From Bedside to Bench and Back Again

Dr. Harris focuses his clinical and research efforts on vitiligo.

The turning point in the career of John Harris, MD, PhD, was sudden and an appealing type of serendipity. He had just completed his PhD studying type 1 diabetes in the lab of Dr. Aldo Rossini at UMass Chan Medical School, where he had become fascinated with autoimmunity. But he had grown frustrated that they couldn’t work directly with human tissues to study the disease.

“It was all mice, rats, and human cells in a dish,” Dr. Harris said. “I had always wanted to do translational research directly with humans, but few people were doing it because at the time it was impossible in type 1 diabetes—you can’t biopsy the pancreas. Aldo told me there were opportunities to study autoimmunity in other tissues and that I should consider rheumatology or dermatology.”

Dr. Harris returned to complete his final two years of medical school and became interested in dermatology when he learned how much inflammation there is in the skin. One night when he was on call, Dr. Rossini asked him to take a look at one of his patients. A 21-year-old woman had been admitted to the ICU with new onset of type 1 diabetes, she had ketoacidosis. While Dr. Harris was listening to her lungs, he noted a giant patch of vitiligo on her back. She told him it first appeared simultaneously with her diabetes, Hashimoto thyroiditis, and Pernicious anemia.

“She had four coincident autoimmune diseases,” he said. “I was staring at her back, realizing I could get a sample of that skin and study vitiligo as a model of type 1 diabetes. It dawned on me that maybe the best way to find a cure for type 1 diabetes was to study human vitiligo instead of a mouse model of diabetes. I was going to be a dermatologist and study vitiligo.”

As an undergraduate at Gordon College, Dr. Harris, who had always been good at science and math, assumed he was on track to become a primary care doctor. But then he was confronted by high-level research and discovery and realized he had a passion for both research and medicine. He enrolled in the MD/PhD program at the University of Massachusetts Chan Medical School. Dr. Harris is now professor and Chair of the Dermatology Department at the Medical School, the founding director of the Vitiligo Clinic and Research Center, and founding director of the Autoimmune Therapeutics Institute.

A brief history of vitiligo treatments

Vitiligo is an autoimmune skin disease affecting more than three million Americans and 74 million globally, with half of all patients younger than 20 when they first get the disease.

Vitiligo is an autoimmune skin disease affecting more than three million Americans and 74 million globally, with half of all patients younger than 20 when they first get the disease.

There are records of vitiligo being treated 3,400 years ago in Egypt following ingestion of seeds from a psoralen-containing plant, Psoralea corylifolia, followed by exposure to sunlight. Phototherapy using psoralen plus ultraviolet A (PUVA) continued to be used as a treatment well into the 20th century. Safer alternatives have since been developed, including narrowband UV-B (nbUVB), topical immunosuppressants, and excimer laser (Brodsky et al. 2017).

Advent of targeted immunotherapy

Research into treatments directed at disease etiology from Dr. Harris’ lab showed that interferon-Ɣ drove the disease and signaled through Janus kinase (JAK) proteins, setting the table for development of JAK inhibitors to treat vitiligo (Harris et al. 2012). A decade later, the FDA approved the first JAK inhibitor, topical ruxolitinib (Rosmarin et al. 2022). There are oral JAK inhibitors in development now, some of which are in phase 3 clinical trials. After nbUVB, ruxolitinib is the most effective treatment available. It has fewer side effects than steroids but is approximately one hundred times more expensive and relapse is rapid following cessation of treatment.

Within a year of cessation of treatment, 40% of vitiligo patients relapse and the unpigmented patches return to the same parts of the body. Using a mouse model, Dr. Harris’ lab, along with three other labs, discovered that resident memory T cells glue themselves to the epidermis in vitiligo, leading to maintained melanocyte cell death and depigmentation (Richmond et al. 2019). When a melanocyte tries to regrow, the T cells engage and lead to repeated cell killing. These memory T cells can be made quiescent with therapy—such as JAK inhibitors, light therapies, or steroids—at which point melanocytes regrow and repigment the skin. As soon as treatment stops, the memory T cells become active once again and trigger depigmentation.

Using a mouse model, Dr. Harris’ lab, along with three other labs, discovered that resident memory T cells glue themselves to the epidermis in vitiligo, leading to maintained melanocyte cell death and depigmentation (Richmond et al. 2019).

Dr. Harris and his colleagues used his mouse model of vitiligo to discover that IL-15 was required for survival of the resident memory T cells (Richmond et al. 2018). Blocking IL-15 with a monoclonal antibody (mAb) against the IL-15 receptor led to disappearance of the memory T cells and essentially erased the memory from the skin.

Based on this discovery, he founded a biotechnology company, Villaris Therapeutics, which developed an mAb to the human IL-15 receptor, which was acquired by Incyte Corporation and recently entered phase 1 clinical trials. Using a mouse model, stopping the treatment does not lead to rapid relapse because the memory T cells are not just quiescent, they’re gone.

Looking for the drivers of autoimmunity

Dr. Harris’ research for the past 15 years has focused on how to turn off vitiligo. “Our mouse model is excellent for coming up with treatments to reverse the disease,” he said. “But we still know very little about what is the trigger that initiates it.”

“Our mouse model is excellent for coming up with treatments to reverse the disease,” he said. “But we still know very little about what is the trigger that initiates it.”

His lab was recently awarded an NIH U01 grant to discover the predictive drivers of autoimmunity. They plan to enroll 200 vitiligo patients and 800 family members, analyzing their genetics, as well as skin and blood biomarkers to determine who is at risk for developing vitiligo.

Dr. Harris wears as many as five hats, sometimes in the same day. That includes building the dermatology department, overseeing clinical operations, treating patients, managing research recruitment, and running a lab that keeps more than 20 investigators busy. He acknowledged that he is only able to do all this because of the support of an amazing vice chair who helps run the clinical part of the department and really good leaders in his lab who help mentor students, perform experiments, and meet with the companies that sponsor the testing of treatments.

“I have three kids at home and some hobbies as well. When I tell people what I do, they usually ask, ‘How are you doing?’” He laughed. “But for me it’s a dream to be able to do everything I’m doing.”

Long-term DF support

Dr. Harris has been the recipient of numerous research awards and grants over the years, but it didn’t come easily.

“I had a difficult time getting NIH funding when I started out,” he said. “My first seven NIH R01 grant applications were rejected. I almost gave up on research and was considering turning solely to clinical dermatology.”

Dr. Harris’s early investigative career began with Dermatology Foundation research support. He was provided a research grant in 2008, a fellowship in 2009, and a career development award in 2010.

“The consistent funding from the Foundation was money that I needed to bridge the gap between starting up and full NIH independent funding.”

In 2014, a pivotal point in his research career, Dr. Harris became the Foundation’s first Stiefel Scholar Awardee. The Charles and Daneen Stiefel Scholar Award, which recognizes outstanding mid-career investigators, comes with funding for three years. He applied that funding to advance his research into skin-resident memory T cells in vitiligo, resulting in the new therapy discussed above, and it carried him over until his eighth RO1 application was finally funded.

“The Foundation encourages people early in their careers, like me, and keeps us engaged,” he said. “It’s good at supporting academic investigation and career development and has built a strong community.”

A career in investigative dermatology

“When I talk to people who are conflicted about whether to choose clinical dermatology or research I say, if you love them equally, you should pick clinical derm,” he said. “Research involves grant funding and lots of negative data, and it’s really hard. But, if you’re successful, it can be very rewarding.”

Dr. Harris believes dermatology physician scientists should be leading the charge in translational research but is concerned that the number of investigative dermatologists is shrinking globally.

“The Foundation encourages people early in their careers, like me, and keeps us engaged,” he said. “It’s good at supporting academic investigation and career development and has built a strong community.”

“The simplicity of forging a path to a career in clinical dermatology makes it hard to bring people into academia and do the important work that drives our field,” he said. “Without that the field can spiral into irrelevance. Being a physician scientist in derm is unique and one reason it’s such fun is that there are so few of us. This makes it easy for us to collaborate and only occasionally compete.”

Dr. Harris thinks of the more than 30 mentors he’s had in his career as a mosaic. Each one contributed an important piece; no one mentor could get him where he is today. He finds this metaphor useful to help those he mentors understand they don’t need to copy what one of their mentors is doing, since it’s already being done.

“Instead, I want to know what they’re passionate about. How are they going to make a unique contribution? Then I suggest they find people who are doing pieces of that and talk to them about their successes and failures. We need to be more open about our failures, too. I think we need to model that for them.”

He knows it can be a liability to do research and be a clinician unless the clinical work synergizes with the research. These days, this is the case, and an investigator has the tools to address questions that are clinically relevant.

“I’m optimistic about the future of derm. It’s an exciting time to be a physician scientist. When I was a student we didn’t have the tools to do translational research. Now the floodgates have opened with so many technologies sampling the skin, pulling it apart into single cells, using single-cell technologies, and all the -omics advances.”

Coming full circle

Dr. Harris doesn’t think the pathways that trigger vitiligo are specific to the disease. Similar pathways may be at work in psoriasis, in which resident memory T cells depend on IL-23, as well as in alopecia areata, graft-versus-host disease, and celiac disease. Nowhere is this more relevant to his work, however, than in type 1 diabetes, the disease that led him to dermatology.

In his Banting Lecture 2009, George Eisenbarth, MD, PhD noted the similarity between the pattern of destruction of 𝛃-cells in the pancreas of type 1 diabetics and the patchy destruction of melanocytes in vitiligo (Eisenbarth 2010). He referred to type 1 diabetes as “vitiligo of the pancreas.” In addition, vitiligo, type 1 diabetes, and many other autoimmune diseases share numerous genetic associations (Spritz and Andersen 2017). Dr. Harris believes this research supports the idea that shared mechanisms drive all autoimmunity and that treatments developed for vitiligo might work for others. This is the basis for the Autoimmune Therapeutics Institute, associated with the UMASS Chan Medical School, of which Dr. Harris is founding director.

Previous studies found that targeting the IL-15 receptor was effective in a mouse diabetes model. Dr. Harris hopes we are closer than we thought to treatments for type 1 diabetes.

“Dermatology is treating skin diseases with a broad array of tools, including leading the charge in the use of biologics. We are discovering new biologics and treatments, not just for clinical dermatology, but for all of medicine. Everybody should want to become a dermatologist because it’s fun, and also for the opportunity for discovery.”

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