BY JERARD HURWITZ 

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.