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Skin in the game

Yale Medicine Magazine, Autumn 2023 (Issue 171) Obesity Special Report
by Mary Ann Littell


A physician-scientist's passions

MANY CREATURES are covered with scales, shells, fur, even quills protecting them from the external environment. Humans, on the other hand, have only their thin, pliable skin. The body’s largest organ, it has a veritable army of immune cells. But what happens when disease sets in?

While some 84.5 million people in the United States—roughly one in four—are affected by skin diseases, the impact is often minimized. “A common misconception is that dermatological disorders are inconsequential—annoying, perhaps, but not serious,” says Keith Choate, MD, PhD, Aaron B. and Marguerite Lerner Professor and chair of dermatology, professor of genetics and pathology, and associate dean for physician-scientist development. “Many people don’t realize that we also treat patients with severe disorders that profoundly affect their lives.”

Consider the nonstop itch of severe atopic dermatitis, the acute discomfort of having up to 90% of your body covered with the silvery scales of psoriasis, or the challenge of a yet-undiagnosed genetic skin disease. These are the patients Choate is drawn to help. Trained in dermatology, human genetics, and pathology, he treats rare and unusual skin conditions that most physicians have never even seen. He does this by understanding the genetics of the disease.

“I walked into dermatology with the idea of treating patients with severe systemic diseases, and I did it at a moment when biologic therapy was just coming into being,” says Choate. “Patients had been treated for decades with less efficacious drugs, including those that damaged their DNA and caused a host of adverse side effects. But with new, precision molecular therapies, we can treat patients with far greater efficacy.”

Choate is a pioneer of several groundbreaking discoveries and collaborator on many more. His work in the laboratory has led to the identification of genetic defects in more than 18 rare disorders. These range from inherited forms of ichthyosis (a disorder featuring scaly skin with or without systemic findings) to severe, sometimes lethal pediatric vascular malformations. This basic genetic work has allowed Choate and colleagues to glean fundamental biologic insights into disease and pave the way for effective therapies for conditions that were previously untreatable.

Equally focused on clinical care, he is known as a physician who takes on the most complicated cases and strives to find solutions. “This is possible because I am part of an institution and a department with tremendous resources and talented people,” he says. “It’s the quality of your colleagues that enables you to do special things.”

A young man’s dream

Choate knew from an early age that he wanted to be a physician. Growing up in rural Connecticut, he admired two primary care doctors who were pillars of the community. “I wanted to be like that,” he says. “I loved the idea of practicing medicine and having the opportunity to effect change in people’s lives.

His education provided a window to a career path combining research and clinical care. At Stanford, where he received his undergraduate degree, he learned the advantages of being part of a research university. As the first individual in his family to consider a career in medicine, Choate sought career advice from a Stanford cardiologist. “I was told that if I wanted to get into medical school, I’d have to do research,” he explains. “This was news to me! But if that’s what it took, I’d do it.”

Choate found a position in the lab of a world-renowned cell biologist. “But the rule was that you had to prepare solutions for two years before you could actually pick up a pipette and do an experiment,” he notes. “Whenever I asked, they always said ‘no.’

Idly paging through a campus research directory one day, Choate noticed an interesting ad. Assistant Professor of Dermatology Paul Khavari, MD, PhD, was seeking a lab assistant. “I went to meet him and found this incredibly charismatic, enthusiastic investigator,” says Choate. “During our chat, he described how to extract plasmid DNA from bacteria. While this is a routine part of laboratory practice, at the time I was fascinated.”

Choate had the good fortune to meet Khavari at a moment when scientific knowledge of human genetics was exploding, and new genetic causes of disease were rapidly being discovered. This was the case for lamellar ichthyosis, a rare genetic skin condition characterized by severe scaling all over the body.

“A few of our Stanford colleagues had developed remarkable retroviral vectors that were being used to modify cells for gene therapy,” says Choate. “So we came up with a wild idea: Why don’t we try to use gene therapy for ichthyosis?”

Choate and Khavari made many trips to a major ichthyosis center at the University of California, San Francisco. “We took skin biopsies and grew out the cells in the lab,” says Choate. “I became quite proficient at growing patient keratinocytes, the primary cells that comprise the skin. It was heady stuff for a 20-year-old. But what was amazing was that we were able to restore the defective gene causing this disease. I then learned how to make skin equivalents that we used to reconstitute corrected skin on mice, achieving the first effective ex vivo gene therapy for genetic skin disease.” This experience fueled Choate’s desire to become a physician-scientist—and kindled his strong interest in dermatology.

The gift of exceptional mentoring

Attracted by its outstanding medical scientist program, Choate returned to Connecticut to attend Yale School of Medicine (YSM) in 1996. He found another brilliant mentor in geneticist Richard Lifton, MD, PhD, now president of The Rockefeller University. “He was really pushing the field forward in understanding the genetic basis of disease,” says Choate.

He continued his work with Lifton through his residency, when the two made another notable discovery studying ichthyosis with confetti, a rare disorder characterized by abnormally thick, scaly skin. Dermatologist Leonard Milstone, MD, had a keen interest in ichthyosis and followed patients from all over the country. He brought Choate a fascinating question. “All the patients developed many white patches, which were, in fact, normal skin,” says Choate. “Len asked, ‘Do you think there’s a way that we can figure out the genetic basis of this disease?’”

They brought the question to Lifton, who thought the white spots represented widespread revertant mosaicism, a naturally occurring phenomenon involving spontaneous correction of a cellular mutation. He suggested that these cells were actually losing the genetic mutation via a process called loss of heterozygosity, a common genetic event in cancer development. In essence, the cells were curing themselves.

“He proposed doing loss of heterozygosity mapping to figure out this problem,” says Choate. “It took five years, but we were able to identify the genetic basis of this disorder as mutations in the gene that encodes keratin-10. My laboratory continues to study mechanisms of genetic self-correction, among many other things."

Giving back as a physician-scientist

Following a postdoctoral fellowship in dermatology and genetics, Choate joined the Yale faculty. In 2015, he became associate director for diversity, equity, and inclusion in the medical-scientist training program, as well as co-director of the Department of Dermatology’s physician-scientist training program. These positions gave him the opportunity to mentor others as he had been mentored.

In 2020, YSM Dean Nancy J. Brown, MD, who arrived at Yale with a long track record of developing mentoring programs, appointed Choate associate dean for physician-scientist development, and he founded the Office of Physician-Scientist and Scientist Development. “The development and retention of physician-scientists has become increasingly difficult, and all early career scientific faculty face challenges,” says Choate. “To address gaps and accelerate career development, we established funding mechanisms and developed resources, including a grant library, a mock study section, professional development courses, and cohort-building activities—all to support early investigators to launch their careers.”

Another component of the program supports international physician-scientists who are ineligible for traditional sources of funding. “With investments from the dean’s office and private donors, we’re providing the means to retain them so they can continue their work in Yale labs,” says Choate.

Named chair of dermatology in 2022, Choate continues to expand the department’s research and clinical services. These efforts are unlocking the secrets of how skin diseases occur—and how to treat them.

His own lab continues a major focus on ichthyosis. Partnering with a patient group, the Foundation for Ichthyosis and Related Skin Types, has enabled his team to enroll patients in clinical trials and compile valuable patient data. “We attend patient support meetings and hold pop-up clinics around the country,” he says. “These events are incredibly powerful, because often this is the first opportunity these patients have to meet a doctor who actually understands their disease.”

In the course of studying mosaic-patterned disorders, Choate’s lab has also identified the genetic basis of another rare disorder, linear porokeratosis. Patients in this study were found to have a mutation in a gene that is key in cholesterol biosynthesis. Armed with this information, the team created a simple topical therapy: a cholesterol-lovastatin combination.

“We then began using this combination therapy to treat patients with disseminated superficial actinic porokeratosis, or DSAP,” adds Choate. “This disorder affects a much larger population. The results were profound. These patients had been treated with myriad therapies, with no success. But with this combination, we were actually curing them. It is now used in common clinical practice.”

He adds: “These are the moments that are the most gratifying. Patients come through our doors because no one has been able to find solutions for them. We seek to find answers. Sometimes these come from a different approach to therapy, and in others, through research. Every day, the faculty of Yale Dermatology are finding ways to change patients’ lives, and that’s at the heart of what we do.”