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A Big Fish in a Small Gene Pool
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Friday, June 5, 1998
COLUMN ONE
A Big Fish in a Small Gene Pool
Undeterred by claims of 'bio-piracy,' a Harvard
professor turned 'DNA prospector' in remote Iceland is
leading a potentially lucrative attempt to conquer
hereditary diseases.
By MARY WILLIAMS WALSH, Times Staff Writer
REYKJAVIK, Iceland--The warrior-priests
who brought Christianity to this remote island
a millennium ago must have been visionaries, at
least of the sort who could foresee any kind of a
future in such forbidding fields of the Lord. But it's
a stretch to say they might have known that the
exhaustive birth and death records they began to
compile on the faithful might one day be the
makings of a multimillion-dollar biotechnology
business.
Yet such are the vagaries of DNA prospecting
here in the North Atlantic. A rare combination of
factors in Iceland--a national fascination with
genealogy, a highly homogeneous population, a past
fraught with disease and disaster, and one man's
entrepreneurial spirit--is transforming this small
land into a unique and potentially lucrative font of
genetic learning.
"We have an opportunity to do the best human
genetics done anywhere in the world," said Kari
Stefansson, a former Harvard Medical School
professor turned "DNA prospector."
His words may sound outlandish, perhaps, but
they are matched by an outsized dream, one of
gathering the entire genealogy of his homeland and
cross-referencing it with Iceland's excellent
collection of medical records dating to 1915.
To this one-of-a-kind database would be added
the DNA samples of countless Icelandic donors,
plus the information gleaned from an extraordinary
collection of tissue samples, preserved in wax
blocks, of every Icelander who has been autopsied
since the 1930s.
The purpose: to identify the precise genetic
causes of the 3,000 to 4,000 diseases that are
believed to be hereditary. Armed with that
information, pharmaceutical companies and others
presumably will have an easier time finding
treatments, diagnostic tests and preventive methods.
A population such as Iceland's is extremely
attractive to genetics researchers, who will travel
the Earth--increasingly, financed by biotechnology
companies--to study secluded peoples with high
incidence of disease. The reason: Disease-causing
genes are believed to stand out more clearly against
a uniform background than against one complicated
by ethnic mixing of the gene pool.
But no one has attempted anything on the scale
of Stefansson's project, for which the
neuropathologist gave up a tenured professorship at
Harvard Medical School two years ago.
"I have no regrets about leaving Harvard to do
this," said Stefansson, who was trying to determine
the genetic causes of multiple sclerosis before
returning to Iceland.
"We are creating new knowledge," said
Stefansson, adding that the database will be
encoded for privacy. "We are building a new
industry in Iceland."
Despite Stefansson's assurances of privacy, his
project has set alarm bells clanging here. Some
Icelanders fear that family health secrets could leak
out via his database and somehow be used against
them, perhaps by private insurers.
In addition, some ethicists have begun alleging
that DNA prospectors like Stefansson are
committing a new offense they call "bio-piracy,"
exploiting remote peoples for their precious DNA,
which could lead to big-money drug patents or even
a Nobel prize.
Drug Giant Is Enlisted; Analysts Take Notice
But such concerns have not deterred Stefansson,
who--with $12 million in venture capital in his
bank account two years ago--founded a company,
deCODE Genetics Inc., and equipped a research
lab that eclipses anything previously available at
Iceland's best hospitals. He has hired a staff of
nearly 200 and signed a multimillion-dollar
contract with the Swiss drug giant Hoffmann-La
Roche to seek the genes that are believed to cause
12 diseases.
In the process, he has caught the eye of
biotechnology securities analysts, who expect his
start-up firm to go public within 12 months.
"It's a company that's come a long way in a short
period of time," said Nick Woolf, an analyst at the
London investment banking house of BA Robertson
Stephens International. He called Stefansson's
arguments in favor of Iceland's special features
"compelling."
Stefansson is looking for other big partners, but
in the meantime, the Hoffmann-La Roche agreement
has brought credibility to his project, as well as the
needed funding to study such well-known scourges
as schizophrenia, Alzheimer's disease, adult-onset
diabetes and stroke.
Happily for Iceland, the terms stipulate that if
Stefansson's project gives rise to any treatments,
Icelanders will get them free.
Although neither Stefansson nor Hoffmann-La
Roche will go into the details of the transaction,
both parties said it will be worth $200 million to
$300 million over five years, plus royalties, if
Stefansson's hunch is right that Iceland's unrivaled
attributes make it an irresistibly fertile hunting
ground for disease-causing genes. The total of all
such deals between pharmaceutical companies and
genomics firms has been estimated at about $2.4
billion as of last November.
"We were very successful in convincing these
guys that we've got a very valuable asset,"
Stefansson said. "And I'm absolutely hellbent on
seeing to it that they're not disappointed."
Iceland a Fertile Spot for Genetic Research
So just what is this asset? Why would
Hoffmann-La Roche, and the other health-based
firms considering partnerships with Stefansson,
want to sink their millions into this treeless and
volcano-studded island sitting astride a fault line in
the North Atlantic?
The answer has to do with Iceland's daunting
history of disease, isolation and natural disaster.
However awful these may have been to live
through, they turn out to be advantages when it
comes to genetic research.
Few non-Icelanders have had the stomach to
move here since the Vikings first settled the island
in 874. Since then, the indigenous population has
twice been harshly "culled": A bubonic plague
outbreak in the 15th century wiped out more than
half the population, and a volcanic eruption in the
18th century caused widespread famine.
These catastrophes severely reduced the number
of people for Icelanders to choose as their mates,
leaving today's population of 270,000 nearly
homogeneous.
"If you choose two [Icelanders] in the 20th
century, it's very likely that they are distantly
related," said Hakon Gudbjartsson, chief computer
engineer for deCODE. "If you go back to the 15th
century, you can more or less connect everybody to
the same ancestors."
Already, geneticists have scoured other odd
corners of the globe, studying small, inbred
populations and the diseases that afflict them. The
South Atlantic islanders of Tristan da Cunha have
been examined for the clues they may offer to
asthma researchers, for example, while the Pima
Indians of Arizona have been studied for diabetes.
In the most well-known example, the genetic
secrets of Huntington's disease were revealed
through research on an isolated community in
Venezuela.
What makes Iceland superior even to these
geneticist-friendly outbacks, said Hoffmann-La
Roche research department spokesman Eckart
Gwinner, is its passion for genealogy and public
record-keeping.
"You have, in Australia and in underdeveloped
countries, populations that are very homogeneous,"
he said. "But with them, you don't have the data.
Iceland has a unique situation concerning the
homogeneity of the population and the connection
with information coming from blood banks and
hospitals and so forth."
As Stefansson tells it, his homeland's public
fascination with social data collection can be
traced to the 9th century, when Iceland established
Europe's first parliamentary democracy, complete
with courts, laws and penalties. One thing this early
political system didn't have was law enforcement,
so the earliest Icelanders had to rely on their
extended families to carry out any sentences the
courts handed down.
"So, it was terribly important to know who was
related to you," Stefansson said.
When the Roman Catholic proselytizers arrived
in their open boats, they improved upon this
record-keeping tendency by maintaining complete
birth, baptism, marriage and death registries at the
parish level. The Lutherans kept up the habit after
the Protestant Reformation, when theirs became the
state religion.
These church registries are the building blocks
of all genealogical research in Iceland, along with
such modern-day aids as census tracts, daily
genealogy columns in the newspapers and the huge
supply of genealogy how-to books and software
available here.
Gudbjartsson, who is overseeing the creation of
deCODE's database, said that within three years the
company will have acquired and computerized all
such Icelandic family data--insofar as it
exists--going back to the 17th century.
While his department does that, deCODE's
laboratory researchers have begun receiving blood
samples from Icelandic medical patients and
extracting the DNA they contain.
The DNA, which can be preserved indefinitely,
will be cross-indexed against the genealogy
database. First, however, both the DNA and the
family trees must be encrypted off-premises by a
government Data Protection Commission to protect
the participants' privacy.
Stefansson, who says DNA-donor anonymity is
the key to maintaining Icelanders' goodwill and
cooperation, has warned participants that they
won't get individual diagnoses or medical advice in
exchange for their blood samples.
"We're discovering the qualities of the group,
not of the individual," he said.
Still, Stefansson's activities and the deeper
issues they raise have shaken up this
mono-industrial nation, where the main scientific
preoccupation up until now has been the careful
management of fish stocks.
"It was like dropping a bomb" when deCODE
appeared on the scene, said Alfred Arnason, chief
geneticist at the Reykjavik blood bank.
Arnason, who is closely watching Stefansson's
project, said he can see the value in acquiring,
cross-referencing and encrypting Iceland's
genealogical and medical data. What he cannot
understand is how Stefansson can sell this
information to companies like Hoffmann-La Roche
without making it proprietary.
And if Stefansson is allowed to copyright his
database, Arnason said, what will become of the
other scientists who now freely use Iceland's
national health records for research, lower in
profile and smaller in scope though their work may
be? What will happen if Stefansson's industrial
clients refrain from publishing their findings until
they can secure patent rights?
"That would hinder science, not enhance it,"
Arnason said. "If he wants to chase genes, that's all
right. Everybody is chasing genes nowadays. But
I'm in favor of everybody having the same right to
do their studies and not to monopolize data."
Arnason and about 200 other Icelandic scientists
recently sent an open letter to the government in
Reykjavik urging a go-slow approach on regulating
DNA prospecting.
Stefansson, for his part, said he understands the
misgivings about the increasing role of private
industry in medical research. But he argued that
human genetics research has become so costly that
it can't progress without the big grants and
enormous pools of shared data that only the private
sector can provide.
"The classical university labs are simply too
small to do advanced research anymore," he said,
recalling his own work on multiple sclerosis at
Harvard. "The only way I saw it financially
possible [to continue] would be to establish a
company."
And, despite the unease Stefansson has aroused
in the Icelandic scientific community, the public
here seems well disposed toward his project--to
say nothing of the jobs, fame and economic
diversification it could mean for Iceland.
"I view this agreement [between deCODE and
Hoffmann-La Roche] as a huge step toward
securing high-technology industries an important
role in the Icelandic economy," Iceland's prime
minister, David Oddsson, said in February when
the deal was announced. Oddsson added that "the
government of Iceland will do its best" to create a
good working environment for Stefansson's
research.
And after a recent television documentary about
deCODE aired here, 70% of the callers to the
station's opinion hotline said they likewise
supported Stefansson's work.
Team Looks Back at Several Generations
In his lab, where panoramic windows overlook
an otherworldly landscape of treeless mountains
rising out of the sea, staff geneticist Hreinn
Stefansson--no relation, or at least not a close one,
to Kari--demonstrated the way deCODE hopes to
use Iceland's special qualities to identify genes.
First, he called up the coded names of several
generations of sick Icelanders on a computer
screen.
"This is a great tool for us, like an overview of
the disease," he said, scrolling through a lengthy
family tree in which the sick people appear as
black dots, the well people as white dots.
Once a researcher like Hreinn Stefansson has
found an extended family that looks promising, he
or she takes the encrypted names back to the
government Data Protection Commission, which
decodes them and contacts the patients' physicians,
asking for blood samples from both patients and
disease-free relatives. Although Kari Stefansson
and his staff are not involved in this step, the
bio-entrepreneur said he has heard of only two
families so far that said no when approached.
The Data Protection Commission then
reencrypts the blood samples and returns them to
deCODE, which begins the process of extracting
the DNA. Next, scanners analyze the DNA,
comparing the genetic patterns of the sick and the
disease-free relatives. These findings are sent to
deCODE's statistical department, which uses them
to calculate the probabilities of damaged genes
occurring in certain positions on the chromosomes.
Using these methods, Kari Stefansson said, his
staff has so far been able to "map" some of the
genes involved in multiple sclerosis; psoriasis;
preeclampsia, a condition marked by dangerously
high blood pressure during pregnancy; and familial
essential tremor, a condition which causes
uncontrollable trembling in the elderly. "Mapping"
a gene means narrowing the number of places
where it might appear on a chromosome from about
3 million to a couple hundred thousand.
Much more work must be done before the
individual genes can be identified, a complicated
process in diseases where more than one gene is
involved. But Hreinn Stefansson said the speed
with which deCODE was able to identify the
location, or "locus," of the familial essential tremor
gene showed how powerful deCODE's methods
are: The search took the lab less than three months.
"We were very happy," he said, "because many
people had been working on this disease for years,
and they hadn't been able to find the locus."
Copyright Los Angeles Times