Remembrances: Phil Leder (1934-2020)

By Michael Gottesman

Thursday, February 6, 2020

Our friend and former colleague Phil Leder, among the world's most accomplished molecular geneticists, died on Sunday, February 2, at age 85. His work with Marshall Nirenberg — namely, the famed Nirenberg and Leder experiments starting at the NIH in 1964, which definitively elucidated the triplet nature of the genetic code and culminated in its full deciphering — helped set the stage for the revolution in molecular genetic research that Phil himself would continue to lead for the next three decades.

Phil's remarkable scientific career at the NIH and later at Harvard brought forth breakthroughs in genetic engineering, immunology, and cancer research. Career highlights included the development of the first recombinant DNA vector system to meet specified safety standards, which he used to clone the gene for globin (the first cloned mammalian gene), and a series of creative experiments involving the c-myc gene and Burkitt's lymphoma that proved that the deregulation of a normal gene can cause cancer.

Phil was recognized for his achievements with the Lasker Award (1987), the National Medal of Science (1989), the Israeli Harvey Prize (1983), the Dutch Heineken Prize (1990), and election to both the National Academy of Sciences and the National Academy of Medicine. His research supported Marshall Nirenberg's Nobel Prize in 1968, and he was a guiding force for Tasuku Honjo, his NIH postdoc in the early 1970s, who would win a 2018 Nobel Prize for cancer therapy.

Phil first came to the NIH in the 1950s as an undergraduate intern in Martha Vaughan's lab in the National Heart Institute (NHI), now known as the National Heart, Lung, and Blood Institute (NHLBI). Upon receiving his medical degree from Harvard Medical School in 1960 and doing a residency at the University of Minnesota Hospitals, he returned to the NIH in 1962, this time as a postdoctoral fellow in U.S. Public Health Service and working in Marshall Nirenberg's laboratory in the NHI Section of Biochemical Genetics. This was a year after Marshall's polyU experiments with Heinrich Matthaei, and Phil went head deep into the coding race. Phil codesigned a Millipore filtration instrument, nicknamed the multi-plater, which tested 45 samples at once, a significant improvement over the single-plater technique testing one sample at a time. (This was his first patent, with Charles Byrne.) Phil and his colleagues radioactively labeled amino acids, bound them to three-nucleotide RNA sequences, and put them through the filter, the essence of the Nirenberg and Leder experiment. The filter caught the ribosomes and enabled the team to decipher the nucleotide codon sequences before the other teams "competing" in the code race.

In a 2012 interview with the American Society for Biochemistry and Molecular Biology, Phil described this period in the early 1960s at the NIH as the most exciting moments of his life. "I would go to bed thinking about the next day's experiments and then jump out of bed in the morning and rush to the laboratory," he said. "I stayed late at night. It was a lot of work, but the intellectual excitement was enormous."

Phil joined the Weizmann Institute in Rehovot, Israel, as a visiting scientist in 1965 and 1966; returned to the NIH as a research medical officer in the National Cancer Institute (NCI) from 1966 to 1969; became head of the Section on Molecular Genetics in the Laboratory of Molecular Genetics in the National Institute of Child Health and Human Development (NICHD) in 1969; and then rose to chief of that lab in 1972. Tasuku Honjo was a postdoc in Phil's lab from 1973 to 1974, and Honjo later said his time there defined his career direction in the study of immunoglobulin genes.

While at the NIH, Phil also taught an important course on DNA replication, transcription, and translation at the NIH for the Foundation for Advanced Education in the Sciences (FAES). This was brand new science, and the course was invariably packed. Phil was a chairman of the FAES Department of Chemistry, FAES vice president from 1970 to 1971, and FAES president from 1971 to 1973.

In 1980 Phil left the NIH for Harvard Medical School, where he was the founding Chairman of the Genetics Department, a position he held until his retirement in 2008. Phil also became a senior researcher at the Howard Hughes Medical Institute in 1986. While at Harvard, he and colleague Timothy Stewart secured the first-ever patent for an animal, the OncoMouse, used to study drugs for cancer treatment. His body of work on the genetic causes of carcinogenesis continues to have profound influence on our understanding of the causes and treatments of cancer.

Phil is survived by his wife of 60 years, Aya Leder; his children, Micki, Tani, and Ben; and eight grandchildren.

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