The Genetic Revolution
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, hair- thin 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- staircase-shape 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 reverse-engineering 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 three-letter "words," which are in turn spelled by four molecular "letters" called nucleotides -- adenine (A), cytosine (C), guanine (G) and thymine (T). By scanning a data base 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 disease -- which 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, CAG -- again 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 with 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 from 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. To 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 did -- only 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 tumor-fighting 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 or 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 a 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 predetermined 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.
CHART: NOT AVAILABLE
CREDIT: From a telephone poll of 500 adult Americans taken for TIME/CNN on Dec. 2 by Yankelovich Partners Inc. Sampling error is plus or minus 4.5%. "Not sures" omitted.
CAPTION: If it were possible, would you want to take a genetic test telling you which diseases you are likely to suffer from later in life?
If you or your spouse were pregnant, would you want the unborn child tested for genetic defects?
Do you think it should be legal for employers to use genetic tests in deciding whom to hire?
CHART: NOT AVAILABLE
CREDIT: Time Graphic by Nigel Holmes
Research by Leslie Dickstein
[TMFONT 1 d #666666 d {Source: Dr. Victor A. McKusick, John Hopkins University}]CAPTION: OUR GENES: WHAT THE MAP SHOWS
FROM THE WHOLE TO THE (MICROSCOPIC) PARTS
With reporting by David Bjerklie, Andrea Dorfman and Christine Gorman/New York and J. Madeleine Nash/Chicago