Introducing Victor Darley-Usmar, PhD, an Alabama Researcher Now Helping in a SEID Study

Day after day, from my bed, I watch my social media newsfeeds for some news on my disease, especially for anything happening locally in Alabama. But news, by nature, often comes when not expected. And this happened in October, while I was watching a video from Open Medicine Foundation of a presentation at the International Association of CFS/ME conference.

Dr. Jon Kaiser was speaking, and he said:
“There’s a researcher named Victor Darley-Usmar at the University of Alabama, who works with the Seahorse company—and I think he’s a genius. He is developing an equation to take all the data that the Seahorse test provides and distill it down into a single number called the—he calls it the ‘BHI,’ the bioenergetic health index. So, you know, it would be like getting a PSA or [inaudible]. You get a bioenergetic health index from a blood sample, looking at white blood cell mitochondrial energy production. So I think that’s the cutting edge of this field, and once we start sending our patients who present with ME/CFS, just as an example, we can start [inaudible] whether their disease severity winds up with the severity in their mitochondrial [inaudible].”

Who is Victor Darley-Usmar, PhD?

Living in a major metropolitan city that has always been absent expert clinical care for my disease and, from 2003 to 2014, no research in the disease, I get excited when the name of a researcher or doctor in my part of Alabama is connected to systemic exertion intolerance disease (aka “SEID” or “ME/CFS”). I wondered just who this “genius” is right here in Birmingham and what has he done that may help people with my disease.

My Google search took me to Wikipedia, which tells me Victor Darley-Usmar, PhD, was born in England and that he is a “free radical biologist and biochemist” and the UAB endowed professor in Mitochondrial Medicine and Pathology. (Note: “UAB” stands for the University of Alabama at Birmingham, which is different from the University of Alabama. UAB is well-known, even internationally, for medical care—especially cardiac and AIDS—and medical research.)

Darley-Usmar’s career journey included stops at the University of Oregon for a postdoctoral fellowship from 1980-1983, appointment as assistant professor at Japan’s Tsukuba Medical School for 2 years, then to Kent, England, to work as a senior biochemist at Wellcome Research Laboratories for 10 years. Then UAB recruited him to the Heart of Dixie, the land of fried chicken and sweet tea, right here in sweet home Alabama. He’s been here for over 20 years.

He has a profile on UAB's website, but he said it needs updating, so he prefers the information in a bio he sent me. It says he’s in the Department of Pathology. “He has received multiple awards for training and mentoring and served as the Associate Dean for Post-Doctoral Education and the Pathology Graduate Program Director,” it says. “He established the UAB Center for Free Radical Biology from 2006-2015 as an international center for research in redox biology.” And, it further says: “In his own research program he has been instrumental in defining how redox biology modifies mitochondrial function in pathology and in recognition of these achievements was awarded a Lifetime Achievement Award by the Society for Free Radical Biology and Medicine in 2012. . . He was a recent recipient of the prestigious 'Creativity is a Decision' and 'Blue Sky' awards from UAB for the Bioenergetic Health Index concept. He has been continuously funded by NIH for 20 years and has published over 300 articles with an H factor of 92.” 

For a recent interview, I found Darley-Usmar in the 5th floor of a Birmingham brick building, part of the UAB campus, which takes up about a third to half of the downtown grid. His office has the standard elements of desk, computer, and chair, but it is rectangular to include a small conference table and a white board attached to the wall opposite his desk. Sitting on the table are a projector and the connected laptop to show charts for explaining the science, which he was glad to have the opportunity to do for this unlearned interviewer.

When he spoke, he sounded very scientific to me, simply because I am accustomed to hearing scientists talk with an accent in news media interviews. And Darley-Usmar still has his, along with the occasional “isn’t it?” that the British add to the end of sentences for emphasis. He’s of short to average height and has a serious but friendly appearance, complete with a beard. He speaks in an even and measured tone that we are used to hearing from scientists: not excitable, but occasionally he gives a joking/witty answer. And he’s patient, as I tried again and again to connect with him to do this interview since I saw him listed as one of the scientists of a recently funded Nevada University study. Finally, with his cooperation, we made it happen.

His First Experience with a “Fatigue Syndrome” Patient

His first connection to what he calls “fatigue syndromes” was as a post-doc in Oregon in 1980, when his boss was asked to help figure out the cause of a patient’s fatigue, suspected to be a mitochondrial dysfunction. They found a deficiency in one of the mitochondrial proteins in that patient. “So I always had the point of view that these were real things because I had one straight off that was real,” he said.

And he said there are documented genetic mitochondrial dysfunctions that cause “fatigue syndromes,” and drugs that alter the mitochondria behavior that cause “fatigue syndromes,” so he figured there could be other mitochondrial-based malfunctions leading to fatigue-causing diseases. “Fatigue, in the end, is a disease of metabolism, isn’t it?” said Darley-Usmar. “And there’s a limit to how many things can go wrong; it’s not infinite.” In some cases, it could be metabolism dysfunction is not the driver of a person’s symptoms but is a result of something else, he said.

(Personal comment: Just imagine what could have happened if he went into studying our disease back then!)

After that experience in Oregon, for about 3 decades, his research was mostly in cells and mice. Then, “About 5 or 6 years ago, I said I want to do research in patients,” he said. He felt the testing was good enough to be “translated” into human experiments. This led him to studying bioenergy health in HIV patients at UAB’s well-known HIV clinic. Those patients, who have seen much progress in treatments preventing death, are still experiencing fatigue and premature aging, he was told. And since he is at UAB, his research has been in patients who are already being cared for through UAB’s clinical care services. He’s also studied bioenergetics in alcoholic liver disease, diabetes, and kidney disease.

(Note from me: This shows how clinical care can help spur more SEID research.)

And he was also told of other “fatigue syndromes” using the test created at Seahorse, such as a post-cancer-treatment fatigue syndrome. “It told me there is an unmet need for a clinical test” of bioenergetic health, he said, in addition to its research usefulness. And that led to his working with Seahorse to create a test to measure it.

About the Test

The Seahorse XFE24 Analyzer

Seahorse Bioenergetics, now Agilent, has created three machines. The company’s website says: “Seahorse XF Analyzers measure the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of live cells in a multi-well plate to interrogate key cellular functions such as mitochondrial respiration and glycolysis. The instruments perform compound addition and mixing, label-free detection, and automatic calculation of OCR and ECAR in real time.” Darley-Usmar said it more plainly: “It measures oxygen and protons.” He said it is a “break-through technology.”

According to Darley-Usmar, this bioenergetic health reading shows the cell’s ability to respond to an ATP (adenosine triphosphate, an energy molecule) demand. So it is measuring the cellular energy production capacity, the cell’s ability to produce energy molecules as needed. And there are so many things that can diminish this capacity, which is why he believes the “fatigue syndromes” likely have many different causes.

The test is not clinically useful, yet, but he and Agilent and UAB and the Foundation for Mitochondrial Medicine, a charity, are working toward that. As Kaiser said, the goal is to take the Seahorse machine readings of multiple factors and have it translated into a one-figure score that says what the cell’s energy production capacity is.

This reminded me of the cardiopulmonary exercise test (CPET), which has been used to show SEID patients are unable to normally use the aerobic system (using oxygen to create energy) a day (or two or three) after they were put under a high-energy demand. In other words, their oxygen-based energy-producing capacity is reduced because of exercising the day before, so they go into a predominant anaerobic (not using oxygen) energy-production system quicker. Anaerobic energy production produces damaging lactic acid and other damaging effects, which is why you can’t last long in an activity if the energy you’re using is mostly from the anaerobic system.

It sounded to me like this bioenergy health index may measure the same thing on a cellular and chemical level in the blood rather than from the gases in the breath and the heart rate, as the CPET does.

Darley-Usmar showed me a chart with a sliding scale of cellular energy-producing capacity (aka bioenergetic health). The top level, he said, may correlate to aerobic energy mode whereas a person with low bioenergetic health, according to the blood test, is more in the anaerobic mode, cellularly speaking. The CPET shows a person has an energy-production problem, but testing the capacity of the cells may give clues as to the reason why, he said.

BHI as a dynamic measure of the response of the body to stress. In this scheme, healthy subjects have a high BHI with a high bioenergetic reserve capacity, high ATP-linked respiration and low proton leak. The population of mitochondria is maintained by regenerative biogenesis. During normal metabolism, a sub-healthy mitochondrial population, still capable of meeting the energetic demand of the cell, accumulates functional defects, which can be repaired or turned over by mitophagy. Chronic metabolic stress induces damage in the mitochondrial respiratory machinery by progressively decreasing mitochondrial function. This manifests as low ATP linked respiration, low reserve capacity and high non-mitochondrial (e.g. ROS generation) respiration. These bioenergetically inefficient, damaged mitochondria exhibit increased proton leak and require higher levels of ATP for maintaining organelle integrity, which increases the basal oxygen consumption. In addition, chronic metabolic stress also promotes mitochondrial superoxide generation leading to increased oxidative stress, which can amplify mitochondrial damage, the population of unhealthy mitochondria and basal cellular energy requirements. The persistence of unhealthy mitochondria damages the mitochondrial DNA (mtDNA), which impairs the integrity of the biogenesis program, leading to a progressive deterioration in bioenergetic function, which we propose can be identified by changes in different parameters of the bioenergetics profile and decreasing BHI.

How He Got Involved in SEID Research

Recent discoveries in our disease have brought our scientists to Darley-Usmar and to mitochondrial function testing, more so than his coming to our field.

I have heard of some theories over the decades in relation to SEID and mitochondria function and the NO/ONOO cycle (increase in nitric oxide and peroxynitrite, causing oxidative stress). But mitochondria-related studies have taken over much of the research interest of our disease in the last two years. This matches the interest of mitochondrial research in general, in other diseases.

His first contact from someone from the SEID field was Dr. Jon Kaiser, with K Pax, who just called him up one day. But then, researchers from Nevada, Ruben Dagda, Phd, and Isabel Silvestre, Phd, asked him to help set up a study they want to do on bioenergetic health in natural killer cells in SEID patients. He plans to visit the research team there this summer.

This networking and camaraderie is often how joint projects come about; it’s word of mouth. “They took the time and effort to try to understand what I was saying about the bionergetic health index,” he said. And they explained their theory to him.

The Nevada-based study, titled “The Bioenergetic Health Index of NK Cells as a Diagnostic Test for Chronic Fatigue Syndrome,” has been funded by the Solve ME/CFS Initiative Ramsey Awards. The abstract points out, “Mitochondrial dysfunction has been reported in CFS. However, the extent by which the metabolic profiles of lymphocytes [natural killer cells] is associated with immune dysfunction remains to be elucidated.”

Previous research, going back to the late 1980s, has revealed that NK cells don’t function well in this disease and seem to die before reaching maturity.

The potential impact of this study is that it may lead to a clinically useful test and may contribute to the knowledge of the disease that may point to a target for a treatment clinical trial.

How Useful Could a Blood Test for BHI Be?

• When you have an intervention to test, this bioenergetic health index can measure whether that intervention is causing a molecular change, thus reducing any fatigue treatment placebo effect corrupting study results. “Lots and lots of people take supplements [for energy], which may or may not have any effect on our biology,” said Darley-Usmar. So it can be measured molecularly whether any of these supplements actually enhance the cellular energy-production capacity.
• If you know the particular mechanism of the diminished cellular energy production in a certain condition, then you can possibly figure out what intervention might improve it. So the test may point to what treatments ought to be tried for different conditions.
• It may be used to predict the outcome of a treatment for some diseases. “If your metabolism is stronger before you have a clinical procedure or therapeutic or intervention, then the chance of your outcome being better goes up,” said Darley-Usmar. Bioenergetic health testing may reveal why some do better on treatments, while others don’t do as well.
• It can be used to see the differing bioenergy health of different cells within one body. For example, a person could have high muscle energy capacity and not feel fatigue, but the immune system energy capacity could be diminished, contributing to a disease. Darley-Usmar already did this with heart valve replacement patients. The cells around the heart were diminished in their bioenergetic health, but the cells in the blood taken from the arm were not.
• In a clinical setting, it can validate the patient complaint of fatigue as being real and objectively measurable and may replace the more painful test of muscle biopsies.
• It may identify those with “fatigue syndromes” that have mitochondrial dysfunction and separate them from those who may have another cause for their fatigue. To achieve this, mitochondrial studies with many SEID subjects are needed.

Recognition of Role of Mitochondrial Dysfunctions in Diseases

There are a few mitochondrial disease clinicians. But the problem is having clinical tests, Darley-Usmar said. But that is improving. “We now know the mitochondria can change the genes in the nucleus pretty dramatically,” he said. “The idea that mitochondria are part of the problem in cardiovascular disease, in diabetes, in neurodegenerative disease is completely accepted at the research level.” But all of this will only get into clinical care when there is a test and a treatment for these mitochondrial dysfunctions. He said there are some interesting drugs “coming into the mitochondrial space.”

Not Yet Connected to Other SEID Researchers at UAB

Darley-Usmar has not yet connected with the two other SEID researchers at UAB: Kevin Fontaine, PhD, who is working with Dr. Peter Rowe; and Jarred Younger, PhD, who is researching SEID and fibromyalgia from the neuroinflammation angle.

But, Darley-Usmar is collaborating with the UAB Undiagnosed Disease Program, and they have people that come in with “fatigue syndromes.” However, to do a study on SEID, he would need to have a clinical connection to patients with SEID.

He is open to helping other researchers of this disease. He described the post-exertional malaise (activity-induced symptom exacerbation) as “a powerful paradigm” for doing a study. He said the patient can be her own baseline for comparison of BHI on good days and bad days.

In closing of our interview, Darley-Usmar showed me flier for a symposium in Birmingham that patients can attend if they are interested in mitochondria and bioenergetics. I don't know if I'll make it. But I'll check into it.