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Reverse transcriptase, a paradigm-busting enzyme

Reverse transcriptase is an enzyme that synthesizes DNA using RNA as a template. Its discovery in 1970, separately by Howard Temin and David Baltimore, was met initially with much skepticism. After all, the central dogma of molecular biology, already enshrined in textbooks of the day, held that information flowed from DNA to RNA to protein. The idea that DNA could be encoded by RNA required rethinking a long list of firmly held notions. Opposition to the idea crumbled quickly, however, as the results were rapidly replicated by others. The enzyme went from being a paradigm-busting phenomenon to a standard item in the molecular biology toolkit in record time. It became invaluable for creating DNA probes complementary to messenger RNA, for instance.

The day that they announced the 1975 Nobel Prize for Physiology or Medicine was one of great rejoicing in the Tumor Virology Laboratory at the Salk Institute. Baltimore and Temin were awarded the prize for their discovery of reverse transcriptase along with Temin's former mentor, Renato Dulbecco, who invented the techniques that led to the discovery. Dulbecco was a member of the Tumor Virology Lab at the time, and Baltimore was an alumnus.  Baltimore's former postdoc, Hung Fan (my thesis adviser) and the incomparable Marguerite Vogt, Dulbecco's long-time collaborator, also held positions at the Lab. The usual 4 p.m. break for tea and cookies morphed into a champagne and cheese party, capped with a congratulatory call to Baltimore.

Reverse transcriptase was found first in retroviruses, which have an RNA genome that is transcribed into DNA and integrated into the host genome. Once integrated, it uses the normal cell machinery for its expression. Such integration can have devastating results, causing somatic mutations and sometimes cancer.  HIV, the virus that causes AIDS, is a retrovirus.

By 1975, it was already clear that many vertebrates had endogenous retroviruses that were inherited vertically—they had essentially become part of the organism. In addition, it turned out that eucaryotic genomes were riddled with 'retrotransposons,' genetic elements that encode a reverse transcriptase that allows the sequences to move about within the genome and amplify their presence. Over 40% of the human genome consists of retrotransposons or defective remnants thereof.  Mobile 'group II introns' that encode a reverse transcriptase activity interrupt conserved genes in mitochondria, chloroplasts and bacteria. 

The existence of reverse transcriptase has done considerable damage to the idea of DNA as a sacrosanct store of genetic information delivered intact from generation to generation. Obviously, tight control must be exerted over reverse transcriptase activity in individual cells to keep the genome from being irreversibly scrambled in the near term. At the same time, reverse-transcribed sequences must be considered as sources of genetic diversity on an evolutionary scale. Beyond that, the use of RNA as a genetic precursor to DNA points to a possible "RNA world" in which life was much different than it is today.

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