In retrospect, many of us had no idea that these efforts would lead to the isolation of RNA polymers that helped define the interactive properties of RNA, DNA and RNA-DNA hybrids, as well as the polynucleotides and oligonucleotides that were instrumental in solving the genetic code. Ironically, the Ochoa-Heppel collaboration eventually yielded the initial polynucleotides used by Marshall Nirenberg, Heinrich Matthaei and their colleagues in experiments that defined the code, carried out during a highly competitive period with Ochoa’s laboratory.
By the late 1950s, Heppel’s laboratory had become a magnet for scientists interested in learning how to work with RNA and oligoribonucleotides. His expertise and store of specific purified enzymes and reagents, coupled with his generosity and hospitality, were legendary. He became a service for those trying to identify oligonucleotide products. This status was exemplified by his realization that Roy Markham (in collaboration with David Lipkin), and Earl Sutherland had unknowingly and independently isolated cyclic AMP; the Markham-Lipkin material was generated by heating ATP with barium hydroxide, while Sutherland, who had discovered its biological importance, had painstakingly isolated miniscule amounts from liver. Chance side-by-side co-chromatography of their preparations by Heppel revealed their identical properties, leading to a marked increase in the availability of cyclic AMP as well as the structure of this biologically important compound. Throughout this period, a large number of talented students, postdoctoral fellows and visiting professors spent time in Leon’s laboratory (Henry Kaplan Marie Lipsett, Nancy Nossal, Gobind Khorana, Maxine Singer, Robert Lehman, Uri Littnauer, Audrey Stevens and many others), all contributing to the exciting and highly productive environment.
By the mid 1960s, Heppel’s interests shifted to proteins localized in the periplasmic region of gram negative bacteria (located in the space between the cell membrane and cell wall) that were released by osmotic shock. In 1967, after 25 years at the NIH, Efraim Racker induced Leon to join the biochemistry department at Cornell University, where he continued and extended these studies to include specific amino acid binding proteins that participated in energy coupled transport into E. coli. His group applied cytochemical methods to establish the localization of a number of phosphatases to enlarged regions of the periplasmic space. By the mid 1970s, Leon began working on cultured animal cells. To gain more experience with animal cells, he spent time working in Henry Rozengurt’s laboratory in London, England. During these visits, he discovered that low levels of ATP altered the permeability of transformed cells and later showed that it acted as a mitogen. Over the ensuing years, which included a period working in Claude Klee’s laboratory at the NIH as a Fogerty Scholar, he showed that the mitogenic effects of ATP depended on the elevation of cAMP levels and activation of protein kinase A. The last research paper published by Leon, in 1997 at the age of 85, provided evidence for a role of the G protein b g subunits in the enhancement of cAMP accumulation and DNA synthesis by adenosine in human cells.
No description of Leon’s legacy would be complete without reference to his unique humor which included long hand written letters (some 10–15 pages in length) summarizing the music played at the latest concert or art exhibit that he and his wife Adelaide attended. Included in these letters were quizzes in which he challenged you to name the restaurants or park depicted in paintings, the date the symphony was first performed, etc.
Leon was tremendously supportive of his associates. Many publications emanating from his laboratory were devoid of his name because he thought its absence would help his students and postdoctoral fellows get jobs. He noted that he stopped doing this when an editor accused him of being uninterested in their work. In a Journal of Biological Chemistry Reflection article summarizing his scientific career, Heppel mentioned nearly all of the people who held positions in his laboratory over the years and noted that the list was small because he preferred to work with a small group which permitted him to carry out experimental work himself. He also noted that he was especially pleased with the performance of women in his laboratory because he was aware that they had difficulties in obtaining positions at the time. In this article, he described the wonderful friendships he formed in research laboratories and acknowledged their role in his career. Those of us who had the good fortune of interacting with Leon during our careers are grateful for his guidance and inspiration. We shall miss him.
Jerard Hurwitz (firstname.lastname@example.org) is a Sloan-Kettering Institute professor and head of the William Randolph Hearst Laboratory of Radiation Biology at the Memorial Sloan-Kettering Cancer Center.
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