Biochemistry during the Life and Times of Hans Krebs and Fritz Lipmann

This essay reviews some of the types of problems under investigation during the period of 1940–1950 and the influence two exceptional scientists would have on my early development as a biochemist. To put my life into some kind of perspective in regard to this particular period, I should provide some data about my early academic situation. I started my graduate studies with a Master’s degree from the Department of Biological Chemistry at the University of Michigan, whose Chairman was Howard B. Lewis. He was a dynamic lecturer and one of the pioneers of research in intermediary metabolism. For my Doctorate degree I moved to Harvard Medical School to work with A. Baird Hastings (see Fig. 3). Both Lewis and Hastings were principal mentors during my career. I then spent 10 years on the faculty of the Department of Physiological Chemistry, School of Medicine, University of Pennsylvania in Philadelphia with a 2-year sabbatical period at the Medical Nobel Institute with Hugo Theorell. Eventually I returned to the Boston area as Head of the Biochemistry Program in the Department of Biology, Massachusetts Institute of Technology. These features of my academic life establish the setting from which I would view the imprint that my seniors, for example, Krebs (Fig. 1) and Lipmann (Fig. 2), would make on my chosen field of intermediary metabolism. The whole approach to biochemical research had a monumental advance with the availability of radioactive or stable isotopes of carbon. In 1939 Hastings (Fig. 3) had been able to arrange for the production of C by our cyclotron in Cambridge. Its very short half-life, however, limited the types of problems that could be finished within a 4–5-h time limit. Despite this, a team of organic chemists and biochemists was able to synthesize two forms of lactic acid, one labeled on the carboxyl carbon (1) and the other on the or carbons (2), feed either one to fasted rats, and then isolate and measure the radioactivity of the liver and muscle glycogen. The initial goal was to determine whether these experiments confirmed the validity of Schoenheimer’s proposal (3) of the Dynamic State of Body Constituents. Indeed, lactic acid did contribute to the pool of glycogen precursors. However, a new finding did emerge, namely, in its conversion to liver glycogen the carboxyl carbon of lactic acid is replaced in part with carbon originating from carbon dioxide (4, 5). Research on the utilization of carbon dioxide as a substrate of reactions had been pioneered by Harland Wood and Chester Werkman (7, 8) in microbial systems, but the existence of this reaction in higher systems had yet to be verified. The Wood-Werkman reaction involves the carboxylation of pyruvate to yield oxalacetate.