They sit in the genes like ticking time bombs.
Within every human cell, 30 to 40 normal genes, and perhaps as many as 100 or more, await a random event that will convert a cell into the progenitor of an uncontrollably growing ball of cells, a cancer.
"We contain the seeds of our own destruction," said Dr. Stuart A. Aaronson of the National Cancer Institute, one of several researchers from across the country who reported new insights into the formation of cancer during the annual meeting of the American Association for the Advancement of Science here.
Called oncogenes, these malevolent transformers are currently the subject of intense scientific scrutiny by researchers probing the causes of cancer.
While oncogene research does not yet offer a cure for America's most feared disease, it does promise advances in early diagnosis -- as early as in the womb. It is also shedding light on other diseases including cystic fibrosis.
Oncogenes were first identified in the mid-1970s by virus experts trying to understand why some viruses cause cancer in animals. Scientists have suspected for decades that cancer was caused by some genetic event, but there had been heated debate about what that change actually was.
The answer came from studying a peculiar virus called a retrovirus. These semi-living entities invade normal cells and bury their own genes in the chromosomes of the human cells. Occasionally, when reproducing, they carry away a piece of a human gene.
In 1975, Drs. J. Michael Bishop and Harold Varmus from the University of California at San Francisco discovered "that cancer-causing genes thought to have somehow become implanted in an infected animal by a virus were in fact the animal's own genes, but genes that had been thrown out of whack so they did not function properly," wrote Edward J. Sylvester in his new book, "Target: Cancer."
What's more, said NCI's Aaronson, "these genes are essential for normal life processes in their normal form." But through alterations caused by such things as cigarette smoke or radiation, "they are being subverted to cause cancer."
At the AAAS meeting, Aaronson reported on recent work showing that one oncogene, called sis, is actually a normal gene that directs the production of a substance called human platelet-derived growth factor, or PDGF.
In the body, PDGF is released into the bloodstream to stimulate specialized cells, with PDGF receptors, to begin multiplying so they can help repair a wound. Once stimulated, these cells begin to divide rapidly. Normally, they do not produce their own PDGF, and when PDGF synthesis is shut off, cell division stops.
But in some kinds of cancer, the sis gene is turned on within the cells that have PDGF-receptors. In essence, they become self-stimulating and begin to grow out of control.
"How stimulating the receptor causes the cell to become cancerous is not known," Aaronson said. Subsequent experiments showed that PDGF produced in the laboratory also had the ability to turn normal cells into cancer cells. But, he said, when the externally supplied PDGF was removed, the cells reverted to normal.
"We are starting to find the normal role of oncogenes," Aaronson said, and that leads to the beginnings of an understanding of how they turn normal cells into cancer cells.
But what is learned about one oncogene is not aways applicable to another.
"There is no commonality between the ways the oncogenes work," said Dr. Indera Verma of the Salk Institute in LaJolla, Calif.
Oncogenes fall into several categories. Those like sis produce growth factors; others produce slightly mutated growth hormone receptors; still others produce a kind of enzyme that goes around the cell sticking phosphate atoms on other essential molecules; some function within the nucleus of the cell where the genes are located.
But, said Aaronson, they all have one thing in common: They all seem to play a role in stimulating cell division and somehow, in the cancerous cells, block the cells from maturing into ones that ultimately stop dividing.
"The cell is hovering on the point of disasterous transformation, yet it needs these genes to survive," said Salk's Verma.
What turns normal genes into oncogenes is not totally known. Classic cancer-causing agents include chemicals in the environment, substances in food, stray bits of radiation and certainly the carcinogens in cigarette smoke. All these substances are believed to have their most profound effect at the genetic level.
What happens after chemicals or radiation attack the genes is not clear because there seem to be several mechanisms for activating an oncogene. These include:
*mutations, in which there is a small change in the protein made by that gene;
*translocations, in which a gene moves from one of the cell's 46 chromosomes to another;
*deregulation, in which an oncogene that normally is turned off in that cell type is turned on; and
*amplification, in which a gene that normally is present only in small amounts in the cell suddenly reproduces itself so that there are hundreds of copies of the gene.
It is also unclear whether oncogene research will lead to new treatments for cancer, but many researchers expect it to produce some advances.
"The first benefits will come from earlier detection of cancer and better methods of diagnosing cancer," NCI's Aaronson said.
Segments of known oncogenes could be used as probes to search for active oncogenes in samples of tissue collected during a biopsy. If active oncogenes are found, cancer treatment could begin even before symptoms appeared. And the earlier a treatment begins, the better the chance of survival.
For example, a few types of cancer appear to be inherited, but no tests have been available to predict which children would be affected.
"Retinoblastoma is the prototype cancer of genetic inheritence" because nearly half of the children of parents who carry the genes for this disorder get the disease, said Dr. Webster K. Cavenee from the University of Cincinnati College of Medicine.
Inherited retinoblastoma causes uncontrolled growth of the eye's retina. It frequently turns up in children younger than 1. The normal treatment is removal of the affected eye. Often both eyes must be removed.
Cavenee's group developed a probe for retinoblastoma that, while not actually identifying an oncogene associated with the disease, does determine whether a special genetic rearrangement associated with the disorder has occurred.
In one woman in her late thirties who previously had a child with retinoblastoma, Cavenee was able to analyze amniotic cells (gathered by amniocentesis from the sac that surrounds the fetus) and show that the baby she was carrying also would suffer the disease.
Normally children are not examined for retinoblastoma until symptoms appear, but because of the early diagnosis, the child was taken into the operating room only days after birth for a careful examination of the eyes. The examination showed evidence of the cancer. Radiation therapy was used to control the tumors without the loss of sight in either eye.
Oncogene research also is shedding light on unrelated diseases. Dr. George F. Vande Woude of the National Cancer Institute's Frederick Cancer Research Facility reported that one oncogene, called met, appears to be closely linked to the gene that causes cystic fibrosis, a disorder that causes lung and digestive system deterioration and death.
The oncogene is frequently found in most carriers of cystic fibrosis in families with a history of the disease, but it is not specific enough to diagnose asymptomatic carriers in the general population.
Other oncogene research involves working to understand the regulatory systems within the genes so that someday it may be possible to actually turn off an oncogene and stop the cancerous growth.
"The task of trying to interrupt that process [of the oncogene turning a cell into a cancer cell] is very difficult," NCI's Aaronson said.
"It is not going to be easy," he said, but the oncogene research "is allowing scientists to think about how they might intervene."