X-Message-Number: 15444 From: "Mark Plus" <> Subject: "The Very Radical Business of Long Life and Eternal Youth" Date: Wed, 24 Jan 2001 17:14:14 -0800 From: http://www.worth.com/cgi-bin/gx.cgi/AppLogic+FTContentServer?pagename=FutureTense/Apps/Xcelerate/View&c=wortharticle&cid=ZZZHVILXAHC&live=true&navpod=wealth&navsection=alternative The Very Radical Business of Long Life and Eternal Youth by Gwen Kinkead February 2001, "Worth" magazine Imagine a world where skin never loses its youthful blush, hearts never seize up and no one ever grows old. This world is the burgeoning business of antiaging. If you could live a long life, would you? Suppose you had a choice: would you live out your expected life span currently 80 years for a woman, 74 for a man or live 122 years, the longest documented human life? Or are you game for 200, even 300? You may get that choice. With the sequencing of the human genome and the advent of computerized tools for searching through thousands of genes at once, excitement is mounting among biologists that the secrets of longer life will be laid bare in the next two to three decades. In the past 10 years, scientists have had astounding success in doubling and tripling the lives of simple organisms such as fruit flies, yeast and microscopic worms, and more complex ones such as mice. Most biologists now say it's conceivable that human beings could be rejiggered to live 150 or 160 years. This kind of talk used to come from charlatans selling miracle elixirs. No more. The scientists issuing these pronouncements are the elite of legitimate investigators at the frontier of aging studies in such top-flight institutions as CalTech, Massachusetts Institute of Technology and the University of California at Los Angeles. "That life span is tunable was very controversial 20 to 25 years ago," says Michael Rose, the brash evolutionary biologist at the University of California at Irvine, who was the first to double the lives of fruit flies by selectively breeding for longevity genes. "But now, since everybody and their cousin Charlie are doing experiments to increase life span, mostly of worms and fruit flies, twofold, threefold, fivefold, no one in this scientific community thinks it's a big deal. "There are no limits to life span," Rose continues. "Since we have organisms like sea anemones and hundreds of thousands of others that do not age in any way, shape or form, we know that aging is not inevitable. Unlike taxes, death we can do something about." Slowing the aging process, Rose asserts, is a "straightforward R&D situation." Not everyone agrees with Rose's assertions or with the notion that human rejiggering should be tried. Some scientists accuse their colleagues of making sensational claims. "There is titanic disagreement among investigators about whether this is fantasy or a scientifically serious possibility," says Charles Harper, executive director of the John Templeton Foundation, which funds scientific and religious research and recently sponsored a symposium on extended and eternal life. "This is cutting-edge futuristic science," he adds. "It is normal for there to be no answers. It's like a Wild West situation with gold strikes and people in a commotion, because this is the period before it gets to textbooks." For all the excitement, science doesn't yet have answers to the most fundamental questions about aging. For example, asks Huber Warner, head of the biology of aging program at the federally funded National Institute on Aging, "Why does a mouse live to be 3 and a human live to 80? What are the biological factors determining that? Second, why do we age differently? If you start with one strain of mice, for example, they die at different times. Third, if we can intervene in this process, how, and if so, would you really want to?" Modern aging theories, of which someone once counted nearly 300, group around two central ideas. The first is that aging is caused by programming. "Programming assumes that age-related change is caused by genetic changes, leading inexorably to death," Warner says. In other words, human beings start to age at birth. The clock is regulated by genes, hormones or the immune system; no one knows which or how. "Overlaid on this," Warner continues, "is the idea that there is a whole host of stochastic [that is, probabilistic and random] events that may shorten life span because they tend to lead to age-related pathologies" like strokes or heart attacks. Work on unlocking the mysteries of aging currently being conducted by biologists, chemists, and medical doctors all over the world follows these two paths. Scientists imagine that aging will be slowed either by taking a pill or by surgery such as gene or stem-cell therapy. Controversy rages over all these techniques. Some are being outlawed, and all are hotly debated. Free Radicals and an Antiaging Pill The case of Eukarion illustrates some of the profound questions surrounding research into aging. Until this past September, Eukarion was another struggling biotech, located in a cinder block building in the 12th tier of industrial parks ringing Boston. But it's on the map now because it's the only company in the world that has developed a pharmaceutical compound clinically proven to lengthen life. This news, splashed in "Science" magazine, was a bombshell. It brought an avalanche of world-wide attention to Bernard Malfroy, the company's neurobiologist founder. Malfroy, a charming, dogged Frenchman with a shock of white hair in a crusader cut, had been a junior member of France's scientific establishment before coming to the United States in 1984, taking posts first at Scripps Research Institute in California and then at Genentech (NYSE: DNA) and Alkermes (Nasdaq: ALKS) before starting Eukarion in 1991. Malfroy hoped that through organic chemistry he could design a drug that would combat the diseases of old age such as Parkinson's and Alzheimer's. His research led him to an organic molecule that is a mimic of superoxide dismutaste, or SOD. SOD is one of the body's antioxidants. These enzymes destroy free radicals, or unstable molecules, that are a by-product of our metabolism and are thought to be a main cause of aging. Free radicals careen around the body, damaging DNA, proteins and lipids and causing malfunctions that show up as the ills of the elderly. SOD, however, has a bad reputation among scientists because it turns unstable oxygen molecules into hydrogen peroxide, a toxin. The higher the dose of SOD, the more hydrogen peroxide is produced, and suddenly SOD quits one of the most infamous bell curves in science. Malfroy bought a license to this SOD mimic, tested it, and, like clinicians before him, found it unstable and unsuitable. Serendipitously, however, he learned of another compound, MnC1602N2H14C1, which had been synthesized in the early 1940s and forgotten. He was curious if it would work as an antioxidant. It did, not only destroying free radicals but also acting as a catalase, an enzyme that converts hydrogen peroxide into water and oxygen. By intuition, good applied science, and luck, Malfroy had found a molecule that did the jobs of superoxide dismutaste as well as catalase and outperformed both. After preliminary tests with rats, mice, pigs and, later, nematodes (tiny transparent earthworms), this compound revealed itself as more powerful than the body's natural defenses against free radicals and thus against aging. Malfroy patented some analogs and, over time, signed up 50 scientists as collaborators. One of the scientists struck gold. Simon Melov, a young Australian molecular gerontologist at the Buck Institute for Age Research, a new private institute in Novato, Calif., couldn't believe his eyes two summers ago. Nematodes that had been fed Eukarion's powerful antioxidant were fresh and wriggling long after they should have been dead. Melov enlisted Gordon Lithgow, a British geneticist at the University of Manchester, for corroboration. Lithgow's lab also had extraordinary results: Adding this antioxidant to the worms' water allowed them to live healthier and longer lives, a mean of 35 days instead of the usual 21 to 24 days, an increase of 50 percent. The impact of these findings could hardly be exaggerated. It was the first evidence in any species of the efficacy of an "antiaging pill," the subject of human fantasies for thousands of years. Melov is trying to replicate his success in mice. In other experiments he's trying to discover if the antioxidant will actually reverse aging in old mice. The results should be known within the year. "If we show results in mice, it is highly likely that it will work in humans," Melov says, and stops to reflect for a minute. "If we get an increase in life span in mice, treating them with drugs, it would be a tremendous paradigm shift," he stammers. "I can't imagine what would happen as a result of that, because that would be such a dramatic breakthrough. You're talking about effectively treating aging with a drug. That's a novel concept with a broad spectrum of implications, from ethical to social." Lithgow agrees that the questions and concerns are legion. For starters, should society license drugs against aging? At what age should people take them? At 18? 40? 60? What side effects to the brain and the rest of the body should be considered acceptable? Is it even ethical to give healthy people a powerful drug? "We are probably 20 years from having a grasp of all the biology we need to come to a rational decision about whether we should go into a clinical trial on people, using Eukarion drugs solely in an aging context," Lithgow says. Scientists believe that the Food and Drug Administration will not approve a drug given solely to prevent or slow aging, because the FDA does not classify aging as a disease. How could efficacy be demonstrated? The drug would have to be tested on humans for decades. However, the FDA does approve drugs that show efficacy against a disease. "We know [this antioxidant] limits the damage caused by strokes, and we hope to be in human trials in June 2001 for strokes and with a gel form for cancer-therapy radiation burns," Malfroy says. "Later, we will apply for its use on neurodegenerative diseases." If Eukarion's antioxidants show no horrendous side effects, they could be on sale as early as 2006 as prescription drugs against stroke. This would open up the possibility that millions of people will take them to prolong life instead. Zapping the Grim Reaper Gene Cynthia Kenyon, a professor of biochemistry and biophysics at the University of California at San Francisco, has identified several genes that control the life span of worms. "We believe the genes are switched on and off in an insulin-like pathway," she says. "One gene, daf-2, controls life spans in the worms and also their ability to go into hibernation if they are starving." By creating mutant worms that lack what Kenyon calls the "grim reaper gene," she has been able to double worms' lives. Kenyon has formed a company with molecular biologist Leonard Guarente of MIT to synthesize an antiaging pill from their discoveries. "Some people live to be 120," Kenyon says. "They're youthful at 90. They're forceful because they age more slowly. Some people think maybe 120 is our maximum life span. Could everyone be changed in such a way that they could be as healthy as those people at 90? The goal is extended youth. We'd make people who are 90 think and feel like 45-year-olds. I think one way to do it would be to make a drug that acts like a hormone and binds to a life-span receptor in humans, if one exists." Kenyon notes that science's view of aging has been completely transformed in the past decade. "We thought that aging occurred in a passive way, that there wasn't much you could do about it. It was just a question of how resistant you were to damage, because the environment was going to damage you and age you," she says. "Now we know, at least in this worm, it's not only regulated internally; it's regulated in a really elaborate way, with lots of inputs and lots of signal integration. We know that this insulin IGF-1 hormone system in the worm determines how fast it ages." Other systems also come into play. Kenyon has dramatically lengthened the lives of worms by removing reproductive cells and altering sensory cells. She speculates that all these changes may increase life span by protecting the animal against oxidative stress. Gary Ruvkun, a professor of genetics at Harvard Medical School, is studying some of the same genes, but he thinks the endocrine system will be shown to control longevity in humans and that its switch will be found in the brain. Since worms' brains have only 302 neurons, he hopes to identify the switch in the next six months. But comparing worms' brains with humans' is much further off. Ruvkun needs a tool not yet available, a gene-expression atlas of both the human and worm brains "so we can see if the same gene in the human brain is regulating aging." If only it were that easy. People are not big worms, says Tom Johnson, a researcher at the University of Colorado at Boulder and one of the pioneers in worm-aging studies. Genetically, worms and humans are remarkably similar, but the genes don't always function in the same way. "To make people think that what we've just discovered in a yeast or a nematode is tomorrow going to be affecting life span in us is just sensationalism. It might have an effect," Johnson says, "but it's going to take us decades to work it out. My kids are going to profit from this. They'll have drugs in their midlife that will make them healthier and longevous. But we don't even have a gene target in a mouse yet. All we have is a gene target in a nematode." Eat Less, Live Longer Sixty years ago, a scientist found that lab rats consuming 30 percent fewer calories lived up to a year longer. A diabolical notion, if you think about it, that if you use less energy, you will live longer. The theory has been tested many times over on many different species and consistently holds true. But does it work for humans? Studies in other primates, our closest relatives, are yielding clues. Monkeys in Baltimore and in Madison, Wis., are on calorie-restricted diets, and though the study has up to 15 more years to go, the diet seems to be slowing the onslaught of old age and disease. These middle-aged monkeys are pretty frisky, too. "We've seen less arthritis in our monkeys here," observes Richard Weindruch, a gerontologist at the University of Wisconsin, "and some tests indicate that they might have better vascular health and less free-radical damage in their skeletal muscle tissue." OK, but why? One idea is that eating less reduces the amount needed to be metabolized and thus reduces oxidative damage. "When an animal enters this diet, a whole set of genes are triggered into action," says Tomas Prolla, a geneticist who works with Weindruch. "If we understood which genes are involved and which of these are critical, then we could design drugs to modulate their actions. You could have the benefits of caloric restriction without the diet." Prolla and Weindruch are using gene chips to hunt through thousands of genes in each organ in the body. To patent the genes and produce life-extension drugs, Prolla and Weindruch are partners in a new company called GenTech Technologies, located in Madison. "Probably, you will need different drugs for major organs, because each may have a specific rate of aging," Prolla says. Thousands of Americans are already on such a diet why wait for a pill? There is even a Web site, maintained by Roy Walford, a pathologist at the University of California at Los Angeles and the author of the 1992 best-seller "Beyond the 120 Year Diet," who believes that humans might one day achieve immortality. The diet is reported to make people skinnier, more tired, less interested in sex, unable to sit on hard chairs and hungrier. Old Cells That Just Won't Die For 12 years, Judith Campisi, a senior scientist at the Lawrence Berkeley National Laboratory, has been studying cell senescence. Cells divide, reproducing themselves for a while, then suddenly stop and become senescent blobs. These blobs not only refuse to die, they possibly wreak havoc in the body. Campisi believes cell senescence is a double-edged sword: helpful early in life because a cell that stops dividing will never become tumorous, but harmful later because the senescent cells spew out junk such as cytokines that cause inflammation and enzymes that degrade surrounding tissue. "We have evidence that the senescent cells are secreting stuff that helps the growth of precancerous cells," Campisi says, but she cautions that more proof is needed. Her ultimate goal is to design a drug that would make senescent cells either die or stop secreting. Three years ago, scientists made a discovery that seemed to explain why cells become senescent. Human tissue cells stop growing in culture after 50 divisions, a phenomenon called the Hayflick limit, after its discoverer, microbiologist Leonard Hayflick. Scientists located the counting device in telemeres, the caps of chromosomes. They found that every time a cell divides, the telemeres get shorter. When they get extremely short, the cell reaches the limit and becomes senescent. In 1997, researchers funded by Geron (Nasdaq: GERN), a California biotech, isolated the enzyme that keeps telemeres from shortening. This discovery set off waves of excitement. It was thought that flooding cells with the enzyme might stop the cells from aging. The problem is that the enzyme causes cells to replicate endlessly, which makes them tumorous. Geron claims to have cultured human tissue cells that have divided 100 times without becoming tumorous, but until the finding is duplicated by other labs, many scientists are withholding judgment. Like most researchers, Judith Campisi thinks the aging process is ultracomplicated. "There are people who believe the key to longevity is telemeres. There are people who believe the key is to prevent oxidative damage. And there are people who believe the key is to prevent, or at least ablate, cell senescence. Probably all these things are right. I don't think there will turn out to be a thousand causes of aging just a few and we will be able to gain power over them. We may need multiple interventions, since we know that brain and muscle cells don't divide and tissue and skin cells do." Genes for the Next Generation Although the theoretical logic of implanting genes in the body is manifold to fight disease, enhance natural defenses like antioxidants, eliminate inherited pathologies this therapy ranks close to the top on the controversy meter. It has cost at least one life that of an 18-year-old volunteer in a trial to test a therapy for a rare liver disease raising widespread fears about safety. But work continues, in both the private and public sectors. Jeffrey Kordower, a neuroscientist at Rush-Presbyterian-St. Luke's Medical Center in Chicago, is one of the few researchers to have had positive results. He has added genes to the brain cells of monkeys to make a chemical that keeps neurons in the brain from dying. This eliminated tremors in monkeys with Parkinson's disease. "Normally, cells don't make that gene in appreciable quantities, so we attached it to a [gutted] virus, which can gain entry into the cell," Kordower explains. "This is a very potent therapy: In case something does go wrong, we will have a way to shut the gene down." Another form of gene therapy is artificial chromosomes. One company, Chromos Molecular Systems, of Vancouver, is trying artificial chromosomes on mice, hoping one day to implant an additional chromosome in people with genetic diseases to cure them. The ramifications are immense. With this technique, parents could choose genes for their children. Therapies like this that could change the germ line the genetic inheritance of the human race that each of us carries are championed by some big-name scientists, such as James Watson, the discoverer of the structure of DNA. Watson has said, "If scientists don't play God, who will?" But others, including Eric Lander, director of the Whitehead Center for Genome Research, in Cambridge, Massachusetts, have called for a ban on any technique that modifies the germ line. A panel of experts convened by the American Association for the Advancement of Science has declared it is irresponsible and dangerous for scientists to experiment with genetic changes in humans that will affect future generations, even if the goal is to cure disease. In the Realm of Sci-Fi: Embryonic Stem Cell Research and Cloning Consider stem cells as each person's private fountain of youth and self-repair kit. Their promise in medicine has received so much praise in the two years since they were first cultured in a laboratory that it's possible to think of the next 40 years of genomics and genetics investigation into the secrets of aging as marking time until embryonic stem cell surgery becomes common practice. Stem cells are found huddled against one side of the 64-cell developing embryo. Called pluripotent because they are all-powerful, stem cells are the cornucopia from which the rest of the body spills. One of the most controversial companies in the United States is inside a brick-and-smoked-glass building in a small biotech park in Worcester, Mass. The work of this tiny, privately held company is at the border of science fiction and the ethically permissible. Its science is apparently outstanding and holds tremendous promise, but the company's future is deeply clouded. That's because Advanced Cell Technology is at the forefront of experiments using human and animal embryos. The company began life as a division of a Maine animal-husbandry outfit, then took a sharp turn in 1995 with the arrival of a soulful-looking, soft-spoken Argentinean named Jose Cibelli. Cibelli was a doctoral candidate at the University of Massachusetts. His adviser had a contract with the Maine company and gave Cibelli the risky job of making transgenic cows (cows that have a gene from another species implanted in them). It was not known at the time whether human DNA that had been inserted into an animal egg whose nucleus had been removed would fuse and live. Dogma stated that the species barrier in reproduction could not be crossed. Cibelli tried this process, called nuclear transfer, 12,000 times. After putting his own DNA from a skin cell into enucleated cow eggs, this Dr. Frankenstein would zap them with electricity. He finally created the first cow-human embryo. Had it lived, it would have been a clone of Cibelli, but it died after 11 days. Cibelli, uneasy about the ethics of the experiment, didn't claim the milestone publicly. But he did file a patent on the technique. The following year, Dolly the sheep was cloned by a similar technique. The resulting furor would human cloning be next? created headlines and demands for legislation around the world. Recently, Pope John Paul II condemned stem-cell research: "These techniques, insofar as they involve the manipulation and destruction of human embryos, are not morally acceptable even when their proposed goal is good in itself." Human cloning has been banned by the European Parliament. Britain currently has not outlawed research using human cloning on the grounds that it may lead to cures for diseases from stroke to Parkinson's. The National Institutes of Health recently agreed to give federal funds to companies and researchers experimenting on stem cells taken from discarded embryos but not those creating embryos by cloning. Advanced Cell Technology executives have vowed never to create a human clone; they're investigating stem cells to cure disease. This past spring, the company announced a remarkable discovery: Somatic cells such as skin cells can be made to grow young and convert to stem cells after being put in an enucleated egg. "It sounds like science fiction, but it's true," says Robert Lanza, head of research at the company. Six cow clones had unmistakable signs that cloning made old cells young again. This holds out the hope that people may one day be able to replace tissues and organs in their bodies with new ones made from their own cells new bone marrow for people needing bone-marrow transplants, or skin for burn victims. "Stem cells want to go on and differentiate into all 200 organs of the body," Cibelli says. "We want to control that division to create just the organ or tissue a person needs, and we don't know how. Whoever learns will win the Nobel Prize." Cibelli stops for a moment. "I can tell you this: The secret of youth is in the female egg. I believe that in the future it's going to be mandatory to have some somatic cells banked, maybe at birth, prepared into stem cells, and when you get sick or start having some aches, say, 'Hey, I need some more cartilage because my joints are painful. Could you prepare some cartilage for me?' 'Sure.' Two or three months later you get an injection into your hip, and voil , no pain. Life is beautiful. If we can prevent old age, why not? If we can prevent suffering, why not? Why not see your grandchildren grow up?" There is no reason we can't go on replacing parts indefinitely. "Each individual should decide when they want to die." Advanced Cell Technology is a spooky place. One of its divisions makes transgenic animals that are turned into medicine factories for humans drugs in the milk of cows or eventually in the eggs of chickens. The animals are also sources of tissue for tissue-replacement surgery in humans. Another division is being planned to clone pets. The idea is that pet and animal cloning will pay for the stem-cell research until stem-cell surgery becomes commonplace. Recently, the company cloned a gaur, an endangered Asian ox, by fusing gaur DNA into the egg of a cow. The clone was due in December. "This should make it possible to help rescue an endangered species. We can save these genes and reintroduce them," Lanza says. Advanced Cell Technology plans to go public that is, if it survives what are sure to be new efforts by Congress to regulate cloning. Why Die? At a recent conference that was sponsored by Advanced Cell Technology, Geron, and the John Templeton Foundation to discuss whether biotechnology should try to "cure" aging as if it were a disease, religious and scientific leaders squared off on the profound question of why we are mortal. The most persuasive defender of a limited life was Leon Kass, a medical doctor and philosopher who teaches for the Committee of Social Thought at the University of Chicago and who is one of the most influential bioethicists in the country. Kass argued that without death there is no morality, nor any humanity. "To number our days is the condition of making them count," he offered. To Gregory Stock, the head of the program of medicine, technology, and society at the University of California at Los Angeles, who championed biotechnology's coming control over nature, defeating death is irresistible. "It's very likely we will not even retain the human form very far into the future," he predicts. What does all this amount to? Unless society halts research into stem cells, cloning and aging, then the power that human-genome sequencing gives scientists to patent life, manipulate it and perhaps even control it will lead to breakthroughs in aging in the next decades. We could become the first generation to control our own destiny, a position human beings have never before occupied. Live Long Prosper Publicly traded companies currently working on cell and gene technologies Printer friendly version _________________________________________________________________ Get your FREE download of MSN Explorer at http://explorer.msn.com Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=15444