Upsetting Dogma

For more than a decade, most scientists have accepted the "central dogma" of molecular biology without question. Stated simply, that dogma holds that the heredity information in living cells is always passed along in the same direction: from the "double helix" DNA molecule to the single-stranded messenger RNA molecule, which in turn directs the synthesis of protein--which is essential to all life. Since the end of May, however, investigators at three separate laboratories have stunned the scientific community by revealing that the central dogma is contradicted by the activities of cancer-producing viruses.

The dogma was challenged experimentally in 1964, when Howard Temin of the University of Wisconsin suggested that certain viruses consisting of only RNA and a protein sheath may cause cancer by making their own DNA once they invade a host cell. This new DNA would then become permanently incorporated in the host cell, giving orders for the production of cancerous cells and more cancer-producing viruses.

Invading Viruses. Teminism, as the theory came to be called, received little support from other scientists; it suggested that RNA could pass genetic information along to DNA, a clear reversal of accepted dogma. But Temin refused to abandon his idea. He knew that tumor-causing RNA viruses somehow inject their deadly message permanently into the host cell; otherwise, the cancer would not be passed on during cell division to future generations of cells. Yet the invading viruses carry with them no DNA of their own. Therefore, Temin reasoned, they must somehow make DNA after invading the host cell. The only way to do this would be by passing information from RNA to DNA.

Last month, Temin with his colleague, Satoshi Mizutani. and David Baltimore of M.I.T. published back-to-back papers in the journal Nature offering experimental evidence that RNA viruses causing cancer in animals are capable of assembling their own DNA. Their work was quickly confirmed by Sol Spiegelman, head of Columbia University's Institute for Cancer Research and one of molecular biology's most brilliant experimenters.

All three researchers confirmed the fact that viral RNA material was indeed producing its own DNA. They labelled four chemical building blocks of DNA with a radioactive isotope of hydrogen called tritium. After mixing the building blocks with viral RNA, the "tracer" element appeared in what was chemically identified as DNA. Thus it was apparent that the RNA had assembled the blocks to form DNA in its own image.

Backwards Reaction. One of Spiegelman's checks was even more convincing. He reasoned that if the RNA had served as a template for DNA, the RNA wou'd be complementary to one strand of the DNA and should be able to join it, forming a double-stranded hybrid. He mixed minute amounts of both molecules and whirled them in a centrifuge for three days. Because the density of RNA is different from that of DNA, the strands gradually separated in the test tube, forming two distinct layers. To his delight there also appeared a third layer, which proved that a product of intermediate density--the combined RNA-DNA molecule--had indeed formed.

This result persuaded Spiegelman to throw his support behind Teminism. "We tend to believe that nature is uniform," he says, "so I was just as skeptical about the Temin hypothesis as everyone else. But there were so many peculiarities that could not be explained by what we already knew that it became clear he really had something."

So far, Spiegelman has tested twelve RNA viruses for this "backwards" reaction. Eight of them, which cause tumors in animals, can do it; four, which do not cause tumors, cannot. Circumstantially at least, the results hint that a virus capable of causing cancer might depend upon this reaction. Researchers are already trying to relate these results to virus activity in humans and identify the enzyme that governs the reaction. It is already known that the transfer of genetic information from DNA to RNA can be blocked; an antibiotic can knock the crucial enzyme out of action. Once the key enzyme that enables RNA to produce DNA is identified, the reverse reaction--and perhaps cancer itself--could conceivably be stopped in the same way.

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