Biology 1970

Reverse Transcriptase: RNA-dependent DNA Polymerase in RNA Viruses

Howard Temin & David Baltimore

Two labs found an enzyme that copies RNA back into DNA — reversing the central dogma and founding retrovirology.

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In depth · the introduction

Everyone knew information in a cell flowed DNA → RNA → protein. Then two labs found an enzyme running it backwards.

The big idea

The "central dogma" of biology said genetic information moves in one direction: from DNA, which is copied into RNA, which is read to build proteins. Reverse seemed impossible — nothing was known that could turn RNA back into DNA.

Then, in 1970, two scientists working separately found exactly that: an enzyme, carried inside certain viruses, that reads an RNA strand and writes a matching DNA strand. They called it reverse transcriptase. Information could flow RNA → DNA after all — and a whole family of viruses turned out to depend on it.

How it came about

For years Howard Temin had insisted that a virus made only of RNA must, somehow, make a DNA copy of itself and slip that copy into the host cell's own genome — a hidden "provirus." Most biologists thought the idea was wrong, because it needed a backwards step no one had ever seen.

Temin (with Satoshi Mizutani) and, quite separately, David Baltimore went looking for the missing enzyme — and both found it inside the virus particles. Their two papers appeared side by side in the same June 1970 issue of Nature. The result was so clean it was repeated and believed within weeks. In 1975 Temin and Baltimore shared the Nobel Prize with Renato Dulbecco.

Why it mattered

It rewrote a rule everyone had been taught, and it founded a field. The viruses that use reverse transcriptase are now called retroviruses — and one of them, discovered a decade later, is HIV. Understanding reverse transcription is exactly what let scientists design the first drugs against AIDS: medicines that jam the enzyme so the virus cannot copy itself.

A way to picture it

Imagine a printing press that only ever goes one way: from a master metal plate (DNA) you print paper copies (RNA), and from the paper you make products (proteins). Reverse transcriptase is a machine that can take a paper copy and cast a brand-new metal plate from it — running the press backwards. A retrovirus arrives carrying only paper, then builds its own plate and quietly files it inside your master archive.

Where it sits

This is the great revision of Crick's 1958 central dogma and the sequel to Watson and Crick's double helix. It opened retrovirology — the study that, a decade later, made sense of HIV — and it handed molecular biology one of its most-used tools, the RT in RT-PCR. The enzyme that keeps our own chromosome ends intact, telomerase, turned out to be a reverse transcriptase too.

The original document

Original source text

D. Baltimore · "RNA-dependent DNA Polymerase in Virions of RNA Tumour Viruses" · Nature 226 (1970): 1209–1211

H. M. Temin & S. Mizutani · "RNA-dependent DNA Polymerase in Virions of Rous Sarcoma Virus" · Nature 226 (1970): 1211–1213

In the issue of 27 June 1970, Nature carried two independent reports — one from Baltimore at MIT, one from Temin and Mizutani at Wisconsin — that reached the same conclusion, and grouped them under the heading "Viral RNA-dependent DNA Polymerase."

The question

Since the mid-1960s Temin had argued, against the consensus, that RNA tumour viruses such as Rous sarcoma virus replicate through a DNA intermediate — a "provirus" integrated into the host chromosome. That demanded an unknown step: copying RNA into DNA, a direction no enzyme was known to take and which seemed to run against the central dogma.

The experiment

Purified virions were gently disrupted with a detergent and incubated with the four deoxyribonucleoside triphosphates and a magnesium salt. The virions synthesized DNA on their own. Crucially, treating the virions with ribonuclease beforehand abolished the synthesis — showing that the template being copied was the viral RNA — and the product behaved as DNA and hybridized back to that RNA.

The finding

Each virion carries its own enzyme, an RNA-dependent DNA polymerase — later named reverse transcriptase — that transcribes the viral RNA genome into DNA. Genetic information can flow RNA → DNA. The result was reproduced within weeks and accepted almost at once.

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Nature · 27 June 1970