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

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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


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