What Does It Mean?

Dr. Thom uses this small hyperbaric chamber in cell and animal model high-pressure research.

Stephen Thom studies the role of microparticles in DCS and other conditions.

A PROFESSOR OF EMERGENCY MEDICINE and researcher at the University of Maryland School of Medicine, Stephen Thom holds medical and doctorate degrees from the University of Rochester. He previously led various clinical programs, including hyperbaric and emergency medicine, and a research lab at the University of Pennsylvania.

What is your academic background?

My medical specialty is emergency medicine. My doctorate in microbiology was specifically in microbial physiology, where my focus was high-pressure gas physiology. I studied the effects of high hydrostatic pressure and various gases — oxygen and the entire array of noble gases — on various microorganisms. That was probably my start in studying things related to dive medicine.

Were you interested in diving before you got involved in this line of research? Are you a diver?

Yes, this goes back to my junior year in college. The only certification available in upstate New York at the time was through the YMCA, so that’s where I got certified. I really enjoy diving, but it’s been quite a few years since my last dive. These days I don’t get many chances to dive, but I still go when I have the opportunity for cushy diving with great visibility and something to see underwater.

Dr. Thom examines cell activation under a microscope.

How did you get started with dive research?

As an undergraduate, I was in a dual biology and geology major program for some time. I chose geology because it was the entry into taking oceanography courses, and I was really focused on that. I was determined to be a marine biologist, which was very popular at the time. A faculty member in the department of microbiology at the medical school was doing high-pressure research. I approached Robert Marquis, the head of that group, and he embraced my interest and accepted an unknown undergrad as a volunteer in his lab. One thing led to another, and Marquis later became my thesis advisor, and the research I did with him became my main interest.

When I was a senior in college, I was undecided if I should stick with my research interest or pursue medicine. Marquis looked at me and said, “Well, Steve, we have a combined M.D. and Ph.D. program here.” Naive undergrad that I was, I gave him a puzzled look and asked, “So I don’t even have to choose?”

I never looked back — I still do both kinds of work. I get to switch from basic science in the lab one day to being an attending physician in the emergency department the next, and I’m delighted with how things have worked out.

What was the main takeaway from your Ph.D. thesis?

Based on biochemical observations, my work demonstrated that so-called inert gases such as helium, argon, and others are not actually biologically inert. We sort of already knew that in terms of the theory on narcotic mechanism, meaning insertion of these gases into membranes and proteins. My work showed that these gases also generate oxidative stress, and we’re still using that principle in some of our research.

It is clearer now than back then, but we still have questions. The major question is simple: So what? What does that really mean — in terms of diving mammals, animals of all kinds, and humans? I do not have an answer yet; we’re still working on it.

Tell us more about your current work.

The University of Maryland recruited me as a professor for emergency medicine and to run a research laboratory. The university promised I would have very little administrative work and a modest clinical commitment, which sounded amazing after I had simultaneously worked multiple jobs in emergency medicine and research for years. I now have a lab with a staff of three: a research assistant who is a lab technician, a research associate who is also junior faculty, and a postdoctoral researcher.

We currently have a National Institutes of Health grant to study vasculogenic stem cells, which are the cells that make new blood vessels. That is a clinical focus mainly for diabetic wound research. On the diving side, we have several grants from the Office of Naval Research, one of which involves central nervous system responses to high pressure. We study the glymphatic system.

What is the glymphatic system?

Until a few years ago, it was dogma that the brain does not have a lymphatic system like the rest of the body. That idea didn’t exactly make sense, but it’s what the data said. It’s now clear and demonstrable that this notion was wrong. There is indeed a circulatory system for fluid other than blood in the brain that supplies brain tissue with nutrients and removes waste products. That system is now called the glymphatic system — a lymphatic system dependent on glial cells. We are looking at the glymphatic function in a model and how it responds to gases under high pressure, just as would occur while diving.

You have previously worked a lot with microparticles and helped revolutionize our understanding of the connection between inflammation and decompression sickness (DCS). Can you tell us more about that?

Microparticles are micrometer-sized vesicles shed from the surface of cells. They contain membrane and cytoplasmic constituents from their parent cells. Rather than just being cell or vessel wall debris, however, they also function as signaling and transport molecules. High pressures of inert gases such as helium, nitrogen, and argon can trigger inflammatory microparticle production.

We are investigating how this trigger effect works on a biochemical level in the model. We started to collect blood samples from humans to see if we could prove the same mechanisms. These humans have ideally experienced high pressure in hyperbaric chambers, but we also want to study open-water divers and those suffering from DCS. We hope to get more information about white cell activation and immune responses with samples from all over the world.

We have published several papers on microparticles and recently have been hopeful that we can advance our understanding with a new project. We’re moderately smarter now than we were a few years ago in terms of what I call the bad actors. Many microparticles are part of normal human health, and only a subset seems to cause injuries.

DCS is one pathological scenario. Our view is that high-pressure exposure is physiological stress, which is important to distinguish as profoundly different from damage. I’m not saying that you are hurting yourself simply by diving. Divers put their bodies in a stressful environment, and the microparticles are a response. For all we know, some of them may be good for you and will not normally hurt you, but as with most things in the extreme, they can injure you if they get to that point.

What was first: the bubble or the microparticle?

I accept that many people don’t like the notion that microparticles may be a central element of DCS and that we have not definitively proven that to be the case. All our work, though, supports that they play a role. We keep trying new angles, considering that maybe we’re wrong and it doesn’t play a part, but we always end up understanding that the theory still holds. This research, which my group has put together over a decade, has me thinking more and more that we have an answer.

Many in this field are married to gas bubbles’ role in decompression, which does not concern me. One element of the gas bubble hypothesis for DCS fundamentally comes down to the bubbles’ nucleation site. From mathematical models going back to the 1960s, the conclusion is that the nucleation site has a half-micron radius — that is, perhaps coincidentally, the size range of a microparticle.

Some years ago we also showed that a subset of microparticles formed in response to high pressure has a gas phase that could hypothetically be a bubble nucleation site. Therefore the question becomes whether gas bubbles are an epiphenomenon for microparticle formation.

Where do you see your research heading in the next 10 years?

I think the microparticle story is not restricted to dive physiology. In 2009 or 2010, when I wrote my first grant on microparticles, you could read the world’s literature on microparticles in an afternoon. Now it would take months to read the tens of thousands of papers about the many disorders that involve microparticles. Like with DCS, there are questions about whether microparticles represent the cart or the horse, and this seems to depend upon the particular disorder and many other variables.

We are doing some work looking at microparticles in diabetic studies, but the other big disorder — at least in my eyes — is carbon monoxide poisoning, which is very common. It is a major problem worldwide and is another area where a role for microparticles evolved very slowly. The more we look, the more we find that microparticles seem to be driving carbon monoxide injuries systemically and, most important, in the brain. And now we find that glymphatic dysfunction in our carbon monoxide model is alarmingly prevalent. That is what our next grant, should we receive it, will cover.

We are comparing our models with carbon monoxide poisoning and DCS. The exact same events occur, showing similar mechanisms with the same secondary messenger systems and inflammatory pathways. There   are brain-to-blood and blood-to-brain communications. These connections also seem to be a factor in another of my emergency medicine interests: traumatic brain injury.

The other project comes from the significant questions I posed earlier: What does all this mean, and how does it help the dive community? With all the new knowledge, can we do something besides treating somebody with DCS in a chamber? Hyperbaric treatment may not always be available. We are looking at pharmaceuticals that can reverse or at least suppress the insult related to microparticles and the inflammatory responses. Many agents — none of them available in your local pharmacy — work in the model. One of these agents, which we have already shown to work in the model, is now approved for investigation in humans with several kinds of infections but not yet for dive injuries.

Those who don’t agree with me when I say that DCS is an inflammatory disease will probably be upset about this line of research. If you can accept that statement, however, there are a lot of potentially useful pharmaceutical agents that are worth investigating as a prophylactic or even therapeutic measure. There’s still a lot to be done.

What do you do in your free time?

I like to kayak, and I create stained glass windows and lamps in my off time, but it really comes down to spending more time in the lab.

Is there anything else you want our readers to know?

It has always been incredibly helpful to connect and collaborate with other scientists and groups. If anyone has the means to safely draw blood from divers — any kind of diving: recreational, provocative technical, scientific, or anything else — before and after a dive, we are always looking for subjects to add to our studies. Safely collecting blood in this context means having an ethical protocol that an institutional review board has approved. I would be delighted to collaborate with anyone interested.

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