Stanford Today Edition: November/December, 1996 Section: Features: Genetic Roulette WWW: Genetic Roulette

Genetic Roulette
The human genome project is ushering in a biotech revolution. Who's watching out for your future in this brave new world?

By Janet Basu
Illustration by Anita Kunz; photographs by Marcos Lujan

The unknown road

David Cox started on the path that would lead him to the Human Genome Project more than two decades ago in a tiny medical consulting room. He was a young pediatrician and geneticist, sitting hunched in a small chair, knee to knee with the parents of a newborn baby with Down syndrome.

Cox is a soft-spoken man with a calm, even manner. He has iron-black hair brushed back from a high forehead and dark eyes; when he looks at you, you feel the full force of his attention. That attention, and a voice that can quiet and soothe, was about all that he could offer these parents. He had few answers to their agonized questions. He could not predict their child's future.

"The family always comes to you expecting the worst, protecting themselves against it," he says. "But often, the worst is not what happens."

Down syndrome causes a loss of brain cells that leaves some children so retarded they cannot feed themselves. But others grow up to lead relatively independent lives. Part of the difference in those outcomes lies in the babies' genes. Somewhere along the extra copy of Chromosome 21 that every Down baby is born with, there's a mutation - almost certainly several mutations - that cause brain cells to degenerate too rapidly.

As a geneticist, Cox knew that if he could compare the chromosomes of many people with Down syndrome, he could find clues to explain why some lose more brain cells than others. He could offer parents a better understanding of their child's genetics. Someday, he might be able to offer treatments to make the children's lives easier. And the same clues might help explain the biology of other brain diseases like Alzheimer's and schizophrenia.

But there was a catch. Finding a single gene was painstakingly difficult. Finding many genes working in combination was technologically impossible at the time.

Imagine that you unravel the spiraling double-helix ladder of human DNA and stretch the rungs out flat on a highway. (The technical term for a rung is a "base pair," two linked amino acids called nucleotides.) Each of the 80,000 or so human genes is a code made up of anywhere from a few hundred to tens of thousands of base pairs, interspersed with sections of "non-coding" DNA. Chromosome 21 stretches along for 37 million rungs.

Finding a mutated version of a few of those base pairs would be like finding a single address along an unknown road, somewhere in North America, without a map.

Fast-forward to 1996

The map that someday may guide the way to answers about Down syndrome and other inherited diseases is being made at startling speed. Cox is one of the cartographers, along with other scientists at Stanford and more than 100 institutions and private companies, racing to chart out the 3 billion base pairs of the human DNA ladder. Halfway through the 15-year, $3 billion federally funded Human Genome Project, the partial maps they've assembled have led to the discovery of hundreds of genes.

The scope of possibilities for this new knowledge is mind-boggling: from new medical treatments tailored to the individual to new ways to predict and prevent disease, to new ways to look at biology itself. James Watson, the Nobel laureate who helped to discover the structure of DNA, calls the blueprint of the genome "the most important set of instruction books [ever] made available to human beings."

But it is only a tiny leap from celebrating the potential of those instructions to wondering who will be able to use them, and to what ends. Will genetic records be used to deny health care or to cut people off from certain jobs? Will society decide that children with "defective" genes should not be born? Will we screen job-seekers for genes linked to alcoholism or violence?

Those are questions that worry not only critics of the Human Genome Project but scientists themselves. From the beginning of the project some geneticists - including Cox - have been taking time out from the lab specifically to tackle the ethical issues that arise as this new knowledge unfolds. It's as if in 1942, the Manhattan Project started out with instructions to study the potential effects of nuclear fission on human health.

The geneticists bring to the debate an important perspective about the limits of scientific knowledge: Genes will help predict and prevent some diseases, they say, but genes are not the perfect fortune-tellers that many people imagine.

Down on the gene farm

It's not surprising that Stanford, a birthplace of the biotechnology revolution, has scientists working on almost every aspect of the new science of "genomics" - knowledge gained from the genome. Members of the Stanford community - from families with inherited diseases to scholars pondering law and ethics - already wrestle with many issues that genomics raises for society.

On the side of scientific discovery, the Stanford Human Genome Center is one of the key sites of the national effort to chart each rung of the DNA ladder for the entire 3-billion-base-pair sequence of the human genome. Cox and his collaborator and fellow genetics professor Richard Myers lead the center, which has used a technology they developed to map more than 6,000 markers along the length of the genome.

Now the Stanford team of 33 scientists and staffers is racing to refine the genetic sequence. They work with other genome centers in a competitive collaboration rather like a quilting bee, sharing their discoveries on the World Wide Web. The entire sequence should be completed by 2005 - or sooner, since the scientists are continually inventing more effective ways of doing the work.

"We wanted to work on therapies," Cox recalls, "but we couldn't do that without maps. Our group and several others decided nobody would get [the maps] done unless we did it."

Stanford researchers also have discovered genes ranging from several that cause rare inherited disorders to the gene for the most common form of skin cancer. They are working to find faster ways to locate genes and understand their function. They're pushing toward the next, more difficult step of gene-finding: locating multiple genes working together to influence disorders like manic depression and heart disease. And they are turning that knowledge into a search for new drugs and treatments. Some of the work will use genes themselves to instruct the body to make its own treatments.

Stanford also has been a nexus of discussion about the implications of gene knowledge. Last year two national conferences, hosted by Nobel laureate Paul Berg and by anthropologist Joan Fujimura, examined the questions raised by genetic testing and the uses of genetic technology. Under Myers' leadership, scientists at the genome center periodically stop what they're doing at the lab bench to host high school biology students who study genetics and ethics. The university's Program in Genomics, Ethics and Society sponsors research into the impact of genomics, drawing on experts across the spectrum from medicine to sociology to law.

The new medicine

To advocates and critics alike, the Human Genome Project will have an impact far beyond the diseases that it might help cure.

Berg, whose work on recombinant DNA helped launch the biotechnology revolution, calls the genome map "a new beginning for biology." Already the genes of organisms ranging from laboratory mice to the AIDS virus are yielding never-before-revealed clues about the mechanisms of living things.

Others predict that genomics will change medicine in the 21st century as profoundly as the 19th-century discovery that germs cause disease.

"Genetics offers the best road to understanding disease at this time," says David Botstein, chair of genetics at Stanford and a national leader in the field. "We can ask: Which genes predispose a person to this disease, what are the factors that work with the gene to cause the disease, and what can you do about it?"

In the next century, "instead of mass medicine, we'll have custom medicine," Botstein says. A drop of blood on a multiple-gene-testing silicon chip will be enough to tell your doctor whether you have a special risk of heart disease or diabetes or several different types of cancer. Prevention will keep high-risk people healthy and lower the overall cost of health care. Treatment will be tailored to match the individual's genetic profile.

It is exactly that individualized gene profile that makes even enthusiasts of the genome project wary.

Gene tests long have been used in prenatal testing. But the next generation of tests will touch many more lives. Geneticists disagree about how much a genetic profile can show, but to an individual it will read like the chart of her lifeline - her chances of developing asthma in childhood, the risk of getting breast cancer in her 40s, or the odds of suffering from Alzheimer's in old age.

This is intimate knowledge, a biography in advance, not just of the individual but of her family. How do we interpret that information? How do we ensure that it doesn't fall into the wrong hands? Do we really want to know this much about ourselves?

It is telling that nearly every geneticist interviewed for this article said he or she would not take a gene test without some assurance that the results could be kept private. Many are worried that the work they do in the lab could someday be used as a tool of discrimination. And ethicists warn that discrimination is only the most predictable of the problems for a society adapting to genomics.

Consider the complexity of human issues discovered by Diane Beeson, professor of sociology at California State University-Hayward and research fellow with Stanford's genomics and ethics program. As part of that program's major study of breast cancer gene tests, she talked to women with family histories of breast cancer.

She tells the story of a woman who chose a double mastectomy at age 28 to prevent breast cancer. Will a gene test tell her to have more surgery to prevent ovarian cancer - or would it reveal that the mastectomy was unnecessary? Another woman worries about whether her young daughter should be tested. A family is angrily divided when one sister wants to take a breast cancer gene test and another sister fears knowing the results.

Americans are drawn into such scenes by a technological imperative, says medical ethicist Barbara Koenig, director of the genomics and ethics program. As a people, we tend to embrace each shiny new scientific revelation and try to adapt to it, whatever the costs.

Koenig is small and trim, with empathetic brown eyes. She has a way of getting straight to the point.

The breast cancer gene test is an example of a rush to use genetic information before we understand what it means, she says. BRCA-1 and BRCA-2, the genetic mutations detected by the test, are linked to breast cancer in only a small number of families. Women in those families can learn whether they have a statistically high risk of cancer, but the test will tell nothing for certain. For most women, the presence of the same mutated gene does not indicate whether they will get cancer or not.

Two companies are offering the test commercially, citing every woman's right to know whether she carries the BRCA genes. In response to that argument, Koenig says, "As health professionals we have a responsibility to tell people when we don't really know anything."

Joan Fujimura says the breast cancer gene test is an example of the type of quandary that genome scientists should be wrestling with, along with the rest of society.

Fujimura is slim, energetic, a questioner; she spends much of her time in the laboratories of molecular biologists studying how they develop new knowledge. She finds scientists no better prepared than the rest of us for the complexities of genetic information.

When they offer a powerful new technology, "the scientists are making policy in our society," she says. "When I talk to scientists, they don't always see that."

Fujimura says even highly influential scientists often see their role as narrowly focused on finding out how nature works, while others in society think of the effect. "Biologists are producing the technology that will shape our future," she says. "It's important for them to think about the culture that will use their technology, what kind of society we want to have."

The limits to knowledge

David Botstein says, "These are social issues, not scientific issues."

That sounds like a scientist's cliché. But Botstein, an originator of some of the major concepts that made the genome project practical, is no ivory tower researcher.

As chair of the genetics department, he has recruited to Stanford a coterie of top scientists, including Myers and Cox, who are helping to push the envelope of genomics. With biochemist Ronald Davis, he led the team that this May sequenced the entire genome of baker's yeast - an important step, because even after millions of years of evolution, yeast genes still can help scientists understand some of the most basic human genes.

And although he claims to have little interest in the social concerns raised by what he calls "the ELSI crowd" - researchers studying the ethical, legal and social implications of genomics - Botstein fields questions about those issues all the time. He speaks to students, alumni, civic groups, legislators and reporters about what's possible with modern genetics and what is not.

Botstein is a natural lecturer. He enjoys the role of the citizen-educator: If society is going to make decisions about genetics, he might as well make sure they are informed decisions. A large man, with a cherubic visage under a crown of dark curls, he uses his booming voice with a blend of authority and comic timing.

He says that in any audience of, say, Stanford alums, his favorites are those asking: "How much can we hope to learn about the interactions of genetics and the environment? Will we actually be able to predict anything by knowing genes? The more thoughtful ones, very quickly, get into the issues of the limits of knowledge."

Those limits - simply practical realities - will prevent most of the outrages that people worry about when they imagine the Brave New World of genomics, Botstein says. He tells audiences to forget designer babies or an engineered human race: It will be mathematically impossible to tinker with enough of our 80,000-gene inheritance to design a "perfect" baby, let alone a "master race."

Botstein does worry about health-care discrimination, calling it a serious social problem. But he points out that it is mostly a problem in the United States - in Europe, there is little incentive to discriminate because everyone is guaranteed some level of health care.

"Most civilized countries have more or less managed to get to this point," he says drily.

The genie uncorked

Paul Billings says that people like Botstein are deluding themselves if they think that health care is the only arena where genetic information can be misused.

Billings is deputy chief of staff at the Veterans Affairs Medical Center in Palo Alto and clinical associate professor of medicine at Stanford. Seven years ago, he was "busy being a mouse geneticist" on the faculty at Harvard when he and a group of colleagues decided to find out what they could about genetic discrimination. The stories that they gleaned transformed his career.

"I started talking about this in 1989 and I haven't stopped since," he says. Tall and rangy, with a big beret always stuck to the back of his balding head, he is constantly on the go, testifying before legislators and scientific conferences on genetic discrimination.

He cites a litany of nightmarish cases: The 24-year-old woman fired from her job after her employer learned of her risk of Huntington's disease, an ailment that usually doesn't strike until after 40; the recruits turned down by the Air Force because they were carriers - but had no symptoms - of sickle cell disease; the two Marines court-martialed for refusing to take a gene test.

Billings has become a forceful advocate for the "asymptomatic ill" - healthy people with only a statistical risk of developing a disease.

In a study published in January, he and his colleagues documented 455 cases in which people were denied insurance or health care - as well as jobs, schooling and the right to adopt children - on the basis of a family history of genetic disease. Billings and his co-authors say these people are the first members of a new social underclass.

"The genie is out of the bottle," he says. "Every risk assessment event could be linked to gene tests: your driver's license, gun permit, home mortgage."

Cox has a counter to that argument. "That genie has been out of the bottle for a long time," he says. "If we got rid of genetics today, we wouldn't be at a loss for ways to classify people and create social inequities."

Like Billings, Cox has stepped outside the laboratory to try to influence the way that gene technologies are used. He is both a scientific leader of the national Human Genome Project and a founding member of its unique spin-off: the ELSI Working Group. The acronym stands for "ethical, legal and social implications." With a mandate from Congress and 5 percent of the genome project's $150 million annual budget, the ELSI program has tackled issues like privacy for families in gene studies, accuracy in gene tests, and genetic discrimination.

"The idea was to have pre-emptive discussions," Cox says. "To consider the effects of this technology before it happens so we won't constantly have to clean up spilt milk." In July, President Clinton appointed Cox to a new National Bioethics Advisory Commission.

With the other members of the ELSI group, Cox can take some credit for laws that limit health insurance companies and employers from discriminating on the basis of genetic tests. Thirteen states, including California, have passed some form of genetic discrimination law, and a measure drafted by Sen. Dianne Feinstein, A.B. '55, was signed recently by President Clinton.

But Cox says that what he's learned in the ELSI process has taught him to be cautious about how much those achievements mean. "You don't legislate away discrimination," he says. "You just make it more painful for people to discriminate. It takes a social belief that discrimination on the basis of genetic information is bad."

No crystal ball

If there is one thing Cox would like to tell people about genes, it is: "It's genetic" doesn't mean "it's inevitable."

If there is one fear he holds for the future, it is that most people will not hear that message. Individuals may make decisions about their own lives, and governments may decide on policies ranging from education to prison time, based on a belief that most geneticists say is false.

"Genes are deterministic, for some things," Cox says. "But the concept that by knowing the genes we can know the fine aspects of what a person is going to look like, what they're going to think or feel - many of the aspects of being uniquely human - is just silly."

"Yet most people find the idea of genetic information useful so they can determine exactly that. I think this is the single biggest misconception concerning what genetics can offer us."

In fact, Cox says that modern genetic discoveries are changing some of geneticists' own beliefs about predictability. The more they learn, the more they find that our genes are not complete predictors of destiny.

Cystic fibrosis, America's most common fatal inherited disease, is a good example. Before the gene was discovered, doctors assumed they could predict the fate of any child carrying the mutated CF gene: a lifetime of serious illness, and a 50-50 chance of dying before 30.

The isolation of the gene in 1989 changed those assumptions. As geneticists had expected, CF is caused by mutations on a single gene. Most children born with the mutated gene do suffer from its life-threatening effects. However, gene tests have now revealed people in CF families with the same mutations and almost no symptoms.

The findings have changed the attitudes of many people with a family history of this disease. Doctors had predicted a big demand for the CF gene test. Instead, many people have opted not to learn if they are carriers of the mutated gene. Some have decided against the prenatal test for CF. The hope - not always realized - is that an afflicted baby's symptoms will be mild.

There's also fear involved: Billings cites one case where a health insurer read the results of a prenatal test for CF and threatened to cut off medical coverage unless the woman agreed to an abortion.

The lesson, geneticists say, is this: Even for a disorder strongly influenced by a single gene, more than one factor influences the way the gene is expressed. The outcome depends on interactions with other genes, with hormones inside the cell and with myriad environmental influences.

Those are just the complexities for the few hundred diseases, like cystic fibrosis and sickle cell anemia, that are unquestionably caused by genes. Much of the research linking genes to traits like obesity or alcoholism is preliminary, based on only a few human subjects - and still on shaky scientific ground, Cox and Billings say.

Some geneticists now doubt whether gene tests will be sensitive risk-detectors after all. The comprehensive gene profile may not be the fortune-teller people imagined.

"Assuming that a genetic mutation means someone has a disease is naive genetic determinism," Koenig says.

Promises and frustrations

No one can better appreciate how much can be learned from genes - and how much more remains to be learned - than John Wagner.

As a doctor at Stanford's Lucile Packard Children's Hospital, he works every day with cystic fibrosis patients and their families. He's seen the rise in hopes that has followed the discovery of the gene.

It's now known that a faulty CF gene produces faulty ion channels, the "portholes" that transport water in and out of cells. Someday that information will lead to relief for symptoms such as mucus-clogged lungs that harbor deadly infections and leave his patients gasping for breath.

Someday, Wagner may be able to cure those symptoms altogether, inserting new genes into cells to command them to make good ion channels. With Phyllis Gardner, associate professor of molecular pharmacology and medicine, he is working with seven young adults who have volunteered to test just such a gene therapy in a preliminary trial.

But when a panel of scientists told the National Institutes of Health last year that gene therapy has been "oversold," with little progress after more than 600 human trials, Wagner did not disagree. He says he is constantly telling his patients: "Just because the gene was cloned, the cure isn't necessarily around the corner.

"The worst part about the discovery of the CF gene was the raised expectations of patients and their families," he says.

Botstein was a member of that NIH panel. He says they all agreed that gene therapy will work someday. "The technology just isn't here yet."

Still, Wagner is often overwhelmed with offers from CF patients to volunteer for medical trials.

"They know that these studies most likely will not benefit them but someone younger," he says. "I really admire that. They know they have the opportunity to give a chance to someone else."

To the scientists, the genome project is akin to building a national highway system, an infrastructure for the hoped-for cures and the unexpected discoveries that will come later. They know that the pace of those discoveries will be uneven and unpredictable - that's the way science usually works.

Meanwhile, for the family that learns that their new baby does not have a dreaded disease, genomics is already a blessing. For a man who carries a gene linked to Alzheimer's disease and has no options for prevention or a cure, the knowledge may be a burden, a curse hanging over his life.

And what about the Down syndrome children who got Cox started on this search?

The map of Chromosome 21 is now comprehensive enough that more than 100 of its 1,000 genes have been identified. Cox and other researchers can compare Down children's chromosomes to look for subtle variations in the ones most affected. "That will allow us to focus in on which genes to look at, to see what those genes do that causes some children's mental retardation to be more severe," he says. From that knowledge perhaps they may be able to think about treatments.

"And that is the goal," Cox says. "We do the maps for this reason." ST

Discoveries in genetics

Some Stanford - and other - contributions

1866 - Gregor Mendel establishes the principles of genetics.

1910 - The basic unit of heredity is dubbed a "gene."

1949 - In the catacombs of Stanford's Jordan Hall, George Beadle and Edward Tatum prove that one gene usually commands the production of one protein to do a specific job in the cell. Their work earns a Nobel Prize in 1958.

1952-53 - Scientists prove that DNA alone is the substance that transmits heredity, and that it has a spiraling, double-helix structure.

1955 - Arthur Kornberg synthesizes DNA in a test tube. The feat earns him a Nobel Prize in 1959 - the same year he brings an entire biochemistry department with him from Washington University to Stanford.

1964 - Charles Yanofsky establishes the basis for cracking the genetic code. He shows the code is co-linear - groups of the chemicals that make up DNA are translated "word for word" into the amino acids that make up proteins.

1964 - Stanford's Philip Hanawalt and Richard B. Setlow of Oak Ridge National Laboratory show that DNA repairs itself.

1971 - Paul Berg and his colleagues join DNA from unrelated species and lay the groundwork for recombinant DNA technology; Berg receives the Nobel Prize in 1980.

1971 - Hugh McDevitt discovers genes that control immune responses to foreign substances - the first suggestion that people may have predictable genetic susceptibilities to certain diseases.

1972 - Ronald Davis and Janet Mertz discover restriction endonucleases, essential for cleaving and "recombining" DNA.

1973 - Stanford's Stanley Cohen and Herbert Boyer of the University of California develop a practical method to clone genes by transplanting them from one species to another. The patents on their processes launch the genetic engineering revolution and earn millions of dollars in royalties for both universities.

1975 - Paul Berg presides over international Asilomar Conference as scientists propose strict standards for safety in their own recombinant DNA research. By the 1980s, the research is determined to be safe and restrictions are relaxed.

1980 - David Botstein and Ronald Davis, both now at Stanford, and Ray White and Mark Skolnick, now at the University of Utah, propose a way to scan the whole genome to pinpoint the location of genes. This "positional cloning" makes gene-finding practical and creates the need for a human genome map.

1984 - Luigi Luca Cavalli-Sforza starts a pilot version of the Human Genome Diversity Project, collecting cell lines from different human populations to study the origins, diversity and unity of the human species. Responding to controversy, the project develops a model ethical framework to protect and respect communities that choose to donate gene samples.

1986 - Medical student Jeremy Nathans finds the genes for color vision and color blindness, working with David Hogness, Douglas Vollrath and Ronald Davis.

1989 - Congress approves a $3 billion, 15-year project to map the entire human genome and compare it to the genomes of mice, fruit flies, yeast and other model organisms. Congress mandates 3-5% of the funds to study the ethical, legal and social implications of genome knowledge.

1990 - An international effort to map the genome for the flowering plant Arabidopsis thaliana begins, led by the Carnegie Institution's Plant Biology Department on the Stanford campus.

1992 - In a step toward a cancer vaccine, Ronald Levy stimulates cancer patients' immune systems with genetically engineered vaccines grown from their own tumors.

1992 - Uta Francke and Eric Shooter show that the "trembler" gene in mice is the same as the gene that causes Charcot-Marie-Tooth syndrome, humans' most common nerve disorder.

1993 - David Cox and Richard Myers are recruited to Stanford from UCSF. Developers of radiation hybrid mapping, a basic tool of the genome search, they join with the DNA Sequencing Technology project headed by David Botstein and Ronald Davis to form the Stanford Human Genome Center.

1993 - Gerald Crabtree develops a genetic "switch" to turn genes on and off.

1993 - Patrick Brown develops genomic mismatch scanning, a fast way to search for genes in families by comparing the genomes of individuals.

1994 - Victor Dzau tests gene alterations on vein grafts. The new genes help make the veins resistant to clogging by plaque after they are grafted onto arteries in heart bypass surgery.

1995 - Patrick Brown and Ronald Davis develop a microarray technique to show which genes are expressed, or "turned on," in a cell. The technique helps change scientists' focus, from a search for individual genes to a search for patterns of gene expression.

1995 - Phyllis Gardner and John Wagner begin trials to test a new type of gene therapy in young adults with cystic fibrosis.

1995 - Some genes found at Stanford in '95: a gene that may be linked to Parkinson's disease; markers for a rare form of epilepsy (Richard Myers and David Cox); genes for two rare inherited diseases, Williams and Marfan syndromes (Uta Francke). Study shows how the uncontrolled growth of tumors starts with a mutation of the gene for p53, a protein essential for the birth and death of cells (Amato Giaccia).

1995 - Stanford Program in Genomics, Ethics and Society is founded. A full-day session of the November 1996 International Conference on Bioethics will review the program's first white paper, on breast cancer gene tests.

1996 - Matthew Scott uses genome maps to locate a human gene similar to one well-studied in fruit flies. It turns out to be the gene for the most common form of human skin cancer.

1996 - An international project led by David Botstein and Ronald Davis at Stanford sequences the entire 12.5 million base-pair genome of baker's yeast. A bacterium was charted out in '95, but this is the first cell with a nucleus to be sequenced. The yeast is put to work testing genes that might have analogous functions in humans.

1996 - Stanford and other genome centers publish first large-scale "maps" of the human genome, with a marker every 500,000 "rungs" on the DNA ladder. Richard Myers and David Cox are leaders in a new phase of the National Human Genome Project: to refine maps and sequence every one of the 3 billion base pairs of DNA ahead of schedule, by 2003.