In Memoriam Stanley J. Korsmeyer, M.D. HHMI investigator did pioneering research on programmed cell death.

Stanley J. Korsmeyer, M.D., a Howard Hughes Medical Institute investigator at the Dana-Farber Cancer Institute and Harvard Medical School, died on March 31, 2005, after a long struggle with lung cancer. He was 54 years old.

Korsmeyer was recognized as an international leader in the field of programmed cell death, and his numerous published research papers opened new vistas in a quartet of disciplines, including immunology, hematology, oncology and genetics.

A revered mentor and gifted speaker, Korsmeyer's pioneering work on the regulation of programmed cell death, also known as apoptosis, led to the identification of many of the key genetic mechanisms that govern cell death and survival. His research also defined the role of cell death in the pathogenesis of human diseases, including lymphomas and other cancers.

In 1985, while studying patients with follicular B cell lymphoma, a cancer of the immune system, Korsmeyer, then an HHMI investigator at Washington University School of Medicine in St. Louis, discovered that these patients carried a gene called BCL - 2 . The activity of this gene was increased due to a disastrous chromosomal mix-up. Shortly afterwards, scientists at the Walter and Eliza Hall Institute of Medical Research in Australia announced that DNA from human BCL - 2 made mouse cells survive longer than normal; during this extra time, some of the cells acquired additional mutations and became malignant.

Korsmeyer and his associates then bred transgenic mice that carried human BCL - 2 and showed that it leads to an excess of B cells—not by making cells grow faster, as other oncogenes do, but by preventing normal cell death.

Korsmeyer's path to medical research was by no means a straight trajectory. Growing up on his family's livestock farm in Beardstown, Illinois, he was intent on becoming a veterinarian. But one of his early mentors, veterinarian Robert Gooden, with whom Korsmeyer worked as a high school student, suggested he take a closer look at the biological sciences. After he was accepted into the University of Illinois as a preveterinary student, Korsmeyer eventually took Gooden's challenge and began premedical studies.

After graduating from the University of Illinois in 1972, Korsmeyer was accepted into the University of Illinois College of Medicine, where his advisor, Paul Heller, pointed him in the direction of hematology. He graduated from medical school in 1976 as a James Scholar, successfully completing an honors program in research. To more fully immerse himself in hematology, Korsmeyer did his internship and residency in medicine from 1976-1979 at the University of California, San Francisco. Following that, he did a postdoctoral fellowship from 1979-1982 in the National Cancer Institute (NCI) laboratories of Thomas Waldmann and Philip Leder.

It was at the NCI that Korsmeyer became interested in chromosomal translocations. For 30 years researchers had known that catastrophic events may arise when two chromosomes inappropriately swap genetic material in a process known as chromosomal translocation. One example of that trouble is found in tumors of blood cells - leukemias and lymphomas. Scientists believed that leukemias and lymphomas developed partly because the genes in two types of white blood cells - the so-called B and T cells of the immune system - were at higher risk for translocation than other genes.

Korsmeyer was best known within the scientific community for his seminal work on BCL - 2 , a gene that was involved in chromosomal translocation, as well as the development of B cell follicular lymphoma, the most common form of malignant lymphoma. His dogged pursuit of BCL - 2 led to his identification of the gene as a new class of cancer-causing gene, an honor that few scientists can claim. In a flurry of papers published in top scientific journals, researchers have shown that BCL - 2 is an antidote to programmed cell death. Korsmeyer and his colleagues showed that BCL -2 enhances a person's chances of developing follicular B cell lymphoma. Allowing B cells to live longer, increases the probability that they will acquire potentially harmful genetic defects, which could lead to cancer.

Korsmeyer's group continued to blaze the BCL-2 trail to identify and characterize the roles of a host of other proteins involved in cell death pathways, including BAX, BAD and BID, which accelerate cell death. As much as he loved basic research, however, Korsmeyer was keenly aware of the need to translate discoveries into practical therapies for patients. To that end, some of his more recent studies fashioned novel strategies for the design of cancer-killing drugs that would selectively trigger cell death. He also played a leadership role as a scientific advisor to the biotechnology company, IDUN Pharmaceutical, Inc., which was recently sold to Pfizer, Inc. Idun is a leader in the discovery and development of innovative human therapeutics that target apoptosis.

Korsmeyer published more than 250 original research articles and was invited to give keynote presentations at numerous meetings during his distinguished career. He was elected to membership in the National Academy of Sciences and the Institute of Medicine, and was recently elected to the American Philosophical Society. His honors include the Bristol-Myers Squibb Award for distinguished achievement in cancer research, the Charles S. Mott Prize of the General Motors Cancer Research Foundation, the 2000 Louisa Gross Horwitz Prize, the first annual Wiley Prize in the Biomedical Sciences, the Leukemia & Lymphoma Society's de Villiers International Achievement Award, the International Award for Cancer Research from the Pezcoller Foundation and the American Association for Cancer Research, and the 2004 A. Clifford Barger Excellence in Mentoring Award from Harvard Medical School.

Korsmeyer is survived by his wife, Susan, and sons, Jason and Evan.

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