Split Personalities: Researchers Who Bridge Disciplines

Across Yale School of Medicine (YSM), a number of researchers work at the intersections of unexpected fields. Often, they found their way there by following intriguing science and asking questions that the approaches of a single field couldn’t answer alone.

The results are laboratories where different disciplines mingle, new opportunities emerge, and surprising science takes place.

The researcher that Christopher Bunick, MD, PhD, became was seeded at a young age. Bunick’s father was a crystallographer who worked to understand materials at the molecular and atomic levels, and his mother was an endocrinologist. Science and medicine were recurring themes in the Bunick household, and when he looks back on his childhood, he thinks about what “a cool environment” it was to grow up in.

Early on, Bunick pursued crystallography, working in his father’s lab during summer breaks in high school and later studying under a structural biologist in college.

“I just fell in love with crystallography,” says Bunick, associate professor of dermatology. “And it was really about seeing molecules at the level of atoms and bonds, understanding how things worked at that very tiny level.”

He went on to earn his MD and PhD at Vanderbilt University and helped establish crystallography as a technique in his advisor’s lab. It was only in his final two years of MD study that Bunick began to consider dermatology as his specialty. His interest was initially spurred by one of his PhD projects that dealt with DNA repair and its link to skin cancer, and it grew as he considered the field’s diversity.

“You’re talking clinical, you’re talking science, you have all of these different therapies, cosmetics, procedures, surgeries, you’ve got immunology, histology—it’s so diverse,” Bunick says “And for a brain like mine that needs constant unique stimulation to satisfy its curiosity, dermatology just seemed like a phenomenal specialty.”

The integration of dermatology and crystallography occurred when Bunick came to YSM, first as a resident and then as a new faculty member. The Department of Dermatology requires physician-scientists to have a primary mentor outside the department. “This way, whatever you study is likely to be novel,” Bunick explains. “And when you bring it back to dermatology, it’s going to help propel the field forward.”

Bunick’s mentor was the late Tom Steitz, PhD, Sterling Professor of Molecular Biophysics and Biochemistry and co-winner of the 2009 Nobel Prize in Chemistry. An expert in structural biology and crystallography, Steitz led pioneering work describing the structure and function of ribosomes, molecules found in all cells that are responsible for making proteins.

“I came in as a young faculty member, and Tom said, ‘Chris, do your thing. Develop what you want. I’ve given you a safe space to do it, and I’ve given you the resources, the environment, the intellectual stimulation,’” Bunick says. “He gave me the environment to learn and the space to let me develop my career, and for that I am very grateful.”

That early work focused on the human skin barrier and keratin—the structural protein found in hair, nails, and the outer layer of skin. Over time, the work also began to encompass clinical applications, namely the molecular mechanisms of dermatology therapeutics. Now, the Bunick Lab is evaluating how the structural properties of dermatology drugs and their interactions with the body relate to drug efficacy and safety.

“It’s that truly translational tie between the molecular science and the clinical outcomes of therapies in patients,” says Bunick.

More recently, the lab has moved in another, more unexpected direction: breast cancer. A researcher at Chapman University reached out to Bunick in 2019 after discovering that a certain type of keratin was upregulated in triple negative breast cancer. They are now exploring cell-surface keratin together as a drug target for this difficult-to-treat cancer.

“As a dermatologist, you wouldn’t expect to become a breast cancer researcher,” he says.

“This is one of the most exciting things about what I do,” he continues. “I tell people in my lab that chance favors the prepared mind. You don’t know what’s going to come your way, but when opportunities have come to us, we’ve tried to take advantage of them.”

The Department of Immunobiology recently welcomed two new faculty members who bring with them insights from physics.

As an undergraduate at Princeton University, Hao Yuan Kueh, PhD, now an associate professor in the department, was initially interested in biology and going to medical school. “But I quickly got discouraged by how unpredictable living systems were,” he says. “You can identify countless genes or molecules as potential drug targets, but only a small fraction will actually prove therapeutically effective.

This search for predictability ultimately led him to abandon a biology major and led him to physics. “I thought, wow, this is beautiful. There are universal laws that can predict exactly what’s going to happen in a system and when.”

But biology quickly started to creep back into this research. As a junior, he used modeling approaches from physics to understand how a circuit of interacting genes that controlled circadian rhythms could oscillate so robustly inside the noisy cell environment.

“And that was an eye–opener because it showed me that biological systems not only function predictably and reliably, but often push the physical limits of what’s possible,” says Kueh.

This experience instilled in Kueh a lasting motivation to uncover the design principles of biological systems—not just how they work, but why they're built the way they are. To Kueh, the molecular circuits that enable immune cells to sense, counter and remember threats in the body represent a fascinating puzzle.

And that’s what he’s working on now. His lab studies molecular circuits in immune cells: how they sense threats so sensitively and quickly, how they orchestrate potent yet specific responses against them, and how they can remember them for such long times after clearance.

Kueh has further come to realize that understanding why immune cell circuits work so well will enable him to better engineer cells as living drugs.

“For us, the big motivation is that immune cells are very well equipped to fight all sorts of different diseases in our body,” says Kueh. “Understanding how they work so well will empower us to program immune cells as next-generation therapeutic agents against various life-threatening diseases.”

Such physics and engineering-informed cell therapies may even work predictably and effectively across individuals and disease subtypes.

“If we understand circuit design principles, and if we systematically lay out how factors like human variation and noise inside cells influence circuit function, then maybe we can build cells to be as robust as, say, electronic and optical systems,” says Kueh.

Kueh’s colleague Armita Nourmohammad, PhD, studies systems. Her lab studies how biological systems learn, and over the past decade, they’ve focused on the immune system.

Nourmohammad’s background is in theoretical physics. As a graduate student, she applied the ideas of physics to study evolution and population dynamics, and how change occurs over long timescales. That work had her thinking about scales on the order of millions of years. When, as a postdoc, she pivoted to the evolution of the immune system, that scale shrank to weeks.

To describe how she approaches immunology from the physics perspective, she points to how we’re able to measure temperature in a room. That room is full of gas particles, the behavior of which underlie the room’s temperature.

“But I can just pull out a thermometer and measure that. I don’t need to know the state of every single molecule in there,” says Nourmohammad, an associate professor of immunobiology at YSM and of biomedical engineering at Yale Engineering. From all of those complex interacting particles emerges a measurable characteristic, she explains, which can also be seen in the social interactions of ants, to molecular interactions, all the way to evolutionary phenomena.

“All of these things have many interacting components,” says Nourmohammad. “We do not need to know all the details, but some details matter. And that’s the trick, to identify what matters and what averages out, in some sense.”

One area her team is exploring is the diverse ecosystem of immune receptors in our bodies. Immune cells have receptors on their surfaces that can bind to and recognize pathogens; they’re a key part of our immune system. There are hundreds of billions of these receptors in our bodies, and they can look quite different from person to person, making it difficult to model or make predictions about their function.

Nourmohammad is using physics to model receptor-pathogen interactions at the atomic level. Her aim is to identify the rules that can generalize from one receptor to another and one person to another. “Atomic interactions should be the same even if you change the type of proteins, so we’re working on physics-inspired machine learning models to do that.”

That information will help guide immune engineering strategies, she says.

But theory is still a part of her work too.

“At the theoretical level, we are really interested in high-level understanding of general learning algorithms in the immune system,” she says. “And that can be at the level of individual immune cells, the population level, and anything in between.

Eric Song, MD, PhD, is busy. He’s finishing up an ophthalmology residency at Yale New Haven Hospital, serving as chief resident. He’s also running a lab at YSM, where, come July, he will be an assistant professor with dual appointments in the ophthalmology and immunobiology departments.

None of this is where he saw himself going when he began his MD-PhD studies at Yale. He got there by following interesting science.

Song began college as a photography major but ultimately switched to biochemistry. After he decided to pursue an MD-PhD, he found himself in the lab of Mark Saltzman, PhD, Sterling Professor of Biomedical Engineering at Yale Engineering, studying brain tumors and how to deliver treatments via nanoparticles. While conducting experiments, Song observed that brain immune cells called microglia were taking up all of his particles. As he searched to figure out why, he decided he needed to learn more about immunology.

With encouragement from Saltzman to reach out to YSM’s immunobiology department, Song eventually found himself pitching his idea to Akiko Iwasaki, PhD, Sterling Professor of Immunobiology. Intrigued, Iwasaki agreed to take on the project.

“That’s a big chance to take on someone. It was the best time of my life,” Song recalls.

In Iwasaki’s lab, Song studied how brain tumors are able to evade immune system attack. He found that the lymphatic system—the network that removes waste, pathogens, and damaged cells via lymph fluid that circulates throughout the body—is different in the brain than it is anywhere else. By manipulating it, he could remove a brain tumor’s immune protection.

“We built up a core idea that immune response exists in the brain, but how we think about it and how we can manipulate is slightly different,” he says.

Song enjoyed research so much he decided he wouldn’t practice clinically after finishing his MD. But upon suggestion from David Hafler, MD, William S. and Lois Stiles Edgerly Professor of Neurology, Song did an ophthalmology rotation and loved it.

“Maybe it’s my photography background, but ophthalmology is very visual,” he says. “You can see the immune cells floating in the eye, and you make a diagnosis. I think that just came natural to me.”

Ophthalmology is also a field where there’s plenty of immunological research to be done, bringing together so many of Song’s interests.

Song is currently leading a lab with three postdoctoral researchers, one PhD student, and a technician. He expresses a lot of gratitude for the team of mentors who’ve supported him and kept him on track as he launches a lab and finishes clinical training. His team is studying the different immune responses in the eye and brain, and how they might be harnessed for therapeutic benefit. Song is also a practicing ophthalmologist with a clinical interest in eye cancer.

“I keep an open mind, and I explore new things,” says Song. “I think that’s where the most interesting things happen, when you start combining things that other people thought were unrelated.”