“The objective is to deliver relief as quickly as possible but to keep working on the problem until we find a cure.” – Gordon Broderick
Dr. Gordon Broderick of Dr. Klimas’ Institute for Neuro Immune Medicine at Nova Southeastern University (NSU) was in a loquacious mood. He likes what he’s seeing from his working group and from the field in general, and as we wandered from NSU poster to poster at the IACFS/ME Conference, he was happy to talk about it.
He’s an interesting guy with a more than interesting approach to Chronic Fatigue Syndrome. He got into the field with the CDC and their big Pharmacogenomics study, but when that work wound down and he was having trouble getting funding, he was about to leave the field.
That changed when he bumped into a Gulf War veteran at a conference in Reno. A big man, probably 6’4″ and 280 pounds, strode rapidly up to him — eliciting alarm in the short and slight Broderick (“I thought he was going to snap me in half and send me home in little Glad bags”) — grabbed his hand, and tearfully thanked him for believing that he was sick.
Probably many professionals who work in this field have defining moments when they decide that no matter what the difficulties they’re encountering, no matter how much working in ME/CFS makes their own lives more difficult in so many ways, that this is what they must do… and this was Broderick’s defining moment. He said he could remember as if it happened yesterday.
Broderick has a unique approach to Chronic Fatigue Syndrome. A master at mathematical modeling and data mining, he analyzes enormous amounts of data to learn how systems work. He and his team use the data they find in the medical literature to produce engineering models of how the system works. Ultimately patterns emerge which show different stable modes of operation, some of which constitute good health and others that reflect chronic illness.
Chronic Illness … er, “Impaired Homeostatic State”
“Illnesses such as these continue to defy a conventional one-piece-at-a-time approach.”
Broderick believes chronic illnesses such as ME/CFS and FM, autoimmune illnesses, diabetes, etc. involve a kind of ‘homeostatic reset’ that enables the body to survive but also includes a kind of ‘stuckness’. Chronic illnesses, in other words, are chronic for a reason. If Broderick’s right, it’s possible that every chronic illness reflects a homeostatic state that is resistant to change.
With the computational power and methods available now, it’s not just about NK cells or T-cells — it’s about how NK and T-cells and B-cells and hormones all work together to produce a disease. You still need the data on NK cell problems because that informs the model but the big picture is coming from the computational end. In fact Broderick would argue you’ll will never understand a complex disease like ME/CFS unless you look at it in it’s entirety – and that means modeling it.
That approach leaves some traditional researchers agog. They don’t the background to understand it and they don’t trust it. There’s simply too much data, too many places for something to go wrong (and too much math) for them to sign on. The NIH, on the other hand, has signed on. Broderick’s one the few ME/CFS researchers able to regularly obtain grants.
Others are starting to take notice of the NSU team’s work. The team has presented several talks to the Nationstal Cancer Institute. The breast cancer community is interested in the hormone/immune model Broderick is developing, and no doubt others will follow.
“We’re an embedded systems biology group. We’re applied scientists.”
Broderick’s approach with his complex computational algorithms seems ivory-towerish, but it’s all in service of a very pragmatic vision. He noted that he comes from a corporate background where investors have limited patience; they demand results, and he’s big believer in incremental results. He’s looking at both the big and little picture: the NSU team he’s a part of is focused partial relief today – or at least soon – for people with Chronic Fatigue Syndrome while they continue to peel back the layers of the onion and get at the source.
Finding FDA-approved drugs that can treat symptoms now is a major concern. If some people with ME/CFS, for instance, share similar inflammatory pathways with rheumatoid arthritis, then it makes sense that they should be given a chance to be treated with those same RA drugs. That means working on validating treatments for repurposed drugs, such as TNF-a blockers or drugs that are under development. Dr. Fletcher has repeatedly called for FDA trials NOW.
The Physicists Come to the Fore
Broderick is what used to be called a “Renaissance man,” and today is called a “polymath.” He followed up his PhD in chemical engineering with post-doctoral work in computer science and biochemistry. This unusual combination makes him uniquely qualified for development of sophisticated mathematical models of biochemical systems. (His eclectic background brings to mind another ME/CFS researcher breaking boundaries – Dr. Kogelnik of the Open Medicine Institute – and his fusion of biology, bioinformatics and computer programming).
Travis Crawford, his associate at NSU, has a Ph.D in biophysics and did post-doc work in systems biology. Broderick said physicists are all over medicine now. It’s not that biology is gone – this is like biology on speed; it’s biology that takes the dynamic interactions of the body into account. This is where biology uses physics, mathematics, and engineering in an attempt to reproduce what’s going on inside living systems.
Crawford said, “There’s nothing more fascinating or a bigger challenge for a physicist than an ‘open self-regulating system’ like the body.” Living organisms are more complex than anything they’ve taken on before, but now they believe they have computational methods to tackle them.
They believe that you can attempt to compensate for the new homeostatic state with treatments, but until you can determine what’s keeping that system in place, it’s going to remain in place. Once you do determine the factors holding the system in place, though, and treat them, the system should be able to return to its normal homeostatic state; i.e. health.
It’s a very different approach to illness. Calling Chronic Fatigue Syndrome the “New York City’ of chronic illness (if you can make it here, you can make it anywhere) Broderick believes demonstrating his approach works here will lead to its being adopted in other disorders. ME/CFS is a hard nut to crack, he said, and if you can crack it in a relatively short period of time with a relatively small budget – as he believes he’s on the way to doing (he really does) – that will lead to opportunities for treatment of other disorders, particularly neuroinflammatory and neurodegenerative ones.
“Our eventual goal is not only to tap into pathogenic immune conversations but also more importantly to re-direct these conversations with a limited number of well-chosen and well-timed pharmaceutical messages”
The Institute team is building three models of neuroinflammatory disease: toxin exposure (GWI), infectious event (ME/CFS), and traumatic brain injury. Taking the system dynamics into effect has at times led to some counter-intuitive options.
The first model, a simple one produced at the CDC some time ago, suggested that the way to get out of the low cortisol problem was to reduce cortisol even more. Their model indicated that briefly sopping up all the cortisol in the system with a binding element would result in what Broderick called a slingshot effect, causing cortisol’s trigger, ACTH, to build up and catapult the system into a new dynamic. Nobody to my knowledge has ever tried this in a human being.
The Institute team’s approach is to use these models in association with the exercise studies to design interventions that occur in time. First, you give an ME/CFS patient X intervention to nudge the system in right direction. Then, as parts of the system reset themselves, another intervention is added to nudge it further, until the patient out of – or at least partially out of – the homeostatic state of illness they’re stuck in. The models will help them figure out which interventions to use, in what order, and at what time points to give them.
Low testosterone levels could be one example: you can flood the body with testosterone, but once you stop doing that the levels plummet again. Something is sapping the system of testosterone. Viruses and immune factors are clearly part of another homeostatic issue for some people with ME/CFS. Some people with ME/CFS can return to health with antivirals or immunomodulators like Ampligen, but most relapse after they stop taking the drug. Broderick isn’t just interested in getting rid of the pathogen; he want to know why the pathogen is there in the first place.
The modeling has been an evolving process. First they modeled the peripheral immune system. Adding the endocrine system demonstrated how different men and women are, and added another field of inquiry. They’ve found that women’s sex hormones (and men’s) strongly affect inflammation, fatigue, cognitive issues, and mood. High estrogen levels appear to push the HPA axis of susceptible women out of whack and into a alternative homeostatic state. Unless it’s low – which often happens in ME/CFS – men’s testosterone protects against HPA axis problems.
- “A Regulatory Barrier to Change” : Why Women Get More Stuck with Chronic Fatigue Syndrome Than Men – A Model of ME/CFS Emerges
“A Fire in the Head’ – Neuroinflammation – A New Direction
Next up is the brain. Taking advantage of a new neuroimaging center opening up at the Univ. of Miami, the NSU team is moving into neuroimaging and neuroinflammation. They’ll build on their previous models of peripheral inflammation and tie them to neuroinflammation in the brain.
Ultimately they should be able to determine what happens in the brain after you introduce a factor – a pathogen, toxin or drug – into the peripheral immune system. That ‘factor’, of course, is the environmental trigger that sparked ME/CFS.
Broderick is particularly fascinated by what role the vagus nerve, the object of much interest in ME/CFS, will play in the model. Broderick called the vagus nerve’s role ‘fascinating’. He likened the vagus nerve to the immune system picking up the phone, calling the brain, and saying, “Boss, we’ve got somebody on board – start the emergency protocol”
It’s not just the body talking to the brain, though; the brain talks back and regulates the immune system as well. The lymphoid organs send information to the brain, and the brain regulates their functioning as well. Broderick likened the immune system in the body to the ‘commander on the ground’ communicating to the rear command (the brain).
Broderick is quite confident in his models. The peripheral immune model has been run so many times and in so many circumstances that he believes it’s solid; the core is complete. The sex hormone and immune model he called a ‘pilot analysis’ but stated it provides a strong basis for understanding.
“Interface Points” for Change Pop Out (Thankfully)
‘(This) structure is very amenable to intervention.’
When first seen, the visual representations of Broderick’s networks – a mass of different colored lines seemingly darting through each other randomly – seem unintelligible until he points out what they mean. The internal parts of the maze are neuroimmune factors; surrounding them are single points – the key symptoms – general fatigue, reduced activity, depression-caused fatigue. The lines connecting the symptoms to the neuroendocrine factors indicate which factors are producing the symptoms.
In every case, a key factor has popped out of the maze to provide a target; i.e., the factor which, if properly targeted, should be able to erase or reduce the symptom. If the model’s prediction is correct, this is a key and very promising finding.
Broderick has dozens of factors in his model. Pain, for instance, could have been mediated by 10 factors; fatigue perhaps by 7 or 8. If that was the case, finding treatment options would have been more difficult. Instead, just a factor or two emerged for many of the major symptoms of the illness.
Broderick calls these key factors ‘interface points’. A lot of interactions occur to produce them, but they are key producers of symptoms.
It’s these interface points that appear to give Broderick assurance that the ‘structure’ of ME/CFS appears to be amenable to intervention. Broderick didn’t say that the treatments to do that were present right now (or that they weren’t present). The thing I took away from our talk is his models do not suggest ME/CFS is a horrid mess. They suggest ME/CFS is understandable and ultimately treatable.
For instance, fatigue and depression appear to be largely mediated by IL-17. Il-4 is another key factor. IL-2 appears to be highly involved in producing mental fatigue. If you affect IL-2 you should be able to increase mental endurance.
Dr. Jarred Younger at Stanford found a similar pattern in his “good day /bad day” study. His network charts looked very similar to Broderick’s: a mass – really more a mess – of complex interactions that made their way back to one factor (leptin) which correlated with fatigue in ME/CFS. Younger’s approach was different; he focused on one symptom – fatigue – and examined more immune factors and watched them over time. The NSU team focused on many symptoms, examined fewer immune factors, and did not watch them over time.
Nobody, in fact, in the ME/CFS field appears to have looked at leptin until Younger did. Younger, by the way, just got a major five-year NIH grant to dig deeper into his leptin and ME/CFS findings. He’ll reprise his “good day/bad day” trial with a much larger group and more factors.
The NSU and Stanford groups are demonstrating that ‘big data’ projects can identify targets that may be relatively easy to manipulate for better health. Broderick noted that the ‘structures’ his work has identified appear to be ‘very amenable’ to intervention. That’s potentially very good news for a disorder that doesn’t seem to be very amenable to much.
NK Cell Mystery Solved
Decreased natural killer (NK) cell functioning has been a key immune finding for ME/CFS – a consistently reproduced finding – until the NIH-funded Katz study found no problems at all with NK cell functioning. Broderick couldn’t figure this out until he got Katz on the phone and dug into the details of the study.
It turned out that Katz had isolated NK cells and then tested them, while the Klimas team always tests them in whole blood. The light bulb went on. Something in the blood was axing the NK cells. Put the NK cells off by themselves and ask them to kill pathogens and they do just fine – but put them in the blood mixed with all the immune factors found there and they poop out.
This fits Broderick’s network approach to the immune system to a T, and possibly makes the problem more amenable to a solution. Instead of fixing the natural killer cells, you may simply have to find out what factor, what cytokine, what immune mediator is turning them off, and block that.
The Klimas team at the NSU Institute for Neuro Immune Medicine easily had more posters at the IACFS/ME conference than any other research group. With modeling efforts underway and with their eyes on repurposed drugs and on identifying new drug targets hopefully we’ll be seeing papers with clinically-applicable results stream out of her group over the next couple of years.