(FORTUNE Magazine) – BUGS -- viruses and bacteria -- cause most minor diseases, and some of the major ones like AIDS. But many of the real killers and cripplers, including cancer, heart disease, rheumatoid arthritis, and Alzheimer's, strike because something that is already part of the body -- a minuscule gene or a single molecule inside a cell -- hasn't done its job. Or the reason may be a combination of the two: say, a genetic weakness that makes a person vulnerable to the pollutants and viruses that can cause some kinds of cancer. Until now those complex diseases have been tough if not impossible to treat, much less prevent. But in the 1990s the prospects are improving dramatically, ! owing to phenomenal strides in understanding the genetic and molecular causes of disease. Novel approaches to treating major maladies at the most basic level ever are beginning to translate into practice. By the year 2000, many medical investigators are convinced, a lot of crippler and killer diseases will be far easier to defeat than they are today. Consider the possibilities: -- Cancer. For the first time, scientists are starting to grasp how cancer originates at the fundamental level of genes and molecules -- and they are putting that knowledge to work. Says Dennis Slamon, a noted researcher at the UCLA medical school: ''The exciting thing is that we never had before an understanding of the molecular biology of cancer. Now we do, and we can use it to help treat the disease.'' Slamon's own findings about the genes involved in ovarian and breast cancer are already helping doctors diagnose and treat patients more precisely. -- Heart disease. The genes that predispose some people to heart disease should be pinpointed by the year 2000. Once that happens, those at risk can be identified far enough in advance to start taking the necessary precautions like avoiding high-cholesterol food and stress -- potentially a far more effective approach than admonishing the world in general to cut down on steak. -- Alzheimer's and Parkinson's diseases. In the next decade, scientists expect to refine an important advance that will prevent the death of brain cells, a characteristic of both ailments. They will do that by infusing into the patients' brains man-made copies of the brain's own ''nerve growth factors,'' proteins that help keep neurons -- nerve cells -- healthy. The technique, already tried successfully in elderly rats, rejuvenates and reenergizes aging brain cells. -- Autoimmune diseases. Says immunologist Dennis A. Carson: ''By the year 2000 we'll eliminate diseases of the immune system like rheumatoid arthritis, diabetes, multiple sclerosis, myasthenia gravis, and many skin disorders.'' Carson directs a research program on rheumatoid arthritis at the University of California at San Diego. Instead of using palliatives that merely suppress symptoms, doctors will be able to get at the basic causes of these diseases -- maybe including AIDS. What's happening is nothing short of a revolution in medical care. Says Paul J. Maddon, chairman of Progenics Pharmaceuticals Inc. of Tarrytown, New York: ''A whole new way of looking at disease -- and doing something about it -- has been opened up.'' Leroy Hood, a Caltech molecular biologist, showed last year how a brain disease can be prevented and cured in mice with the new molecular techniques. Now he audaciously predicts that advances in medical treatment in the coming decade will overshadow those of the past 2,000 years. The new assault on disease is proceeding along two main fronts: molecular biology and gene therapy. In its ultimate form, gene therapy means replacing a missing or malfunctioning gene with the correct one. By contrast, the molecular approach singles out one stage in the evolution of a disease and blocks it with molecules that have been either chemically synthesized or cloned by genetic engineering. For example, an infused nerve growth factor molecule docks with a receptor on a shriveled brain cell, setting off a signaling mechanism. That signal tells the genes in the cell to start making proteins that can restore it to normal vigor. Often the molecular and the genetic approaches intersect, because genetic defects -- either inherited or induced by chemicals, radiation, or viral damage -- figure prominently in many diseases. For instance, rheumatoid arthritis and early-onset or Type I diabetes occur in people genetically predisposed to them. If a gene makes a single misstep in the assembly of a protein, that changes the genetic message, much as a misplaced letter can alter the meaning of a word. Put together defectively, the protein fails to function as it should -- and medical havoc can result. A typical case: In cystic fibrosis, the most lethal disease among white Americans that is caused by a single defective gene, that gene can produce a malfunction in a protein that modulates the passage of chemicals out of cells in the lungs and elsewhere. One result is congestion in the lungs that leads to infection and often an early death. PIONEERING researchers like Ronald Crystal of the National Institutes of Health (NIH) in Bethesda, Maryland, are seeking to perfect gene replacement for cystic fibrosis. The gene for the disease was discovered only in 1989. Last year scientists showed in test-tube experiments that cultured cystic fibrosis cells become normal when a properly functioning gene is introduced. But much has yet to be learned about gene therapy. The long-term effects of incorporating new genetic material into cells are still unknown, so when researchers first used the technique in people last year, they took a cautious approach. Since September, at NIH, a 4-year-old Texas girl suffering from a rare enzyme defect called adenosine deaminase (ADA) deficiency -- the ''bubble boy'' disease (see diagram below) -- has been getting injections of cells containing a correctly functioning gene for ADA. In the past, children with the most severe variants of this condition had to be confined to germ-free plastic tents to prevent exposure to common infections that could kill them. Now the gene therapy seems to be working. As the cells circulate through the girl's bloodstream, they make the needed ADA enzyme. For the first time in her life she has a normal level of protective white blood cells. She has experienced no side effects and is feeling ''very well,'' her doctors report. Similar therapy began in January on a 9-year-old girl with the same disorder. (The girls' names are being kept secret to spare their families unwanted publicity.) ''By the year 2000 gene therapy will be in general use,'' says W. French Anderson, an NIH hematologist who helped apply the technique to the two girls. His colleague Ronald Crystal and others are using cystic fibrosis and similar rare defects involving a single gene as a doorway toward treatment of more complex and widespread disorders such as chronic bronchitis and emphysema, which claim millions of victims. Replacing defective genes with healthy ones could work with many other kinds of disease -- cancer, high blood pressure, heart attacks caused by a genetic propensity to overproduce cholesterol. Tests are just starting at NIH on gene therapy for malignant melanoma, a vicious form of skin cancer. ANY PROMISES of medical miracles must be taken with a large dose of caution. Anderson counsels patience for parents of children with genetic diseases other than ADA deficiency -- for example, phenylketonuria (PKU), sickle-cell anemia, and cystic fibrosis. ''Gene therapy for other conditions is not going to happen tomorrow,'' he says. ''This is like the moonshot. The rocket has just cleared the platform, but we're not near the moon yet. Except for healing a few children now, it will take years to expand therapy to other diseases.'' Even when that happens, it won't mean longer life for all. Obviously scientists hope to extend the lives of youngsters who now die early. Those with cystic fibrosis, for example, often succumb in their teens or 20s. But the natural human life span seems genetically set at about 85. A major aim of the new medicine is to make more of the twilight years pain-free, happy, and productive. That couldn't be more timely, since the aged make up an ever larger part of the population of the industrialized world. Scientists want to ensure that body and mind function well in aging people. ''As people outlive heart disease and cancer, we don't want to wind up with bodies that are working well and brains that are not,'' says Leonard Schleifer, CEO of Regeneron Pharmaceuticals Inc. in Tarrytown, New York. Bolstered by about $70 million raised from venture capitalists and from such companies as Amgen Inc. and Japan's Sumitomo Chemical, three-year-old Regeneron has suddenly catapulted into the forefront of this field. Schleifer notes that if the new efforts to arrest Alzheimer's disease and similar neurological disorders succeed, they could drastically cut U.S. health care costs by keeping older people out of hospitals and nursing homes. The gathering molecular attack on brain disorders depends on pinpointing and sorting out signaling molecules in the brain and using them as healing agents. ''We can now think about preventing progressive degeneration and loss of nerve-cell function and about nerve regeneration -- something we wouldn't have thought of doing a few years ago,'' says Schleifer. Recent evidence links tiny mutations in one or more genes to faulty proteins that may cause some cases of Alzheimer's, which involves neuron degeneration. In March, Regeneron scientists identified a substance in the brain that protects cells damaged by Parkinson's disease. The company expects to begin clinical trials of some of its compounds in a few years. Existing treatments of brain disorders try to mimic or block the action of neurotransmitters such as dopamine or catecholamines, which act as message carriers between nerve cells. By contrast, nerve growth factors work directly on the interior of neurons, influencing their basic mechanism. Growth factor molecules dock onto neurons and through intermediary signaling molecules modulate the synthesis of proteins needed for nerve-cell regeneration. Recent research has turned up a fascinating sidelight on Alzheimer's: The best preventive may be to keep your brain active by learning as much as you can. In 1987, Robert Katzman and a team from the University of California at San Diego studied more than 5,000 older people in Shanghai. They found that the dementia accompanying Alzheimer's occurred much more often in those with no formal education. Signaling molecules like those that maintain the health of neurons also make the immune system run. Known as lymphokines, they include the interleukins and interferons used to help treat certain cancers. What excites researchers is the similarity in the destructive processes of many of the so-called autoimmune diseases. Within the past few months, initial tests on sufferers from severe forms of rheumatoid arthritis and a smaller number of patients with multiple sclerosis have shown much promise. The tests involved an application of monoclonal antibodies, the body's defensive proteins, made by Centocor Inc. of Malvern, Pennsylvania. In both cases the antibodies suppressed a group of normally protective immune system cells that can go haywire and attack the body's own tissues. OUT OF 50 long-term arthritis sufferers with symptoms so severe that conventional medication could no longer help them, three-fourths responded to a single dose of antibodies with dramatically reduced pain and swelling. The same antibodies also worked well on the six patients with multiple sclerosis; one felt so good that he threw away his cane and started jogging. Centocor CEO Hubert J. P. Schoemaker calls this development ''a major breakthrough if it holds up in large trials.'' Other company and university researchers are trying to turn off the immune response at a later stage. Icos Corp. of Bothell, Washington, is seeking ways to block the entry of the berserk immune cells into inflamed joints. (For a look at some nonscientific goings-on at Icos, see following story.) Immunex of Seattle proposes to sop up the offending cells with free-floating copies of receptors, or docking ports, for the interleukins that help initiate the immune response. As a variation on this theme, Synergen of Boulder, Colorado, has begun clinical trials of a receptor blocker that lands on tissue cells and switches off the inflammatory response. As the Centocor tests suggest, therapies for one autoimmune disease can be patterned on those already shown to work on another. Common threads are also being discovered in the origins of different cancers -- a development that many researchers in this field consider their biggest advance ever. Says Samuel Broder, director of the National Cancer Institute: ''Cancer research has achieved an astonishing level of excitement.'' Understanding the molecular mechanism of cancer really began in the 1970s and 1980s with the discovery of the first broad family of genes, known as oncogenes, that accelerate the development of cancer. Normally oncogenes help regulate growth in a developing organism. After it matures, they turn off and stay that way unless something happens to activate them -- for example, damage induced by a chemical, radiation, or a virus, though rarely an ordinary one like flu. Then they produce the uncontrolled growth that is cancer. In the past few years scientists have also begun to identify a family of so- called tumor suppressor genes that retard cancer growth. Generally cancer is a multistage process. A series of damaging mutations to both oncogenes and tumor suppressor genes apparently must take place for cancer to develop. Genes with ''point mutations,'' in effect misspelled letters in the sentence-long string of amino acids that make up a gene, can result in defective proteins. A protein, for instance, may be intended to act as a receptor on the surface of a cell. But because it fails to fold into the proper shape, it cannot receive the intended signal correctly. Or some receptors never turn off, which UCLA's Slamon likens to ''a stuck green traffic light.'' Some of these findings are already being applied to diagnosis and therapy. Slamon and his colleagues found in 1989 that multiple copies of one oncogene occur in some women with breast and ovarian cancers. The more copies of the gene, the more serious the disease. The UCLA researchers established a startling statistical correlation between survival time in ovarian cancer and the number of copies of the gene in a patient. With a single copy a patient lives, on average, five years and two months from the time of the initial diagnosis; with two to five copies, 2 1/2 years; with more than five copies, only eight months. As a result, doctors now treat women with multiple copies of the gene more aggressively with existing drugs. In December a research team led by Stephen H. Friend of Massachusetts General Hospital in Boston achieved a further insight into the biology of cancer. The researchers identified a genetic factor in the rare Li-Fraumeni syndrome, which is believed to affect only a few hundred families around the world. That's strong evidence that a general predisposition to cancer can be inherited. Members of these families are particularly susceptible to breast cancer and brain tumors. Broder of the National Cancer Institute sees the tricky technique of gene transfer as an eventual cancer treatment. NCI researcher Steven Rosenberg and his colleagues made medical history a year ago when they inserted new genetic material into white blood cells in the lab and then put the cells back into cancer patients. The aim was mainly to track the cells as they fight cancer and move throughout the body. The first application of gene therapy to controlling cancer started at NIH in January on patients with malignant melanomas; it will take at least a year to get useful results. Yet another new cancer treatment, perhaps the most spectacular of all, is already being tested in people. Instead of killing cancer cells, scientists from Columbia University and Memorial Sloan-Kettering Cancer Center make them behave normally by attaching a specially designed molecule that activates a remedial enzyme (see second diagram). Says Columbia chemist Ronald Breslow, a developer of the new drug: ''In a cancer cell, that enzyme is not functioning, at least not in a maximal way. So instead of becoming a normal adult cell, a cancer cell continues its juvenile pattern of dividing, dividing, dividing.'' Although tests of improved versions of the drug are just starting, one patient with a supposedly incurable cancer has been kept alive for five years with an earlier variety. Eastman Kodak's Sterling Drug is collaborating with the researchers on further development. No one is promising that cancer will be eliminated by the year 2000 -- if ever. It has been identified in 2,000- to 3,000-year-old Egyptian mummies and will doubtless continue to plague mankind. Some of its causes are beyond medical control. Despite all the publicity in recent years about the link between cigarette smoking and lung cancer, for instance, more young American women than ever are smoking -- and more are dying of lung cancer. BUT THE ADVENT of the new molecular and genetic medicine should make a big difference. Among other things, it will lead to earlier detection of susceptible people who can then be warned directly about the particular danger to them of smoking or working in a chemical plant. Earlier detection would also result in earlier treatment, when cancer can be dealt with most efficiently. The other great killer, heart disease, may be the toughest of all because of its complexity. In a few families a single gene defect has been traced that can lead to hugely elevated cholesterol levels and cause heart attacks in children as young as 6. But researchers are just beginning to puzzle out the role of multiple gene interactions that can cause heart problems in the population at large. ''When you get to heart disease, the interactions may be totally baffling,'' says W. Maxwell Cowan, chief scientific officer of the Howard Hughes Medical Institute, a leading sponsor of research in molecular and genetic medicine. Work on the genetics of high blood pressure is also just getting under way. For example, Eric Lander, a researcher at MIT's Whitehead Institute, is tracing the genetic interactions that may influence hypertension in rats. By the year 2000 doctors should be able to identify genetic predisposition to heart disease and treat people accordingly. The new molecular and genetic medicine still faces myriad unsolved problems. One of the biggest is to decipher how the proteins that genes produce exert their influence on multiple targets. For example, those defective flow- modulating proteins in cystic fibrosis damage not only the victims' lungs but also the pancreas. Says Cowan: ''We've just opened the door, and some of the investigators on the leading edge have begun to put their foot inside.'' Still, investigators are more hopeful than ever. They now have tools in hand that they could only dream of a few years ago, including mice whose immune systems have been transplanted, in effect, from humans. That gives scientists the first living animal models into which they can introduce diseases of the immune system ranging from AIDS to multiple sclerosis, and where they can test new treatments. Just gathering speed is the Genome Initiative, an ambitious effort to decode the structure of the estimated l00,000 genes that make up man's genetic blueprint. About 98% of those genes remain unidentified, and mapping them could set off an avalanche of medical advances.

BOX: GIVING A SICK CHILD A NEW GENE

The treatment: A child with the deficiency gets bolstering injections.

Withdrawn blood cells are separated; the red ones are returned.

A viral particle inserts a new gene into the separated white cells.

The white cells go,into plastic bags to stimulate their growth.

The child gets back the cells, which now make the enzyme properly.

BOX: MAKING CANCER CELLS HEALTHY

In the diagram, specially designed drug molecules -- shaped like door handles for a tighter fit -- lock onto receptors on the surface of an immature red blood cell infected with a cancer-causing virus. The drug activates an enzyme that causes the cell to behave normally instead of continuing to multiply uncontrolled, as a cancerous cell does.