Dr. Matthew Scharff's Remarkable Journey as an Immunology Pioneer

On May 9, 2015, Matthew Scharff, M.D., distinguished professor of cell biology and of medicine and the Harry Eagle Chair in Cancer Research/National Women’s Division, was awarded the American Association of Immunologists’ first BioLegend Herzenberg Award, which recognizes outstanding contributions to the field of immunology in B-cell biology. The following is a look at Dr. Scharff’s extraordinary career as a scientist and mentor.

Dr. Scharff with Linda Sherman, AAI president.
(Courtesy of the American Association of Immunologists.)If you’d known Matthew Scharff as a Brooklyn schoolboy in the 1930s, you wouldn’t have imagined that he’d become a preeminent immunologist—one whose research has paved the way for significant treatments for rheumatoid arthritis and cancer. He didn’t learn how to read until the third grade (likely due to dyslexia, which was little understood at the time). He struggled with math. Teachers advised him to avoid a career in science, even though he liked biology.

Dr. Scharff did well in school despite these challenges and was accepted to Brown University, where he studied English. But biology still called. By his junior year he had switched majors, aiming for a career in medicine—an idea planted by his salesman father, “who kept pointing out to me that the only people on the block who had food and a car were physicians,” said Dr. Scharff. “I was lucky that you could get into medical school back then with very little math.” He enrolled at the NYU School of Medicine in 1954.

An Affinity for the Lab

Research, rather than clinical practice, would become his career focus. NYU had just begun encouraging medical students to do research, and Dr. Scharff took to it like a bacterium to nutrient broth.

“I remember asking one of my lab instructors how antibodies could have such incredible diversity,” Dr. Scharff recalled, “and he pointed me to Burnet and Fenner’s Production of Antibodies, which proposed the clonal selection theory of antibody diversity,” one of the founding ideas of molecular immunology. Discovering the mechanisms responsible for antibody diversity would become Dr. Scharff’s lifelong mission. He began these studies by taking a year off from medical school to work in immunology labs supported by a National Institutes of Health (NIH) Post-Sophomore Fellowship, the predecessor of the Medical Scientist Training Program.

After an internship and residency at Boston City Hospital, Dr. Scharff landed a postdoctoral fellowship at the NIH, courtesy of the “doctor draft.” At that time, in the early 1960s, military draftees with M.D.s could serve in the Public Health Service instead of the armed forces if they had scientific sponsors. Dr. Scharff found one in Harry Eagle, M.D., the world’s foremost authority on tissue culture.

The Path to Einstein

As fate would have it, his mentor soon left the NIH for Einstein, crushing young Dr. Scharff’s hopes for solving one of the great technical challenges in immunology at that time: how to grow antibody-forming cells in culture. He thrived nonetheless, mastering emerging molecular biology techniques in virology, which would prove useful for his later immunology work.

Dr. Dominick P. Purpura, former Einstein dean (third from left), and Richard M. Joel, president of Yeshiva University (third from right), with the College of Medicine’s newly minted (in 2005) distinguished professors (from left): Drs. Stanley Nathenson, Michael V.L. Bennett, Susan Band Horwitz, Matthew Scharff and Albert KupermanDr. Eagle made amends for leaving the NIH by inviting Dr. Scharff to join Einstein’s new department of cell biology in 1963.

“It was a golden time at Einstein,” recalled Dr. Scharff. “The College of Medicine was just 10 years old and full of new energy and enthusiasm. Dr. Eagle insisted on an open and sharing environment, and another new faculty member, Jacob Maizel, had just developed SDS gels [making it possible to separate and analyze macromolecules such as DNA and RNA]. This allowed people to do groundbreaking experiments almost daily.”

With the help of some excellent postdoctoral fellows, Dr. Scharff finally did find a way to coax antibody-forming cells to grow continuously: by adapting myeloma tumors to cell culture. (Myelomas are cancers of the blood’s plasma cells, also known as B cells, which produce antibodies.) He used these cell lines to generate cell hybrids (different cell types fused together), allowing him to study how antibody production is regulated.

These findings laid the foundation for his later contributions—most notably, facilitating the production of monoclonal antibodies (identical antibodies made by a single clone of cells). Such antibodies come from hybridomas—cell lines made by fusing an antibody-producing B cell with a non-antibody-producing myeloma cell—and Dr. Scharff’s lab discovered that using polyethylene glycol (a compound with many uses in medicine as well as industry) greatly increased the number of hybridomas that can be formed.

Monoclonal antibodies have revolutionized the field of immunology and fueled the creation of scores of diagnostic reagents and therapeutic agents, including powerful treatments for rheumatoid arthritis and cancer. For the last 40 years, as director of the Hybridoma Facility, Dr. Scharff has helped many Einstein faculty members make the monoclonal antibodies required for their research.

A Trailblazing Researcher

“The importance of Matty’s work cannot be overstated,” said Liise-anne Pirofski, M.D., the Selma and Dr. Jacques Mitrani Chair in Biomedical Research at Einstein. “Every time you make or use a monoclonal antibody to find a receptor or a protein, do FACS [fluorescence-activated cell sorting] or develop a monoclonal antibody that you hope to translate into a therapeutic, you are benefitting from Matty’s perfection of hybridoma technology.”

If Dr. Scharff’s career had ended then and there, he would still have earned a spot in immunology’s pantheon. But he would go on to make many other contributions. For example, with Betty Diamond, M.D., he showed that autoantibodies, which cause type 1 diabetes and other autoimmune diseases, arise during the response to foreign antigens. In collaboration with Winfried Edelmann, Ph.D., he described how normal DNA repair mechanisms become error-prone in B cells; the resulting increase in B-cell mutations contributes greatly to antibody diversity and increases the likelihood that at least one variety of antibody will have high affinity for a particular antigen. These and other accomplishments have been reported in 300 scientific papers, and led to his election to the National Academy of Sciences and the American Academy of Arts and Sciences, along with many individual awards.

Dr. Scharff with Dr. Harry Eagle, after receiving his New York Academy of Medicine Award. For his first five years at Einstein, Dr. Scharff kept his hand in the clinic, seeing patients at least one morning a week. He also consulted on infectious disease and taught physical diagnosis. “I liked taking care of patients, but found medicine static and science wonderful,” he said. “I also found it hard to keep up my clinical skills while devoting the time it took to move my research in new directions.” And thanks to his major leadership role over the years—including chairing or co-chairing search committees for the last three deans—he has helped move Einstein in new directions as well.

A Devoted Mentor

Throughout his career, Dr. Scharff has taken a special interest in training the next generation of scientists. Many of his 60 students and fellows have become scientific leaders, and he has won prestigious national and local mentoring and teaching awards and served on national committees such as those for postdoctoral fellowships granted by the Jane Coffin Childs Fund and the Helen Hay Whitney Foundation.

“I’m particularly proud of that,” he said. “Someone will eventually make this or that discovery, but training others to be good scientists has more permanence.”

“As a mentor, Matty has always been able to view all students and postdoctoral fellows as individuals with human complexities, and to aptly coax them toward their own proper paths,” said David Margulies, M.D., Ph.D. (class of 1978), a noted immunology researcher at the National Institute of Allergy and Infectious Diseases who studied under Dr. Scharff. “He listens carefully and perceives well. All these traits are expressed with a self-deprecating good humor and a sensitive but sometimes disarming honesty.”

Dr. Pirofski, another former trainee, added: “Matty’s mentoring went far beyond his support for my work scientifically. He introduced me to people in the field of antibody immunity and infectious diseases who gave me opportunities to discuss my work and ideas. He has been my advocate in every stage of my professional development.”

Arturo Casadevall, M.D., Ph.D., a former professor of microbiology & immunology and of medicine at Einstein who is now at the Johns Hopkins School of Public Health, agreed, noting that “Matty Scharff is a terrific mentor not only because he teaches the finest art in science but also because he puts the needs of his trainees ahead of his own. He’s able to combine outstanding science with great humanity, and that’s what makes him so special.”

Now 82, Dr. Scharff is principal investigator on two NIH grants—one lasting through 2018. He intends to conduct research for as long as his mind and body allow.

“Editor’s Note: Home page image courtesy of the American Association of Immunologists.”