Memorial Resolution of the Faculty of the University of Wisconsin-Madison on the Death of Professor Howard M. Temin
On February 9, 1994, Dr. Howard M. Temin, Professor of Oncology at the University of Wisconsin-Madison, died from an adenocarcinoma of the lung after 17 months of determined resistance to that disease. His wife, Dr. Rayla Greenberg Temin, and daughters, Sarah and Miriam, were with him at their home in Madison, Wisconsin. Howard Temin, a consummate autodidact and experimentalist, had apprised himself of current therapies for this tumor, been so treated, and had gone on to accept two new experimental therapies. This need to understand in detail and to learn by experimentation was also fundamental to his life-long pursuit of the genetic analysis of retroviruses. (This family of viruses is so named, because as Howard Temin showed, it carries RNA in its virus particle which it copies into DNA in the infected cell.)
Howard Temin began to investigate viruses as a young graduate student at the California Institute of Technology in the late 1950s with Dr. Renato Dulbecco. He refined and characterized an assay for the cancer-causing Rous Sarcoma Virus (RSV) in cell culture. The quantitative focus assay remains a standard tool used for genetic studies of many oncogenic viruses in cell culture today.
Temin moved to the McArdle Laboratory for Cancer Research at the University of Wisconsin Medical School in 1960, where he continued to characterize the life cycle of RSV in chicken cells in culture. His observations led him to propose that RSV synthesized from its RNA a DNA provirus by which it maintained itself in infected cells. This heretical view was met with general disdain; current wisdom ordained that genetic information could flow only from DNA to RNA and not the reverse. Temin supported his hypothesis with varied genetic and biochemical findings, but failed to win its acceptance. Only when he and his colleague, Dr. Satoshi Mizutani, in 1970 identified (as did Dr. David Baltimore) an enzymatic activity that synthesized DNA and used an RNA template did the scientific community accept his "provirus hypothesis". This enzyme, termed reverse transcriptase, mediates the reverse-flow of genetic information that had been previously unacceptable to biologists.
The importance of Howard Temin's provirus hypothesis is twofold. First, it extends far beyond RSV: many genetic elements from Ty-elements in yeast to Human Immunodeficiency Virus (HIV) in people use reverse transcription to propagate themselves. Second, Howard Temin's use of determined, insightful experimentation to test an unpopular hypothesis is a striking example of how the focused work of one scientist can change how we all think. He was awarded the Nobel prize in physiology or medicine in 1975 for these contributions.
In the following years Howard Temin, his students and postdoctoral fellows pursued two intertwined problems of retrovirology: how, in detail, does this family of viruses replicate, and what is the origin and extent of retroviral genetic variation? These pursuits led them to appreciate that retroviruses exquisitely regulate synthesis of viral nucleic acids at all steps of their life-cycle including that of the RNA genome, its DNA copy which is integrated into the host cell's DNA as the provirus, and messenger RNAs copied from the provirus. They demonstrated that viral messenger RNAs are spliced (that is, derived from a long primary RNA molecule by linking non-contiguous tracts and eliminating the intervening sequences), but that some of the long primary RNA molecules must remain intact to serve as progeny genomic RNAs. They identified the retroviral int gene required for integration of the provirus and the nucleotide changes imposed on the provirus as a consequence of its mechanism of synthesis and integration. To analyze retroviral genetic variation, they developed helper cells that provide all trans-acting viral genes (these encode the viral proteins that contribute to the virus particle) so that retroviral derivatives containing only retroviral cis-acting genetic elements (signals intrinsic to viral nucleic acids) can replicate and be packaged in these cells. These helper cells were used to measure composite rates of a variety of retroviral mutational events to be 2 × 10-5 per base per round of replication, which is dramatically higher than that found for similar mutations in cellular DNA.
All of these studies have contributed to the practical application of retroviruses to gene therapy. Howard Temin and his colleagues developed derivatives of retroviruses, termed retroviral vectors, that can be propagated in helper cells which on infecting normal cells can introduce genetic information but cannot spread by infection to additional cells. Such retroviral vectors are the tool of choice for most current trials for human gene therapies.
During these years of extraordinary scientific productivity Howard Temin was anything but a reclusive investigator. He served on the editorial boards of numerous journals and scientific advisory boards including, until the time of his death, the National Cancer Advisory Board. Temin also pioneered an intensive course for advanced undergraduate and graduate students in virology, which he taught with Dr. Bill McClain for more than 20 years. He trained more than 60 graduate students and postdoctoral fellows with a dedicated thoughtfulness. He also identified major social problems that he felt both qualified and compelled to tackle. His colleagues in McArdle had introduced him to the chemistry and biological activities of the carcinogenic polycyclic aromatic hydrocarbons generated in cigarette smoke. He used his national prominence as a position from which to attack smoking as the major environmental contributor to human cancer. Before the Human Immunodeficiency Virus (HIV) received its name, Howard Temin recognized that AIDS would reach epidemic proportions internationally, and he worked hard to increase U.S. funding of peer-reviewed research on HIV. He both chaired the subcommittee on AIDS for the National Cancer Advisory Board and served on the World Health Organization Advisory Council on HIV and AIDS.
In addition to the Nobel Prize, Temin received numerous awards in recognition of his work including nine honorary degrees, the Bertner Award, the Albert Lasker Award in Basic Medical Research, and the National Medal of Science in 1992. He was chosen for the first Hilldale Award in the Biological Sciences at the University of Wisconsin-Madison in 1986 and held the American Cancer Society Professorship of Viral Oncology and Cell Biology, the Harold P. Rusch Professorship of Cancer Research, and the Steenbock Professorship of Biological Sciences. Temin was elected to the prestigious National Academy of Sciences U.S.A. in 1974.
Howard Temin combined an intense appreciation of science, how to conduct it and how to train colleagues in it, with a recognition of the debt that scientists owe to the citizens who fund the research. He strove to understand the life cycle of retroviruses and to use that understanding to benefit society. He and his colleagues were developing a chimeric derivative of HIV as a potential vaccine for HIV when he died at age 59.
- William F. Dove
- William H. McClain
- Janet E. Mertz
- Roland R. Rueckert
- Bill Sugden, Chair