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HIV, Heart Disease, Diabetes … and Chronic Fatigue Syndrome? The Unutmaz Project to Decode ME/CFS

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Note: You can listen to Dr. Unutmaz’ webinar HERE.

Reprinted with the kind permission of Cort Johnson and Health Rising.

By Cort Johnson

Dr. Derya Unutmaz is one of those researchers we want in the ME/CFS field; he’s well-published, he’s an ace in immune system functioning, he has his own laboratory, and he’s doing cutting edge work. Suzanne Vernon described meeting in San Francisco with Esther Dyson, a technology analyst and “angel investor” who is particularly interested in healthcare solutions.  [Esther Dyson is the daughter of eclectic physicist and visionary Freeman Dyson, who was the subject of the book “The Starship and the Canoe”.]

Dr. Unutmaz is studying HIV, heart disease, cancer, and now ME/CFS. Esther Dyson suggested getting in touch with Unutmaz. Upon doing so Dr. Unutmaz said heck yes, he’s interested in checking out Chronic  Fatigue Syndrome – and now, armed with 50 samples from the SolveME/CFS Biobank, we have a new investigator in the field looking at people with Chronic Fatigue Syndrome using some of the hottest technology going.

That’s good news….

The Good, the Bad and the Ugly of the Immune System

Unutmaz spent the first part of the Solve ME/CFS Initiative’s webinar going over the good, the bad, and the ugly of the immune system functioning.

The good side of the immune system protects us against bacteria, viruses, fungi, and pathogens and helps maintain the beneficial microflora (the microbiome) in our bodies.  The bad occurs when autoimmune processes attack the body, and the “ugly” occurs when inflammation runs amok in the immune system’s zeal to clear the invaders (the “destroy the village in order to save it” approach). The immune system run amok – the Spanish Flu killed more people than World War I.

Unumatz touched on the mighty Spanish Flu that wreaked havoc during World War I. Killing some 15 million people, the Spanish Flu is a good example of an immune response that did more harm than good.  Studies of the victims found that their lungs had essentially been fried – not by the flu bug, but by the ferocious immune response to the bug.  In an interesting twist, it was not the elderly or sickly who were hit hardest – it was the young people with their robust immune responses who died in the greatest numbers.  [Dr. Unutmaz didn’t mention it, but later research indicated they’d probably been exposed to a type of flu bug their systems had never seen before.  That sent their immune system bananas, but the immune systems of older people who had been exposed to a somewhat similar flu virus didn’t over-react – and they mostly survived.]

Inflammation

Every time you have an infection the body’s immune response leaps to clear the pathogen. [That response often includes using free radicals to kill the pathogens, and this can damage other cells as well.] As the invader is subdued, the immune response sends out a new signal that calls for immune cells to repair the damage caused. If that restorative immune response doesn’t occur because the immune system has become dysregulated or because an infection persists, you’re in a state of chronic inflammation.

While it’s clear that some people with ME/CFS have high levels of inflammation, studies suggest that most people have more mildly elevated inflammation.  Inflammation is inflammation, though, and even lower levels of inflammation can have quite negative effects over time. Inflammation didn’t used to be taken seriously, but in the past ten years it has been. Called the “silent killer”, low levels of inflammation are associated with almost all the major killers in the western world including heart disease, cancer, diabetes, and respiratory illnesses.

Unutmaz’s hypothesis puts Chronic Fatigue Syndrome in the same company as these major disorders; he proposes that chronic inflammation is responsible for most of the symptoms of ME/CFS.

The ME/CFS field abounds in hypotheses involving inflammation. There are the “localized pockets of inflammation” hypothesis (Van Elzakker and the vagus nerve), the central nervous system over-responding to low levels of  inflammation hypothesis (Miller’s basal ganglia and Younger’s leptin), and the central nervous system inflammation hypothesis (Watanabe’s neuroinflammation study).

Decoding the Immune Response

Unutmaz’s approach starts with “decoding” the immune response in ME/CFS with a focus on the T-cells that maintain the balance between inflammation and autoimmunity effector T-cells and normal immune functioning effector T-cells.  Unumatz is a T-cell expert.

When your T-cells, mulling about in their “naïve” unactivated states, encounter evidence that a pathogen is present (or has been taken care of) they become activated and differentiate into different types of T-cells depending on which pathogen they need to fight off, or they can turn into T-cells that turn the immune response in a certain direction. Unutmaz has authored dozens of studies on T-cells.

  • T-cell Types
  • T regulatory cells – suppress or calm down the immune response once a pathogen has been wiped out.
  • TfH cells – enhance B-cell activity and contribute to autoimmunity.
  • Th1 cells – fight off bacteria and viruses and contribute to autoimmunity.
  • Th2 cells – fight off parasites and contribute to allergies and asthma.
  • Th17 cells –fight off bacteria and fungi and contribute to autoimmunity and inflammation.

Once your immune system has fought off an infection, your cytotoxic (pathogen killing) T-cells die off leaving behind two types of T memory cells that will allow you to rapidly mount an immune response if the pathogen appears again.  One type moves into lymph nodes while the other heads out to the front lines – such as the skin or any mucous membranes (mouth, gut, etc.) – where invaders are most likely to strike.

The gut with its hundred trillion (yes, that’s trillion) or so bacteria is kind of an immune nightmare waiting to happen.  A couple million or so bacteria making their way out of the gut into the blood stream apparently can put a severe strain on the immune system in a couple of ways.

First the immune system has to get rid of them. They may be perfectly good bacteria in the gut, but location is everything and good gut bacteria become bad bacteria when they exit the gut.  Fighting off all these different kinds of bacteria–without developing an autoimmunity that attacks our own tissues as well–is apparently not an easy task.

Dr. Unutmaz on Decoding the Immune Response

Chronic gut bacteria leakage out of the gut also increases our chances of developing a state of chronic systemic inflammation that could, Unumatz warned, lead to something like a heart attack (!) [or in some cases, perhaps something like ME/CFS.  We’re awaiting the publication of a SolveME/CFS study that looked at the gut flora before and after exercise.]

The Big Gun

Unutmaz’s flow cytometer will not only allow him to precisely determine what kind of immune cell populations are present but what they’re doing. Inflammation could, then, be an important factor in the development and persistence of ME/CFS.  How does Unumatz propose to determine how important a factor it is?

He’s using a flow cytometer, a laser-guided machine that allows him to fluorescently label and then pick out individual cells like specific antibodies or types of B- or T-cells.  Unumatz can use his flow cytometer to determine about 200 different kinds of immune cell subpopulations. He can also isolate immune cells, trigger their activation, and see what kinds of cytokines they’re making.

Personalized Medicine

“It is more important to know what kind of a person has a disease than to know what kind of a disease a person has.” – Hippocrates

While people may have the same disease, their reasons–their pathways to getting the disease–may be different.  [This makes perfect sense when we look at the extraordinarily different responses to treatment some people with the same disorder have.  Look at neuropathic pain: doctors have at least ten options for treating neuropathic pain. Some work for some people and others don’t work at all and no one, at this point, knows what, if anything, is going to work for anyone.  That’s because there are a lot of pathways to producing neuropathic pain.  When you look at the many treatments that work in at least somebody with ME/CFS, you can probably magnify that heterogeneity tenfold for this disease.] To be  really effective, Unumatz  believes medical practitioners are going to have to treat individuals, not disorders, and that’s his ultimate focus. Unutmaz will attempt to discern unique immune pathways that distinguish ME/CFS from other disorders.

Look at any scatterplot of findings in a group of ME/CFS patients (or any other disorder) and you’ll typically see a huge range of results. Even if the ME/CFS group as a whole has higher readings than another group you’ll still typically find people with lower or low normal readings.  Something else is clearly going on in these people but medicine in its zeal to find treatments that fit the “average patient” mostly pretends like they are not there.

[Of course people with ME/CFS are renowned for their ability to not fit medical norms and therefore slip through the cracks. You can make the case this scenario fits ME/CFS as a disorder: because it doesn’t fit the medical system’s picture of a normal disorder, it’ been pushed to the side and ignored. The hope is that Unumatz, with his intense immune analyses, is going to find a fit for ME/CFS, or more likely a fit for subgroups of ME/CFS patients. ]

Uncovering the Immune Landscape’s Underlying Disease That’s going to take a lot of data, but that obtaining lots of immune data and finding the different signatures present in it what Unumatz is all about. Unumatz described creating algorithms and using them to do complex bioinformatics analyses on hundreds of different immune parameters to build “immunological landscapes”. Unutmaz is uncovering the different immune landscapes present in different disorders.

That data includes immune profiling, functional assays that will determine how the innate (early) and adaptive (late) immune systems are functioning, plus the different genomic factors (genes, genomics, epigenetics) that affect how our immune system responds in real time.

Unumatz collected immune information on over a thousand patients with all sorts of disorders (including the fifty ME/CFS patients). Then he’s using a “systems biology approach” to understand at a detailed level how chronic inflammation translates into different disorders.  He’s attempting to find an answer to a big question: what tips an underlying inflammatory state into chronic fatigue syndrome, or  a cardiovascular disease, or diabetes, or cancer?

“This research project is so incredibly important because it enables us to understand what ME/CFS is and compared to what.”– Suzanne Vernon, Research Director, Solve ME/CFS

[We saw a gene expression profiling study at the Stanford Symposium on ME/CFS which found that ME/CFS looked most like other inflammatory disorders].  Now we have Unumatz creating the ability to compare extensive immune data, created on a variety of levels in ME/CFS, with other extensive immune profiles associated with a wide range of different disorders.

We’ll see how the heterogeneity in ME/CFS will come into play, but if it’s successful, this work could define a unique or more likely a series of unique immune ME/CFS signatures that define the subgroups in this disorder.  This is about producing biomarkers on a very detailed immune level.

Unumatz is finishing up his work with the ME/CFS groups immune data. He hopes to generate good enough pilot data from the fifty ME/CFS patients to apply for a major NIH grant.

Unumatz’s approach appears to take care of the concerns, recently stated in the AHRQ report, that ME/CFS diagnostic biomarker studies are not testing their results against people with similar disorders and similar symptoms. Unumatz will probably be testing the ME/CFS results against every prominent inflammatory disorder known.

Unumatz’s goal is to eventually be able to produce diagnostics that can zero in on solutions on an individual basis. These solutions will, he believes, include ways to reprogram the immune system so that drugs are no longer needed. [This smacks of Broderick’s work to find tipping points in ME/CFS that he can use to push the system back into a state of healthy homeostasis.]

New Digs

“JAX Genomic Medicine will discover the precise genomic causes of disease [and] develop individualized diagnostics, treatments and cures.” Unumatz’s lab is moving to the Jackson Laboratory of Genomic Medicine in Connecticut. This fascinating 180,000 sq. ft. non-profit Institute being built on 17 acres in Connecticut is opening this fall.

Talk about “build it and they will come,” the laboratory boasts that “within 10 years, it will house 300 biomedical researchers, technicians, and support staff in state-of-the-art computing facilities and laboratories.” It’s all about developing genomic techniques that will lead to the development of personalized medicine.

Note that we’re way beyond just genetics at this point; this is genomics – a field that looks at the genes you were born with (genetics), the things that happened to you that affected those genetics (epigenomics), and your gene expression now.

The Solve ME/CFS BioBank

You can begin with this project to see just how really effective a BioBank like the Solve ME/CFS BioBank can be. Suzanne Vernon noted that the genomic data from Patrick McGowan’s epigenomics project stored in the Solve ME/CFS BioBank excited Dr. Unumatz and contributed to his taking on this project.

Protecting the Gut – The gut with its potentially huge impact on immune functioning, and, in particular, inflammation, is gathering more and more attention. Calling the gut a “very exciting area.”  Unumatz noted that everyone ends up having a different flora which has been impacted by that individual’s diet, by antibiotic use, by the pathogens we’ve come into contact with, etc.,  but he could not provide practical solutions.

[Researchers, really, are the last people we want to ask about treatment. They tend to be very cautious. They’re not going to say anything that isn’t backed up by a study and they’re not doctors and the good ones know they’re not doctors.]

Unumatz noted that researchers are still learning the impact the gut flora has on the body. The big problem for many people with HIV, for instance, is not the virus – it’s mostly gone – but the inflammation left over from when the virus was active. They believe that inflammation sparked by HIV caused gut damage that resulted in bacterial leakage outside of the gut. The damaged gut may be feeding the inflammation that’s now present in HIV-AIDS patients.

Unumatz couldn’t give prescriptions for repairing the gut, but he could provide some personal evidence of the effects diet can have on immune functioning. He’s obviously healthy enough, but even this healthy-enough guy has found, by looking at his own immune functioning regularly, that changing his diet has definitely affected his immune functioning.  One wonders what more effects it may have on the chronically ill.


About the Author: Cort Johnson has had ME/CFS for over 30 years. The founder of Phoenix Rising and Health Rising, Cort has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort’s and other bloggers’ work at Health Rising.

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