July 2010

Leon A. Heppel (1912–2010)


Leon A. Heppel, who carried out pioneering work in the areas of physiology and nucleic acid biochemistry, passed away on April 9 at the age of 97 in Ithaca, N.Y.


Photo credit: Office of History, National Institutes of Health.

Leon A. Heppel, born to a poor Mormon family in Granger, Utah, received his doctorate in biochemistry from the University of California, Berkeley (1937) and his medical degree from the University of Rochester (1941). His research efforts during this period revealed that Na+ and K+ ions were capable of crossing animal membranes, contrary to the entrenched belief that the lipid cell membrane prevented the passage of hydrophilic metals. He often mentioned that, years later, he enjoyed being asked if he was the son of the Heppel who discovered the Na+/K+ membrane permeability.

After completing his medical internship at Strong Memorial Hospital in Rochester, N.Y., in 1942, Heppel and his medical school classmate, Arthur Kornberg, joined the U.S. Public Health Service during the early part of World War II. Heppel was assigned to the National Institute of Health, where, under orders from the Navy, he carried out toxicology research. During this period Leon, together with Herbert Tabor, Bernard Horecker (the only trained enzymologist in the group) and Arthur Kornberg (who, due to Heppel’s efforts, was reassigned to the NIH from sea duty) jointly organized a self-educating luncheon club to learn enzymology. By 1948, this effort matured into a new enzyme section at the NIH, headed by Kornberg, which included Horecker and Heppel.

In the early 1950s, in collaboration with his longtime colleague Russell Hilmoe, Heppel focused on enzymes that hydrolyzed RNA, particularly spleen phosphodiesterase. The nature of the products formed and the phosphodiester bond hydrolyzed by this enzyme were elucidated by Heppel during a sabbatical period at the Molteno Institute in Cambridge, England (1953) in collaboration with Roy Markham and John D. Smith. Their laboratory had developed cutting-edge methodologies that separated and identified RNA fragments using paper chromatography and paper electrophoresis. These studies demonstrated that the natural configuration of the internucleotide linkage in RNA was 3’-5’ rather than 2’-5’. In collaboration with Paul Whitfield, a graduate student in Markham’s laboratory at that time, Heppel demonstrated that the hydrolysis of RNA by pancreatic RNase occurred through a cyclic oligonucleotide, which was isolated and elegantly characterized.

In 1955 (soon after I joined the enzyme section at the NIH as a postdoctoral fellow with Bernie Horecker), Severo Ochoa presented a seminar on the work he and Marianne Grunberg-Manago carried out on the isolation of polynucleotide phosphorylase (PNPase) from Azotobacter vinelandii, the same enzyme independently discovered in Escherichia coli by Uri Littauer and Kornberg. Ochoa presented evidence that the enzyme catalyzed the production of long polymers from ribonucleoside diphosphate, but the nature of the phosphodiester bond formed was unclear. As Heppel was the premier expert in analyzing the structure of oligoribonucleotides, Ochoa proposed a collaborative study with Leon to define the nature of the products formed by PNPase. These joint studies (which included Maxine Singer, a young postdoctoral fellow in Leon’s laboratory at that time) rapidly elucidated the mechanism of action of PNPase.

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 (j-hurwitz@ski.mskcc.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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