A Division of Biochange, Unlimited

From the LA Times   Sunday, July 25, 1999

       CUTTING EDGE / FRONTIERS: Four Fields That Have Been Shaped by, and Are Shaping Southern CA


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

                                                               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?
                                                                                                                      * * *
                                                      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.
                                                                                                                      * * *
                                                      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
                                                      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."
                                                                                                                      * * *
                                                      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.
                                                                                                                      * * *
                                                      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
                                                      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.
                                                                                                                       - - -

                                                 Paul Jacobs Is a Times Staff Writer Who Covers Biotechnology