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Serendipity in action

Yale Medicine Magazine, Spring 2024 (Issue 172) Women's Health Special Report
by Steve Hamm


A dermatologist's 'buddy' leads him toward a revolutionary treatment for cancer, infections, and transplants.

Mounted on a Cedar Street office wall of Richard L. Edelson, MD, Anthony N. Brady Professor of Dermatology at Yale School of Medicine (YSM), is a framed artwork that serves him as a daily inspiration. Under the title “The Three Princes of Serendip” is a group of four desert scenes that includes a pregnant woman riding a camel; camel footprints in the sand; human hand- and footprints in the sand; and a path cutting between cultivated fields.

The four scenes are derived from a Persian fairy tale whose heroes discover the precise identity of a lost camel through a combination of close observation of trail-side clues and previously gained knowledge. In the early 18th century, the British writer Horace Walpole read the tale in French and coined the English word serendipity. “Serendipity refers to the chance, unexpected occurrence landing on the prepared mind,” says Edelson. “I owe my career from start to the present to my buddy serendipity.”

Last year, Edelson embarked on the latest in a career-long series of ambitious inquiries into the nature and treatment of disease. He is a co-principal investigator on a $24.8 million grant—the first to be awarded in President Biden’s Cancer Moonshot program.

The project is called “Curing the Uncurable via RNA-Encoded Immunogene Tuning,” or CUREIT. The CUREIT research team, comprising scientists at Yale School of Medicine, Emory University, and the University of Georgia, is harnessing the human immune system to strive to develop personalized therapeutic vaccines to fight cancer, lupus, and emerging infections.

One of the key technologies the scientists are using is messenger RNA (mRNA), which entered the public consciousness in the early days of the COVID-19 pandemic when it was first used to quickly create vaccines that prevented or reduced the severity of SARS-CoV-2 infection. Edelson thought mRNA could also be used in combination with technology he has developed to manipulate the human immune system in powerful new ways: serendipity met science.

A record of Aha! moments

At age 78, a point in life when many professionals have wound down their careers, Edelson is charging into yet another endeavor with major potential consequences for medical science. This project may be the capstone on a career that includes a series of pioneering breakthroughs in immuno-oncology as well as stints at the helm of YSM’s Department of Dermatology and the Yale Cancer Center.

"This is another major step on the pathway of his incredible journey," says Michael Girardi, MD, Evans Professor of Dermatology, who has known Edelson for 35 years. "Throughout his career, he has been able to see clearly what is possible. He sees through the murkiness and ends up being right about what is going on."

Edelson has dermatology in his DNA. When he was growing up in suburban New Jersey, his father ran a local dermatology practice, and young Rick expected that he would someday follow in his dad’s footsteps. But the war in Vietnam set his life on a different path. At the time he earned his MD from Yale School of Medicine in 1970, male graduates were required to serve in the deployed military, or if competitively selected, perform research at the National Institutes of Health. Along with 19 fellow YSM classmates, Edelson was selected by the NIH and began combining highly specialized clinical care with advanced scientific research.

Almost immediately, he made a major discovery. In 1972, he was working at the NIH in Bethesda, Maryland, and was put in charge of a ward of lymphoma patients whose illness presented as rashes and bumps on their skin. Scientists had recently identified two distinct classes of white blood cells known as lymphocytes—B and T cells—as key elements of the adaptive immune system.

Edelson found that in patients with lymphoma of the skin, the cancer most often had arisen from their T cells, which normally help the body’s immune system ward off pathogens. In these patients, however, the T cells developed mutations that caused the cancerous cells to accumulate in the skin before spreading to other tissues. Edelson named the disease cutaneous T-cell lymphoma (CTCL) and began looking for biologically based treatments for it. He was just 27 years old.

After Edelson completed his NIH fellowship, Columbia University College of Physicians and Surgeons hired him as an assistant professor in 1975, and he advanced to full professor by 1980. In 1982, as leader of the Columbia University Cancer Center Immunology Program, he invented the breakthrough treatment for CTCL: photopheresis, a form of cellular immunotherapy.

Edelson devised a process for drawing blood from cancer patients using an IV; running it through a machine in which light “turned on” a drug called 8-MOP (methoxsalen) to kill cancer cells in the blood; and then returning the blood to patients’ bodies. He had hoped that many of his patients’ cancer cells could be killed, thus stalling the malignancy’s progression.

But then Edelson’s buddy serendipity entered the picture: he was stunned to find that after just three such treatments, two of five patients became cancer-free. “We had treated only 5% of the malignant cells, but they were cured,” Edelson explains, surmising that activation of anticancer immunity had done the rest. “We had accidentally immunized those two successfully treated patients even though available immunologic knowledge at the time could not explain how that happened,” he says.

To better understand the biological mechanisms, Edelson performed experiments using rodents. In 1973, researchers Ralph Steinman and Zanvil Cohn at The Rockefeller University had identified dendritic cells as specialized white blood cells that can selectively activate the immune system to attack microbial invaders or cancerous cells.

An international clinical study, led by Edelson and published in The New England Journal of Medicine, extended the original success to a larger group of CTCL patients. Edelson’s laboratory teams, first at Columbia and later at Yale, then set out on a 40-year odyssey to elucidate the scientific mechanism enabling the treatment’s successes, with the hope that ultimately it could be therapeutically applied to a larger range of cancers and immunologically caused diseases.

This journey, while tortuous, finally unraveled the mystery. Along with his closest laboratory colleagues, he ultimately discovered how the body signals monocytes—another type of white blood cell in the blood—to become dendritic cells; these are now recognized as the master switches of the immune system. “Serendipity works,” he says. “We never could have made that discovery purely on purpose.”

Paul Schneiderman, MD, a dermatologist in Long Island, New York, who worked alongside Edelson at the NIH and later joined the Yale faculty, marvels at his ingenuity: “Doctors had known about skin lymphomas for more than 40 years, but we didn’t really know what it was until Rick came along,” he says.

The first FDA-approved immunotherapy

Edelson then focused on developing a process for mass-producing dendritic cells from regular white blood cells so that he could amplify the effect of photopheresis. He invented what he called a “Rube Goldberg machine” made up of tubes, plastic plates, and mechanical hardware. This innovative treatment, delivered by a refined medical device, became the first FDA-approved immunotherapy for any cancer in 1988; and driven by Edelson’s subsequent research, it has been miniaturized and can now be scaled for experiments in rodents or treatment of humans.

In essence, Edelson had conceived of the idea of immunizing patients against their own cancers, or alternatively applying it to reverse rejection of transplanted organs or benefit patients with autoimmune disorders. The treatment is now regularly administered in nearly all medical centers in the United States and Europe.

In 1986, Yale recruited him to be the head of the Department of Dermatology. “Yale was so strong in immunobiology, I felt I really had to be there to mature this field,” he says.

Working with colleagues at Yale and elsewhere, Edelson further developed photopheresis techniques and added a major new step to the process—removing cells from the machine and modifying them to enhance their specificity for cancer cells. This innovation, now called transimmunization, may be adaptable to a broader range of cancers and immunologically mediated diseases, based on his team’s experimental results.

A passion for mentorship, team building, and fun

During those years, Edelson wasn’t just a clinician and a researcher; he was also a leader. Former students and colleagues describe him as being inspirational, supportive, good-humored, and adept in building a positive and creative institutional culture both at the Yale Cancer Center and within the Department of Dermatology. It was on his watch, as director of the Yale Cancer Center, that Smilow Cancer Hospital was conceived and built.

As department head, Edelson created a family-like atmosphere. He hosted faculty and staff parties at his own home for years and took colleagues to interesting out-of-the-way places for retreats. One exemplary retreat took place in Saratoga Springs, New York, where the attendees participated in a group bike ride, attended a concert, and went to the horse races. It was a team-building triumph.

Associates say that Edelson is passionate about mentorship of younger colleagues and students. He focused on recruiting people into the Department of Dermatology’s residency and fellowship programs and helping them succeed, taking a succession of young research scientists under his wing. Since then, 13 trainees he mentored have become heads of dermatology departments at prominent universities, and many more have developed academic prominence.

As a mentor, Edelson not only gives sound advice but also supports his people when they encounter problems. Jonathan Leventhal, MD, associate professor, director of the Dermatology Residency Program, and director of the Onco-Dermatology Program at Smilow Cancer Hospital, remembers a time early in his Yale career when he observed rashes on the skin of clinical trial participants who received an experimental cancer treatment—apparently a side effect.

After Leventhal published his observations, the pharmaceutical company whose therapy was being tested “wasn’t happy” with him. Worried that he might have made a mistake, he sought Edelson’s advice. “Rick said, ‘Jon, what you did was in the best interests of your patients and medicine. I have your back,’” Leventhal recalls.

To further the impact of medical science research, Edelson is an energetic and helpful research partner, say his scientist colleagues. Jennifer Schneiderman, MD, MS, professor of pediatrics at Feinberg School of Medicine, Northwestern University, says that Edelson has shared insights from his expanding knowledge of immuno-oncology to refine her techniques for using the same biological mechanisms to improve treatment of children after bone marrow transplantation by suppressing immune system reactions. Her group is now working on modifying the process to enhance the patients’ tolerance to transplanted organs. Of Edelson, she says: “He figured out the pivot point of our immune system—how it enhances attacks on certain things and settles down other things.”

Shooting for the moon

Edelson’s efforts are now focused on the Biden Cancer Moonshot and the CUREIT project, along with projects funded by the Gates Foundation to control emerging microbial infections. As part of this work, he and his laboratory mates are deeply engaged with Philip Santangelo, PhD, at Emory University, an internationally respected expert in designing mRNA to fight cancer and pandemic-causing viruses.

Within his own lab on Cedar Street, Edelson has assembled an A-Team of scientists—each with a deep reservoir of domain knowledge. The researchers have refined the core processes of creating and manipulating dendritic cells to the point where equipment that once filled a room has been reduced to a device the size of a microscope slide. Now, using mRNA, “we’re developing the ability to create immune reactions that attack specific types of diseased cells,” says Edelson.

The beauty of this approach is its simplicity—the scientists are essentially combining two well-understood technologies to do something new. “People assume that technology has to get more complicated to work better,” says Aaron Vassall, MD, an associate research scientist and molecular biologist at YSM, who as a medical student was mentored by Edelson and is now a key faculty member on the CUREIT team. “We may show there’s an alternative path that’s not complicated or expensive.”

Francine Foss, MD, professor of medicine (hematology) and of dermatology at YSM, says the CUREIT project has the potential to accelerate the development of new treatments for a wide variety of diseases, including cancers, autoimmune diseases, and preventive and therapeutic vaccinations against viruses. “This CUREIT project has the potential to shave years off the process of bringing new treatments to the clinic,” she says.

When Edelson started out, cancer research and immunology were still in their relative infancies, and the two domains were not seen as being closely related. Edelson became one of the first cancer immunologists and has made a career of building bridges between the two disciplines. And he’s not done yet. “I’ll keep riding this motorcycle until the wheels fall off,” he jokes.

In actuality, he hopes that within the three-year life of the Biden Cancer Moonshot grant, the research team will be on the way to developing a new generation of treatments. Says Edelson: “Our efforts are being driven by a team of talented and committed close colleagues. I would like us to make enough progress in this new field so that they don’t need me anymore.”

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