Genes or Chromosomes?

Article excerpt

Searching anew for the origins of cancer.

Peter Duesberg of U.C. Berkeley has recently pointed out that virtually all solid malignant tumors have the wrong number of chromosomes; usually too many. Sometimes they may have several copies of a given chromosome, Cells with the wrong number of chromosomes are said to be "aneuploid"; those with the right number are "diploid." This is not a new discovery. When researchers such as Theodor Boveri studied cancer cells under the microscope a century ago, the first thing they noticed was the abundance of chromosomes. Amazingly, the correct number-46 in humans-was not determined until 1956, three years after Watson and Crick had described the much smaller, less visible double helix of DNA.

Boveri predicted in 1914 that aneuploidy would turn out to be the cause of cancer, and today Duesberg believes he was right. A recent article in the Economist about his cancer theories noted: "Dr. Duesberg achieved notoriety more than ten years ago for his hypothesis that the human immunodeficiency virus, HIV, does not cause AIDS. In terms of challenging conventional wisdom, that was a hard act to follow. The aneuploidy hypothesis, however, appears a worthy successor." Nonetheless, "the ubiquity of aneuploidy in cancers does need explaining."

Boveri's discovery was forgotten by the mid-1970's. The new theory was that gene mutations cause cancer. Michael Bishop and Harold Varmus won the Nobel Prize for discovering cellular (as opposed to viral) "oncogenes," but their ability to cause cancer is still in doubt. Later, Varmus became the director of the National Institutes of Health. For the last ao years or so the vast bulk of research funds at the disposal of the National Cancer Institute and other agencies has been devoted to the hunt for cancer genes.

Last summer, Robert A. Weinberg and William Hahn of MIT announced that the mutation of three genes was "sufficient to transform a normal human cell to one capable of producing a tumor." The New York Times duly came through with a page-one article-one of many the newspaper has published in the past 15 years about new cancer genes. But it was not reassuring to learn, in the commentary in Nature, that the most recent find had come "after more than 15 years of trying." What about all those earlier cancer genes?

When Duesberg's lab at Berkeley asked to see the cell lines generated by Weinberg's "three genes," they turned out to be aneuploid. This finding was published in the Proceedings of the National Academy of Sciences (March 28), with sample cells from each (of two) cell lines depicted. One had 78 chromosomes, another 82-almost double the right number. The significance of aneuploidy is that each chromosome carries anything from several hundred to thousands of genes, so that if a cell has two or three, or worse, 30 or 40 extra chromosomes, the number of genes at work in the cell has been greatly increased. Their added output is probably sufficient to override the control mechanisms that ensure the normal cell doesn't take on a life of its own, as cancer cells do. If a cell has extra chromosomes, then, and out of its thousands of extra genes a handful are mutated, how can we be sure that it is the few mutations, and not the huge DNA increment, that causes the cancer? Diploid cancer cells are what is needed to prove Duesberg wrong. (We are not talking about leukemia, where diploid cells are common.)

I phoned Weinberg's lab, and he picked up himself-a very confident voice. I asked him, first, if it is true that most solid cancers are aneuploid. His books on cancer research have not mentioned aneuploidy.

"Yes it is," he said. "But there are exceptions, and it is not true that aneuploidy is an inevitable prerequisite for making a tumor, as Duesberg would imply."

The cell lines sent to Duesberg's lab were apparently aneuploid, I said.

"That's what he says," Weinberg replied, "but we analyzed the same ones more carefully, and one of the cell lines we sent him is perfectly diploid. …