A worm no bigger than this comma (,) which goes by the name ofCaenorhabditis elegans, has much to teach Homo sapiens, when itcomes to cancer-causing genes.C. elegans is a soil-dwelling nematode with a millimeter-long bodynumbering fewer than 1,000 cells, and about 15,000 genes containing100 million base pairs.One of its genes, ced-9, was discovered two years ago by molecularbiologist H. Robert Horvitz of the Howard Hughes Medical Institute atMIT. "ced" stands for "cell death, abnormal," Horvitz told BioWorldToday. It was the ninth mutant apoptosis gene found so far in C.elegans. This gene controls the process by which the nematode protectsits healthy cells from death by suicide. One of its mutant forms keepsthose unwanted cells alive too. The ced-9 gene encodes a protein,CED-9, with 280 amino acids.A similar gene in humans, bcl-2, performs a similar function, savingcells from premature apoptosis. But abnormal bcl-2, Horvitz said,"causes cells to survive that should die, and this makes it a cancer-causing gene." The letters "bcl" stand for "B-cell lymphoma.""This gene is distinctive," Horvitz observed, "and probably providesour first insight into an alternative oncogenic mechanism."Concretely, mutant bcl-2 appears to cause cancer in humans because itover-expresses its gene product, Bcl-2, in the immune system's B cells.This leads to too little cell death _ which is precisely what mutant ced-9 accomplishes in nematodes.The two gene products have similar protein sequences. Horvitz insertedbcl-2 genes into the C. elegans genome, and found that "those humansequences worked in the transgenic worm almost as well as its ownnative ced-9."What that means," he surmised, "is probably that evolution hasconserved the entire pathway of programmed cell death, fromroundworm to human. And what we learn about cell death in thenematode is very likely to be relevant to cell death, and the diseases itcauses, in humans."The number of cells in an individual, Horvitz pointed out, reflect twoantagonistic processes: cell division and cell loss. In some cancers, toomuch cell division produces too many cells. In cancers caused by bcl-2,too little cell death produces too many cells. Too much of the normalBcl-2, apparently leads to malignancy, because it prevents cell suicide.How do bcl-2 and ced-9 do their jobs of forestalling apoptosis, insickness and in health? Horvitz reports new insights on this question inthe current Nature, titled: "Activation of C. elegans cell death proteinCED-9 by an amino-acid substitution in a domain conserved in Bcl-2."When a normal copy of the bcl-2 gene falls under the control of aregulator for another immune system molecule, immunoglobulin H, itexpresses its normal protein, Bcl-2, but in the wrong place, namely inB cells. This imposes suicide prevention on the cells, and B-celllymphoma on their human hosts. (One such lymphoma victim wasreportedly Jackie Kennedy Onassis.)This blocking of cell death was comparable to that of a recentlydiscovered mutation in nematode gene ced-9. It too kept unwantedcells alive.Horvitz asked the question: "Did this roundworm mutation prevent cellsuicide in the same way as the known human cancer-causing mutations_ by over-expressing a perfectly normal gene?"The answer is `No,' he answered, "and that's what's new."As his Nature paper describes, the nematode's subversion of its ced-9gene to preventing cells that should die from dying results from a pointmutation in a single amino acid of its CED-9 protein, from a glycine toa glutamic acid."This alteration of a highly conserved residue," Horvitz emphasizes,"suggests that some kinds of cancer could be caused by the samesingle-amino-acid change." He reflects that "It's not very often you getsingle mutations in one amino acid that make a protein more active. It'susually the reverse. So it looks as if there may well be a new class ofmutation that could lead to oncogenesis."For biotechnology, Horvitz proposes, this new molecularunderstanding could be put to work now in drug discovery, "to findways of intervening, and controlling, the process of programmed celldeath."
-- David N. Leff Science Editor
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