Download Article: The Genetic Revolution

The Genetic Revolution
New technology enables us to improve on
nature. How far should we go?
By Philip Elmer-Dewitt
Dissolved in a test tube, the essence of
life is a clear liquid. To the naked eye it looks
just like water. But when it is stirred, the
“water” turns out to be as sticky as molasses,
clinging to a glass rod and forming long, hairthin threads. “You get the feeling this is really
different stuff,” says Dr. Francis Collins in his
molecular-biology laboratory at the National
Institutes of Health. Collins heads a mammoth
effort to catalog the library of biological data
locked in those threads; a challenge he
compares, not inaccurately, with splitting the
atom or going to the moon.
In his
laboratory at the
University of
Southern California,
Dr. W. French
Anderson looks at
the same clear liquid
and sees not a
library but a
pharmacy.
Anderson’s goal, his
obsession, is to find the wonder drugs hidden in
that test tube. Someday, he says, doctors will
simply diagnose their patients’ illnesses, give
them the proper snippets of molecular thread
and send them home cured.
This thread of life, of course, is
deoxyribonucleic acid, the spiral-staircaseshape molecule found in the nucleus of cells.
Scientists have known since 1952 that DNA is
the basic stuff of heredity. They’ve known its
chemical structure since 1953. They know that
human DNA acts like a biological computer
program some 3 billion bits long that spells out
the instructions for making proteins, the basic
building blocks of life.
But everything the genetic engineers
have accomplished during the past half-century
is just a preamble to the work that Collins and
Anderson and legions of colleagues are doing
now. Collins leads the Human Genome Project, a
15-year effort to draw the first detailed map
of every nook and cranny and gene in human
DNA. Anderson, who pioneered the first
successful human-gene-therapy operations, is
leading the campaign to put information about
DNA to use as quickly as possible in the
treatment and prevention of human diseases.
What they and other researchers are
plotting is nothing less than a biomedical
revolution. Like Silicon Valley pirates reverseengineering a computer chip to steal a
competitor’s secrets, genetic
engineers are decoding life’s
molecular secrets and trying to
use that knowledge to reverse
the natural course of disease.
DNA in their hands has become
both a blueprint and a drug, a
pharmacological substance of
extraordinary potency that can treat not just
symptoms or the diseases that cause them but
also the imperfections in DNA that make
people susceptible to a disease.
And that’s just the beginning. The
ability to manipulate genes-in animals and
plants, as well as humans-could eventually
change everything: what we eat, what we wear,
how we live, how we die and how we see
ourselves in relation to our fate.
It will not be an easy transition. Even
as the first benefits of the genetic revolution
begin to trickle in, people have started to
wonder what those benefits will cost. A
TIME/CNN poll found respondents profoundly
ambivalent about genetic research and deeply
divided over its applications. Asked whether
they would take a genetic test that could tell
them what diseases they were likely to suffer
later in life, nearly as many people said they
would prefer to remain ignorant (49%) as said
they would like to know (50%). Most people
strongly oppose human genetic engineering for
any purpose except to cure disease or grow
more food. A substantial majority (58%) think
altering human genes is against the will of God.
The respondents also put their finger
on what may prove to be the most worrisome
development of the genetic age: the likelihood
that the secrets hidden in people’s genes will
someday be used against them. A drop of blood
or a lock of hair contains all the genetic
information a potential employer or insurer
would need to determine whether someone is at
risk of contracting a long list of debilitating
diseases. Of those polled, 90% said they
thought it should be against the law for
insurance companies to use genetic tests to
decide whom to insure. Yet such practices are,
in fact, quite legal. Jeremy Rifkin, a longtime
opponent of some forms of genetic engineering,
is now marshaling his resources to fight what
he perceives to be the most serious new threat
to civil liberties. “Genetic privacy will be the
major constitutional issue of the next
generation,” says Rifkin.
No matter what path the genetic
revolution takes, the first step is to find the
genes: the discrete segments of DNA that are
the basic units of heredity. For scientists
racing to map the human genome (as the
complete set of genes is called), the past year
has been extraordinarily productive. With
automated cloning equipment and rough
computerized maps to steer them through the
vast stretches of DNA, scientists are finding
human genes at the rate of more than one a
day. In the past 12 months they have located
the genes for Huntington’s disease, Lou
Gehrig’s disease, the so-called bubble-boy
disease, the disease featured in the film
Lorenzo’s Oil, a major form of ataxia, and a
common kind of colon cancer, among others.
Scientists expect to zero in on the first
breast-cancer gene any week now.
Locating a gene from scratch, says
Collins, is like “trying to find a burned-out light
bulb in a house located somewhere between the
East and West coasts without knowing the
state, much less the town or street the house
is on.” Even the most comprehensive DNA
chart available-the human-genome map
completed late last year by Daniel Cohen and
colleagues at the Center for the Study of
Human Polymorphism in Paris-is terribly
sketchy and riddled with errors.
That’s why the Human Genome Project
is so important. The goal, says Collins, director
of the National Center for Human Genome
Research, is to find by the year 2005 not just
the location of 100,000 or so genes, but the
exact sequence of their constituent chemical
parts. If the human genome is an encyclopedia
divided into 23 “chapters” (chromosome pairs),
each gene “sentence” is composed of threeletter “words,” which are in turn spelled by
four molecular “letters” called nucleotidesadenine (A), cytosine (C), guanine (G), and
thymine (T). By scanning a database containing
the complete sequence of letters, researchers
could quickly end up at a particular gene’s front
door.
But even with the best of tools, the
progress is uneven. DNA, it turns out, is full of
surprises. As scientists unravel the secrets of
the genome, they are discovering that what
they learned from Gregor Mendel is woefully
incomplete. The textbook model of inheritance
that Mendel found in his garden peas-in which a
trait like the color of a flower is determined by
a single gene-is almost never seen in human
DNA. Even a seemingly straightforward
characteristic in humans, eye
color, for instance, can involve
the interaction of several genes.
And a complex gene, like the one
that causes cystic fibrosis, can
go wrong in any number of
places. Scientists have already counted 350
different sites where the cystic fibrosis gene
mutates, and more are being uncovered almost
every week.
No gene was harder to pin down than
the one implicated in Huntington’s diseasewhich was finally located after a decade-long
search last year. Not only did it turn out to be
tucked into a particularly hard-to-reach spot
on the tip of chromosome 4, but it was what
scientists call a “stuttering gene.” Hidden in
its DNA is a sequence of nucleotides that spells
out the same genetic word-in this case CAGagain and again. The normal version of this
gene contains anywhere from 11 to perhaps 34
copies of this three-letter stutter. The
defective Huntington’s gene, researchers
discovered, has from 37 to about 100.
Scientists still don’t know how the stutter
causes the disease, but the severity of the
symptoms and their onset seem to be roughly
linked to the number of repeats. In people
with 80 to 100 repeats, for example, the
disease comes swiftly-often in childhood.
Once a broken gene is found, what
next? Fix it, of course. But how? There are
no tweezers small enough to pry out and
replace bad nucleotides one letter at a time,
and there probably never will be. So gene
engineers have come up with a variety of
indirect strategies for getting the same result.
The most direct approach is to find a
healthy copy of the missing gene and transplant
it into the affected cells. That’s the strategy
Anderson, teaming up wit Drs. Michael Blaese
and Kenneth Culver at the National Institutes
of Health, used in a landmark experiment three
years ago. The disease the team targeted was
severe combined immunodeficiency (SCID),
often called the bubble-boy disease because its
most famous victim was encased in a plastic
bubble during his short life to protect him
from infection. One form of SCID called ADA
deficiency is caused by a defect that blocks
production of adenosine deaminase, a key
enzyme; without it, important immune-system
blood cells are immobilized.
A few years ago, doctors began to
treat patients with a form of bovine ADA; as a
result they could survive outside a bubble, but
some of them still tended to be sickly. A
better treatment was needed, and Anderson
thought he had the answer. In the world’s
first approved gene therapy trial, his team
extracted white blood cells form two young
Ohio girls with the disease, inserted normal
ADA genes into the cells, and reinjected them.
The hope was that the blood cells would begin
churning out enough natural ADA to boost the
immune system measurably. They did. Last
May the patients, now 7 and 12, appeared at a
press conference, thriving as never before, to
assume their honorary posts as “research
ambassadors” for the March of Dimes.
Impressive as the experiment was,
scientists knew that the girls had been treated
but not cured. The altered blood cells died out
after several months, and the patients had to
return to the hospital periodically to repeat
the procedure. The achieve a full cure, gene
therapists would have to get to the source of
the problem: the long-lasting stem cells that
reside in bone marrow and produce all the
white blood cells that circulate in the
bloodstream.
And that’s precisely what Blaese didonly a week before the triumphant press
conference last May. Going back to one of the
original Ohio girls, he inserted healthy ADA
genes into stem cells he had coaxed out of her
bone marrow. He then inserted the altered
cells into the bloodstream, hoping they would
find their way back to the marrow. The same
experiment has since been repeated several
times on infants, whose stem cells are even
more abundant and easier to reach. The
children seem to be thriving, but no results
have been published.
The ADA experiments created a rush
to try similar techniques on other diseases,
including cystic fibrosis, cancer and AIDS.
More than 40 trials are under way around the
world, making gene therapy the hottest new
area of medical research. The hardest part of
all these efforts is getting the right genes into
the cells that need them. Generally, the genes
must be carried by some sort of delivery
vehicle, which scientists call a vector. For its
vector, Anderson’s team used an infectious
agent known as a retrovirus-a specialized virus
containing RNA (a single-strand cousin of DNA)
that has a knack for finding its way to a cell’s
genome and making itself at home.
Retroviruses can be dangerous (HIV is the
most notorious), but scientists have ways of
altering them so that they don’t cause disease.
Still, the small risk that retroviruses used in
gene therapy could do serious harm to patients
makes them less than ideal.
Many other vectors are now being
tested. Dr. Ronald Crystal of New York
Hospital-Cornell Medical Center was jogging
one day when he had the inspired notion of
delivering genes to the lungs of cystic fibrosis
patients using the adenovirus
that causes the common cold.
“This is a virus that has taken
millions of years to evolve to
do what it does-get into the
lung,” says Crystal, who plans
to begin a new set of trials
with the virus in the next month or so. One of
his challenges is to render the adenovirus
harmless and keep it from spreading out of
control. “We want to cure cystic fibrosis,” he
says. “We don’t want to infect the whole town.”
But vectors may not have to be viruses.
Some researchers are working on ways to
inject DNA directly into human cells. To treat
patients with malignant melanoma, a deadly skin
cancer, a team led by Dr. Gary Nabel at the
university of Michigan encased a tumorfighting gene in liposomes, harmless little
bubbles of fat. The genes found their way into
the proper cells, and in at least one case the
tumors shrank.
While many scientists are practicing
genetic engineering on human cells, others are
working with animals and plants-usually for the
ultimate benefit of humans. A considerable
amount of AIDS research uses mice with
immune systems containing transplanted human
genes. Scientists in England and at Washington
University have produced a line of transgenic
pigs whose cells produce human proteins that
can suppress the immune response. Hearts,
livers and other organs from these animals
could, in theory, be transplanted into human
patients without being attacked and destroyed.
Whole herds of dairy cows are now
being injected with a genetically engineered
growth hormone (BST) so that they will
produce more milk
than ordinary cattle.
Companies such as
Monsanto and
Calgene are set to
market
bioengineered plant products, including
tomatoes that ripen without rotting. And
researchers are talking about drought-tolerant
grass that would need almost no mowing.
For all the fevered work being done,
however, science is still far away from the
Brave New World vision of engineering a
perfect human-or even a perfect tomato. Much
more research is needed before gene therapy
becomes commonplace, and many diseases will
take decades to conquer, if they can be
conquered at all.
In the short run, the most practical
way to use the new technology will be in genetic
screening. Doctors will be able to detect all
sorts of flaws in DNA long before they can be
fixed. In some cases the knowledge may lead
to treatments that delay the onset of the
disease of soften its effects. Someone with a
genetic predisposition to heart disease, for
example, could follow a low-fat diet. And if
scientists determine that a vital protein is
missing because the gene that was supposed to
make it is defective, they might be able to give
the patient an artificial version of the protein.
But in other instances, almost nothing can be
done to stop the ravages brought on by genetic
mutations.
Therein lies the dilemma currently
posed by the genetic revolution. Do people
want to know about genetic defects that can’t
be corrected yet? Vicki Balogh of Trenton,
Michigan, is facing such a moment of truth
right now, as she awaits the results of a test
that will tell her whether she carries the gene
for ataxia. The degenerative disease killed her
mother at 52 and has already started to
destroy the nerve fibers in the brain and spinal
cord of three of Vicki’s brothers. “I’m 35, and
that’s young enough to make a career change,”
says Balogh, a manager at Ameritech. “I’ve
always wanted to be a teacher, but if I have
ataxia, well…”
The danger for many people in whom a
genetic disease has been diagnosed is that if
they leave their job (and their insurance), they
may never get another. A report by the
National Academy of Sciences last year found
that Americans are already losing their jobs
and health insurance based on information
uncovered in genetic screens. In one case, a
California health maintenance organization
discovered that the fetus a client was carrying
had the gene for cystic fibrosis. The HMO
told her it would pay for an abortion, but that
if she chose to have the child, it would not pay
for any treatments. The woman had the child,
and the threat of lawsuit forced the HMO to
back down.
When the issues are genetic screening
and abortion, ethical values often clash with
practicality and parental rights. With health
costs going out of control, there will be
increasing pressure on parents not to bring to
term a child that will be a drain on the medical
system. Those who doubt that a eugenics
movement reminiscent of the Nazi era could
get started in this day and age have only to
look at the example of China, which last month
announced a program of abortions, forced
sterilization and marriage bans to “avoid new
births of inferior quality and heighten the
standards” of the country.
“You’re going to see craziness you won’t
believe,” says George Annas, a Boston
University professor of health law. He thinks
it is only a matter of time before someone
sweeps up Bill Clinton’s hair trimmings at a
barbershop, runs a genome scan on the DNA in
the hair cells and publishes the list of diseases
to which the President is heir. Under current
law, there is nothing Clinton or anyone else
could do to stop it. Annas is worried that
samples from routine blood tests on ordinary
citizens could be screened and that the genetic
information might eventually find its way into
vast DNA data banks, a prospect James
Watson, the co-discoverer of the molecule’s
structure, has called “repulsive.” To prevent
misuse of this information, Annas has proposed
a series of guidelines that would, among other
things, prevent genetic data collected for one
purpose from being used for another. But
given how ineffective U.S. computer-privacy
laws have proved so far, he is not optimistic.
There is already talk of a genetic
backlash, a revolt against the notion that we
are our genes, or, as one critic put it, that our
Genes R Us. John Maddox, editor of the
journal Nature, warns that the greatest pitfall
of the genome project may be what he calls the
“inescapable triumphalism” that accompanies a
rush of discoveries, leaving the impression that
geneticists know a lot more than they do.
Studies claiming to have found genes for
alcoholism, for instance, have not held up under
scrutiny, but many people still assume such
complex behaviors may be predetermine by
heredity.
Even if there were a gene for, say,
criminal activity, what would society do about
it? Gregory Carey, a behavior geneticist at the
University of Colorado, points out that “we
already have a true genetic marker, detectable
before birth, that predicts violence.” The
individuals with this genotype, he says, are nine
times as likely to get arrested and convicted
for a violent act as people without the genes.
He asks, “Do you know the high-risk marker I’m
talking about” that’s right: being male.”
Columnist William Safire, commenting
on the Senator Packwood follies, observed that
our diaries reveal our youthful selves to our
aging selves, and that we should not be
surprised if what we see sometimes makes us
wince. Annas suggests that the genetic
revolution has reversed that proposition. Our
genes, he says, could serve as “future diaries”
that will reveal our aging selves to our youthful
selves.
Someday, says Harvard molecular
biologist Walter Gilbert, that diary-the entire
genetic record-will fit on a single CD-ROM.
“We look upon ourselves as having an infinite
potential,” he writes in The Code of Codes. “To
recognize that we are determined, in a certain
sense, by a finite collection of information that
is knowable will change our view of ourselves.
It is the closing of an intellectual frontier, with
which we will have to come to terms.”
That process has already begun-most
poignantly for those who have been screened
for a disease gene and tested positive. For
some there is hope in the work of scientists
like Collins and Anderson, who have discovered
that the DNA molecule is not only highly subtle
and complex, but correctable as well. The rest
may take comfort in the fact that life, even
after the genetic revolution, is still a poker
game. Our genes are simply the cards we are
dealt. What matters most is how we play the
hand.