Keith Choate, MD, PhD, associate dean for physician-scientist development, works in Yale School of Medicine’s departments of dermatology, genetics, and pathology. The pioneer of several groundbreaking discoveries and collaborator on many more, Choate spoke with Yale Medicine Magazine editor Adrian Bonenberger about the interdisciplinary nature of his work, the special culture at Yale, and skin disorders.
What’s unique about studying skin disorders as a human geneticist?
When the function of the skin is disrupted, disease is readily apparent with clinical examination in our dermatology clinics. When there’s inflammation, the skin often turns red and itchy; when a mutation occurs in a specific cell type, we see skin lesions arise. Sometimes these are benign, such as nevi (moles) and cherry angiomas; and other times these are malignant, as in basal cell carcinoma and melanoma. We’ve focused our work on inherited skin disorders and congenital malformations, which have provided fundamental insights into skin biology.
During an early research project, studying ichthyosis with confetti, I realized that there were so many patients who have genetic diseases for which we didn’t have any clear understanding. As I was carrying out my postdoctoral training with Rick Lifton [Richard Lifton, MD, PhD, the former chair of the Department of Genetics], when human genome sequencing came into being and it allowed us to study a whole host of conditions for which we had incomplete understanding. It was collaborations with my pediatric dermatology colleagues such as Richard Antaya, MD, and dermatopathology colleagues like Jennifer McNiff, MD, and Christine Ko, MD, that enabled us to make really rapid progress. We quickly solved a series of disorders, finding the genetic basis of certain aggressive infantile vascular tumors and other congenital malformations such as nevus sebaceus, which appears as hairless waxy patches on the scalp. What was really remarkable is that we often found that these congenital malformations were caused by mutations in the same genes which can cause a host of cancers.
We solved a number of these disorders. And while sometimes they show up only in the skin because they’re mosaic (caused by a mutation that exists within a specific subset of cells), when that mutation happens is really important. If it happens earlier in development, during the formation of inner layers of the embryo, before cells have decided what they’re going to become, you can have that mutant clone show up all over your body. This insight led us to identify that mutations in oncogenes appearing in skin and bone cause the cutaneous-skeletal hypophosphatemia syndrome, a condition where kids have not only skin lesions but also profoundly debilitating rickets. This provided the first evidence that Ras mutations could cause hypophosphatemic rickets.
Much of biology is iterative. We know something, it helps us discover the next step. But the thing that’s exceptional about genetic approaches to disease is that if we know the disease has a genetic basis, we can be agnostic with respect to its cause. Using relatively simple genetic technologies, we can rapidly identify new pathways underlying disease, which can inform new approaches to treatment.
What drew you to dermatology as a career?
In clinical practice, one becomes deeply involved in the lives of patients. What matters to them most is their disease. With atopic dermatitis, for example, the itch can literally drive people mad. Acne can be disfiguring. The rare genetic disorders I study impact almost every domain of life. Dermatologic disease has a significant impact on mental health and well-being, and intervening at the right moment can change a patient’s life.
It’s also an immensely satisfying field, especially now. Dermatology readily allows translation. To sample a piece of tissue, even from the youngest infant, is feasible with minimal discomfort. You take cells, culture them in a lab, interrogate their genome, and then correlate the things we find in the laboratory with clinical observations—which in turn feeds into therapy. An example of this was our effort to understand a relatively rare disorder, linearporokeratosis. This goes back to the idea of mosaicism. We found a series of individuals who had stripes of skin that were scaly or red or both. We found that in fact, each and every one of the patients had a germline mutation in a gene that was important for cholesterol biosynthesis, and a second mutation that showed up in those stripes, which conferred disease to those stripes. Knowing the genetic basis allowed us to create a simple topical therapy for this rare condition, which we’d ultimately find effective for the more common disorder, disseminated superficial actinic porokeratosis.
Science has sequenced the entire human genome, about 21,000 genes. But we understand only about 5,000 of them. There’s a lot of work still to be done, and it requires clinical insight. Physician-scientists have a unique opportunity to apply the lens of their scientific understanding to clinical care, but also to bring critical clinical insights back to the laboratory to conduct translational investigation which can lead to a new generation of therapies.
What characteristics set YSM apart from other institutions?
Yale has distinct advantages that help make it uniquely well equipped to develop physician-scientist careers. We have an extraordinary collaborative research environment, exceptional trainees, and the infrastructure necessary to take on big questions.
As much as we know today that we didn’t know 10 or 20 years ago, there’s still a great deal more to do when it comes to understanding our skin and how it works.
I’ve recently taken on the role of associate dean for physician-scientist development, and I lead a great team at the Office of Physician-Scientist and Scientist Development, which is charged with helping to launch the careers of developing faculty across fields at the medical school. It’s exciting work, since the faculty we train today will be the ones who shape our understanding of science and medicine for generations to come.