Jeff Smith knows how to take calculated risks.
He played semiprofessional poker in college, landing a seat at the World Series of Poker at age 21. The game taught him to keep cool under pressure and to make smart bets when the stakes are high.
Now Smith applies those skills as a physician-scientist at Harvard Medical School.
“A lot of science is knowing what to pursue, when to take the big shots, and when to fold your project,” he said.
Smith loves to tackle experiments that are far from guaranteed to work but that offer big rewards if they do — in the form of deeper insights for biologists and better treatments for patients with hard-to-manage autoimmune conditions that affect the skin.
“Taking those calculated risks is important, and you should be excited to take them in science,” he said. “You may have a low probability of success, but if you hit, it really makes an impact.”
Getting under the skin
As part of the Harvard Dermatology Residency Training Program, Smith sees patients at several HMS-affiliated hospitals. As part of a physician-scientist research track supported by the hospitals and the National Institutes of Health, he conducts research in the lab of Andrew Kruse, professor of biological chemistry and molecular pharmacology in the Blavatnik Institute at HMS.
Practicing dermatology has given Smith a deep understanding of the difficulties doctors and patients face when it comes to certain diseases that manifest in the skin but can affect multiple organ systems. Many of these conditions have unclear causes and don’t yet have effective, narrowly targeted treatments.
Among these are the autoimmune disease lupus; systemic sclerosis, also known as scleroderma, a hardening of skin and connective tissue; and dermatomyositis, a rare inflammatory disease that causes rashes and muscle weakness. These diseases can seriously reduce people’s quality of life. Some forms can be deadly.
While certain therapies are available, “a lot of the medications we use are nonspecific, acting more broadly in the body than desired and therefore often causing side effects,” said Smith.
Because there aren’t treatments that can target whatever cells, molecules, or proteins drive systemic sclerosis, for example, many patients need to take drugs that suppress immune activity in general.
“We’re kind of taking a mallet to the immune system,” Smith said.
Developing targeted therapies for the diseases Smith specializes in could improve or save the lives of millions of people worldwide. He believes the best strategy for doing so is to reveal the illnesses’ deepest biological roots.
“Autoimmune skin diseases are really tough to treat effectively, especially if you don’t understand what’s causing them,” he said.
Looking for answers in the lab
Smith is placing a bet on G protein-coupled receptors, or GPCRs. The largest family of cell membrane receptors in the human body, GPCRs are involved in a startling array of bodily functions. An estimated one third of all FDA-approved drugs, including beta blockers and antihistamines, act on GPCRs.
GPCRs are masters at receiving and interpreting signals from the environment and instigating responses from cells. By binding to hormones and neurotransmitters, they influence our mood and behavior. By binding to molecules that enter our mouths and noses, they help us taste and smell. GPCRs are involved in inflammation, reproduction, autonomic nervous system activity, maintaining the body’s salt and water balances, and more.
“GPCRs are the crux of the human condition,” said Smith. “They’re our gatekeepers, helping our bodies respond in so many different contexts.”
Smith’s bet rides in part on determining whether patients with systemic sclerosis have autoantibodies — antibodies made by the immune system to attack proteins in a person’s body — that bind to particular GPCRs.
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Conceived with fellow lab members, including postdoc Meredith Skiba, the idea doesn’t come out of left field. For instance, autoantibodies against one type of GPCR, the thyroid stimulating hormone receptor, have been found to cause autoimmune thyroid disease.
Smith is trying to identify GPCRs associated with systemic sclerosis by screening serum samples from patients to see if they bind to any of the hundreds of known GPCRs. If they do, he might then be able to explain how the disease arises at the molecular level — and provide a solid foundation for developing new drugs that target those GPCRs.
“There’s a good chance that this isn’t the cause,” Smith readily volunteers. “But I think it’s one of those high-risk projects that’s worth pursuing because of the difference it could make if it pans out.”
Toward targeted treatments
Smith started out interested in cell receptors as a college student in Washington State, where he grew up. He applied to Duke University for his MD-PhD in 2012 because it was “the Mecca of GPCR biology.” A few weeks after he arrived, his soon-to-be mentor, Robert Lefkowitz, shared the Nobel Prize in Chemistry for discovering and illuminating the GPCR family. (Smith’s current lab head, Kruse, studied with Lefkowitz’s co-recipient, Brian Kobilka.)
Part of what fascinates Smith about GPCRs is their complexity.
In a simple system, one type of molecule would bind to one type of receptor. But GPCRs aren’t as straightforward.
Consider chemokines, some of Smith’s favorite molecules, which bind to certain GPCRs to recruit white blood cells to infection sites. It turns out that multiple kinds of chemokines can bind to the same type of GPCR, and one kind of chemokine can bind to many types of GPCRs.
“There’s some redundancy, there’s cross pollination, and there can be promiscuity in these receptors,” said Smith. “We’re still learning all the details as a field, but in short the signaling is much more complicated than we initially appreciated.”
Plus, in a simple system, a molecule binding to a receptor would switch it on or off. Instead, researchers are finding that the same GPCR might tell a cell to activate response A, or response B, or response C, or responses A and B, depending on what molecule binds to it and perhaps even in what context.
For instance, Smith’s other favorite molecule, arrestin, was named for its ability to turn off GPCRs. Then researchers found that arrestin sometimes activates GPCRs.
Such complexity serves as catnip for curious biologists. It also suggests that it’s possible to develop fine-tuned drugs that elicit specific responses from specific GPCRs, maximizing treatment benefit while minimizing unwanted effects.
An opioid such as morphine, which binds to GPCRs, relieves pain but can also suppress breathing, cause constipation, and lead to tolerance over time that requires higher doses to achieve the same level of pain control.
“Could we develop drugs that give us the analgesia but without the respiratory depression?” Smith asked.
Or could he point the way to drugs that “tune the immune system,” whether through GPCRs or other receptors, to better treat lupus and its ilk.
Researchers have only recently begun to grasp the scope of GPCRs’ capabilities and decision-making. Smith has already enriched the field by revealing interactions between specific molecules and GPCRs and by discovering a new GPCR pathway, and he continues to investigate.
Probing receptor dynamics “is harder and less lucrative than figuring out what cards the guy across the table is holding,” he said. “However, it’s far more interesting.”
Dermatology drew Smith in while he was completing his medical training. It initially appealed to him as a specialty where cell receptor dynamics could literally be seen in people’s skin. He soon went “all in” when he found dermatologists to be “incredibly down to Earth,” the cases “incredibly interesting,” and the profession a chance to develop long-term relationships with patients.
“I knew early on that I wanted to spend my medical career seeing the same patients, watching their kids grow, getting invited to their weddings and such,” he said.
“That kind of humanity in medicine is so important and wonderful. You can really distill down a lot of the most important aspects about life by helping others through their challenging times.”
Embracing failure
The son of a Boston Red Sox fan, Smith learned another valuable lesson about science from playing baseball in high school: being comfortable with low success rates.
“If you bat .300, meaning you hit the ball 30 percent of the times you’re at bat, you’re considered for the Baseball Hall of Fame,” he said. “I think if you hit 10 to 20 percent of your hypotheses in science, then you’re doing pretty well too.”
Science, baseball, and poker require embracing and learning from failure, he said. “You have to fail quickly, adapt to those failures, and try a different strategy the next time around.”
He credits his lab head and campus environment for supporting such uncertain, swing-for-the-fences work, especially when funding and other pressures lead many researchers worldwide to pursue incremental discoveries.
“One of the things that’s phenomenal about Andrew is he is an innovative scientist who is willing to go after big questions and support people who do the same,” he said.
This summer — three years after he arrived at HMS — Smith will continue as a postdoctoral research fellow in the Kruse lab and become an HMS instructor in dermatology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute, where his clinics will focus on patients with autoimmune skin and connective tissue diseases.
He plans to keep exploring receptor biology, tethering his research to patient care, and taking leaps when things feel right.
“You have to prepare, then trust your instincts,” he said. “There are times you have to put all your chips in.”
