February 2010

Retrospective: Edwin G. Krebs (1918–2009)

Our Beloved “Reluctant” Biochemist

 

Edwin-KrebsEdwin G. Krebs, a giant of biochemistry in the 20th century, died Dec. 21 in Seattle. He was 91. His discovery of protein phosphorylation as a regulatory mechanism (with Edmond Fischer) touched all aspects of biomedical science and profoundly influenced therapeutic approaches now widely used in clinical care. Ed’s life story epitomizes his commitment to family and colleagues, excellence in research and service to the biochemical community.

Ed Krebs was born in Lansing, Iowa, on June 6, 1918, the son of a Presbyterian minister and a schoolteacher. His father died suddenly when Ed was 15 and, at the height of the Great Depression, the family moved to Urbana, Ill., for financial reasons. It was there that Krebs completed high school and earned a degree in chemistry from the University of Illinois in 1940. As an undergraduate, he became enamored with organic chemistry but eventually chose to become a physician, largely because he won a scholarship to attend Washington University School of Medicine in St. Louis.

The principal responsibility of a medical school during the war years was to train physicians for the armed forces. However, Krebs also was encouraged to participate in “medical research.” After graduating from medical school in 1943 and doing 18 months of residency training in internal medicine at Barnes Hospital in St. Louis, Krebs went on active duty as a medical officer in the Navy. After being discharged from the Navy in 1946, Krebs returned to St. Louis with plans of becoming an academic internist. However, all of the hospital positions were filled by returning veterans, and, as a temporary measure, Krebs was advised to study basic science as a postdoctoral fellow at Washington University. Largely because of his background in chemistry, he was accepted into the laboratory of future Nobel laureates Carl and Gerty Cori in the department of biochemistry. After two years in the Cori lab doing research on the interaction of protamine with rabbit muscle phosphorylase, Ed became so captivated with biochemistry that this intially reluctant biochemist never returned to internal medicine. The next step was to find a permanent faculty position.

During his naval service, Ed’s ship had gone to Seattle. The tranquil waters of the Puget Sound and the natural beauty of the city left a lasting impression. So, in 1948, he happily accepted a position as assistant professor of biochemistry in the fledgling University of Washington School of Medicine. Under the capable leadership of Hans Neurath, the department of biochemistry was being expanded to incorporate expertise in protein chemistry and enzymology. This included the recruitment of Edmond Fischer in 1953— a talented and charismatic Swiss biochemist with experience in the enzymatic analysis of potato phosphorylase. Thus, a lifelong friendship and a formidable research partnership was forged.

Krebs-Phosphatase
This iconic image depicts the protein phosphorylation-dephosphorylation process as elucidated by Edwin Krebs and Edmond Fisher in their seminal 1955 Journal of Biological Chemistry paper (1).

Together, Ed (Krebs) and Eddy (Fischer) determined the mechanism by which 5’-AMP served as an activator of phosphorylase b. They found that ATP was required for phosphorylase activation and, in a somewhat unusual experiment, discovered that calcium, leaching from filter paper used to clarify the extract, was an important co-factor. By using gamma-32P-labeled ATP, they demonstrated that phosphate was incorporated into a specific serine residue of phosphorylase, thereby yielding the activated phosphorylase  form. This landmark paper was published in the Journal of Biological Chemistry in 1955 (1). Subsequently, Krebs, Fischer and colleagues confirmed that this phosphorylation is mediated by a phosphorylase  kinase, which is itself controlled by a cAMP-responsive kinase, leading to the idea of a kinase cascade. In 1968, Krebs purified this cAMP-dependent protein kinase (PKA).

At this point in his career, interests in teaching and certain aspects of administration motivated Krebs. In 1968, he was attracted by the opportunity to become the founding chairman of the department of biological chemistry at the University of California, Davis, and stayed for a period of eight years. Ed also embarked on his long association with the American Society for Biochemistry and Molecular Biology, initially by joining the editorial board of the Journal of Biological Chemistry. In 1972, he became associate editor for the journal and remained in this position for more than 20 years. He also served as the president of ASBMB  in 1985. In 1977, he returned to the University of Washington as chairman of the department of pharmacology. What he liked most about both positions, he said, was the responsibility of selecting good faculty members for the departments. At UW he was also appointed an investigator for the Howard Hughes Medical Institute.

After achieving his goals as department chair in 1983, Krebs refocused his efforts on research and training junior scientists. At this later stage in his career, he set his sights on solving new problems in signal transduction. His laboratory contributed to the analysis of phosphotyrosine signaling events and published key findings that were instrumental in the discovery of a new phosphorylation cascade— the MAP kinase pathway.

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COMMENTS:

I performed 2 years of post doctoral research on rabbit heart phosphorylase under Doctor Krebs. I still feel that I am a student learning of new advances in biochemistry from him. I was deeply moved and saddened to read of his passing. Louis Schliselfeld

 

I was deeply moved by the passing of Ed Krebs. John Scott captured what we all who knew him feel at his passing. Like many, we learned of his great joy of science and boundless ability to encourage the best science through his role as an editor. Later, at meetings of the editorial board of The JBC, I was able truly to appreciate his insights and to value his advice to me concerning my career path. Few will be as sorely missed as Ed Krebs. He left a legacy that we both admire and should try to emulate in some modest way. Craig C. Malbon Leading Professor and Director, DMDRC Department of Pharmacology SUNY-Stony Brook

 

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