected by the NIH. (A small privately funded Etanercept/mifepristone pilot trial is reportedly underway in ME/CFS.)
It’s encouraging to note, though, that despite the clear differences Dr. Klimas has found in ME/CFS and GWI, her models suggested that the same treatment, which is designed to tamp down neuroinflammation and restabilize the HPA axis, should work for both of them.
In summary, Dr. Klimas’s new infusion of money into GWI will help her assess treatments for GWI that may help for ME/CFS as well, and – more importantly – it gives her the funds she needs to continue building and refining the computational biology models that’s she’s been using to understand ME/CFS as well.
A Federally Funded Strategic Plan for ME/CFS?
This week on Sept 4th, the National Institute of Neurological Disorders and Stroke (NINDS) ME/CFS Working Group will present a plan it’s spent a year on that’s designed to move ME/CFS forward to the NANDS Study Council. This is our one big chance for immediate action. Note that this is entirely a NINDS action.
(One would have hoped that the NIH Working Group would be the one presenting a strategic plan for ME/CFS to the NIH itself but that group is continuing its almost 20 years record of disappointment.) The way out – the way to a more robust NIH effort – right now leads to NINDS, the home of Vicky Whittemore and Walter Koroshetz. The presentation is scheduled to be webcast starting around 1:30 PM EST.