It seemed like a dicey thing – a talk on chronic fatigue syndrome (ME/CFS) that seemingly had little to do with the conference. The Brain Science Conference is a small conference series which began in 1990 and has been going ever since. Its goal is basically to provide brain researchers with a diverse set of talks on their field.
Mixed in amongst the talks on Parkinson’s, Epilepsy, neurotoxins, pain circuits and neurodevelopment was a session simply titled “Chronic Fatigue Syndrome”. The two talks: “Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a multisystem illness invisible in plain sight”, by Lucinda Bateman, MD; and, “Developing new technologies to unravel chronic fatigue syndrome“, by Ron Davis PhD, didn’t even pretend to make an explicit connection with brain science. I wondered how many people would show up and how the talks would be received. I readied myself for a paltry turnout but the small conference room was full.
How the Brain Science Conference had managed to insert a session on the basics of chronic fatigue syndrome (Dr. Bateman) and innovative tools for understanding it (Ron Davis) was a mystery to me, until, that is, I talked to the person sitting next to me. I’d snuck into the conference. I was camping out in Flagstaff when Janet Dafoe, Ron’s wife, informed me that Ron was going to speaking on ME/CFS that weekend in Sedona – just an hour away.
After asking if I could attend the session, Ron said he thought I could probably sneak in – so I did. Furtively sitting at a table in the corner, I looked to the right to find a woman staring at me. Who are you, she said? It turned out she was the conference organizer and she was happy to have me there. 🙂
I was certainly happy to be there. It was a treat listening to these pros.
Dr. Bateman: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a multisystem illness invisible in plain sight
“These patients are trapped inside of a body that isn’t working”.
Dr. Bateman started by blunting stating, “I’m here to get all of you to start thinking of this illness”. She aimed to give them a talk they would remember — and she did. First, she hit them between the eyes with one of those chronic fatigue syndrome stories that could keep one up at night.
She took them back to 1979 to a young woman on a high school cross country team who had taken time off to heal from a stress fracture. Her stress fracture healed, but her body mysteriously fell apart. Instead of leaving her stronger, running left her fatigued, nauseous and prone to vomiting. By her senior year in the early 1980’s – well before chronic fatigue syndrome even had a name in the U.S. – she’d had to abandon all physical exercise.
She struggled on and was able to complete her college degree and become a preschool teacher, but had trouble maintaining a regular work schedule. A severe respiratory illness triggered problems with insomnia that continue to this day. On one of her many attempts to figure out what the heck was happening to her, she was misdiagnosed with schizo-affective disorder.
As time went on, she got worse and worse. By the time she saw Dr. Bateman, our former runner and teacher had trouble reading and comprehending the printed word on her worst days. It took only a few simple tests to indicate that her autonomic nervous system had gone haywire. Upon standing, her heart rate zoomed from 67 to 130, while her pulse pressure (the difference between systolic and diastolic pressure) dropped from a normal 61 to a decidedly low 29.
According to Wikipedia, a pulse pressure of 25 mmHg or less signifies either congestive heart failure or cardiogenic shock. It’s usually associated with significant blood loss due to trauma (aka a significant injury). In ME/CFS, it probably just reflects extremely low blood volume. Remarkably, this woman – who could hardly stand without her system collapsing – had had a tilt table test before seeing Dr. Bateman but was told it was negative because she hadn’t passed out. A cardiopulmonary exercise test of this former runner indicated that her VO2 max was now 16 – 25% of normal.
Compression socks, midrodrine and propanolol helped, but even with these therapies she still meets the criteria for postural orthostatic tachycardia syndrome (POTS). At 37, she can manage about 4-6 hours upright – not standing upright but sitting upright. Over half her life has now been spent ill.
Dr. Bateman moved onto some key characteristics of the disease. There’s the inability to reproduce energy production after an exercise challenge – still probably the most startling study result ever found in ME/CFS. It’s a result that goes to the core of this disease. After showing that result to a guru of exercise physiology, Dr. Bateman reported he said, “If that’s true then it’s unique”. Yet, that finding has actually been demonstrated in studies containing 51 patients, 22 patients, 15 patients and six patients – but apparently not yet to the guru’s satisfaction.
Over ten years since this finding appeared, we still lack the definitive study that would prove to him and others that something has gone badly awry with energy production and exercise in ME/CFS. Why that study hasn’t been done is a mystery to me. It would also explain ME/CFS in simple, basic terms that everyone could understand.
My view is that the best way to wake up the research community to the seriousness and uniqueness of this disease would be with a large, rigorously controlled, two-day exercise study that irrevocably demonstrated the presence of a unique energy deficit in chronic fatigue syndrome (ME/CFS).
Dr. Bateman highlighted the weird sleep problems in ME/CFS – the high alpha waves at a time they should be low, and the low delta waves at a time they should be high). (ME/CFS patients brains are in sleep mode when they are awake, and in awake mode when they’re asleep.) She suggested that central sensitivity may be responsible for a lot of the sleep problems in ME/CFS.
Continuing with this theme, Dr. Bateman talked about the “wired and tired” issues, the too-exhausted-to-sleep problems and the over-signaling; i.e. the unrelenting brain activation that leaves the brain highly sensitive to any kind of stimuli and keeps it from settling down, resting and rejuvenating.
That shows in the sympathetic overdrive and the increased heart rates during sleep and the reduced heart rate variability. With the loss of HPA axis stability comes problems with circadian rhythms.
Spitting out some eye-opening statistics – the disease affects from 800,000 to 2 million Americans, is responsible for $17-24 billion in economic losses yearly but is undiagnosed in 80% of patients, is not taught in medical school, and gets about $13 million in funding from the NIH — Dr. Bateman asked: how one earth does a disease this common and this serious get overlooked?
She asserted that part of the problem is just the way our medical system works. By and large, the U.S. medical system is not concerned about viruses – which triggers many people’s illnesses – and has a rudimentary understanding of the immune and endocrine system. Cellular metabolism – possibly a very big deal in ME/CFS – is hardly on its radar at all.
That said, Dr. Bateman said that she firmly believed that early diagnosis and proper early treatment could change the prognosis for many. She also believes that we know 90% of what we need to know about ME/CFS and if we could get more cross-talk across specialties going, we could figure this thing out. On that positive note, Ron Davis came in.
Ron Davis: Developing new technologies to unravel chronic fatigue syndrome
Davis provided a different tack. Describing the technologies his lab is developing that may be helpful in many diseases, he again and again used ME/CFS to demonstrate its worth.
He started out by noting that chronic fatigue syndrome (ME/CFS) is more common than HIV, Parkinson’s and multiple sclerosis, and too wondered how such a common disease could be so unknown. It’s the lowest funded of any major disease. ME/CFS receives just 0.1% of the money that goes to HIV research.
Davis was on a roll, joking and delivering pointed comments to the audience. He said his job description was “reducing noise”; i.e. finding ways to deliver vast amounts of meaningful clean data, cheaply and efficiently. Davis presented a cornucopia of new technologies his lab was working.
First up was the nanoneedle. With its 2,500 electrodes per cm measuring whatever they are measuring 200 times a second, the nanoneedle is capable of providing a billion data points in one sample. There was the test able to detect antibodies with 10,000 times more sensitivity than standard Elisa tests and the the wearable biosensors that electrically analyze very small amounts of sweat, and eventually cytokines and other immune factors. (They could determine what’s happening to people with ME/CFS as they descend into PEM). There was the miniaturized energy harvesting device which uses movement in the blood to generate energy and monitor what’s going on there. (It’s so small you can’t see it.) The way to levitate cells and so on.
It was mind-boggling stuff and then it was onto ME/CFS and Davis’s grand fishing expedition.
The Grand Fishing Expedition
Davis said that when you don’t have a clear pathophysiological pathway, you look everywhere. We have two grand fishing expeditions underway in ME/CFS; Davis’s Open Medicine Foundation study and Avindra Nath’s intramural study at the NIH. Medicine research is now so complex that the two hardly overlap. Davis is focusing on getting molecular observations and Nath is including things like metabolic chambers, growing neurons in a dish, autonomic nervous system testing and exercise.
Davis noted that most of the “fishing holes” will not pan out, but in a process of addition by subtraction, the negative results allow you to move past dead ends and onto new possibilities. The key is that you don’t step over something by pretending to know more than you know.
The Severe Patient Big Data Study contains 20 ME/CFS patients – so sick they never leave their house – and their families. Because the disease is so prominent in them, Davis believes they may provide a clearer signal. Davis listed 30 tests and gave some early results.
Viruses – In a major surprise, Davis has thus far found no evidence of viral activity in the severely ill. In fact, Davis is finding less viral activity in the severely ill patients than in the healthy controls. The severely ill patients are so clean that Davis is searching for a reason why. He believes their immune systems may be so activated that they’re able to immediately repel pathogens. His search for viruses is not done yet but – he’ll go after RNA viruses next – but thus far, there’s been no cheese down the viral tunne!
Toxins – Heavy metal contamination can wreak havoc with many body systems, but no evidence of heavy metal contamination has emerged.
High Omega-3 Levels – Omega 3 is the good omega oil but omega-6 (at the right level) provides important functions as well. In general, the ratio of the severely ill patients’ omega-3 to omega-6 levels is out of balance. Davis chalked up the too high omega-3 levels to supplementation and an excellent diet :).
Cell Lysis – too many cells dying and dumping their DNA into the blood can cause problems – but not in ME/CFS.
Mitochondria Levels – energy production in ME/CFS patients could be impaired by low levels of mitochondria but the numbers of mitochondria are fine.
Inflammation – evidence of inflammation is present, but Davis warned that we don’t know what is triggering that inflammation and what positive effects it might be having. He noted that the immune activation could be present without a trigger.
Energy Production – Dramatic differences are continuing to show up in metabolic testing (metabolomics). With one third of metabolites greater than two standard deviations below normal, metabolomics is providing the best window into ME/CFS yet. The severely ill patients are showing significantly more metabolomic abnormalities than the moderately ill ME/CFS patients. That suggests that Davis’s idea that the severely ill provide a clearer picture of this disease could be true.
Genes – The genomic studies have identified a gene new to ME/CFS research which has been found, if I remember correctly, in every severely ill patient. Expressed mainly in the brain, the gene has been connected to autism – an interesting connection given Bob Naviaux’s findings of similar metabolomic results in the two diseases. Davis suspects that ME/CFS is primarily a metabolic disease and is not centered in the brain. That would be good news given the difficulty of studying the brain and accessing it via treatments.
In general, Davis believes the genetic predisposition to ME/CFS is different; instead of featuring a couple of rare polymorphisms, it appears to be manifesting as increased levels of a series of common polymorphisms. Showing that, he said, requires a different kind of approach from what most geneticists do.
Finding a biomarker, Davis said, is essential for proving to the world that ME/CFS is not all in one’s head. He holds out the most promise for the nanoneedle and its billion data points. Thus far, the stats are impressive. The nanoneedle has found dramatic declines in the energy production of all 17 ME/CFS patients but none of the healthy controls when faced with a stressor. The relatively small sample size becomes less significant in the face of a statistical finding like that. (The possibility that that result could be caused by chance is 5×10(-7) (or, if I can get my zero’s correct p<.0000007).) You hardly ever see probability factors that strong in biology.
The nanoneedle has clearly uncovered something dramatically different happening in ME/CFS patients. It’ll be exciting to see how the nanoneedle tests out in other diseases and to learn more about exactly what it is uncovering. As it is now, its potential seems immense. After all the bad luck with ME/,CFS the nano-needle is a case of serendipity striking. It basically fell into our laps – Davis’s lab began working on it before he got heavily involved in ME/CFS, and here it is playing a major role in Davis’s search for the cause of ME/CFS.
The OMF’s blood flow study is another case of serendipity striking. it came about when SJSU researchers heard about Davis’s work and approached him. Davis said the results were too preliminary to talk about that, but thus far, ME/CFS patients’ red blood cells were showing reduced deformability and slowed movement. Davis wants a smaller capillary tube to mimic the blood flow through the smaller capillaries, so his lab is doing what it does and creating one.
During the question period, Davis acknowledged that the sedentariness the severely ill ME/CFS experience is likely having massive physiological effects. In truth there’s no way to tell how much effect it’s having. You can find sedentary healthy controls to match up with sedentary but still somewhat active ME/CFS patients, but it’s impossible to find healthy controls who’ve laid in bed for a year. The closest match are astronauts who laid in bed for a month to mimic the effects of space flight, but Davis’s attempt to access NASA’s blood samples failed. (The samples had been lost).
Since the conference, the Open Medicine Foundation has opened a new ME/CFS Center at Harvard, led by long time Davis collaborator, Ron Tompkins. Tompkins, who has participated in numerous studies on sepsis and burns, will be extensively analyzing muscle biopsies of ME/CFS patients. Almost all the studies of ME/CFS have analyzed the blood, but Davis felt that direct analysis of muscle cells could be critically important. A blog on that is upcoming.
The talks were received with real interest. In fact, I had got the feeling that they were amongst the two most interesting talks in the conference. Both speakers were treated to a bunch of questions. Dr. Bateman waved off my surprise at the reception they got stating the researchers are always interested when they hear about ME/CFS, it’s the doctors she had trouble with. The conference organizer stopped by to remark about how fascinating the talks were. She seemed genuine.
Thinking about it I could see why. It’s probably not often that researchers are treated to a fascinating field they probably know nothing about – one goal of the conference – and in such an enticing way. Nobody is better than Dr. Bateman at explicating the clinical side of this illness in a clear and vivid way and Ron Davis was at his best – cajoling, joking with, and even gently taunting his audience. These guys are pros. My one thought as I left the talk was how we could get this duo to take their talk on the road…