Not Beyond Reasonable Doubt: Howard Temin’s Provirus Hypothesis Revisited

Abstract

During the 1960s, Howard M. Temin (1934-1994), dared to advocate a "heretical" hypothesis that appeared to be at variance with the central dogma of molecular biology, understood by many to imply that information transfer in nature occurred only from DNA to RNA. Temin's provirus hypothesis offered a simple explanation of both virus replication and viral-induced cancer and stated that Rous sarcoma virus, an RNA virus, is replicated via a DNA intermediate. Popular accounts of this scientific episode, written after the discovery of an RNA-directed DNA polymerase in 1970, tend to describe the reaction to his proposition as ardent opposition. Typically these accounts use a [Symbol: see text]molecular biology' standpoint emphasizing the central dogma's part in its rejection. In this article, however, this episode will be examined from a joint perspective of virology and experimental cancer research. From this perspective it is clear that Temin's work was well within the epistemological and methodological boundaries of virology and cancer research. Still, scientists did have reasons to doubt the provirus hypothesis, but these do not seem to be good enough to either justify an account that portrays Temin as a renegade or his ideas as heretical.

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“…128 As the historian Susie Fisher has noted, his idea in this early iteration was a 'genetic' explanation for the action of tumour viruses that 'contained no statement about the molecular nature of the provirus'. 129 In theory, it was not really very different from the previously offered explanations for lysogeny, but the implications, as his fellow-Nobelist David Baltimore later observed, were quite heretical: Howard's solution was chemically simple but without precedent: if the RNA were copied into DNA, then everything would fall into line … Conceptually, a snap-but totally unacceptable to almost everyone then in molecular biology because it ran counter to the guiding dogma, that DNA makes RNA makes protein. 130 What fed Temin's conviction of the rightness of his idea, Baltimore added, was the stability of the cells transformed by RSV:…”

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“…In 1964, he provided the results of hybridization experiments demonstrating in the genome of infected cells the presence of DNA sequences able to hybridize with the viral RNA (Temin 1964). Historians have shown that these experiments did not convince the community of biologists, not because of the allegiance of the latter to the Central Dogma, but because the signals were low and not easily distinguishable from the background noise (Marcum 2002;Fisher 2010). The demonstration of the model came from the isolation and characterization in 1970 by David Baltimore and Howard Temin himself of an RNAdependent DNA polymerase (Baltimore 1970;Temin and Mizutani 1970).…”

Not just “a clever way to detect whether DNA really made RNA”1: The invention of DNA–RNA hybridization and its outcome1Judson (1979, p. 440).

“…This experiment brought him into direct conflict with facts formerly produced at Spiegelman's laboratory (Doi & Spiegelman, 1962) that clearly showed that RNA bacteriophage (MS-2) do not replicate by making a DNA copy of their genome. I have argued elsewhere that Spiegelman's authoritative standing in the field and the quality of the work performed at his laboratory contributed significantly to the rejection of Temin's provirus hypothesis (Fisher, 2010). Also, biologists interested in embryology and development, processes in which synthesis of new proteins was known to occur, used the technique to detect synthesis of new RNA.…”