BIOTECHNOLOGY : Developments in Genetic Engineering Continue at a Blistering Pace. Some Cheer Researchers On; Others Would Slam on the Brakes.

Paul Jacobs is a Times staff writer who covers biotechnology

We're almost 50 years into the biotechnology age and scientists still can't keep a lid on their enthusiasm. Why should they? Why should anyone? The newfound ability to decipher and manipulate genes, spurred by the promise of profits, has already resulted in developments that startle: Bacteria produce human insulin and other hormones; soybeans grow antibodies to the herpes virus; sheep produce milk rich in blood-clotting proteins; crops contain their own pesticides.

There are 79 biotech drugs on the market, and hundreds more in various stages of testing--a fleet of battleships being readied to head off forces already beginning to kill and maim an aging baby boom generation: cancer, heart disease, and brain disorders such as Alzheimer's and Parkinson's. In the blooming field of agricultural biotech, researchers are working on a second wave of genetically engineered crops, enriched with vitamins, proteins and heart-friendly fats. Moreover, it no longer seems farfetched to suggest that we'll soon test routinely for hundreds of genetic defects and then fix the problem with the genetic equivalent of duct tape: gene splicing. Researchers are injecting raw genes into damaged heart muscle to reverse the effects of heart attacks and transplanting rejuvenated brain cells to replace defective circuitry. There is even talk of attacking aging itself, with enzymes to turn back that ever-ticking biological clock.

So why, as we tip over the edge of the next millennium, do some practitioners of the new science apologize--cooling their zeal with a breath of caution? Why do environmentalists talk of Frankencrops and Frankenfoods, and ethicists fret over efforts to smooth away human variability?

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Don't talk to Bryon Vouga, 30, about the importance of the biotech revolution. The Anaheim Hills high school teacher found out that his kidneys were failing at age 16, when he flunked a high school sports physical. Soon he was one of 200,000 Americans who keep themselves alive by using dialysis to remove impurities from their blood. Like most dialysis patients, Vouga also was anemic because his kidneys did not produce enough of a hormone called erythropoietin, which stimulates the growth of red blood cells. He was so anemic, he recalls, that he'd drive his truck to Fullerton Community College, then snooze under the camper shell and miss all of his classes.

His life changed in 1989, when Amgen, the Thousand Oaks biotech company, began mass-producing a genetically engineered hormone under the brand name Epogen. Vouga's still on dialysis, after two unsuccessful kidney transplants and while waiting for a third. But he's now also an avid bicyclist. Last month he took off from Huntington Beach, heading for Jacksonville, Fla., on a 2,700-mile journey sponsored by the National Kidney Foundation, with the backing of Amgen. If all goes well, he'll be finishing about now, after stopping three times a week for his regular dialysis.

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The age of biotech was not born like the nuclear era, in a flash of light followed by a mushroom cloud over a shaking desert. It began with a pair of junior researchers working in a lab in England in the early 1950s. There, in a brilliant flash of intellectual light, Englishman Francis Crick and American James Watson figured out the structure of DNA, a long, thread-like molecule already shown to be the chemical of heredity, the instruction manual for most living things.

"There's no question that the discovery set the stage for everything that has happened over the next 50 years," says Caltech President David Baltimore, whose own biotech research won a Nobel Prize. "That discovery came out of the blue. It wasn't one of those things where there was lots of incremental progress."

Watson and Crick discovered not just the architecture of a pretty molecule--the spiraling staircase of the renowned double-helix--but that the structure explained how heredity worked on a molecular level, how the DNA copies itself over and over as cells multiply.

It took from 1961 to 1965 to crack the genetic code, recalls Marshall Nirenberg, chief of the laboratory of biochemical genetics at the National Heart, Lung and Blood Institute, and one of dozens of scientists who owe their Nobel prizes to work on genes. He and others figured out that the chemical building blocks in DNA (adenosine, thymine, guanine and cytosine--identified as the letters A, T, G and C) were arranged in three-letter "words" along the length of the molecule, and that each word identified an amino acid to be moved into place to form proteins, like adding so many beads to a string. "It became really obvious to me that you could program cells," said Nirenberg. Place fragments of DNA into them, "and the cells will follow the instructions," he says.

Over the next decade, scientists at Stanford University and UC San Francisco found ways of doing just that: genetic engineering. It allowed production of human hormones like Epogen in fast-growing animal or bacterial cells. Deciphering the DNA of disease-causing microbes led to the discovery of new targets for antibiotics and new sorts of vaccines. Decoding the DNA of tumor cells revealed defective genes responsible for the uncontrolled growth that is cancer. At least in theory, it seemed, damaged and mutated genes could be replaced with healthy ones, a process called gene therapy.

It sounded easy. USC's Dr. W. French Anderson knows better. He's spent a distinguished career preparing for the day when he can pluck a healthy gene from one individual and then slip millions of copies into the cells of someone suffering from a hereditary disease. In 1990, while at the National Institutes of Health in Maryland, Anderson was part of a team that made the first serious attempt to do just that. The patients were girls, age 4 and 9, suffering from a rare genetic disorder that left them helpless to fight off infection. The researchers removed white cells from the children, then treated the cells with a healthy gene that makes their missing enzyme, ADA.

Nine years later both are still alive and living normal lives. But Anderson cannot say to what extent that is due to the gene therapy or to drug treatments to supply the enzyme.

A year ago, in a thoughtful review of 300 gene therapy experiments in 3,000 patients, Anderson concluded: "Except for anecdotal reports of individual patients being helped, there is still no conclusive evidence that a gene-therapy protocol has been successful in the treatment of a human disease." Talk to him, though, and he flashes the passionate certitude of a scientific evangelist: "There's no doubt that gene therapy will revolutionize medicine over the next quarter century."

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About one in every 2,500 caucasian children will be born with cystic fibrosis, making it one of the most common inherited diseases. Researchers discovered the gene responsible for this disease just a decade ago. Those who carry a single copy of it have no symptoms. It's only when each parent is a carrier that there's a chance--one out of four--that a baby will be born with the disorder. Dr. Wayne Grody, professor of medical genetics at UCLA, conducted one of the first mass screenings to identify carriers. He and a colleague gently brushed cells from the inside of the cheeks of 3,000 pregnant volunteers at UCLA and Kaiser Permanente clinics. Using techniques for multiplying and checking the women's DNA, the team identified 55 carriers among the women, but only one case in which both expectant parents carried the genetic defect. For reasons not yet understood, not all children born with defective cystic fibrosis genes develop the full-blown symptoms. Yet when the couple learned that their fetus had two defective genes, the woman terminated her pregnancy. Grody believes that test and that option will soon be available to all women.

Dr. Leroy Hood talks about the day when doctors will check their patients' genetic makeup as routinely as they reach for a thermometer. The University of Washington researcher's work is at the core of biotech's transformation of medicine. In the 1980s, while at Caltech, he and colleagues developed a high-speed method for determining the order of the letters that represent the chemical building blocks of DNA. To read out the 3 billion letters contained in a normal set of human chromosomes, even scanning at 10 letters a second, would take 10 years. But machines developed by Applied Biosystems, a company that Hood helped establish, zip through the job.

By the year 2003, the federally sponsored Human Genome Project expects to finish a careful reading out of human DNA, with information on up to 100,000 genes--all but a few totally unknown today. Private companies say they will do it even sooner. "In 10, 15, 20 years, we'll know between 100 and 200 genes that cause many of the common diseases," Hood says. DNA "fingerprints" will be used to project a person's health.

organic farmers for decades have sprayed their fields with a bacterium, Bacillus thuringiensis, or Bt, a microbe that produces natural pesticides. After identifying the genes that produce the toxins, scientists began splicing them into the crops, giving the genetically engineered plants an internal pesticide supply. Quietly, these and other genetically modified plants have displaced conventional ones, accounting for 50% of all soybeans in the United States this year and 30% of corn.

One of the first companies to put Bt into a crop and market the seeds was Mycogen, a San Diego firm now part of Dow Chemical. The former CEO and chairman of Mycogen, Jerry Caulder, remembers reading environmentalist Rachel Carson's classic warning on the hazards of pesticide pollution. He says his company's early use of the Bt genes was an alternative to that scourge. Such efforts were crude compared to a second wave of biotech plants under development. "We want to use the plant's own natural defenses rather than an exotic gene like Bt," says Caulder, who heads Akkadix, a new, privately held biotech company.

Soon, he and others say, there will be crops that thrive on less fertilizer and water. And plants that produce oils with more of the good lipids that promote a healthy heart. And plants engineered to produce industrial chemicals, fibers and pharmaceuticals. "Why not produce silk in soybeans?" asks Caulder.

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Some worry about the accelerating pace of biotech discovery. Bacteria that produce human insulin are fermented in carefully contained factories. But the Sierra Club's executive director, Carl Pope, is among those who have sounded alarms about genetically modified plants, which take root wherever their seeds happen to land. Will they spread unchecked like weeds across the landscape, or worse still, transfer pesticide resistance to create new breeds of superweeds that will choke out desirable plants? And what about eating foods that contain their own engineered pesticides? So far, U.S. consumers seem unperturbed, but many Europeans are wary of eating genetically modified foods, and several large supermarket chains have raced to get them off grocery shelves.

Ethicists are repulsed by other possibilities for genetic manipulation. Two years ago, Scottish scientists revealed they had cloned the first mammal--taking the DNA from an adult sheep and creating "Dolly." Suddenly, human cloning--picture those Hitler clones in "The Boys From Brazil"--seemed entirely feasible. Also troublesome is the recent work using "stem cells" generated from human embryos and fetuses to refurbish damaged hearts and brains.

More modest applications of the new technology have ethical implications as well. Human growth hormone is useful in treating children whose own bodies don't produce enough. But what do you say to parents who see an advantage to their child's being two or three inches taller? Epogen has already been used--misused, many say--to boost the red blood cell count, and thus the energy, of competitive cyclists. And what about new drugs that might help someone think more clearly? Says Alexander M. Capron, co-director of USC's Pacific Center for Health Policy and Ethics: "One person's correction is another person's enhancement."

And the biotech revolution isn't giving us much time to weigh these issues.

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