Subject: Research: Robot Apprentices Date: Published: 11/10/86 173 lines Source: Wall Street Journal. Copyright Dow Jones & Co. Inc. Technology (A Special Report): Research --- Robot Apprentices: New Machines Are Dramatically Changing The Study of Life's Building Blocks --- By Marilyn Chase THE WIZARDS of biotechnology are tipping their hats to a new breed of silent and tireless laboratory assistant -- machines. Back in 1980, scientists in the new field were startled by the debut of a generation of laboratory instruments that promised to automate their painstaking manual arts, creating and analyzing the basic building blocks of life at the push of a button. Some researchers were doubtful; others, downright derisive. "Gene-splicing for idiots," one skeptic scoffed. Today, these robot apprentices -- unassuming gray metal cabinets with racks of chemicals and computer screens -- are revolutionizing biotechnology. Machines sequence (or break down) and synthesize (build up) rare proteins a molecule at a time. Other machines synthesize DNA (deoxyribonucleic acid), the raw material of genes. Another machine soon will automate the laborious task of DNA sequencing, including some day the mammoth task of deciphering the entire human genetic code -- three billion base pairs or units long. "You can't overstate the impact of these DNA synthesizers. It's awesome," says Gerald Zon, chief of the laboratory of molecular pharmacology at the Federal Drug Administration's Center for Drugs and Biologicals. "They do in hours what it used to take a trained chemist weeks or months to do. They've revolutionized the way molecular biologists attack, and even think about, their research problems." These aides are helping scientists to address the enigmas of genetic diseases, cancer and AIDS (acquired immune deficiency syndrome), and companies to construct whole new waves of biological products. These machines enable scientists to decipher, design and duplicate pieces of life's most fundamental building process. That process goes like this: DNA forms RNA (ribonucleic acid), which then makes the proteins that set the body's form and function. Those proteins also determine the body's state of health or sickness. DNA to RNA to protein: Within that chain lie many targets. One such target presented itself to Genentech Inc. The San Francisco-based company, seeking a new treatment for dwarfism, set out to artificially create growth hormone, a protein produced in the pituitary gland that sparks normal growth and maturation. A central problem in the synthesizing process was creating DNA probes -- short fragments of synthetic DNA that focus on a particular gene. Using the probes as fishhooks, the real gene for the growth hormone can be found; then the gene is stitched onto a bacterium, which acts as a living factory to churn out a synthetic version of the growth hormone. Several years ago, it was a process severely limited by a lack of DNA. The probes had to be constructed by hand, a painstaking method that often took weeks. These days, with the DNA synthesizers, the process has become routine. Genentech's senior scientist, Mark Matteucci, runs a "probe shop" that cranks out DNA fragments to order and passes them out all over the company. "People who need a piece of DNA just fill out a request for one made to a specific sequence," he says. "If they're in a hurry, they can have it in a couple days." The impact of that production pace isn't lost on the research labs or the bottom lines. Such ease means "people are doing a lot more projects on a much grander scale," Mr. Matteucci says. Protropin (the trade name for growth hormone) now is Genentech's flagship product: In the first nine months of 1986, sales of the hormone hit $29.1 million -- about 30% of Genentech's revenue. The machines range from $10,000 to more than $100,000. In 1985, roughly $61 million of protein sequencers, protein synthesizers and DNA synthesizers were sold, according to Philip Rotheim of Business Communications Co., a Stamford, Conn., market-research firm. Applied Biosystems Inc., Foster City, Calif., dominates the market, claiming a 70% share of the market for DNA and protein synthesizers, and more than 95% of the market for protein sequencers. For the biotech companies, the computerized assistants have become essential for most every medical product. "These machines affect every product we make," declares Thomas White, vice president of research at Emeryville, Calif.-based Cetus Corp. Cetus has used machine-made DNA probes to identify the genes later used to make products being tested as anti-cancer agents: Colony Stimulating Factor 1, a protein that sparks growth of white blood cells; Interleuken-2, a protein that encourages growth of immunity-boosting T-cells; and Tumor Necrosis Factor, a protein believed to attack malignant cells directly. Cetus uses the protein synthesizers to create other products as well. Synthetic proteins can be injected into animals to make them produce antibodies that fulfill special functions -- for example, antibodies that home in on a cancer-provoking gene found in tumors, including bladder and colon. Before automated lab apprentices were available, a half-dozen Cetus scientists manually made about 50 genes a year. "Now we do 500 or 600," says Mr. White. "And we've reduced the department to two technicians who operate the machines, overseen by one Ph.D. who can do other things too because he's freed from routine work." The University of California at San Francisco Medical School is one of many institutions engaged in automating research into new AIDS diagnostic tests, novel therapies and potential vaccines. Daniel Stites, director of the UCSF immunology lab, is searching for areas on the AIDS virus's protein coat that are the most "immunodominant" -- that is, the most likely to give rise to protective antibodies or natural killer cells. Next he'll try to engineer a "designer protein" combining all of these immunodominant regions. Synthetics also provide the advantage of being safer in many risky types of research, including AIDS. And although scientists have leaned toward the synthetics in the past, machine-made products allow for an almost never-ending supply for research. Raphael Stricker, assistant professor of laboratory medicine at UCSF, discovered a special protein on the surface of blood platelets that causes coagulation. But patients with AIDS have an antibody that binds to this protein and destroys the platelet, blocking coagulation and leading to bleeding, bruising and hemorrhaging. "If we can figure out what the protein is, we can make a monoclonal antibody to it," Dr. Stricker says. Cloned to home in on that protein alone, the monoclonal would bind to it and theoretically crowd out the harmful, platelet-destroying kind. "This kind of therapy has been thought about for some time -- but it would be impossible without the machines," he says. Some of the more futuristic and far-reaching uses of gene machines are being conducted at the FDA and at the National Cancer Institute in Bethesda, Md. Several research groups are creating synthetic DNA analogues or look-alikes in an effort to stop progression of DNA-to-RNA-to-protein. The groups hope it may have potential use as weapons against new diseases like AIDS, as well as old killers like lung cancer. John Minna, branch chief of the NCI-Navy Medical Oncology Unit, is using the machines to identify which genes are turned on in lung cancer -- with potentially far-reaching diagnostic and therapeutic uses. "If we could target our preventative efforts, it would make it easier to prevent," he says. "Most exciting is the question of specific therapies." He is looking at a family of DNA analogues or look-alikes called anti-sense compounds that seek to block the translation of RNA into protein. "If we could insert the anti-sense of the tumor gene, you could turn off the malignant process," he adds, though he concedes this is pretty futuristic stuff. And on a more basic level, the machines can help companies overcome an old nemesis: boredom. At Chiron Corp. in Emeryville, for example, scientists are awaiting a new DNA sequencer to break down the genes of the AIDS virus. The task is so repetitive and dull, says Philip Barr, a senior scientist, that "you couldn't persuade a person to do it. But it's easy to persuade a machine -- just push the button." --- Ms. Chase reports on science and medicine from The Wall Street Journal's San Francisco bureau. (This article is made available here by Dow Jones Co. for the personal and non-commercial use of callers to this bbs, in the hope that it will be of some help to those who are suffering from the disease and others who are seeking to help them.)