Article 1 of 200
Cover Stories/Features/Long Life
The Hunt For The Youth Pill: From cell-immortalizing drugs to
cloned organs, biotech finds new ways to fight against time's toll.
David Stipp
10/11/1999
Fortune Magazine
Time Inc.
Page 199+
(Copyright Time Inc. 1999)
Larry Ellison has the good life down pat--health, youthful good looks,
vast wealth, a fast sailboat, airplanes, and more gorgeous amours than a
Hollywood hunk. But like every potentate from King Tut to Howard
Hughes, Oracle's celebrity CEO faces the same dread certainty that
gnaws at you and me--no matter how well we succeed, we're fated to
lose it all to that pitiless serial mugger, old age. Unlike most of us, though,
Ellison is doing something about it: A foundation he set up has quietly
begun pumping some $20 million annually into basic research on aging.
Only a decade ago, a middle-aged billionaire seeking to speed the quest
for anti-aging medicines would have seemed a faintly ridiculous
figure--gerontology, the study of aging, was mainly an arena for sterile
academic debate. But thanks to a flurry of discoveries during the past few
years, Ellison's bequest seems visionary. No less an authority than
Francis Collins, director of the National Human Genome Research
Institute, recently predicted that by 2030 the genes involved in aging
would be "fully cataloged" and clinical trials of life-extending drugs would
be under way.
The commercial potential of such medicines is staggering. The customer
base might number up to--well, whatever the world population is when
the drugs ship. A truly potent anti-aging pill would trigger the social
equivalent of the Big Bang, exploding countless things we take for
granted about the economy, retirement, personal relationships, politics.
Much of the fallout would be awful, warns Leonard Hayflick, a senior
statesman in gerontology. Imagine the world if medical science had
permitted Stalin to live into the 1990s.
If Ellison's foundation is helping set the stage for this revolution, a batch of
new companies hoping to capitalize on advances in aging research
represents the auditioning actors. It's considered bad form at such
companies to opine about longevity pills--that prospect is still too far
down the road to attract serious money from venture capitalists. Instead,
these entrepreneurs stress that basic research on aging should yield
potent therapies for old-age diseases in the not-too-distant future. In
business terms, this pragmatic spin is as important as a Nobel
Prize-winning discovery--it's enabling gerontologists, whose field has long
been tarred by association with charlatans, to put together respectable
commercial ventures that attract big bucks and top talent.
The first company to pull off this clever feat of packaging is Geron , a
Menlo Park, Calif., concern that has given the world a taste of the
provocative things to come from the science of aging. In the past two
years, Geron has made a breakthrough on aging at the cellular level and
has forged into research on rejuvenating worn-out tissues with cells from
human embryos. Along the way, the bold little company has achieved the
highest buzz-to-equity ratio in biotech history.
Formed by a truck-leasing entrepreneur turned medical visionary, Geron
made its first splash by isolating the gene for telomerase, a substance that
can retard aging in cells. The finding probably won't lead to anti-aging
pills. But it has stirred huge scientific and commercial interest--in theory,
telomerase-based drugs could help fight everything from cancer to
osteoporosis to wrinkles.
Last fall Geron disclosed its second stunning advance: Its academic
collaborators had isolated human embryonic stem cells, or ESCs, for the
first time. Extracted from aborted fetuses and embryos discarded by
fertility clinics, ESCs are like tightly packed cornucopias primed to
explode--all of the body's 200-plus cell types come flying out of them
during gestation. Grown in the lab, ESCs offer the spectacular promise of
generating replacement organs. But Geron 's announcement sparked
heated debate--antiabortionists vehemently oppose studies involving
aborted fetuses.
Geron , whose name comes from the ancient Greek for "old codger,"
has from the start barreled in where others tiptoe. It was launched by a
medical-school dropout named Michael West to make a frontal assault
on aging. After college, West built up a family-owned truck business in
Michigan. Then, following his father's death in 1980, he sold the company
to pursue his longtime dream of becoming a renowned scientist. "I
decided the most meaningful thing I could do with my life was tackle
aging," says West. "It's the most central problem of the human condition."
After earning a biology Ph.D. in 1989, West entered medical school in
Dallas. But soon he began playing hooky to investigate a major mystery:
Why do aging cells lose their proliferative vigor and die?
His interest in the question sprang from one of gerontology's biggest
discoveries: In 1961, Hayflick and a colleague showed that most cells
possess a sort of inner counter that limits the number of times they divide
before going into terminal decline. In human cells, this "Hayflick limit" is
reached after 20 to 100 splits. The finding inspired a theory of aging
called cell senescence, which holds that the body's deterioration over
time is largely due to cells running out of proliferative steam. If that's true,
then elucidating the cellular counter might show how to retard aging.
To West--who's known for pursuing pet ideas with inspired
bullheadedness--these ideas seemed like a company waiting to happen.
But most investors he approached with his first business plan didn't agree.
Since no one knew what set the Hayflick limit or exactly how it might
drive the aging process, West proposed a blue-sky program of R&D on
cell senescence--the stuff of dreams, not investment returns. "I got kicked
out of a lot of conference rooms," he says.
While poring over studies on cellular aging, he ran across one that
suggested a sharper focus. The subject was telomeres, cap-like pieces of
DNA on the ends of chromosomes, the coiled-up strands of genes in
cells.
Telomeres had long been implicated in cellular aging. Scientists knew they
get progressively shorter as chromosomes are copied during cell division.
According to one theory, telomeres get used up after a set number of
divisions, rendering chromosomes vulnerable to damage. That makes
cells old and sickly.
Certain cells can divide endlessly, though, including the precursors of
sperm and egg cells. So can cancer cells. What happens to those cells'
telomeres? If they remained long, that would suggest the existence of an
enzyme the theorists called telomerase, a kind of Zeus juice that could
confer immortality on cells by maintaining their telomeres.
West initially regarded the theory as far-fetched--no one had been able
to isolate telomerase. But the report that grabbed his attention provided
strong circumstantial evidence of its existence: It showed that telomeres
don't shorten in dividing reproductive cells, just as predicted. Another
study revealed signs of telomerase activity in cancer cells--again, just as
predicted.
As he became convinced the theory was right, West spun a new pitch.
Geron would try to isolate telomerase and use it to synthesize drugs to
treat cancer and certain age-related diseases. In 1992 venture capitalists
led by Kleiner Perkins Caufield & Byers invested $7.5 million to get the
company off the ground, and West left med school to help pilot it.
Alexander Barkas, then a partner at the VC firm, was named chairman of
the startup, which was installed in a modest building a few miles from the
firm's Silicon Valley office.
The company quickly assembled a scientific team led by Calvin Harley, a
Canadian biologist known for helping establish that telomerase is active in
tumor cells. A former American Cyanamid executive named Ronald
Eastman was named CEO. Geron also lined up a glittering set of
advisers, including Hayflick and James D. Watson, the Nobel laureate
who co-discovered DNA's structure.
The stellar brain trust was critical, for it put Geron at the center of a
far-flung web of academic labs investigating telomerase, which gave it an
edge over its rivals in the race to isolate the enzyme, including Amgen,
biotech's biggest player. Geron 's in-house efforts were impressive too.
At one point, says West, "we were going through wheelbarrows of pig
testicles, trying to purify the enzyme"-- pigs, like all animals, were thought
to have a bit of a likeness to Zeus in their procreative parts.
Geron jumped to an early lead in 1994 when its team isolated a piece of
telomerase that serves as the enzyme's genetic template for rebuilding
shortened telomeres. But the main part of the enzyme, which does the
actual rebuilding, eluded scientists--it seemed that telomerase in most
cells existed only transiently, in tiny amounts.
The following year, Carol Greider, at Cold Spring Harbor Laboratory on
Long Island, reported finding what appeared to be two further pieces of
telomerase in protozoa called Tetrahymena. This was a milestone:
Animals from protozoa on up probably have similar versions of the key
enzyme, so the report gave telomerase seekers a rough idea of what to
look for in human cells.
Amgen seized on the clue and in early 1997 announced that its team had
isolated a piece of the human gene for telomerase. The finding suggested
Amgen was closing in on the whole enzyme and about to leave Geron in
the dust. "We had a big scare," says West. "Then we realized they had
the wrong gene."
The gene found by Amgen makes a protein closely resembling one of the
protozoa molecules discovered by Greider, now at Johns Hopkins
University. Geron , however, evaluated Greider's findings and decided
not to pursue them, says Harley, a trim, self-contained man who chooses
words with care. Though the mammalian versions of the molecules she
found are closely associated with telomerase, he explains, they don't
appear essential to its function. Only once its active core was found could
researchers use it to design drugs that would block the enzyme in order
to stop tumor cells from dividing or, alternatively, develop telomerase
boosters to invigorate aged cells.
Just as Amgen seemed to pull ahead, Geron stole a march on it. In late
1996 a University of Colorado team led by Nobel laureate biochemist
Thomas Cech had isolated telomerase in another type of protozoa called
Euplotes. When the university put commercial rights to the finding up for
grabs, the big players in the race dithered, allowing Geron to seize
them--and add Cech's team as helpers.
Over the following weeks Geron and the Colorado researchers
feverishly scoured data banks of human genes for a likeness of the
Euplotes telomerase gene. One night a graduate student in Cech's lab hit
pay dirt: He spotted a telltale similarity to the gene in a DNA fragment
extracted from the cells of a patient's inflamed tonsils. The discovery
made sense--telomerase is probably activated in rapidly dividing immune
cells at an infection site.
Working around the clock, Geron 's team isolated the human gene
whence the fragment had come. When its success was announced on
Aug. 15, 1997, the company's share price more than doubled, closing at
$14, on a volume greater than its number of shares outstanding. The race
had a close finish--a week later a rival team at the Whitehead Institute in
Cambridge, Mass., working with Merck, reported that it too had the
gene. Says a former Geron researcher: "Cech saved our ass."
With telomerase in its pocket, Geron seems to have a golden future as
biotech's top aging play. Yet soon after its telomerase discovery, say
former insiders, the company chose quietly to de-emphasize research on
aging and instead focus on the nearer-term opportunity to develop cancer
treatments.
This paradoxical move actually made a lot of sense. By the time the
telomerase gene was discovered, gerontologists had moved away from
the idea that cell senescence is what makes us grow old. The brain's
neurons, for instance, rarely divide, so how could reaching the Hayflick
limit explain the deterioration of an aging brain? Most scientists now think
that the limit is only indirectly related to aging--its main role is to prevent
cells' proliferative powers from getting out of control and causing cancer.
Not all of Geron 's top researchers took kindly to its shift away from
long-term research on aging. Several quit. Says one who declines to be
named: "I joined Geron to work on aging. Ninety million other
companies are working on cancer." But when asked about this, Thomas
Okarma, who recently was named Geron 's CEO after serving as its vice
president of research and development, is blunt: " Geron really isn't an
aging company," he says. He argues that the company stands to hit a
home run with cancer drugs, which it's pursuing with Pharmacia &
Upjohn and Japan's Kyowa Hakko.
An anticancer success would help Geron fund the development of
telomerase boosters for diseases of aging. Geron maintains that such
drugs should help treat degenerative diseases, even if they have no effect
on body-wide aging. That's a reasonable hope. As their telomeres
shorten with age, cells in some tissues get woozy and spew harmful
substances that apparently underlie problems such as osteoporosis,
sagging skin, and macular degeneration, a leading cause of blindness,
says Judith Campisi, a Geron adviser at Lawrence Berkeley National
Laboratory in Berkeley, Calif. Telomerase-boosting drugs are likely to
face a high hurdle at the Food and Drug Administration, for they might
increase the risk of cancer. But it may be possible to treat diseases and
minimize the cancer risk by raising cells' telomerase levels transiently, says
Okarma.
Investors seem to buy Geron 's strategy: The company's market
capitalization, recently about $175 million, is hefty for an early- stage
biotech firm. Still, it's not clear that blocking telomerase will turn immortal
tumor cells into withered crones. And Geron 's gene scoop doesn't
guarantee it will be first to market with telomerase- based drugs. "There
are several genes associated with telomerase that may be important for
developing cancer therapeutics," contends Murray Robinson, Amgen's
director of cancer research. "This is still a developing story."
As Geron 's anticancer initiative took off, West, who served as its chief
scout for new technologies, organized a new assault on aging based on
embryonic stem cells. Once again he was playing the gutsy
frontiersman--ESCs would soon become one of the hottest topics in
medicine, thanks largely to Geron 's audacious push to turn them into
instruments of rejuvenation.
West's fascination with ESCs began with a bizarre experience.
Occasionally, primordial cells run amok in embryos, spawning tumors
that contain a mishmash of semi-formed body parts. When dissecting one
of these "teratomas" in medical school, says West, "I saw an incisor and
molar inside. That made me wonder whether we could do the same thing
in the lab to address the wear and tear of aging"--in a flash he saw how
ESCs might engender everything from new neurons for Alzheimer's
victims to entire replacement hearts for cardiac patients.
In 1995, West heard that University of Wisconsin biologist James A.
Thomson had isolated monkeys' ESCs. Scientists had long known that
ESCs arise soon after an egg cell is fertilized--they were first isolated in
mice in 1981. But most species' ESCs had proved elusive, for the cells
exist only fleetingly before turning into their specialized
progeny--everything from brain to muscle cells.
A few days after Thomson's finding was announced, West showed up at
his lab to cut a deal: Geron would fund his obvious next step, isolating
human ESCs, in return for patent rights based on the work. Geron also
enlisted Thomson's two main rivals to pursue the same goal. The funding
offer was hard to refuse--researchers are barred from using federal
grants for experiments using human embryos.
Boiling with schemes for using ESCs, West urged Geron 's top brass to
let him spin off an ESC company. When the plan was nixed, he resigned
in February 1998 to co-found Origen Therapeutics, a business in
Burlingame, Calif., that focused on the ESCs of chickens. Among other
things, he envisioned using the cells to create flocks of genetically
engineered hens with desired traits. But he soon put chickens out of his
mind when he heard about an astonishing experiment led by James Robl,
a cloning expert at the University of Massachusetts veterinary school.
The process of cloning is like installing a new CEO to restructure a
company. Using tiny pipettes, scientists first suck out an egg cell's
chromosomes--its master-control molecules. Then they implant DNA
from another animal of the same species. Manhandling an egg this way
causes even more inner strife than "Chainsaw" Al did at Sunbeam-- the
cells usually fail to develop. But sometimes a little-understood miracle
occurs: The implanted DNA reverts to its embryonic state, the same
do-anything mode that enables ESCs to generate a multitude of tissues.
When this happens, the reprogrammed egg cells can be implanted in
surrogate mothers' wombs to engender exact genetic duplicates, or
clones, of the animal that donated the substitute DNA.
In 1997 scientists at the Roslin Institute near Edinburgh cloned Dolly from
an adult sheep's DNA this way. But a year before Dolly made headlines,
Robl and one of his graduate students, Jose Cibelli, quietly pushed further
than the Scots would into the brave new bioworld. After taking cells from
Cibelli's blood and from the inside of his cheek, they fused 52 of them
with cow eggs from which the DNA- containing nuclei had been
removed. One of those hybrids reportedly survived and divided multiple
times in the test tube--it seemingly was beginning to act like a human
embryo.
Was it Cibelli II in the making?
Very unlikely, say cell biologists. For one thing, the human DNA in such
hybrid cells probably couldn't regulate cow-derived mitochondria, cellular
units that serve as energy dynamos. That mismatch alone would likely kill
a hybrid before it formed an embryo.
Still, the researchers had misgivings about the experiment, so they
discarded the cells and kept quiet about it. Meanwhile, they put their
skills to work cloning genetically altered cows for a company Robl had
co-founded to generate herds that make human drugs in their milk:
Advanced Cell Technology of Worcester, Mass., a unit of Avian Farms,
a poultry concern in Waterville, Me. A few months after leaving Geron ,
West visited Advanced Cell to talk about cloning. When told of the
undisclosed human/cow research, he was seized by the same epiphany
he'd had when dissecting the teratoma--he envisioned using ESC-like
hybrid cells to form tissue replacements. He soon left Origen to become
Advanced Cell's CEO.
As West began pursuing his new tissue-replacement dream, his old
company seemed to butt in: Thomson, Geron 's collaborator, reported
he had isolated cells thought to be human ESCs, and another of its
collaborators reported finding "ESC-like" cells. Those were major coups,
boosting Geron 's stock by 74%. But a week later West himself jumped
into the limelight by going public with the human/cow experiment.
Suddenly Geron seemed to have a potent rival in its effort to turn
primordial cells into spare body parts for the elderly.
West's bold move, however, also generated considerable heat. Fellow
scientists attacked him for publicizing an unsubstantiated study. President
Clinton asked the U.S. National Bioethics Advisory Committee to
investigate the ethics of creating hybrid cells. Geron 's Okarma asserted
that West had irresponsibly "clouded the horizon" for research on
embryonic cells.
West counters that hybrids hold vast promise for the aged. He envisions
placing the DNA from a patient's cells in cow eggs, inducing the DNA to
revert to the embryonic state. The resulting cells would then be used to
form youthful copies of the patient's tissues. In theory, implanting such
patient-derived tissues would pose less risk of immune rejection than
ones derived from ESCs. Such tissues would also skirt ethical issues
about using embryos.
Trying to do all this in secret was untenable, West argues. "If 60 Minutes
came knocking on the door with cameras running, we'd have looked
really bad," he adds. "But we didn't have enough data to publish. So the
only thing we could do was put out a press release." Its appearance right
after Geron 's announcement, he insists, was a coincidence.
Geron officials don't buy that. But in an ironic turnabout, they seemed to
be reading from West's script a few months later when announcing their
company's purchase of Roslin Bio-Med, a company formed by the
creators of Dolly the sheep, for $25 million in stock. Using Roslin's
cloning techniques, they explained, Geron will pursue a goal similar to
Advanced Cell's. Geron hopes to induce the DNA in patients' cells to
revert to the embryonic stage. The cells might then form
immune-compatible replacement tissues, skirting the controversy
surrounding ESCs.
Both companies face an enormous challenge: getting primordial cells to
differentiate into well-formed tissues in the lab instead of spinning out a
monstrous mishmash. In embryos, tissue generation is driven by complex
signaling among layers of developing cells. Replicating this
three-dimensional interplay without creating 3-D cellular matrices in the
lab may be extremely difficult. But fabricating such matrices may be
untenable, for they would probably bear some resemblance to embryos.
Indeed, some antiabortion advocates feel that even ESCs are too
person-like to experiment with. In a position paper recently issued by
U.S. Senator Sam Brownback of Kansas, who opposes ESC research,
early-stage embryos were equated with people: "That some individuals
would be destroyed in the name of medical science constitutes a threat to
us all," it darkly declared.
There may be a less fractious way to rejuvenate worn-out body parts:
Extract "tissue specific" stem cells from adults, then multiply them in the
lab to make replacement tissues. (If stem cells were money, an
embryonic stem cell would be like a $10,000 bill, changeable into any
other denomination of bill or coin; a tissue- specific stem cell, by
comparison, would be like a $50 bill, changeable into only a few smaller
denominations.) Since tissue- specific cells can be harvested from adult
volunteers, there's no controversy about their source. And they're
probably simpler to manipulate than ESCs. cntd' |
