Robert T. Schimke (1932 – 2014)

Robert T. Schimke Robert T. Schimke

Robert Tod Schimke, an emeritus professor of biology at Stanford University, died Sept. 6 at age 81. An outstanding scientist, he had spent almost his entire career at Stanford, where he was renowned as irreverent, creative and unpretentious and as a leader, scholar and teacher with high values and standards. Students at all levels gained from their association with him, flourished and grew. He left behind an enviable legacy.

ACCOLADES

In recognition of his many contributions to science, Schimke received the following accolades:

  • the Boris Pregel Award from the New York Academy of Sciences (1974)
  • the William C. Rose Award from the ASBMB (1983)
  • the Alfred P. Sloan Jr. Prize from the General Motors Cancer Research Foundation (1985)
  • the Lila and Murray Gruber Memorial Cancer Research Award from the American Academy of Dermatology (1988)

FIND OUT MORE

Schimke’s art collection
ASBMB Today feature

Schimke was born in Spokane, Wash., in 1932. He earned both A.B. (1954) and M.D. (1958) degrees from Stanford and completed a two-year residency training at the Massachusetts General Hospital in Boston. He then served in the Public Health Service at the National Institutes of Health in Bethesda, Md., from 1960 to 1966 before he returned to Stanford in the pharmacology department in the School of Medicine. He served as chairman of the department from 1970 to 1973. He then moved to the biological sciences department, which he chaired from1978 to 1982. He was named the American Cancer Society research professor of biology in 1983.

Schimke made several pioneering discoveries. In the 1960s, while working in the Biochemical Pharmacology Laboratory at what was then the National Institutes of Arthritis and Metabolic Diseases, he demonstrated that the rate of protein degradation can be regulated, an important mechanism controlling protein levels in cells. While researchers had assumed that steady-state level of proteins in cells resulted from the balance between synthesis and degradation rates, they had devoted far more attention to studying the regulation of synthesis. Schimke showed that, for both arginase and tryptophan pyrrolase, degradation rates were regulated and that degradation rates and synthesis rates together controlled steady-state levels. This work established protein turnover as a major field of biochemistry.

He was also a leading early contributor in demonstrating hormonal control of gene expression. In his tryptophan pyrrolase work, Schimke showed that the increase in its activity resulting from the administration of hydrocortisone or tryptophan is a product of both enzyme synthesis and enzyme stabilization.

“Studying the time course of changing enzyme levels as well as the enzyme's incorporation and loss of isotopic amino acids in response to the two agents, (Schimke’s team) showed that hydrocortisone increased the rate of tryptophan pyrrolase synthesis whereas tryptophan decreased the rate of its degradation,” a 2007 tribute in the Journal of Biological Chemistry said. “This led to their conclusion that ‘rates of enzyme synthesis are mediated by hormonal action, whereas substrates or cofactors act by altering the rate of enzyme degradation.’” This work was selected as a JBC Classic article.

Schimke’s group explored extensively the role of hormone action in gene regulation by studying estrogen effects on ovalbumin synthesis in hen oviduct. Advances in novel technology, including those allowing isolation of specific mRNAs by immunoprecipitation of polysomes carrying ovalbumin nascent chains, marked this work. Importantly, this work emerged during the dawn of recombinant DNA technology and modern molecular biology, and Schimke and colleagues were the first to express a eukaryotic gene, dihydrofolate reductase in E. coli.

In the late 1970s, Schimke and his lab studied the mechanism of resistance to the killing effects of the cancer drug methotrexate in tissue culture cells. As this work progressed and DNA technology advanced, it became clear that the major mechanism for drug resistance was an increase in gene copy number, amplification of the gene that was the drug target – in this case, dihydrofolate reductase. Schimke and his colleagues used cDNA sequences complementary to dihydrofolate reductase mRNA to quantitate dihydrofolate reductase mRNA and gene copies in both the sensitive and resistant lines. They found that the dihydrofolate reductase gene multiplied selectively about 200 times in the resistant line. Similarly, they showed that when the resistant cell line grew in the absence of methotrexate, it eventually lost its resistance due to a decrease in the dihydrofolate reductase gene copy number. Thus, they concluded that selective multiplication of the dihydrofolate reductase gene accounted for the overproduction of dihydrofolate reductase.

“In the paper, Schimke suggested that the extra genetic material might have resulted from a number of processes including tandem duplications, unequal exchanges between sister chromatids, disproportionate replication of specific genes and retention of specific chromosomal fragments,” the JBC tribute said. This work was selected as a JBC Classic article.

The importance of this pioneering work went well beyond resistance to chemotherapeutic agents and established, surprisingly, that genomes can be quite unstable. Furthermore, the clinical implications were important, as one of the other major mechanisms of drug resistance in cancer patients was amplification of the gene for P-glycoprotein, the multidrug transporter that effectively reduced drug levels in cells by pumping the drug out of the cells.

IN MEMORY

Donations may be made to:
Robert T. Schimke Graduate Fellowship Fund
Department of Biology
Gilbert Hall
Stanford, CA 94305-5020

 

Other spinoffs of this work included the induction of gene amplification in tissue culture cells as one method by biotechnology companies to produce large amounts of proteins for therapeutic use. This approach has been used to produce proteins such as erythropoietin and tissue plasminogen activator. Pursuing the mechanisms underlying selective gene amplification led to Schimke’s discovery that the selective pressures on cells from interruption of cell-cycle events were critical for induction of genomic instability leading to gene amplification.

In 1995, Schimke, long an avid and competitive cyclist, was hit by a car while riding in the hills behind the Stanford campus. The accident left him a quadriplegic and confined to a wheelchair. Partly due to the accident, he became an emeritus professor and turned to his other life passion: painting.

In spite of limited dexterity in his arms and hands, he produced more than 400 works of art that testify to the same energy, originality, creativity and indefatigable spirit that characterized his research. His paintings have been exhibited at Silicon Valley Open Studios, Stanford’s Center for Integrated Systems and the Google corporate headquarters. Others are on display at Genentech, Amgen, the National Institutes of Health, the headquarters of the American Society for Biochemistry and Molecular Biology, the Stanford University biology department, and the Jennie Smoly Caruthers Biotechnology Building at the University of Colorado Boulder.

Throughout his career, Schimke was a forceful and effective leader. In addition to serving as chairman of two departments at Stanford, he served as a member of the editorial board (1975 – 1981) and as an associate editor (1983 – 2002) for the JBC. His leadership was instrumental in establishing the high standards of the journal. He was elected president of the ASBMB in 1988. He served on countless advisory boards. He won election to the National Academy of Sciences in 1976 and to the Institute of Medicine in 1983.

On a more personal level, he was certainly one of a kind – a maverick more interested in new ideas and opening up new areas of thought than in conforming to any so-called accepted standards. As an illustration, he was fond of giving seminars with no slides and only the minimal use of a chalkboard. More than one person noted that he managed to get more across in an hour this way than someone showing 50 fancy slides. He developed and relished having a reputation as a critical, practical, no-nonsense scientist.

Schimke mentored more than 100 undergraduates, graduate students and postdoctoral fellows in his laboratory, and many went on to have distinguished careers and leadership positions in the biomedical sciences. The enduring love, respect, admiration and appreciation of his students and colleagues were periodically demonstrated by reunions that drew dozens of former lab members from around the world. Schimke relished their success and always was delighted to learn of their recent research. He was a force of nature, impossible to replace.

Robert D. Simoni ( rdsimoni@stanford.edu) is a professor at Stanford University. Ralph A. Bradshaw ( rab@cgl.ucsf.edu) is a professor at the University of California, San Francisco.