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.


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In the late 70s as a Ph.D. ('81) student in entomology with a biochemistry minor at Cornell, I took the course in macromolecular synthesis that Dr. Heppel co-taught with David Wilson. Leon was an excellent teacher, and I'm happy to hear my impression of him as a caring and kindly mentor is echoed in the comments of others. Jeff Shapiro


Jerry, good job! I do have one comment. My memory of the cyclic AMP story is somewhat different. Leon had gotten a letter from Markham describing his work and 'filed' it in the huge pile of unanswered (and unopened) mail on his desk. Later, I don't recall how long, he got a letter from Sutherland describing his newly isolated compound. Leon realized that the two compounds were similar in chromatographic properties. He turned over the pile on his desk until he found Markham's letter and then sent it to Sutherland and sent Sutherland's letter to Markham. Very best, Maxine


Dr. Heppel was predeceased by his wife of 62 years, Adelaide. He is survived by his sons and their spouses, David and Jane Heppel of Clarksville, MD, and Alan Heppel and Michael Lyons of Los Angeles, CA; his grandchildren, Jennifer Heppel of Chicago, IL, and Christopher and Molly Martin of Clarksville; as well as many other family members.


Very nice article Jerry! I'm so sorry to hear that Leon is gone. I was a graduate student with Dr. Ray Wu in the laboratory next door in 1971 and 72. We then moved labs further away, when I worked together with Ken Marians. I never got the art quiz answers right, a uniform zero performance, although I particularly liked the Degas ballerinas. Leon took me walking around Beebe Lake and reminded me that it is natural beauty right outside the lab. I remember the wild flowers in particular. On these walks Leon lamented that "People don't care if you are a NAS member or made great discoveries. They just ask "What have you done lately". He also described he and his wife as two old people waving goodbye to children, first going off to college and then moving away. Gail & I are having to do that now, and so the memory of Leon's words is strong. Bob Bambara



  • A great man with a great sense of humor. Dr. Heppel came into Dick McCarty's lab one morning devastated by a letter from NIH requiring notarized verification that he was still alive for continued funding. The next morning Cynthia Coleman (McCarty's Technician), Mark Anderson, and I sang "Good Morning" to him - brought tears to his eyes. He was convinced that noone cared about him anymore. Bruce Wallin '78

  • While I was on graduate student rotation in Dick McCarty's neighboring lab to Heppel's and Wu's labs in 1968, and Dr. Heppel became a member of my Doctoral Committee, Dr. Heppel came in with a letter from the NIH that devastated him. It required that he get notarized verification that he was still alive. The next morning Cynthia Coleman (McCarty's technician, Mark Anderson (another student) and I went to Dr. Heppel's office and sang "Good Morning Dr. Heppel" to him which brought tears to his eyes. He was sure that noone cared about him anymore. A great man with a great sense of humor. Bruce Wallin '78

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