In 1997, Terrie Tarbox, then 40 years old, was a nurse serving with a U.S. Army medical unit in West Hartford, CT. A marathon runner, she watched her diet and health, so she was mystified when her legs suddenly swelled and reddened. She tried all of the conventional treatments for skin inflammation, but the condition kept getting worse. She developed a rash on her face and arms. Embarrassed, she grew bangs to cover her forehead and always wore long-sleeved shirts.
That was just the beginning. Tarbox easily became short of breath, and she had three bouts of pneumonia in quick succession. Next, her vision became cloudy. Then she began experiencing severe pain in her joints. In 1999, doctors arrived at a diagnosis: She had sarcoidosis, a rare disease characterized by the growth of tiny clusters of inflammatory cells called granulomas that form most often in the lungs, lymph nodes, and skin. In many cases, skin rashes are the first sign of the disease.
Throughout history, poets and philosophers have referred to the eyes as being windows to the soul. In recent times, it has become equally clear that the skin is a critically important window into the human body and its diseases. Many systemic diseases can be detected by dermatologists—not just sarcoidosis but also lupus, lymphoma, fungal infections, and of course, melanoma.“You can identify so many systemic diseases by careful analysis of the skin,” said Richard Edelson, MD ’70, the Aaron B. and Marguerite Lerner Professor of Dermatology and chair of the Department of Dermatology at Yale School of Medicine. When dermatologists are called in for hospital consultations, they frequently help identify systemic problems—in addition to reducing length-of-stay and readmission rates. In dermatology, Edelson said, “We strive to do more than just look and characterize, but see and interpret.”
That last bit is a modified quote from Aaron Lerner, MD, PhD, the physician-scientist who was the founding chairman of Yale Dermatology in 1955 and a key influence on Edelson during his time as a medical student. Lerner, who died in 2007, interwove clinical care with pathology and focused the department on research into the fundamental mechanisms of human skin. By the conclusion of Lerner’s 30-year chairmanship, the department had grown to eight faculty members. Edelson, his successor, expanded and diversified the department to 40 faculty members. Today Yale Dermatology drives some the most important trends in dermatology by drawing on the fields of immuno-oncology, genetics, and dermatopathology. It’s also a leader in advancing pedagogy. For instance, Jean Bolognia, MD, professor of dermatology, is the senior editor of the fourth edition of Dermatology, the textbook that has become the standard for residency programs around the world, andDermatology Essentials.
The department has also participated in a major shift in medical research: interdisciplinary collaborations. Dermatology faculty members now work with faculty in other departments of the medical school and other schools in the university. For example, Michael Girardi, MD, professor of dermatology and department vice chair, is exploring the use of biodegradable nanotechnology in the treatment and prevention of skin cancer along with W. Mark Saltzman, PhD, the Goizueta Foundation Professor of Biomedical Engineering, Chemical and Environmental Engineering, and Physiology. They’re developing strategies aimed at decreasing the need for surgery. “It’s critical to form highly collaborative teams with different perspectives on science and disease,” said Girardi. With more than 1,500 skin-related diseases, there’s a lot to see and interpret with collaborators.
A medical mystery solved
Terrie Tarbox’s journey illustrates a number of the major trends in dermatology. After her diagnosis, she underwent conventional treatments, including taking the steroid prednisone. The treatments either didn’t work at all or worked for only a short time. Because of sarcoidosis, she had to use a wheelchair and take opioids to control the pain. She was forced to take medical retirement from the Army.
Relief came for Tarbox in 2018 when Brett King, MD, PhD, associate professor of dermatology, and William Damsky, MD, PhD, assistant professor in dermatology and dermatopathology, began treating her with tofacitinib (Xeljanz), a type of drug known as a Janus kinase (JAK) inhibitor, at the VA Connecticut Healthcare System. The drug was given off-label but the results were remarkable. Her vision improved, she felt less pain, and her skin cleared up completely. Tarbox can now visit with family and friends, and she and her husband look forward to traveling as the threat of COVID-19 lifts. Her advice to other people who get skin rashes that they can’t shake: “Go to a specialist. Sometimes you have to look deeper.”
About the same time, Damsky and King launched a trial to test tofacitinib on 10 additional sarcoidosis patients. The results were overwhelmingly positive. Six of the patients saw their skin clear up completely, and the others experienced significant improvements. Internal organs also showed marked improvements in several cases. And most patients were able to discontinue conventional immunosuppressive therapies, including prednisone.
For the researchers, the improvements helped expand their understanding of the molecules that perpetuate inflammation in sarcoidosis and how JAK inhibitors like tofacitinib work in this disease. They found that the therapy shut off interferon gamma, an important protein that misfires and triggers sarcoidosis. “We still don’t know why sarcoidosis occurs. It’s probably a combination of genetics, environment, and bad luck,” Damsky said. “But now we have a better understanding of the signals that cause inflammation in sarcoidosis and how to turn them off.”
Where the immune system meets cancer
Immunotherapy, which activates or suppresses the immune system, has been one of the most significant advances in the treatment of disease in the past two decades. Using JAK inhibitors for sarcoidosis is one example. Another target is melanoma. In fact, nowhere has immunotherapy been more effective than in the treatment of cancer. That’s why Yale School of Medicine and Yale Cancer Center established the Yale Center for Immuno-Oncology in 2018. The center seeks to leverage advances in immunobiology to develop next-generation drug therapies for cancer. “We’re producing paradigm-changing science in understanding how the immune system fights cancer, and we’re developing new cancer therapies that save lives,” said the director, Marcus Bosenberg, MD, PhD, professor of dermatology, pathology, and immunobiology.
Work at the center has already shown results. In one collaboration, led by Aaron Ring, MD, PhD, assistant professor of immunobiology, researchers used modeling techniques to identify a mutation of the interleukin-18 protein that would be capable of suppressing tumors that have resisted traditional IL-18 therapies. Then they genetically engineered the mutated protein so that it could be mass-produced. Clinical trials began in July. Normally, it takes more than a decade to advance a new drug from discovery to trial. Thanks to new technologies, this one took just four years.
In his own research, Bosenberg studies the genetics and cellular changes that produce melanoma, the leading cause of skin cancer deaths in the United States. He’s a co-director of the Yale Specialized Program of Research Excellence (SPORE) in Skin Cancer, which was established 14 years ago and was led by Ruth Halaban, PhD, a senior research scientist in dermatology. She is one of the pioneers in understanding the gene mutations that produce melanoma. Bosenberg and other researchers working under the SPORE funding umbrella have made significant advances in understanding and developing therapies for melanomas triggered by the BRAF oncogene. Their work has helped lower the number of annual deaths from melanoma in the United States from an average of 9,008 between 2012 and 2016 to an expected 7,180 this year.
Exploring the fundamentals
A critical element in all of these research and drug-discovery processes is deepening medical science’s understanding of the fundamental mechanisms of genes and cells. No longer is it considered satisfactory to target cancers and other diseases with shotgun-blast therapies; now, researchers are producing new knowledge and helping to develop therapies targeted to the specific gene mutations and combinations of mutations occurring in an individual patient.
Massive parallel gene sequencing technologies enable technicians to perform whole-genome sequencing for individuals for less than $1,000. That means clinicians and researchers can more easily identify inherited genetic patterns in individuals and families.
To Keith Choate, MD, PhD, professor of dermatology, pathology, and genetics, it’s the cross-pollination of expertise in genetics, pathology, and clinical care at Yale that leads to breakthroughs in developing treatments for diseases. Yale researchers benefit from the raw computing power and analytical expertise of the Yale Center for Genome Analysis and the interdisciplinary clinical resources of Yale Medicine. Choate has established an international skin disease registry that enables families to submit information and get diagnoses for rare genetic diseases, while providing samples to power new discoveries. Then there’s the genetic skin disorders clinic at Yale, which attracts people with rare skin diseases from all over the world.
A good example of the power of combining genetics, pathology, and clinical observation is the way Yale researchers and clinicians produced an effective treatment for linear porokeratosis, a rare skin disease that manifests as rashes appearing in lines along a limb, the trunk, head, or neck, and the more common disorder, disseminated superficial actinic porokeratosis, which appears in sun-exposed areas of susceptible individuals. By studying diseased cells collected through biopsies and comparing them with normal skin cells, Choate and his colleagues were able to associate these disorders with gene mutations in the mevalonate pathway, a metabolic pathway that converts mevalonic acid into cholesterol, among other important molecules. The researchers produced a novel hypothesis: that a topical therapy that would replenish cholesterol and block the accumulation of toxic metabolites could alleviate porokeratosis. They tested a cream containing cholesterol and lovastatin on patients with linear and disseminated porokeratosis. It worked; the lesions cleared in weeks, and there were no adverse side effects.
Another prime example of the value of fundamental research is the work being done by Peggy Myung, MD, PhD, an associate professor of dermatology and of pathology. Myung studies the mechanics of follicle cells and hair development at the microscopic and molecular levels. As a child, she was fascinated to learn that salamanders and newts could regenerate tails or legs that were lost through injury. As a medical resident, she imagined that science will one day enable humans to regenerate body parts. She wanted to participate in that research; that’s why she focuses on understanding hair, one of the few body structures that humans can regenerate.
Myung is exploring the biochemical signals related to mammal skin cells “deciding” to remain normal skin or start to develop into hair follicles during embryo development. She is aided in her research by advances in technology. For instance, RNA sequencing enables scientists to observe differences in cells they could not previously detect, which helps them understand why one cell produces follicles and another does not. This work could help researchers better understand a number of cancers, including basal cell carcinoma, that hijack the signals used to form healthy normal tissues and use them instead to promote excessive growth. Another potential outcome: developing techniques for naturally regenerating hair follicles in adults who have lost hair due to burns, chemotherapy, or other causes. “The overall goal of our work is to develop treatments that are more preventive and less invasive by using the same mechanisms our body normally uses,” Myung said.
Using the body to cure itself
The past two decades have brought major advances in the understanding of how numerous skin-related diseases and disorders develop. Those insights paved the way for the development of biologic therapies, which are increasingly used throughout medicine, in many ways replacing such older and less specific immunosuppressive drugs as prednisone. Yale Dermatology is prominently positioned at that advancing front.
As an example, Edelson pioneered the first FDA-approved immunotherapy for a rare but dangerous cancer, cutaneous T-cell lymphoma (CTCL), using a process he labeled extracorporeal photochemotherapy (ECP). In this process, some of a patient’s blood is drawn and treated with a combination of chemicals and ultraviolet light, causing white blood cells to mature into dendritic cells (DC), which are master switches of the immune system. The DC cells are then reinfused into the patient’s body, where they kill CTCL cells.
Girardi and his lab mates are also working to discover and develop new agents against CTCL. These include deploying monoclonal antibodies to find and destroy CTCL cells and targeting drugs that modulate signals between genes and proteins. For instance, Girardi’s group recently identified a drug in development for another cancer that showed potent activity against CTCL cells by blocking the BCL-2 protein, a regulator protein that slows the rate of cell death in lymphomas. Girardi was able to open a small investigator-initiated clinical study that showed encouraging safety and efficacy against CTCL, which could lead to a potential larger clinical trial down the line.
Teaching and Learning
The dermatology department also offers innovative medical school, residency, and postdoctoral fellowship programs that have been instrumental in faculty development for both the department and the field on a national and international level in recent decades. One-third of the current Yale Dermatology faculty is homegrown. More than 60 graduates of Yale Dermatology training programs are full-time faculty in university departments throughout the country. Besides Edelson at Yale, graduates include department chairs at Harvard, Stanford, and seven other universities.
In the medical school, the curriculum introduced six years ago integrates dermatology with teaching about the immune system, immunology, microbiology, and diseases. At the same time, the curriculum humanizes dermatology, giving students more intensive contact with patients and helping them learn how to better listen to and communicate with them. Fourth-year students who plan on pursuing careers in dermatology are required to write an essay about a patient they have come to know well, with a focus on people of color from New Haven. “We’re teaching medical students and residents to relate to and appreciate and care for people who may be very different from what they traditionally have known,” said Mary Tomayko, MD, PhD, associate professor of dermatology and of pathology, and director of dermatology medical student education.
At the residency and fellowship levels, the department integrates clinical care with research and reinforces the links between dermatology and other aspects of medicine. The dermatology residency program offers a special training track in investigative dermatology, and an elite group of fellows participate in the National Institutes of Health Training Grant program for physician-scientists. In both programs, students are required to work with two mentors, one in dermatology and the other in another medical school department. That arrangement not only broadens the students’ understanding, but also brings new knowledge and collaborations into the dermatology department.
A recent graduate of the residency research track, Anna Eisenstein, MD, PhD, who is now an instructor at Yale School of Medicine, has been studying the connections between skin disease and food allergies. In her research, she found that some preservatives in food and over-the-counter medications might be causing or exacerbating allergies. “This is the first deep exploration of how preservatives can harm us and trigger food allergies, but it’s just a first step,” she said.
These teaching programs are helping to prepare the physician-scientists of the future. Their brains and creativity are needed. While tremendous advances have been made in recent years in understanding basic biology and genetics, and in the treatment of skin-related diseases, major challenges remain—in better understanding the causes of disease; developing more targeted therapies, including biologics; and reducing harmful side effects. Further understanding of the skin will allow us to look ever deeper into the rest of the body.