FORTUNE feature article on GERN: stock should soar above 15.
Good Luck,
Jack Blackmerlin
"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.
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." |
