The world is understandably giddy, and a bit apprehensive, about this whole adventure. It conjures a future in which doctors use handy strands of DNA to correct hereditary defects, cure chronic illnesses, even enhance people’s IQs. Those days are still a long way off, but gene transplantation is only one example of how genetic science is transforming medicine. While we await the advent of designer humans, more and more diseases will be linked to quirks in the chromosomes. Fetuses will be screened for a wider range of congenital defects. Perhaps most important, biotechnology will spawn new treatments for a host of common illnesses.
Until recently, developing a new medicine was a matter of trial and error. Researchers simply tested the therapeutic effects of different molecules. When something worked, the reason was often a mystery. Since the 1970s, recombinant DNA technology has offered a more rational approach. A researcher can now start by isolating the gene that prompts human cells to make some crucial chemical. Then, by splicing that gene into bacterial cells, he can turn a cell culture into a little factory. Genetic engineers have used this trick to synthesize such products as human insulin (the hormone that diabetics lack), interferons (proteins that help suppress viruses and cancers) and tissue plasminogen activator (a clot-dissolving enzyme that can rescue heart-attack victims). Only 12 such medicines have reached the market, but more than 100 are in development. “What we’ve seen,” says Harvard geneticist Philip Leder, “is only the very beginning.”
Cancer researchers are particularly excited about a class of proteins known as colony stimulating factors, or CSFs. The body uses these factors to regulate the production of different types of blood cells. They’re found only in tiny amounts in human tissue, but biotechnology labs can now mass-produce them in culture. The Food and Drug Administration is close to approving two of these agents, G-CSF and GM-CSF, as treatments to help cancer patients tolerate higher doses of lifesaving chemotherapy. And experts foresee other applications as well. Some call CSFs the penicillin of the ’90s.
Chemotherapy and radiation are potent killers of tumor cells. The trouble is, they can be just as hard on healthy tissues. High-dose chemotherapy kills the white blood cells that protect the body from infection and it devastates the bone-marrow cells that would normally mature to replace them. Transplanted bone marrow can help restore the immune system, but recovery takes up to 60 days. During that time the slightest infection can be lethal. By speeding the transformation of bone-marrow cells into bacteria-fighting white cells called granulocytes and macrophages, the new CSFs can reduce the recovery time by half. In clinical trials, bone-marrow recipients who get CSF therapy experience fewer infections, require fewer antibiotics and spend less time in the hospital than those who don’t receive CSFs.
The new CSFs have yet to be studied extensively outside the cancer wards, but broader uses aren’t hard to envision. Either of the new factors could give people with AIDS or severe burn injuries a hedge against infection. They could also help people fight off bacteria that resist antibiotics. CSFs won’t replace antibiotics as a treatment for routine ailments, concedes Malcolm Moore, a researcher at New York’s Memorial Sloan-Kettering Cancer Center and the discoverer of G-CSF. But for many patients, they’ll provide an invaluable alternative.
Bone-marrow cells aren’t the only ones that find growth factors stimulating. Throughout the body, different growth factors prompt cells to move around or multiply - and not always for the better. Excessive I cell growth can cause such varied afflictions as cancer, arthritis and heart disease. As genetic engineers devise new ways to suppress growth factors as well as stimulate them, those illnesses may all become more manageable.
Heart disease, as America’s leading cause of death, provides particularly rich opportunities. Contrary to popular belief, fat and cholesterol don’t simply clog coronary arteries as sludge would a sewer pipe. The trouble begins when the endothelial cells that line the surface of the artery recruit white blood cells to remove such substances from within the arterial wall. As the white cells consume the offending detritus, they and other cells start churning out growth factors, which cause a proliferation of arterial tissue. That tissue buildup is what blocks the flow of blood (chart).
Several labs are working on ways to suppress these overactive growth factors, and though their innovations are far from clinical use, they could eventually transform cardiology. Dr. Victor Dzau, chief of cardiovascular medicine at Stanford University, is working to develop “antisense” DNA molecules. In a test tube, these agents block the genes that enable cells to make particular growth factors. Sneaking antisense into the right cells would theoretically nip the problem in the bud. Dr. Lewis Williams of the Howard Hughes Medical Institute and the University of California, San Francisco, is taking a different tack. He and his colleagues are developing artificial receptors that bind with a key culprit - platelet-derived growth factor, or PDGF - before it can prompt arterial cells to multiply. Unfortunately, curing heart disease won’t be quite as simple as paralyzing the responsible growth factors. The challenge, as Lewis observes, is to protect people’s arteries without compromising their ability to produce new tissue when it’s needed.
The promise of biotechnology extends far beyond cancer and heart disease. Molecular biology has utterly transformed the study of the mind in recent decades; scientists now regard thought and feeling not as intangible essences but as the consequence of 10 billion neurons communicating with one another through chemicals called neurotransmitters. By speeding or impeding the passage of specific transmitters into neurons, genetically engineered drugs could give people unprecedented control over their mental states.
Anxiety is a good example. Scientists know that at least two neurotransmitters - one called CRF and another called GABA - help determine how tense a person feels. CRF is a natural upper. Released in response to stress, it speeds the activity of brain cells and (by triggering other hormones) activates the heart, lungs and muscles. GABA, a natural sedative, is released continually to keep neuronal activity under control. Today’s most common anxiety drugs work by enhancing its effect. When a drug like Valium latches onto a GABA receptor, GABA enters the neuron more freely and the neuron becomes less active. But because these drugs bind readily to different classes of GABA receptors, they suppress a range of normal brain functions.
Several biotech companies are now working on less scattershot treatments. Scientists at the Connecticut-based Neurogen Corp. have engineered cells that exhibit only particular classes of GABA receptors. They’re now developing drugs that interact only with specific regions of particular receptor types. Company president Philip Whitcome predicts that the first of these silver-bullet molecules will be ready for clinical trials by next year. Meanwhile, in a separate effort, researchers at Baltimore’s Nova Corp. are developing agents that block the action of CRF. Because CRF’s natural function is to cause anxiety, notes neuroscientist and Nova founder Solomon Snyder, an effective CRF blocker might prevent the sensation without producing any side effects at all.
These are dazzling innovations. Yet none is truly original. “The body is a remarkable pharmacopoeia,” Whitcome observes. “Its cells and molecules are brilliantly designed to maintain equilibrium. We’re just learning to take better advantage of it. "
Tissue buildup is what blocks coronary arteries. Synthetic molecules might stop the process.
White blood cells enter the arterial tissue to consume foreign material.
The cells release growth factors, which stimulate tissue production, narrowing the arterial passage.
Synthetic receptor would lock up growth factor, preventing tissue buildup.
