Ralph A. Reisfeld, PhD: In Memoriam (1926–2020)

Abstract

The sad news that Ralph A. Reisfeld, PhD, passed away on December 6, 2020 reached us early this year, and we would like to reflect on Ralph's long career and distinctive contribution to biomedical science and in particular to the field of cancer research. Ralph was well known for his work in biochemistry and tumor immunology and was a role model to many of his fellows and friends worldwide.Ralph was born on April 23, 1926 in Stuttgart Germany. He was the only son of Alfred and Erna Reisfeld, who were Jewish. In 1938, Ralph and his parents escaped to safety in Switzerland several days before “Kristallnacht.” For Ralph, life as a refugee was difficult, but he was grateful to the Swiss for their shelter because most of Ralph's family were killed by the National Socialists in concentration camps in Germany and Poland. Underlining his forgiving personality, Ralph never forgot his German roots, and throughout his career he made a concerted effort to develop professional and social ties with scientists from Germany. In his laboratories, he sponsored, trained, and mentored many young German scientists and young scientists from all over the world. He also never lost his love for history, which was a common subject of conversations with him.In 1947, Ralph was sponsored by the Schlesinger family of New York to immigrate to America. He had no resources, but he was anxious to begin a new life. During the ship voyage, he won $50 in a lottery, an event he took as a good omen for the future. After arriving in New York, Ralph went to work on a dairy farm in Vermont and Long Island to earn money for college. The very long days and the work ethic that farming life required stayed with him throughout his highly productive life.In 1948, Ralph began college at Rutgers University (New Brunswick, NJ), and received a Bachelor of Science Degree in Agriculture in 1952. As a student at Rutgers University, he was invited to visit with Albert Einstein in his home. They had both attended the same high school in Zurich. He considered his meeting with Einstein to be a life changing event, as his discussions with Einstein prompted him to become a scientist instead of studying history.In 1957, Ralph received a PhD in biochemistry from Ohio State University (Columbus, OH). He began his scientific career working in endocrinology at the NCI, at the NIH, in Maryland. At the NCI, he first purified and characterized human chorionic gonadotropin. A few years later, Ralph moved to Merck Sharp & Dohme in New Jersey to continue pursuing his interest in the biochemical characterization of pituitary hormones. In 1962, at Merck, he adapted PAGE and cellulose ion-exchange chromatography to this task and published an article in Nature that is still one of the most cited publications in biomedical research.In 1963, Ralph returned to the NIH as a staff scientist at the Laboratory of Immunology at the National Institute of Allergy and Infectious Diseases (Bethesda, MD), where he pioneered the characterization of immunoglobulin light chains and human histocompatibility antigens. These achievements were recognized worldwide, and his publications are listed among those that were most frequently cited in biomedical research in the following decades.In 1970, Ralph accepted the position of professor and member at the Scripps Clinic and Research Foundation (La Jolla, CA), where he continued researching serologic and molecular characterization of human MHC antigens, resulting in more than 100 publications from 1970 to 1980. Ralph was among a small group of investigators who first recognized β2-microglobulin as the light chain of MHC class I antigens. This molecular characterization of MHC facilitated the understanding of the rejection of transplanted organs.In 1976, Ralph began to work in cancer research and accomplished the biochemical and functional characterization of several melanoma- and neuroblastoma-associated antigens. He recognized their potential as therapeutic targets and developed an array of mAbs for this purpose. Ralph's group was one of the first in the world to embrace mAb technology. He supported the pioneering work of his post-doctoral fellows and associates in establishing techniques that would much later become mainstream and have tremendous impact in translation to the clinic. Several of his trainees moved to early biotechnology or pharmaceutical companies eager to develop mAbs.He was the first to characterize a melanoma-associated chondroitin sulfate proteoglycan, and demonstrated the eradication of established human melanoma and neuroblastoma tumors in nude mice by antibody-directed effector cells. The discovery of disialogangliosides, GD2 and GD3, as coreceptors of certain integrins added an important biological function to target structures previously thought to be biologically inert. In 1984, the first monoclonal anti-GD2 antibody was generated in Ralph's laboratory. This pioneering work laid the foundation for an arsenal of immunotherapeutics that were subsequently developed and are now critical to cancer treatment worldwide.In the following decade, Ralph's research focused on the development of anti-GD2 antibody constructs through protein engineering, which fostered the generation of humanized versions, antibody–drug conjugates, radio-immunoconjugates, and antibody-cytokine fusion proteins (immunocytokines). In his laboratory, these anti-GD2 constructs were tested in various preclinical cancer models to determine efficacy and mechanism of immunologic response. His findings provided the foundation for the clinical development of the anti-ganglioside GD2 antibody ch14.18. In 1989, at a time when there were no guidelines in place for antibodies generated by recombinant DNA technology, ch14.18 was the first human mouse chimeric antibody submitted to the FDA under an investigational new drug application.Through the resourceful identification of various vendors necessary to provide the required data, Ralph played a key role in the compilation of the chemistry, manufacturing, and controls package that was critical to enabling phase I/II clinical trials of ch14.18. Accordingly, ch14.18 was tested in phase III clinical trials by major cooperative pediatric oncology groups in the United States and Europe and was found to have efficacy in children with high-risk neuroblastoma. Today, ch14.18 is an FDA- and European Medicines Agency–approved drug that helps children worldwide to survive this disease. For many years, Ralph proudly displayed in his office the picture of a young boy who was one of the early recipients of ch14.18 and had his cancer go into remission.Ralph's excitement for both basic discovery and clinical application was evident to all that were privileged to meet and work with him; in his later years, he often noted how grateful he was that some of his work had an impact on treating cancer and helping children with neuroblastoma. His exemplary ability to bridge the gap between basic science and clinical application motivated his colleagues for scientific cooperation and demonstrated the tremendous translational value of basic scientific research.Ralph published more than 400 articles and received two 7-year Outstanding Investigator Awards from the NCI, underscoring his outstanding and long-lasting research achievements. He belonged to many professional societies, including the American Association for Cancer Research, to which he has been a member since 1976. He was also a member of many research grant committees, advisory groups, and editorial boards including Cancer Research and Clinical Cancer Research. In 2012, at the age of 86, and after more than 50 years in scientific research, Ralph retired from The Scripps Research Institute as Professor Emeritus.As Professor Emeritus, with his enormous experience, extensive network, and outstanding mentoring skills, Ralph continued to tutor young scientists and to support basic research and clinical scientists with their careers.Ralph frequently stated that the career achievement that he was most proud of was training and mentoring well over 100 young scientists and postdoctoral fellows, many of whom went on to conduct outstanding scientific research, to achieve Nobel Prize recognition, and to lead many prominent private companies and scientific institutions. Ralph nurtured the talent of his students and peers and always encouraged scientists to build their own ideas. He was guided by the Churchill motto, “we make a life with what we give,” and what a magnificent life Ralph gave to science.Ralph is survived by his daughter Deborah, son Daniel, daughter-in-law Lynn, and grandchildren Andrew and Lauren. His beloved wife Louise, to whom he was married for 57 years, died 7 years ago. Ralph and Louise shared a passion for classical music and loved visiting Vienna. In their later years, they made annual December trips to Vienna to attend the opera and to visit the Christmas market.Ralph was not only an outstanding scientist and enthusiastic personality, he was a lifelong and supportive friend to his students, colleagues, and collaborators. We will miss him dearly and will never forget his sense of humor, charm, and passion for science.