CAN THE AGING SLOW ?

For researchers studying aging as well as for the rest of the human population, getting inexorably older and feeling none too happy about it,the rules have always been simple, organisms are born, they live a more or less prescribed number of years and they die. If you watch your weight, eat right and get plenty of exercise, you can perhaps negotiate the terms a little, squeezing out a bit more time here and there. But tripling life-spans? Quadrupling life-spans? Eliminating the very idea of life-spans? Not an option. Or so it seemed. But now the rules are quietly being broken. scientists said that the old way of thinking about senescence needs to be challenged. In laboratories around the world, investigators are beginning to suspect, to their growing surprise and excitement, that what works in flies and worms may work for people too. From species to species, genus to genus, the cellular mechanisms responsible for aging appear to be the same.

Armed with that knowledge, a new breed of longevity specialists is beginning to tease out answers to two of the great mysteries of life, Why do we age? And even more important, What can we do about it? The clues are tantalizing. In some research centers, investigators are studying an area at the tip of chromosomes that appears to shorten, fuselike, as we grow older. Extinguish the chemical fire that consumes the fuse, and you might be able to bring aging to a halt. Elsewhere, scientists are studying how the waste produced when a cell consumes food can contaminate its innards, a process that can lead to the bodywide breakdowns we associate with aging. Clean up the cells, and you should be able to buck up the entire organism. Still elsewhere, geneticists are beginning to map the very genes that direct us to get old in the first place. After mapping genes, the next logical step is manipulating them, and once you start reweaving the DNA that codes for life itself, anything is theoretically possible. Most promising of all is the possibility that scientists may someday not only lengthen life-spans but improve them as well.

Researchers are starting to talk about the likelihood of people living well into their second centuries with the smooth skin, firm muscles, clear vision, high energy and vigorous sexual capabilities they once could enjoy only in youth. For human beings, the sea change in aging has been a long time in coming. In the past decade or two, there has been an explosion in new therapies designed to slow the senescence process from melatonin to antioxidants to hormone-replacement therapy to the intrigueing hormonal precursor known as DHEA. Popular as some of these treatments are, what they promise is modest: a few years added here and there, and an increased likelihood that those years will be healthy ones. What the new wave of researchers is looking for is life extension that's not so much incremental as exponential. Not just a year here or there, but a doubling or tripling of human life expectancy. History shows it's possible. In 1900 the life expectancy for a person born in the world was 47 years. At mid-century, it was little better.

After 1950, however, things started to stir. In a single year, subtle improvements in medical care caused the 47 year figure to jump 2%. The next year it jumped another 2%; then another, For four decades, that pattern has roughly continued, a compounding of existential interest that, according to study, has pushed the average life expectancy to nearly 76, with many Americans living well beyond. The people of many Asian nations have experienced similar gains. Indians born in 1983 could expect to live about 52 years; now the average life span exceeds 61. The improvement is most pronounced in Japan, where the average life expectancy for both men and women is now the highest in the world. As recently as 1940, Japanese men could expect to live only 35.4 years and women 43.6; since then, average longevity has shot up to 76 years for men and nearly 83 for women, thanks to better nutrition, improved sanitation and medical breakthroughs such as the use of antibiotics and advanced surgical techniques.

The number of Japanese aged 100 years or more has jumped from 153 in 1963 to nearly more 7,000 today. But what if the medical breakthroughs were more dramatic? If living to the century mark involves little more than riding the demographic wave, how much further than 100 is it possible to go? Is 150 reasonable? 200? What about 300? And if not, why not? The body, after all, is just a machine albeit a wet, cranky, willful one-and, as with all machines, it should be possible to extend the warranty. A Researcher, James Vaupel said there is no evidence we know of that human life expectancy is close to its ultimate limit, if there is an ultimate limit. In the same way that the modem era of genetics research began in 1953 when the DNA double helix was identified, the modem era of aging research is thought to have begun in 1961' when anatomist Leonard Hayflick made an equally significant discovery.

Hayflick had been troubled by the question of where aging begins. Is it the cells themselves that falter, dragging the whole human organism down with them? Or could cells live on indefinitely were it not for some age-related deterioration in the higher tissues they make up? To find out, Hayffick harvested cells from fetal tissue and transferred them to a Petri dish. Freed from the responsibility of doing anything to keep a larger organism alive, the cells did the only other thing they knew how to do: divide. Shortly after they were placed in culture, they doubled their number. Then they doubled the doubling. The cycle repeated itself about 100 most troublesome by-products of this times, until all at once it stopped. From then on, the cells did something a lot like aging. They consumed less food; their membranes deteriorated; and the culture as a whole languished. Hayflick repeated the experiment, but this time used cells from a 70-year-old, and found that cellular aging began much earlier, after 20 or 30 doublings.

The cells from the older human were older themselves. What we were seeing, says Hayffick now a professor at the University of California, San Francisco, was Cellular aging growing old in the microcosm of a Petri dish. For gerontologists, this was monumental stuff. If human tissue behaved in the body the same way it did in the dish, they felt, it meant that somewhere in the viscera of each cell there was an actuarial hourglass that gave it only so much time to live and no more. If the clock could be found-and, more important, reset-both the cells and the larger corpus that gave rise to them might be made immortal. Of course, hypothesizing the existence of such a cellular timekeeper was one thing; finding it and manipulating it were something else again. In the years since, senescence scientists have taken two approaches to achieving this goal.

The first idea that researchers have explored is broadly thought of as the cellulardamage model of aging. For any complex system-whether it's made of inorganic metal or protoplasmic goo-the mere act of doing the work it was designed to do carries a price. No sooner does the hardware begin operating than its parts begin wearing out and its journey to the junkyard begins. Cells are not spared this fate, and one of the functions that takes the most out of them is the job of processing food. Like all organisms, cells produce waste as they metabolize energy. One of the most troublesome by products of the process is a species of oxygen molecule known as a free radical-essentially an ordinary molecule with an extra electron. This addition creates an electrical imbalance that the molecule seeks to rectify by careening about, trying to bond with other molecules or structures, including DNA.

A lifetime of this can lead to a lot of damaged cells, which may produce a range of disorders, including cancer and the more generalized symptoms of aging like wrinkles and arthritis. In recent years, some nutritionists have advocated diets high in fruits and vegetables containing carotenoids; substances that act as antioxidants by sopping up free radicals and carrying them out of the body. But antioxidants have an uneven record. In some studies they seem to be associated with a dramatic reduction in cancer or other diseases; in others, some antioxidants, such as beta-carotene, actually seem to be associated with an increase. In either event, few contemporary aging researchers think self medicating at a salad bar is the best way to extend the human life-span. Far more promising might be new research into another by-product of cellular metabolism: glycosylation, or what cooks call browning.When foods like turkey, bread and caramel are heated, proteins bind with sugars, causing the surface to darken and, in some cases, turn soft and sticky. In the 1970s, biochemists hypothesized that the same reaction might occur in the bodies of people suffering from diabetes, as excess glucose combined with proteins in the course of metabolism.

When sugars and proteins bond, they attract other proteins, which form a sticky, weblike network that could stiffen joints, block arteries and cloud clear tissues like the lens of the eye, leading to cataracts. Since diabetics suffer from all these ailments, the biochemists guessed they were right. But joint pain, circulatory disease and poor vision sound an awful lot like the symptoms of aging. Was it possible that as the cells of nondiabetics metabolize sugars, the same glycosylation process might take place, only much slower? The idea that the geand tragedy of aging and dying might be nothing more than a body-wide process of caramelization was humbling, but more research provided still more proof. Studies of the collagen sac between the brain and skull in diabetics and the elderly turned up brown pigment characteristic of advanced glycosylation.

The glycosylation process is like the free-radical process, says Dr. Robert Butler, head of the International Longevity Center at Mount Sinai Medical Center in New York City. It's a natural phenomenon that keeps us alive but also helps lead to aging. In the years since the caramel theory was first advanced, the gooey glycosylation residue has been given an appropriate acronym: AGES, for advanced glycosylation end products. If residue from AGES does indeed gum up the body's works, however, there may now be a way to get things unstuck. Investigators at the Picower Institute for Medical Research in New York are working on a drug that acts as an AGES solvent. Known as pimagedine, the medication dissolves the connections between the AGES protein and the proteins that cluster around it. In one study, 18 patients taking pimagedine showed reduced blood levels of lipoproteins, the substances that act as precursors of artery-clogging cholesterol. In another, rats taking pimagedine did not exhibit any signs of heart disease. We're at the early stages of development, but we have a theory and proof of concept, says Dr. Richard Bucala, a Picower researcher. The biochemistry of glycosylation occurs in a lot of medical conditions, so it's not a great leap to aging.

An alternative to changing the way cells process nutrients is giving them less to process in the first place. Studies have shown that rats whose caloric intake is 30% lower than that of a control group tend to live 30% to 40% longer. In humans, that would translate to a spartan diet of just 1,400 calories a day in exchange for 30 extra years of life. Just how this business of swapping food for time works is not entirely clear, but George Roth, molecular physiologist with the National Institute on Aging in Bethesda, Maryland, has some ideas. When animals are placed on caloric restriction, Roth explains, the first thing that happens is that their body temperature drops about PC. Lower temperature means a less vigorous metabolism, which means less food is processed. In order to compensate for the reduction in diet, Roth says, the animals switch from a growth mode into what can be thought of as a survival mode. They get fewer calories, so they burn fewer.

Cold and hungry is no way to go through life, but the condition has rewards. When metabolism slows, all its attendant processes do too, including cell division. Since, as Hayffick discovered, the number of divisions is limited, animals that go through them slowly may be able to save a few away for later in life. Roth, who has already observed the life-extending effectiveness of caloric restriction in rodents, is conducting similar experiments with primates. Even if they succeed, however, trying to apply the treatment to humans could prove dicey, especially for Americans. In a nation of consumers for whom caloric belt tightening can mean little more than a smaller serving of French fries with their bacon cheeseburgers, the belief that people would be willing to reduce what they eat by a full third is probably unrealistic.

Roth finds this frustrating, I think caloric restriction could take us beyond a life-span of 80, he says, maybe even 120. After all, you rarely see a fat centenarian. Given dietary habits, it may be more practical to find out what part of the metabolic system caloric restriction affects and then imitate that action pharmacologically. Essentially, explains Roth, we'd use a pill to trick a cell into thinking less food is coming in. Even if Roth succeeds, the impact of his work may be limited. In the world of anti aging, caloric reduction is essentially maintenance, little more than patching holes in a slowly sinking ship and hoping you can stay ahead of the water it's still taking on. What senescence researchers really want is a way to get down into the body's engine room-the genes themselves-and rebuild things from the boilers up. Remarkably, it appears there may be a way. Although he made history when he discovered the limits on cell replication in the lab, Hayflick left a question unanswered: why the cells die. In the years following his work biologists mapping human chromosomes looked for a gene that enforced cellular mortality, but found nothing. One thing that did catch their eyes, however, was a small area at the tip of chromosomes that had no discernible purpose.

Dubbed a telomere, the sequence of nucleic acids did not appear to code for any traits. Instead it resembled nothing so much as the plastic cuff at the end of a shoelace that keeps the rest of the strand from unraveling.But weren't completely inert. One thing they almost always appeared to do was grow shorter. Each time a cell divided, the daughter cells it produced had a little less telomere to play with. Finally, when the cell reached its Hayflick limit of 100 or so replications, the telomere was reduced to a mere nub. At that point, the cell quit replicating. Once it did, researchers theorized, the genes previously covered by the telomere became exposed and active, producing proteins that triggered the tissue deterioration associated with aging. While most every cell in the human body exhibited telomere loss, a few didn't. Among those spared were sperm and cancer cells-just the cells characterized by their ability to divide not just 100 times, but thousands. The next step for scientists was obvious: study the cells with little or no replication limit and find out what mechanism kept their -and their lives-so long.

In 1984 molecular biologists Carol Greider and Elizabeth Blackburn, then with the University of California, Berkeley, did just that. Working with a single-cell pond organism, they discovered a telomere-preserving enzyme they dubbed telomerase. Five years later, Gregg Morin at Yale University confirmed their work, identifying the same substance in cancer cells. In the Petri dish, the agent of eternal life had been found. The moment telomerase was discovered, says Hayflick, it was clear that for immortal cells at least, this was a way to circumvent the inevitability of aging and dying. Telomerase has now been found in the precursor cells that give rise to human eggs, in the stem cells that give rise to blood cells and in up to 95% of cancer cells. Since telomerase keeps these tenacious cells going, is it reasonable to assume that the same enzyme could be used artificially to help mortal cells-and the body itself-exceed their programmed life-span?

Two biologists Calvin Harley and Greider are trying to find out looking for the genes that direct telomerase production, beheving they might be able to manipulate them so that the spigot for the enzyme can be turned on and off at will. I think we are going to see fundamental medicines for aging, Harley says. With a pill, with cell therapy, I think we may be able to treat aging in very specific areas. Of course, telomerase therapy has obvious problems. Dosing tissues with precisely the enzyme that helps turn healthy cells cancerous strikes many skeptics as less than a life-extending brainstorm, and even advocates of telomeres therapy don't pretend that such treatments could yet be considered safe. Moreover, how easy it would be to manipulate the telomeres gene in the first place is an open question, since merely locating it among the 100,000 or so we carry in each cell can be a mind-numbing job. But even as Harley begins his search, other genes implicated in aging have already been flushed out of hiding.

At McGill University, Hekimi's long-lived nematodes have helped expose a few of them. He created his little überworms by crossing and recrossing individuals that lived longer naturally, slowly extending the life-spans of later generations. He then searched the animals' chromosomes until he found the mutated gene responsible, a gene he dubbed Clock-1. The Clock-1. gene is critical in setting fife span, He says. More important, with cloning and genetic mapping, we were able to determine just which protein the gene created to get that job done. After locating three other nematode clock genes, He went looking for similar ones in people. He found one whose amino acid schematic nearly mirrored Clock-I. The Clock-1 genes in the two species are so very similar, he says, that it's possible the whole clock system works the same way. If we find a of the human clock genes, we can perhaps slow them down just a little, so we can extend life. In California, Michael Rose, who created the aged fruit flies, has not yet found the genes responsible for his insects' longevity, but does believe genetic manipulation can be a key to prolonging life. Manipulating any senescence genes could be years-indeed, decades-away. But the alternative-subjecting human beings to the same selective mating processes applied to lab animals-is out of the moral question. We're not going to be breeding humans the way we breed fruit flies, he says. We have to find some less fascistic method of intervening in aging. Meanwhile, more and more genes involved in the aging process are giving up their secrets.

At the Veterans Affairs Medical Center in Seattle, a group led by molecular geneticist Gerard Schellenberg has identified the human gene responsible for the disorder known as Werner's syndrome. People suffering from Werner's start life normally, but by the time they reach their 20s begin a process of eerily accelerated aging, exhibiting such ailments as heart disease, osteoporosis and atherosclerosis. Typically they die by their late 40s. Schellenberg’s work is noteworthy not only because he found the gene behind such misery, but because he knows how it works. The genetic sequence he discovered codes for the enzyme helicase, which is responsible for unzipping the DNA double helix before it replicates. If this unzipping is disrupted, helicase can't tweeze out mutations that randomly occur and instead allows them to pass through to the next cellular generation. Collect enough glitches, and diseases of aging develop. We know that DNA is being damaged at a high rate, he says. Knowing that a helicase is responsible gets us closer to solving the mystery. If the mystery indeed is solved, the benefits could be enormous. Schellenberg suspects that the same helicase deficit that accelerates senescence in Werner's sufferers might, in a more measured form, cause aging in others.

To prove this, he will create a strain of mouse that carries a mutant helicase gene so that he can learn how the enzyme works, and more important how it can be manipulated Depending upon what Schellenberg learns from these mice, it might be possible to sidestep genetics and simply use helicase boosters to slow aging in both Werner's patients and healthy people. Running parallel to Schellenberg's work are studies being conducted at the New York State Institute for Basic Research into the more devastating Werner's like disorder known as progeria. People suffering from progeria grow old precociously too, but at a much faster rate; they are claimed by the infirmities of age in their 20s or teens. W. Ted Brown, chairman of the Institute's Department of Human Genetics, believes that progeria, like Werner's, is triggered by a single mutated gene.

That genetic miswiring may spur activity in the countless other genes that play a role in aging. Understanding all the genes, says Brown, will help us understand aging in general. The problem facing any scientist trying to find a genetic lever on the aging process is the sheer number of genes involved. Geneticist George Martin at the University of Washington in Seattle, who was involved in the discovery of the Werner's gene, believes that even if only a few master-clock genes directly guide aging in humans, up to 7,000 more might be peripherally involved. Re-engineering even one of these is an exquisitely complex process. Re-engineering all 7,000 would be impossible. For the time being, therefore, many researchers are shifting their focus to goals are more achievable. If the genes responsible for regulating senescence can't yet be manipulated, they wonder, is it possible to directly treat parts of the body they affect? Jerry Shay, a biologist specializing in cancer research at the University of Texas Southwestern Medical Center in Dallas, does not rule it out. Instead of engineering genes, he says, we might be able to squirt some chemical to trigger telomerase at a particular site.

The enzyme would turn on for a few weeks, change the expression of cells and revert them to a younger profile. We wouldn’t have to treat the whole body. Still other researchers are using what they've learned about and the other cellular mechanisms to attack the diseases that keep the very old from becoming still older. Researchers at Geron Pharmaceuticals recently published a study in which telemerase RNA was used to block the enzyme in a cancer culture, leading to whitering of telomeres and the death of the non – longer so profile cells. Elswhere, investigators are looking into using the anti caramelization drug pimagedine to help clear arteries and improve cardiac health. Remove hearth disease from the constellation of late illnesses, and you add three years to the national life expectancy.

The detection of a gene that seems to confer protection against Alzheimer's disease may help treat yet another scourge of the aged. While none of these therapies would take human beings anywhere near the tripled and quadrupled life-spans achieved in fruit flies and nematodes, they could at least improve our life expectancies-the number of years even our shortened and caramelgummed cells would allow us to achieve if illness: did not claim us first. For much of the time our species has been on the planet, that figure is thought to have been a mere 20 years barely long enough for contemporary people living contemporary lives to move out of their parents' home. The fact that those lives now routinely exceed 80 years is a monumental achievement. A little more progress in studying telomeres, glycosylation and other aspects of senescence science, and researchers like Butler believe there's no reason today's adults could not realistically hope to see 120. For people dreaming of immortality, that prospect may fall a little short. But for those of us who are contemplating a life that ends around age 80, four or five additional decades sounds like a splendid first step.

THE TIPS OF CHROMOSOMES

Telomeres are DNA sequences that cap chromosomes, protecting them the way a plastic cuff protects a shoelace. Each time a cell divides, the telomeres of its daughter cells become shorter and shorter. After about 100 replications, the telomeres are dramatically reduced, and the cell can no longer reproduce.

FREE RADICALS

Inside the mitochondria of cells, normal metabolism produces unstable oxygen molecules known. as free radicals. The molecules ricochet around the cells, damaging DNA and other structures.

CARAMELIZATION

Excess sugars can bind with proteins, forming a sticky, weblike coating. Over time, the buildup of this substance can stiffen joints, block arteries and cloud clear tissue.

WHAT IS AVAILABLE NOW

If you're serious about fighting the aging process-and a regimen of exercise and low-fat food isn't doing it for you-plenty of self-styled remedies are available by prescription or at health-food stores. None of them will make you any younger. Some should be taken only under a doctor's care. Some might actually do some good.

HUMAN-GROWTH HORMONE

PROMISE. Responsible for growth spurts in teenagers, hormone also restores lost muscle mass and redistributes fat cells in the elderly.

REALITY CHECK. HGH is expensive more $20,000 for a year's supply and has been shown to trigger such serious side effects as diabetes and heart disease.

MELATONIN

PROMISE. A proven natural antidote for insomnia, this hormone is also being investigated as a stress reducer and anticancer agent.

REALITY CHECK. Take too much melatonin (more than.5 mg) and you could feel groggy the next day. The hormone may lessen the side effects of standard chemotherapy, but the jury’s still out on that.

DHEA

PROMISE. The theory is that by boosting levels of this precursor to the sex hormones estrogen and testosterone- levels of which fall off with age-you can reset your body's internal clock and fool it into thinking it is decades younger. Enthusiasts claim DHEA gives them more energy, restores muscle tone, boosts their cognitive abilities and perks up their libido.

REALITY CHECK. No evidence exists that the hormone either slows aging or reverses it. Mice treated with DHEA do tend to act younger and friskier, but it's hard to extrapolate these results to humans. And there is a theoretical danger that taking DHEA could confer a greater risk for developing prostate or breast cancer.

ANTIOXIDANTS

PROMISE. By scooping up "free radicals" before they can damage cells in the body, antioxidants like beta-carotene could help stave off cancer, heart disease and other agerelated illnesses.

REALITY CHECK. Clinical trials have produced conflicting results. One study showed that beta-carotene supplements can actually increase the risk of cancer and heart disease for some people.

ALTERNATIVES FROM ASIA

There is something terribly smug about the way Westerners talk of modern medicine, as if nothing of value was discovered before the 19th century, when Louis Pasteur identified microbes as a main agent of disease. But the general public is more open-minded than the medical establishment, and in recent years people all over the world have sought alternative medicines, especially, from traditional Chinese practitioners who have been accumulating wisdom for thousands of years. Chinese experts offer many remedies for the ravages of aging-medicines that can improve the quality of life, even if they do not greatly increase potential longevity. Some ingredients, like ginseng, have been used for centuries, while others, such as the enzyme SOD, have been identified only recently. Of the wealth of alternative tonics, probably none has been subjected to the kind of rigorous scientific testing that would satisfy, say, the U.S. Food and Drug Administration. But traditional medicine boasts millions of satisfied customers who believe in its efficacy. And as any student of the placebo effect knows, belief in a drug goes a long way toward insuring its success.

SOD ENZYME

Superoxide dismutase, widely known as SOD, is an enzyme that occurs naturally in the human body and, among other things, helps the functioning of the nervous system. Extra doses of the chemical, it is believed, can retard the constant loss of brain cells, which are not replaced as a person grows older. Hundreds of daily tonics, including the best-selling Yi Shou Bao, contain SOD, but the key ingredient is missing in many fake products. Buyers should stick to reputable medicine shops.

GINSENG

A root that comes in Asian, American and Siberian varieties, ginseng is touted for everything from enhancing sex to prolonging life. A more realistic assessment is that ginseng helps keep blood pressure under control by acting on the adrenal -lands. It is often taken daily as tea or in pill form.

GINKGO BILOBA

Like many traditional medicines, this extract from the leaves of a japanese tree is promoted as a brain tonic. Taken in capsule form, it purportedly improves memory and fosters clear thinking. Another claim is that it enhances blood circulation by preventing the hardening of arteries.

LINGZHI

Made from mushrooms, this remedy is said to cure fatigue, relieve asthma, improve digestion and boost sexual stamina. More credible are claims that it bolsters the immune system and helps the liver remove toxic substances from the blood. It is often recommended to people with a family history of cancer.

ASTRAGALUS

Also called huang qi or milk-vetch root, astragalus is ground into powder or cooked in soup. It is known for boosting the body's energy, which the Chinese call qi, thereby relieving stress and fatigue, The root is also said to be good for the lungs, warding off coughs and colds.

GAMMA VAMA SUAN

Also known as gamma linolenic acid, it is most often extracted from the oils of primrose, cherry kernel, walnut and fish. It supposedly protects brain cells by helping to eliminate excessive fat and sugar from the blood. San Ming Yang Sheng Wang is a favorite potion containing this drug.

WHAT MAY BE NEXT

Futurists like to speculate about the means by which we may defeat the aging process (and a few cryonics shops have already started taking orders). Some antiaging technologies have a basis in science; they also have a long way to go

CRYONICS

PROMISE. By freezing the entire body-or, to save storage costs, just the head and brain-cryonicists hope to preserve a patient who has died until a time when physicians will be able to thaw and repair the frozen tissues, cure the disease that caused death, and then bring the person back to life.

REALITY CHECK. Preliminary animal studies show that some tissues (rat hearts, for example) can be cryopreserved and then revived in spite of the extensive damage that freezing does to cells. Whether these techniques will work for entire organisms, especially ones that have ceased living, is not clear. Even so, some 60 people in the U.S. have paid to have their bodies-or at least their headspreserved indefinitely.

NANOTECHNOLOGY

PROMISE. With continued progress in microminiaturization, scientists who believe in nanotechnology - technology that operates on the molecular, or nanometer, scale-predict that we will someday be able to build microscopic devices that will be injected into the body to fight disease at the cellular levelexcising tumors, say, or cleaning out clogged arteries.

REALITY CHECK. Microsurgery, which replaces the surgeon's hands with probes and scalpels, has yet to become routine, and its smallest tools are still hundreds of times as large as a nanotech machine. Even if the tools can someday be radically shrunk and mounted onto robots the size of a molecule, patients might balk at the idea of invisible, artificially intelligent machines roaming around inside their body,

TELOMERE THERAPHY

PROMISE. Is it possible to lengthen life by extending the within every cell of the body? In his new novel, Holy Fire, science fiction author Bruce Sterling describes just such a procedure. His heroine, a 95-year-old woman with lots of disposable income, gets a complete cellular makeover in which new genetic material is spliced onto the ends of each chromosome. Result: a posthuman, twentysomething.

REALITY CHECK. To operate successfully on all the body's chromosomes, doctors would have to penetrate each cell without killing it-something that has never been done with today's most advanced techniques. Even if scientists learned how to break and then repair the bonds that hold our cells together, there is still no evidence that extending would result in longer life.

THE BRAIN KILLER

Devastating for victims and families, Alzheimer's is now being recognized as the disease of the century. The part where the memory is gone, it's dead. The thoughts come to a void, and then there's nothing. Of all the incurable diseases, the degenerative brain disorder known as Alzheimer's may be the cruelest, because it kills its victims twice. In Alzheimer's, the mind dies first: names, dates, places-the interior scrapbook of an entire life-fade into mists of nonrecognition. The simplest tasks-tying a shoelace, cutting meat with a knife, telling time-become insurmountable. Then, the body dies. No longer able to walk or control elemental functions, the victim lies curled in a fetal position, gradually sinking into coma and death. On average, the decline occurs in six to eight years, although some sufferers linger as long as 20 .Experts now call Alzheimer's, the disease of the century. The causes are unknown. And while medical scientists are beginning to make strides in analyzing the chemical processes of the brain, Alzheimer's remains irreversible. It strikes people of every ethnic and socioeconomic group, and the number of cases is expanding apace with the rapid growth of the nation's elderly population. It claims more than 120,000 lives a year, making it the fourth leading cause of death among the old, after heart disease, cancer and stroke.

ANGUISH

Alzheimer's may be even more devastating for the families of victims. They drive themselves to physical and emotional exhaustion while rendering continuous care, and experience the anguish of seeing a loved one turn into a witless stranger who no longer even remembers who they are. And amid all this, they may see their life savings consumed in the crushing task of caring for a doomed patient. It's only going to get worse. Yet Alzheimer's is a disease that health policy makers somehow overlooked in their grand planning. Neither Medicare nor most private health-insurance programs pay for the custodial care its victims need. Before qualifying for federal-state Medicaid, a family must spend its way into virtual poverty Occasionally, spouses become divorced in order to protect what is left of their savings.The in middle class is absolutely wiped out. And even those who can afford to pay $50,000 or more a year for a nursing home are often turned away because Alzheimer's patients are too much trouble. Finally, they threw her out. Until recently, Alzheimer's was considered an exotic disorder. Within the last decade, refined investigative techniques have provided new clues about what causes memory and judgment to break down in the brains of victims. These discoveries raise the possibility, for the first time, that specific treatments can be found.

TWISTED NERVE FIBERS

The typical senile dementia of the elderly used to be blamed largely on impaired blood circulation to the brain and was thought to be an inevitable part of growing old. In 1906, Alois Alzheimer, a German neurologist, encountered a woman who showed all the signs of severe dementia-memory loss, disorientation and hallucinations-even though she was only 51. After her death, Alzheimer examined her brain and discovered that parts of it contained clumps of twisted nerve-cell fibers that he called neurofibrillary tangles. For decades afterward, physicians regarded cases of the kind Alzheimer described as rather rare and confined to the relatively young. In fact, they called the syndrome, presenile dementia. But in the 1960s, researchers armed with electron microscopes discovered the same neurofibrillary tangles in brain tissue from elderly patients with dementia. It soon became clear that the disease is neither presenile nor rare. Alzheimer's accounts for more than half of all cases of senile dementia. The other cases are most often caused by a succession of small strokes that knock out increasingly large amounts of brain tissue, or by a variety of conditions, some of them treatable, that produce mental confusion. These include depression, thyroid disease, deficiencies in certain vitamins, adverse drug reactions, anemia and alcoholism..

MEMORY LOSS

Alzheimer's usually occurs after 65, although it can strike in the 40s. But according to study, even elderly people who have trouble remembering where they put their glasses or can't recall names as quickly as they once did may just be showing normal age-related forgetfulness. They need to be reassured that these subjective symptoms are benign and consistent with good health. Signs of real trouble come when memory loss begins to affect a person's work or social life-a teacher can't remember the names of his students at the end of the semester, or a doctor forgets appointments. Typically, patients in this phase deny their problem or try to belittle it. Although fading memory is the most common early sign, trouble with language or personality changes may be among the first symptoms. Some patients believe the trouble is with their eyes because they aren't able to follow words on a page. Or they may go for a glass of milk and end up in the bedroom instead of the kitchen. Another dominant symptom may be apraxia, difficulty in performing rote gestures such as hair combing. The victim has trouble making appropriate judgments. As the disease worsens, the patient may, confuse the hot and cold handles in the shower and burn himself. Finally, the sufferer becomes incontinent, forgetting where to relieve himself By this time, the patient may not know where he lives, or the season of the year, and may even have forgotten the name of his spouse.

FULL TIME CARE

Some victims may become agitated and even sociopathic. A man was nearly picked up as a sex offender because he pulled down his pants and urinated on the sidewalk in front of some children. Another patient, a woman, was prosecuted for shoplifting by a grocery chain, though her son, her doctor and the police explained that she didn't even know she was in a store. A retired Air Force officer recalls that his wife suddenly began pummeling him while they were driving along a highway at 55 miles an hour. I'm driving with one hand and holding her back with the other. A man in a van next to us almost crashed. I'm sure he thought I was beating her. At this point, the patient obviously needs full-time care. In the last stage of Alzheimer's, the victim loses the ability to speak much at all, just saying yes or OK to everything. Gradually, he becomes unable to walk and may develop contractures of the face, arms and legs. Often, death is the result of pneumonia, which may be caused by inhaling food into the lungs.

DIAGNOSIS

The only sure way to diagnose Alzheimer's is to take a biopsy of brain tissue, which might disclose the telltale neurofibrillary tangles. But most doctors rely on less drastic tests. Often, these eliminate other possible causes of a patient's symptoms, rather than simply show the presence of Alzheimer's. Blood tests may indicate anemia, thyroid abnormalities or vitamin B-12 deficiencies that could be the source of trouble. CAT scans and the more recently developed nuclear-magnetic-resonance (NMR) technique for looking inside the skull will reveal signs of strokes or brain tumors. As part of the workup, patients are given tests of memory, attention span, language, spatial ability and abstract reasoning. In one such exam, they are asked to name the year, season, day of the week and month and to count backward from 100 by sevens. A considerable number of Alzheimer's victims display a trait called intrusion in replying to the questions. They may, for example, give the number of the year when they were asked the day of the week. Patients may also be asked to follow a three-point instruction such as Take a paper in your right band, fold it in half and put it on the floor. Taken together, such tests not only can suggest a diagnosis, but also indicate remaining abilities that can be used effectively in care. Although the disease is irreversible, Alzheimer's patients are by no means beyond help. In the early stages, when depression is often a major symptom, treatment with conventional antidepressant drugs can not only help but even postpone the need for institutionalization. Behavior therapy can also slow down the inexorable process of mental deterioration. Memory crutches in the early phase might include keeping a simple list of routine chores.

SELF-HELP

But the pressure of 24-hour care eventually becomes too great for most people, however loving, to withstand. Besides helping victims with mundane tasks like going to the bathroom, staff volunteers take patients on walks, conduct current events classes and show old movies. Study shows that music is familiar to them emotionally even if their memory is gone. Even if they can't remember the words, they can tap their feet or whistle. One of Care Program, one puts volunteers in the homes of Alzheimer's patients to give their families much-needed periods of rest. Program volunteers undergo an unusual training course. They are asked to perform such tasks as threading a needle while wearing vision-distorting glasses, or shuffling cards while wearing gloves, to illustrate the physical burdens of both the patients and the elderly spouses who must care for them. But in the end, most patients need the full-time attention of a nursing home. They deals with many patients in advanced senility. The home stresses patterning, an individually tailored program in which the patient bathes, dresses and eats according to the schedule he followed at home. Alzheimer's patients are much more comfortable in a structured setting.

Equally important, patients are kept out of bed and engaged in activity as much as possible. They attend group sessions in which they are reminded of familiar objects, like autumn leaves, and listen to music. If we can keep them physically well and active, we can bring them further along and stave off the the last stage of vegetation, says Ryan. Although the cause of Alzheimer's remains elusive, researchers are turning up clues at an accelerating pace. In 1976, scientists at three labs in Britain simultaneously found that Alzheimer's victims show a marked lack of an enzyme responsible for synthesizing acetylcholine, one of the brain chemicals, or neurotransmitters, responsible for carrying impulses between nerve cells. This gave us a real handle for research, an enormous impetus, says Dr. Peter Davies, one of the researchers. Although there is evidence that other neurotransmitters, such as noradrenalin, may also be involved, reduced levels of acetylcholine seem to be a hallmark of Alzheimer's and can account for many of the characteristic symptoms of the disease. For example, volunteers given scopolamine, a drug that blocks the action of acetylcholine, show lapses in memory.

And recently other researchers found that the brains of Alzheimer's victims exhibit a dramatic loss of neurons in the basal nucleus, a small area deep within the brain, where, as it happens, most acetylcholine is normally produced. In recent years, researchers have found other clues to the pathology of Alzheimer's. Among the most promising: They discovered some years ago that the neurofibrillary tangles originally described by Alzheimer consist mostly of minute threads twisted into the shape of a double helix, and he called them paired helical filaments (PHF), Outside the nerve cells, Alzheimer's brains show a formation called plaques, knobby patches of dying nerve fibers that are clustered around a core of material called amyloid. Whether the accumulating tangles and plaques are the cause or the result of the disease process is one of the tantalizing mysteries of Alzheimer's. Researchers are trying to determine the molecular composition of these abnormal structures to see what led to their development. They have found that the PHF, for example, are made of cementlike proteins that can't be broken down by ordinary techniques in the lab, which may explain why the disease is irreversible.

HIPPOCAMPUS BLOCKAGE

One of the key areas of the brain for processing new information and putting it into the human memory bank is the hippocampus, below the cerebral cortex. Researchers reported highly specific areas of damage adjacent to this region in five Alzheimer's patients. If the input and output to the hippocampus are blocked, your brain will simply not be able to acquire new memories. We think this is a superb way to explain some types of memory loss patients get in the early stages.

REDUCED RNA

In the normal brain, protein is being synthesized continuously, and a key chemical in the making of protein is RNA. But the study has discovered that the regions of the brain in Alzheimer's patients where the plaques and tangles seem to be particularly numerous show a marked reduction in RNA and protein synthesis. After RNA has done its job of making protein, it is removed by an enzyme. Recently, Reseachers found evidence of excessive activity of this enzyme in Alzheimer's brains, which may account for decreased protein synthesis.

GENETICS

Inheritance clearly plays a role in about 10 to 15 percent of Alzheimer's cases: the children of these victims have a 50 percent risk of developing the disease. Symptoms usually develop earlier than age 65 in these cases and the progress of the disease is unusually rapid and severe. Even among the rest of Alzheimer's victims, as many as a third have had a close relative with the disease. According to study, the younger the relative is when he gets the disease, the greater the risk for others in the family. But if a parent got Alzheimer's after age 70, there's very little increased risk. Another indication of genetic involvement lies in the fact that virtually anyone with Down's syndrome-a form of mental retardation caused by an extra chromosome in the body's cells-develops what seems to be Alzheimer's after the age of 35 or 40. Study has found that families with an Alzbeimer's victim are three times more likely than others to also have a member with Down's syndrome. Since an extra chromosome is the culprit in Down's, that's where scientists, using the new recombinant DNA technology, are looking for the gene that may cause Alzheimer's.

SLOW VIRUSES

Several neurological diseases that produce dementialike symptoms are known to be caused by slow viruses, organisms that lie dormant for long periods before causing any symptoms. So far, however, attempts to transmit such a putative virus to experimental animals by inoculating them with brain tissue from Alzheimer's victims have been unsuccessful, leaving the issue unresolved. Researchers concede that taken together the Alzheimer's evidence to date resembles a jigsaw puzzle. In fact, the disease might have not one, but several interlocking causes-viruses, toxins or genes. Still, using the clues available, doctors are taking the first hopeful steps in testing treatments for the disease. The discovery that patients have a deficiency of acetylcholine prompted researchers to try drugs that would raise levels of the neurotransmitter. The most effective of these has been a drug called physostigmine. It increases levels of acetylcholine by blocking the action of an enzyme that normally removes it from the brain. Resechers of medicine reports clinically significant improvement in 3 of 11 patients taking oral doses of physostigmine. The best were made to look like they had looked 1 1/2 years earlier. Drugs that raise acetylcholine levels may not work in patients with advanced Alzheimer's, researchers suspect, simply because they don't have enough acetylcholine-producing brain cells left. So far, the most promising results have been obtained by the study that reasoned, not enough of a drug gets into a patient's brain when it is given orally. So it suggests to implant a small pump under the skin of the abdomen in four Alzheimer's victims. By means of a catheter inserted through a tiny hole in the skull, the pump delivered a continual flow of an acetylcholinelike drug called bethanechol directly into the ventricles of the brain. As judged by their own families, the patients have shown improvement in such previously impaired activities as reading, personal hygiene, conversation and social activity for as long as a year. Reseachers hope to test the infusion pump on more patients, and using a variety of other more promising drugs.

EXCITING TIME

Scientists compare the current status of Alzheimer's to the challenge they faced with heart disease three decades ago. It, too, was once thought to be an inevitable part of aging. Then came drugs to control high blood pressure and recognition of the role of diet in atherosclerosis, both of which may help account for the present decline in coronary mortality. So, researchers hope, it might eventually go with Alzheimer's. These are exciting times. More is known than ever, and more will be known next year. In the meantime, what seems needed is to keep the Alzheimer's tragedy in the public eye and make sure there is no slackening of the research effort. The way I deal with my grief is by sharing it, talking to people about Alzheimer's, trying to get funding for research. and makes public appearances to tell her mother's story There's an enormous need to come out of the closet, she says, and to share the information, the awareness and the pain.

THE GERMS AROUND US

Rapid fire discoveries are revealing how the body's immune system endlessly fights off disease and occasionally goes awry It's a jungle out there, teeming with hordes of unseen enemies. Bacteria, viruses, fungi and parasites fill the air. They cluster on every surface, from the restaurant table to the living-room sofa. They abound in lakes and in pools, flourish in the soil and disport themselves among the flora and fauna. This menagerie of microscopic organisms, most of them potentially harmful or even lethal, has a favorite target: the human body. In fact, the tantalizing human prey is a walking repository of just the kind of stuff the tiny predators need to survive, thrive and reproduce.

Humans are under constant siege by these voracious adversaries. Germs of every description strive tirelessly to invade the comfortably warm and bountiful body, entering through the skin or by way of the eyes, nose, ears and mouth.. Fortunately for man's survival, most of them fail in their assault. They are repelled by the tough barrier of the skin, overcome by the natural pesticides in sweat, saliva and tears, dissolved by stomach acids or trapped in the sticky mucus of the nose or throat before being expelled by a sneeze or a cough. But the organisms are extraordinarily persistent, and some occasionally breach the outer defenses. After entering the bloodstream and tissues, they multiply at an alarming rate and begin destroying vital body cells.

The invaders soon receive a rude shock, for they encounter one of nature's most incredible and complex creations: the human immune system. Inside the body, a trillion highly specialized cells, regulated by dozens of remarkable proteins and honed by hundreds of millions of years of evolution, launch an unending battle against the alien organisms. It is high-pitched biological warfare, orchestrated with such skill and precision that illness in the average human being is relatively rare.

Early warning cells constantly monitor the bloodstream and tissues for signs of the enemy. With the gusto of Pac-Man, they gobble up anything that is foreign to the body. They envelop dust particles, pollutants, microorganisms and even the debris of battle: remnants of invaders and infected or damaged body cells. Other early warners direct the production of unique killer cells, each designed to attack and destroy a particular type of intruder. Some of the killers, alerted to body cells

Painful shot: two-month-old Austin Reed is inoculated with an experimental vaccine against meningitis that have become cancerous, may annihilate these too. Endowed with such specialized weapons, the properly functioning immune system is a formidable barrier to disease. Even when an infection is severe enough to overcome the system's initial response and cause illness, the immune cells are usually able to regroup, call up reinforcements and eventually rout the invaders. But when the system is weakened by previous illness or advancing age, for example, the body becomes more vulnerable to cancers and a host of infectious diseases. And should the system overreact or go awry, it can cause troublesome allergies and serious disorders called autoimmune diseases. As they probe the intricate workings of the immune system, scientists are awestruck. It is an enormous edifice, like a cathedral, says Nobel Laureate Baruj Benacerraf, president of Boston's Dana Farber Cancer Institute. The immune system is compared favorably with the most complex organ of them all, the brain. The immune system has a phenomenal ability for dealing with information, for learning and memory, for creating and storing and using information, explains Immunologist William Paul of the National Institutes of Health (NIH). Declares Dr. Stephen Sherwin, director of clinical research at Genentech: It's an incredible system. It recognizes molecules that have never been in the body before. It can differentiate between what belongs there and what doesn't.

Knowledge about the inner workings of the immune system has undergone an astonishing explosion in the past five years. Although researchers began to pry loose its secrets in the late 19th century, it was not until after World War 11 that the pace of discovery began to quicken, boosted by such achievements as the deciphering of the genetic code and recombinant DNA technology. But no early advances can match those of recent years, which have enabled doctors to devise - ingenious new treatments for a host of disorders. Says Immunologist John Kappler, of the National Jewish Center for Immunology and Respiratory Medicine in Denver: The field is progressing so rapidly that the journals are out of date by the time they are published.

Kappler is not exaggerating. In the past few months alone, dozens of new immune discoveries and promising therapies have been reported. Researchers announced in March that by activating certain immune cells, they had increased by 20% the five-year survival rate of patients in the early stages of lung cancer. In the same month, European scientists reported eliminating the need for insulin shots in some diabetic children by administering a drug that suppresses the immune system. Researchers in Colombia have tested a malaria vaccine that. unlike previous efforts, seems to provide protection against the disease. Advances have come so fast, says Dana-Farber's Benacerraf, that we're now on the threshold of being able to activate the different components of the immune system at will to provide therapies for cancer and even for AIDS. In fact, it is the AIDS epidemic that has spurred much of the recent interest in immunology. The AIDS virus strikes a key component of the immune system, destroys it, and in so doing virtually knocks out the entire system. Nothing illustrates the importance of a healthy immune system more dramatically than the disastrous consequences of its loss. AIDS sufferers become vulnerable to many kinds of invading organisms. Fungal growths corrode the skin and lungs. Normally dormant parasites in the lungs become active, causing Pneumocystis carinii pneumonia. As viruses and bacteria multiply out of control, competing for body cells and destroying them far faster than they can be replaced, victims can be stricken with severe cases of herpes and tuberculosis. What is more, they lose their resistance to some types of cancer, particularly Kaposi's sarcoma. Tragic as it is, says Dr. Anthony Fauci, the AIDS research coordinator for the National Institutes of Health, the AIDS epidemic has provided important new insights into the immune system. AIDS is the perfect disease for studying the immune system, he explains. The virus destroys one of the major cells of the system. So now nature is doing the experiment. It has just pulled out a major chip, and we're watching everything else go haywire. On the other hand, AIDS Expert Robert Gallo of the National Cancer Institute believes that much of the progress in AIDS research would have been impossible without discoveries about the immune system made shortly before the epidemic bloomed. If AIDS had come along in the 1970s, he says, we'd still be looking under rocks for the cause.

Now, however, scientists have a good grasp not only of the broad workings of the immune system but of many of the nittygritty details as well. In a typical infection, for example, a flu virus burrows into a cell in the lining of an air passage, takes over the machinery of the cell, and orders it to produce more flu viruses. Quickly engorged, the invaded cell bursts, releasing new viruses to infiltrate other cells and replicate further. Left unchecked, the onslaught would eventually kill enough cells to cause death. But the intruders soon encounter roving scavenger cells called phagocytes, which simply engulf and digest them. These defenders-monocytes, neutrophils and macrophages-secrete substances that dilate nearby blood vessels and make them more permeable, enabling even more defenders to get from the bloodstream to the infection site. Other proteins, those belonging to the complement system, aid in this process.

Upon meeting a virus, the macrophage, which moves about, amoeba-like, on long cellular extensions known as pseudopods (false feet), does more than just ingest the intruder. It has another, even more important function. On its surface, like virtuatly all body cells, the macrophage carries MHC (for major histocompatibility complex) molecules, protein badges that enable other immune cells to recognize the macrophage as friend, or self, and not attack it. After digesting the virus, the macrophage proudly displays strips of protein from the virus in the grooves of some of its MHC molecules. Once a bit of protein which is part of the virus's own identity molecule, or antigen-is nestled in the groove of the macrophage's MHC molecule, it acts as a red flag for the immune system, warning it that a particular type of virus is loose in the body.

At this point, it's still a race between the immune system and the virus, says Dr.Carl Nathan of Cornell University Medical College. The virus is trying to replicate before the immune system has a chance to gear up. In order to mobilize the system, the macrophage must find-or literally bump into-a helper T cell, the battle manager of the immune system. The catch is that only a tiny fraction of the billions of T cells in the body are capable of attaching to the antigen of this particular flu virus and taking action. To increase its odds of meeting up with an appropriate T cell, the macrophage probably moves from the body tissue into the nearest lymph node, through which helper T cells of all kinds continually pass. Robert Coffman, a scientist at Palo Alto's DNAX Research Institute, likens the site to a busy Manhattan sidewalk. If you walk the street enough, he says, pretty soon you'll run into almost everyone who lives in New York City. When the macrophage finally runs into a compatible helper T cell, it inserts its antigen-bearing MHC molecule into a T-cell receptor shaped to receive it, much as a key would fit into a lock. The macrophage then secretes a protein called interieukin-1, a chemical signal that causes the T cell to begin replicating. Simultaneously, interleukin-I acts on the body's central thermo stat, causing a fever, which may depress viral activity and enhance the immune response.

The rapidly multiplying helper T cells now begin releasing a flood of their own chemical signals, the so-called lymphokines, which include gamma interferon and other types of interleukin. These stimulate the defense system even more, spurring the proliferation of phagocytes, including macrophages, and other immune fighters something like a draft call in wartime. The result is the familiar swelling and inflammation of an infection.

At the same time, other helper T cells in the lymph nodes move to couple with yet another kind of immune fighter, the B cells. Releasing still more chemicals, the helper T cells stimulate the B cells to reproduce. These proliferating B cells then mature into plasma cells, which DNAX's Coffman calls dedicated antibody factories, that begin to mass-produce antibodies. Antibodies are proteins capable of recognizing and binding specifically to the flu virus that triggered the alarm. Circulating in the blood to seek out their quarry, they begin attaching themselves to the viruses, signaling the macrophages and other immune scavengers to move in for the kill.

Meanwhile, gamma interferon released by the T cells has not only slowed viral replication but also whipped the macrophages into a feeding fury. Their cell membranes become ruffled, their feet more numerous and their appetites ferocious. They don't necessarily eat faster, notes Dr. Richard Johnston Jr. of the University of Pennsylvania School of Medicine, but they kill better.

The flu viruses, however, are not finished yet. Those still multiplying inside the body's cells are momentarily safe from scavengers and antibodies, but the free lunch is over quickly. While the B cells are being activated, other helper T cells have been creating an army of killer T cells. These killers recognize the flu-ridden cells because, like macrophages, infected cells display a bit of viral antigen on their outer membranes. Says Coffman: For many viral infections, the most important response is the killer T cell. Viruses live inside cells, so it's essential to kill not only the viruses themselves but those cells that are infected with the virus

The killer T cells are relentless. Docking with infected cells, they shoot lethal proteins at the cell membrane. Holes form where the protein molecules hit, and the cell, dying, leaks out its insides. To ensure that the cell and its viral occupants are destroyed, the killer T cells then deliver the coup de grace by transmitting a signal that causes the cell to chew up DNA from both itself and the virus. Explains Dr. Irving Weissman of Stanford: This is an overlapping, dual system of killing that ensures that the seed of viral production will be eliminated from the body.

When victory over the virus is achieved, the wildly accelerating responses of the immune system slow, then shut down. Scientists believe that still other immune specialists, known as suppressor T cells, call off the battle. As the carnage wanes, the B cells and T cells perform a last, vastly important task: they form memory cells that circulate in the bloodstream and lymph system for many years, primed to spring into action should the same strain of flu virus ever attack again. In addition, the body is protected by specialized antibodies, strategically deployed in mucus, saliva and tears, that immediately recognize any return of this particular virus.

While a healthy immune system may take as long as three weeks to complete the job against a specific flu virus, its next response to the same viral strain reaches full force immediately, and the invaders are overcome before they can do any significant damage. In other words, the body has become immune-but only to that specific virus. You probably wouldn't even know you'd been reinfected, says Carl Nathan. The immune system has a short track and a long track, and it all depends on whether it's a first encounter or you've seen it before.

How did this astonishing biochemical system develop? The first stages in its evolution are a mystery. But scientists have deduced from the study of primitive species that rudimentary mechanisms against infection existed in various forms of life more than a billion years ago. The first inkling of such progenitors came in 1883, when Russian Zoologist Elie Metchnikoff stuck a rose thorn into the larva of a starfish and a short time later observed that the thorn had been completely surrounded by cells. The cells were phagocytes. These little guys go back in evolution a very long way, says Carol Reinisch of the Tufts School of Veterinary Medicine. They have the ability to distinguish between self and nonself, which is the crucial distinction.

Over the eons, these primitive defenders developed increasingly sophisticated weapons to fight off microorganisms, which could mutate far more rapidly and thus evolve faster than higher forms of life. But it was probably not until about 600 million years ago, about the time vertebrates began to emerge, that the modern immune system, with its T cells and B cells, began to take shape. Once in place, these two cell types must have quickly evened the odds, since they have the remarkable ability of producing, respectively, a staggering variety of killer T cells and antibodies capable of attacking any invader.

How these immune cells produce such diversity was elucidated during the mid-1970s by Immunologist Susumu Tonegawa, now at M.I.T., who in 1987 was awarded the Nobel Prize for his achievement. Tonegawa proved that the B-cell genes that dictate the production of antibodies occur in distinct segments. These pieces, like cards in the hands of a Las Vegas dealer, are constantly and speedily shuffled into different combinations. Coupled with mutations that occur as B cells divide into plasma cells, such genes, in theory at least, could account for as many as 10 million antibody variations. Other scientists have shown that T cells have a similar mechanism. Thus within the slowly evolving human being, the immune system is undergoing a rapid internal evolution of its own. And a good thing too. If all we had to meet the microorganisms was true evolution, says NIH'S William Paul, we'd long ago have disappeared from the face of the earth.

Long before scientists even began to unravel the mysteries of this remarkable system, the ancients were aware of immunity. They knew from experience that anyone who survived certain diseases would not be likely to get them again. As early as the IIth century, Chinese doctors were manipulating the immune system. By blowing pulverized scabs from a smallpox victim into their patients' nostrils, they could often induce a mild case of the disease that prevented a more severe onslaught. In the 1700s, people rubbed their skin with dried scabs to protect themselves against the disease.

These primitive practices were introduced to England and the American colonies. In 1721 and 1722, during a smallpox epidemic, a Boston doctor named Zabdiel Boylston scratched the skin of his six year old son and 285 other people and rubbed pus from smallpox scabs into the wounds. All but six of his patients survived. A much safer approach to immunology was made in 1796, when Edward Jenner decided it was more than coincidence that milkmaids stricken with a mild form of the cattle disease called cowpox were rarely victims of smallpox. He inoculated James Phipps, 8, with cowpox, then exposed him to smallpox six weeks later. The boy never came down with the disease, confirming that the immunization had worked. More than a century and a half passed before scientists knew the reason: the antigens on the cowpox virus are so similar to those on the smallpox virus that they can prime the immune system to repel a smallpox infection.

In 1880 Louis Pasteur, a French microbiologist, concocted a vaccine against chicken cholera after discovering that weakened cholera organisms, while incapable of making chickens sick, would immunize them against the malady. Pasteur, who is credited with founding the science of immunology, went on to create a human rabies vaccine from the brains of rabies-infected sheep and rabbits

Building on Pasteur's work, 20th century scientists have learned to mass-produce bacteria and viruses, then weaken or kill them and use them as the major ingredient in vaccines for such varied diseases as typhus, yellow fever, influenza, polio, measles and rubella. Unfortunately, the vaccines occasionally cause the disease they are designed to ward off. (Reason: the killed viruses sometimes survive, while the weakened versions often fail to cause an immune response.) In general, however, the vaccines have been quite effective; in recent years the National Academy of Sciences has reported only a handful of polio and diphtheria cases and only a few deaths caused by whooping cough and rubella. Maurice Hillemen, director of Pennsylvania's Merck Institute for Therapeutic Research, characterizes the early vaccine era as the stumbling along period.

These days the explosive growth of both molecular biology and immunology has enabled vaccine makers to take a safer and more effective approach to their work. Instead of using dead or attenuated bacteria or viruses, they remove from the bug's surface the marker protein, or antigen, that provokes the immune response. Employing gene-splicing techniques, they mass-produce the antigen, or a portion of it, and use it as the prime ingredient of the vaccine.

Researchers are also creating vaccines that consist largely of antigens synthesized from chemicals on the laboratory shelf When these vaccines prove ineffective, scientists can now usually determine why. Says M.I.T. Molecular Biologist Malcolm Gefter: Today, when a vaccine doesn't elicit a protective response, it is possible to detect what is or is not working-the B cells, the T cells, the lymphokines, whatever. Scientists can then fix the vaccine. For example, the 1985 vaccine against Hemophilus influenzae Type B, which causes bacterial meningitis, was only partially effective; although it protected older children, it did not work for babies under two years, who are most at risk. The antigen used to make the original vaccine has been re-engineered to make it more potent, and the new vaccine is being tested in infants.

Despite such advanced techniques, it seems tougher than ever to create new vaccines. Some viruses, bacteria and parasites are so complex and well evolved in their defenses against an immune reaction that no vaccine strategy has yet been entirely effective. Flu viruses, for example, mutate rapidly, continually changing their antigens in the process. As a result, an immune system strengthened by a flu shot against last year's predominant strain of flu will probably not be helped by it this year. The common cold virus is also troublesome, because it comes in at least 100 identifiable varieties. The parasite that causes malaria poses still other problems: it penetrates cells so quickly that it is hidden from antibodies. To complicate matters, it goes through three stages of life, displaying different antigens in each stage. Because none of the malaria vaccines yet developed can cope with these diverse strategies, the affliction is still rampant in the tropics.

Such challenges to the vaccine makers, however, pale in comparison with that presented by the AIDS virus. Says M.I.T's Gefter: We're looking at a strong, well devolved, well-designed organism that is doing whatever it can to protect itself. The AIDS virus mutates twice as fast as the flu bug. It can lie dormant in body cells, where antibodies cannot attack it, without revealing its telltale antigen (a dead giveaway to killer cells). New findings indicate that the virus also uses immunological decoys that provoke impotent immune responses. Worst of all, the AIDS virus is unique in that it can mount a speedy and lethal attack on helper T cells, which cripples the immune system before it can counterattack. This means that to prevent an AIDS infection from taking hold, a vaccine must stimulate the immune system to incapacitate the AIDS virus immediately after exposure, before it can penetrate the helper T cells.

Scientists are scrutinizing the AIDS virus for any sections of its outer coat that remain unchanged during its rapid mutations. With antigens from these sections, they hope to produce a vaccine that will remain effective despite many mutations. A group led by Dr. Daniel Zagury at the Pierre and Marie Curie University in Paris has created one such vaccine, which he claims produces a weak immune reaction. Zagury and several volunteers went so far as to inoculate themselves with the vaccine last year. Even so, many researchers, Merck's Hilleman among them, believe the prospects for an AIDS vaccine are dismal. Others disagree. We've known about the tricks of this virus for only a year or so, says Gefter. With a better understanding of its strategems and with the genetic engineering tools we have, we can design sophisticated vaccines tailor made to the life cycle of the AIDS virus.

Even without provocation by the AIDS virus or other infectious organisms, the immune system can sometimes go awry. Often, entirely on its own, it can over respond, fail to respond or turn against the body it is designed to protect with the same lethal fury it directs against invaders and cancerous cells. Some 80 immune system deficiencies have been identified so far. About one in 400 people has at least one immune-system component missing or malfunctioning, usually for genetic reasons. In one in 10,000 people, the deficiency leads to serious disorders. Perhaps the most tragic example is severe combined immunodeficiency disease, a rare condition in which both B cells and T cells are lacking. The most famous SCID victim, a Texas boy named David, lived for twelve years in a germ-free bubble while doctors searched in vain for a cure for his disease. He died in 1984, four months after receiving a bone-marrow transplant that doctors hoped would supply his missing immune cells.

As hay fever and other allergy sufferers will testify, the immune system can sometimes react to pollen, animal dander,molds and drugs that are normally harmless. In allergy victims, however, the immune system goes into high gear at the appearance of these substances, or allergens. It begins producing antibodies called immunoglobulin E, which attach themselves to mast cells located in the tissues of the skin, in the linings of the respiratory and intestinal tracts, and around the blood vessels. The mast cells promptly begin to release a number of chemical signals, including histamine, a substance that dilates blood vessels and makes it easier for cells to pass through the capillary walls.

These changes, meant to expedite the arrival of immune cells, cause the inflammation and swelling associated with allergic reactions. Allergy sufferers are now treated with antihistamines, which temporarily block the immune response, as well as steroid nasal sprays and inhalers, which reduce inflammation. But more effective help may be on the way. Scientists have synthesized bits of protein molecules that prevent immunoglobulin E antibodies from setting off an allergic reaction.

One of the more devastating errors of the immune system involves its failure to distinguish between self and nonself, resulting in so-called autoimmune diseases, which can be crippling and sometimes fatal. Dozens of disorders that once mystified doctors are now thought to be autoimmune. Among them: Type I diabetes,myasthenia gravis, multiple sclerosis rheumatoid arthritis and systemic lupus. erythernatosus. In these and other autoimmune diseases, the immune system mounts a selective and ferocious assault against parts of the body, destroying cells or cell components that it mistakenly identifies as alien.

Type I diabetes, for example, which afflicts 1.5 million Americans and is brought on by an insufficient supply of insulin, was for years believed to be caused by a virus. Researchers have now shown that it probably results from a defective immune system. For reasons that are not yet clear, immune cells invade the pancreas and destroy the beta cells, which produce insulin. When this happens, the body cannot convert sugar into the energy that cells need to function. The cells starve, and the unconverted sugar builds up in the bloodstream, damaging the fragile lining of blood vessels. Complications associated with Type I diabetes include heart and kidney disease, poor circulation, eye problems and stroke.

However incomplete, the emerging understanding of the immune system's role in Type I diabetes has le to an experimental treatment. In Canada and Europe, researchers have weaned diabetics from their insulin shots after giving them cyclosporine, a drug used in organ transplants to suppress the immune system. Doses of cyclosporine, which works by dampening T-cell attacks on the beta cells, have provided dramatic results: many patients have been able to discontinue their insulin shots for up to a year. Still, by undermining the entire immune system, cyclosporine leaves the diabetic more vulnerable to other diseases. And when given in high doses, it can have serious side effects, including kidney damage.

In an attempt to find a more selective treatment for Type I diabetes, researchers are trying to figure out exactly why the immune system attacks the beta cells. Last October a Stanford University team discovered errant forms of a gene that controls the development and growth of the culprit T cells. The team's conjecture: in Type I diabetics, this gene produces a protein badge that differs slightly from the norm in structure, causing the immune system to attack the beta cells. Eventually, the group hopes to find a way to neutralize the harmful effects of the molecule and thus eliminate the need for immune suppressants like cyclosporine.

Another autoimmune disease, myasthenia gravis, a neuromuscular disorder that afflicts 15,000 Americans, is caused by antibodies that attack vital links in the nervous system, and leads to gradual loss of muscular control. Initial studies suggest that small doses of cyclosporine may be effective in blunting the symptoms of the disease. Some researchers, however, are searching for a more selective remedy that involves mass-producing antibodies that are specific to one antigen. These so called monoclonal antibodies are designed to immobilize only those B cells that produce the antibodies responsible for the disease.

Some of the most promising new therapies arising from recent research involve the chemical signals, or lymphokines, that regulate the immune system. These extraordinary proteins have a bewildering array of names and functions. There are, for instance, three types of interferon-alpha, beta and gamma. Alpha alone comes in more than a dozen varieties. Interleukins are similarly prolific. We are already up to interleukin-7 and interteukin-8, says Immunologist Lloyd Old, of the Memorial Sloan-Kettering Cancer Center in Manhattan, and one can expect that we will go on from there. Scientists have so far discovered at least five different colony-stimulating factors, which cause cells in the bone marrow to mature and differentiate into red and white blood cells. Each of the players seems to have a vital, if sometimes overlapping, role.

Using bioengineering techniques, medical researchers have begun to mass-produce these substances and use them, sometimes in combined cocktails, to boost the immune system against specific diseases. In clinical trials at Boston's New England Deaconess Hospital, Dr. Jerome Groopman has found that granulocyte-macrophage colony-stimulating factor reverses bone marrow failure and boosts white-cell counts in AIDS patients. Gamma interferon seems to remedy the defective functioning of monocytes and macrophages in a wide variety of diseases. Alpha interferon has been particularly effective against two types of leukemia and non-Hodgkin's lymphoma, a cancer of the lymph system. Says Dr. Jordan Gutterman, of Houston's M.D. Anderson Hospital and Tumor Institute: There are ten different tumors in which potentially important anti tumor activity by interferon has been demonstrated.

Interleukin-2 has shown promising results in treating advanced skin and kidney cancers. In fact, says Gutterman, there appears to be tremendous synergy between alpha interferon and IL-2 in attacking cancer cells. While IL-2 works to make the killer cells more potent, he explains, they have to recognize something unique on the surface of the cancer cell in order to kill it. That something is an antigen, and interferon seems to make it more visible to the killer cells.

Scientists are proceeding cautiously with the new therapies. In any substance that is immunologically active, observes Genentech's Sherwin, you run the risk of tilting the balance in an unfavorable way. We don't know all of the answers yet. That may be an understatement. Immunologist Leroy Hood of the California Institute of Technology is certain that the lymphokines discovered so far are just the tip of the iceberg and that more subcategories of T cells will be found, He emphasizes that scientists do not yet fully understand, among other things, how B and T cells differentiate, and how the immune system's genes are turned on and off at different times. In the truest sense, he says, immunology is just in its youth. Still, says Sherwin, there's an enormous amount we know now that we didn't know five years ago, and five years from now we'll know even more. Immunology may indeed still be in its youth, but it is

growing up fast.

THE BODY ‘S DEFENSES

Some of the immune system's biggest battles are directed not against harmful intruders but against potentially lifesaving organ transplants. New hearts and kidneys in adults have become fairly commonplace, and top surgeons have even attempted the daunting feat of transplanting multiple abdominal organs into infants and toddlers. Today's organ recipients are indebted to a drug called cyclosporine, which has revolutionized transplantation technology in the past decade. Unlike immunological treatments for AII)s and cancer, cyclosporine works by temporarily suppressing the body's natural defenses, thus preventing the rejection of grafted tissue.

The miracle of cyclosporine comes at a steep price. The drug can cause severe damage to the kidneys as well as allow cancerous tumors to develop. Moreover, cyclosporine costs as much as $6,000 for a year's supply, and patients may need it for life. Still, declares Calvin Stiller, chief of transplantation at University Hospital in London, Ont., cyclosporine clearly stands out as the most important medical discovery in transplantation. It changed the field.

Ever since the pioneering transplant the 1960s, the chief obstacle to the full recovery of transplant patients has been the immune system's xenophobic zeal to destroy anything that is foreign to the body. Once the alien threat has been identified, agents known as helper T cells unleash the powerful immune response that attacks grafted tissue. During the 1970s, physicians found that they could minimize this reaction by more closely matching the MHC proteins, or immunological dog tags, of a donor with those of the recipient. Even so, they could not completely eliminate the rejection response. To make matters worse, the only drugs available to weaken it shut down the defensive system completely, leaving patients vulnerable to viruses, bacteria or tumors. The triple threat of rejection, infection and malignancy kept transplant surgery to a minimum. Enter cyclosporine. Discovered in 1970 by a scientist at Sandoz, a Swiss pharmaceutical company, the drug was nearly abandoned as worthless. Unexpectedly, however, researchers found that it was a highly selective suppressor of helper T cells. By preventing the activation of the T cells, the drug interferes with the body's instinct to attack a transplanted organ. Yet unlike other suppressants, it does not affect other parts of the immune system. Cyclosporine is thus able to dampen the rejection reaction while leaving a large part of the body's infection-fighting defenses intact.

Physicians began testing the drug on humans in 1978. The results were dramatic. Both rejection and infection continued to be problems, but survival rates one year after transplantation rose from 32% to 70% for liver patients and from 54% to 77% for kidney patients. By early 1980, recalls Thomas Starzl of the University of Pittsburgh, a leading transplant surgeon, we had a sense that there was a tremendous change in outlook in both kidneys and livers, and that enthusiasm quickly spread to the heart. Cyclosporine is highly toxic, however, and researchers have begun to look for alternatives. Ideally, they foresee a therapy that would prevent rejection but also persuade the immune system to tolerate a transplanted organ even after treatment is halted.

For now, surgeons and their patients must still walk the tightrope between the natural potency of the immune system and the perils of suppressing it. The balancing act is especially tricky in the most difficult of operations: multiple abdominal transplants. Doctors in the U.S. have tried such surgery only four times in the past four years. Just one patient, now seriously ill, survives. Tenmonth-old Michael Steward of Chicago received a new liver, pancreas, small intestine and part of the stomach in February to correct a congenital defect. Last week, a record 6 1/2 months after a similar operation, three year old Tabatha Foster of Madisonville,Ky., succumbed to cancer. The lesson: physicians have a great deal more to learn before they can manipulate the immune system at will.

THERAPIES BOLSTER AGAINST CANCER

For more than 30 years, doctors have been trying to rally the weakened immune systems of cancer patients to fight the disease. Only recently, however, have therapies been developed that bring some of the body's own most potent weapons to bear in the struggle to repel invaders ranging from cancer to the AIDS virus. Those weapons include antibodies, tumor-killing blood cells and the chemical messengers that regulate them.

One promising approach is the use of interleukin-2, one of the proteins called lymphokines, which are produced by the immune system. IL-2 is now being administered in various ways to stimulate the white blood cells that attack tumors. Expensive-upwards of more $80,000 for one course of treatment-and dangerous, IL-2 is usually reserved for patients with advanced cancer. Amy Hance, 25, of Bloomington, Ill., reached that stage early this year. Melanoma, a deadly skin cancer, had spread to her liver, spleen, stomach and lungs. The determined Hance opted for experimental IL-2 therapy, even though side effects-including fever, massive fluid retention, anemia, nausea, vomiting, diarrhea and heart and lung problems had killed several patients.

At the University of Chicago's Billings Hospital, her blood was run through a machine to separate out white cells, which were incubated for several days in IL-2 to turn them into LAKs, or lymphokine-activated killer cells. The cells were then dripped back into a vein, along with IL-2. Her temperature shot up, and severe nausea set in. I never think of the symptoms as bad, because I know there's this big fight going on in there, says Hance. Her bold gamble paid off after 42 weeks of treatment, her tumors had shrunk by 80%.

IL-2 appears to stimulate certain immature white cells to mature into killer cells that destroy cancer. Since 1984, when the treatment was developed by Dr. Steven Rosenberg of the National Cancer Institute, more than 400 Americans have received it. Though there have been some spectacular successes, IL-2 is clearly no cure for cancer. Five percent to 10% of patients experience complete remission, and more have partial ones. But the majority reap no benefit at all. Given the expense and the risks, the treatment has come in for some sharp criticism. Even so, University of Pennsylvania Oncologist Kevin Fox notes that IL-2 therapy is the only treatment that works at all on advanced melanoma and kidney cancer. Admits Rosenberg: It's a treatment in its infancy.

Rosenberg is working on a new and potentially more powerful therapy called TILS, for tumor-infiltrating lymphocytes. In tests on mice, he notes, these cells appear 50 to 100 times more potent than LAK. TILs are actually killer T cells that, like LAK cells, can attack cancer cells. To produce them, researchers expose malignant cells removed from the patient to IL-2. The tissue includes killer T cells that have launched a weak attack with a sharp boost from the IL-2, they replicate and proceed to destroy the cancer. A month later, the newly potent T cells, vastly increased in number, are then infused into the patient, followed by additional IL-2.

Eight of Rosenberg's first nine patients, who had not responded to other treatments, had good responses to TILS. One has been in complete remission for five months. Tumors have dramatically shrunk in others, and, because patients have been exposed to IL-2 only briefly, side effects have been mild. Rosenberg is convinced that the future of cancer therapy lies in finding the right combinations of immune-system regulators, including the interleukins and interferons. Other researchers have high hopes for monoclonal antibodies that can carry drugs or radiation directly to tumors or help other immune-system cells kill the cancer cells. Every year, says Rosenberg, 485,000 Americans die of cancer. We desperately need new treatments. One dream has been to harness the body's own defense mechanisms. It has turned out to be an extraordinarily difficult and challenging job. And it will not be finished for some time.

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