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Brave New World

Genetics 101:

Dip your toes into the genome pool of knowledge

    When complete, the knowledge contained in the human sequence promises to be a great boost to science and medicine, genome researchers say. The project has already accelerated the identification of genes associated with human diseases and the development of new drugs to treat them. Proponents say the new knowledge will provide extraordinary benefits for basic research, the biotech industry and improved health of the citizenry.

    But as history has proven, scientific knowledge can create societal problems. In some ways, despite its medical benefits, the genome project is a social Pandora's Box--magical, yet fraught with questions of insurance and employment discrimination, eugenics and bio-social engineering. Some social scientists believe knowledge derived from the genome could lead to a Huxleyan future in which parents choose the traits of their offspring and society shuns the genetically abnormal and sick. This is an extreme vision, to be sure, but to some degree that future has already arrived.

    The Blueprint of Life

    Human Genome Project researchers have done very little actual human DNA sequencing thus far, perhaps only about a million base-pairs of sequence. "That's nothing," translates Chris Martin, co-head of the sequencing group at Lawrence Berkeley National Laboratory's Human Genome Center.

    Nevertheless, researchers at genome centers around the country and abroad say they are ahead of schedule in completing a task nearly as important. In addition to sequencing the DNA of a number of lower research organisms, they are rapidly identifying unique genetic markers along the entire length of human DNA--the equivalent of mile markers along a highway--which facilitate the discovery of interesting new genes, including those associated with elusive human diseases.

    By most accounts, the sequencing technology has progressed over the past five years to the point where cost-effective sequencing of the 3 billion human base pairs over the next decade seems a realistic goal.

    Until the early 1950s, there was no consensus among scientists about what genes were even made of, though the concept of genes as a unit of hereditary information has been around for 130 years. In 1865, Augustinian monk Gregor Mendel published the results of his breeding experiments with peas that laid the groundwork for all of modern genetics.

    Using a series of elegant experiments, Mendel formulated a theory that genetic traits were passed unchanged from one generation to the next in units he named Merkmales (now called genes), and that each plant's characteristics depended on the interaction of two of these Merkmales, one inherited from each parent. He was able to show that a plant did not always reflect each trait it carried, but that the hidden trait would resurface in subsequent generations.

    These days, most college students of science begin cloning genes before they're of legal drinking age, and any intelligent high school kid can tell you why parents with brown eyes can have a blue-eyed child. (It's because the parents both carry a hidden copy of the gene for blue eyes, which is dominated by the gene for brown eyes. The blue-eyed child thus inherited a copy of the blue-eye gene from each brown-eyed parent.)

    In the 1940s, however, scientists knew only that chromosomes carried hereditary information. While a few had suggested that DNA might be the molecule of heredity, the theory wasn't widely accepted. DNA consists of a backbone of sugar-phosphate molecules, each bearing a "base"--abbreviated A, T, G, or C for adenine, thymine, guanine or cytosine--and many scientists questioned the ability of a molecule with such a limited number of building blocks to beget the vast diversity of proteins present in human cells. Proteins themselves were seen as a more likely candidate for storage of genetic information, since they are made of 20 building blocks known as amino acids.

    But the world of science was turned on its head in 1953 when a pair of Cambridge researchers, Francis Crick and James Watson, made the most important discovery since quantum mechanics and relativity. They used models and X-ray diffraction studies to demonstrate that DNA has a double-helical structure, a theory that immediately suggested how the molecule might reproduce itself by using one strand as a template for synthesis of the other. Their theory was soon verified by other researchers, and DNA was widely accepted as the blueprint of life.

    Uncharted Territory

    When first proposed during the late 1980s, the genome project generated considerable controversy within the scientific community. Because most basic research in the United States is funded by the federal government, many investigators considered the project "Big Science," which would drain federal funds away from their smaller projects.

    Some scientists also questioned the wisdom of sequencing the entire genome when only a very small portion, maybe 5 percent, is believed to be code for human proteins. A large percentage of human DNA consists of repetitive sequences, considered by many scientists to be "junk"--uninteresting, probably nonfunctional evolutionary remnants that would be a waste of money to sequence.

    Some scientists argued for construction of a lower-resolution road map of the genome, which would allow researchers to find genes of interest, and urged that only regions of chromosomes believed to be biologically important should actually be sequenced. "I am particularly uninterested in the sequence of the entire human genome because I believe that level of detail is not very useful," proclaimed Nobel laureate David Baltimore at a 1992 roundtable discussion to discuss the merits and drawbacks of the project.

    Human chromosomes, however, are still largely uncharted territory in which gene hunters expect to find the unexpected. "There's an awful lot of biology we don't understand yet," says the Lawrence Berkeley's Chris Martin. "Not only do we not have the answers--we don't even know all the questions. Having a pure and full catalog of the information is what I think should be available to researchers, just like if I wanted a comprehensive dictionary, I want the whole thing, not just what someone else says are the important words."

    Genome researchers, who have so far been given about $928 million toward their task, believe the project is cost-effective, despite the price of sequencing the so-called genetic garbage. According to Dr. Rick Myers, director of the Human Genome Center at Stanford University, the cost per base when a small lab sequences a gene is about $5, compared to the genome project's current cost of about 50 cents per base. Ultimately, Myers says, the cost should drop to about 10 cents per base at the big centers with improved technology.

    Since individual academic labs receive most of their money from the federal government, up-front investment in the genome project will ultimately save the government money, genome researchers say. "As long as biology is there, people are going to find new genes and sequence the genome in bits and pieces," argues Dr. Mohandas Narla, director of the Human Genome Center at Lawrence Berkeley National Laboratory, "so all this is really going to do is really get all that information in one chunk in a very comprehensive way. The genome project will be done one way or the other--in small-scale cottage industry or at five or ten centers around the world."

    Myers adds that the initial dissent from the biological community has largely died down as useful data from the project has become available. In addition to human DNA, researchers are sequencing the DNA of commonly used research organisms--fruit flies, yeast, the plant Arabidopsis, the roundworm C. elegans, numerous bacteria and the mouse (a project nearly as extensive as the human genome).

    "Even people who were skeptical have benefited so much," he says. "The yeast community, for example, will have their yeast genome available completely by the end of the year. Worm and fruit fly are being sequenced, and the human genome project has huge numbers of markers and maps."

    The genome project will also benefit society at large, scientists say. The discovery of a disease gene is often a first step to understanding and treating the disease. With a gene on hand, researchers can determine the sequence of amino acids in the protein and conduct other experiments that may provide clues about protein function. Knowledge of how the protein works can be crucial in designing a treatment.

    The completed human DNA sequence will also be a potential gold mine for companies searching for new treatments. "It's hard to believe there won't be significant new drugs coming out significantly sooner because of [the genome project], and these drugs are worth $500 million a year in sales," says Martin, adding that the project's goal is certainly not to make a bunch of companies rich. "The project is likely to pay for itself with the lives of the people who survive because of the ability to be treated."

    Not everyone, however, is in it for love of science and humanity. Human DNA sequences have already been the focus of more than a few patent skirmishes. Although some genes have been patented by industry and academia, many scientists believe it's only kosher to patent a gene whose function has been determined, or to patent a product that uses a DNA sequence in a particular way. Unknown sequences are considered public property.

    Former NIH researcher J. Craig Venter came under fire from his peers by breaching this understanding. In 1991, Venter attempted to patent some 2,500 DNA sequences--not genes necessarily--that he had isolated without any knowledge of their function. The scientific community cried foul and the patent application was ultimately withdrawn by the NIH amid the controversy. Venter moved on to the private sector, where his sequences are now being used by industry scientists.

    "The idea that someone should get a blanket patent for a sequence is distasteful," Myers says, reflecting the view of many of his colleagues.

    Biology by Computer

    In the current practice of molecular biology, individual researchers routinely sequence regions of DNA they find interesting and enter the results into a computer database accessible to scientists worldwide.

    The availability of this genetic database has changed the way people do science. When a researcher isolates, say, a mutant fruit fly gene that causes the fly to grow an extra set of wings, one of the first orders of business would be to sequence the DNA and compare it to other sequences in the database. Similarity to a known gene from another species could offer some insight into how such a gene might function on the molecular level. For this very reason, in fact, the genome project aims to sequence not just the human DNA, but also the DNA of commonly used research organisms.

    In computer-assisted biology, a scientist might isolate a human disease gene, then use the database to find a similar gene in fruit flies and conduct genetic and biological experiments in the lower organism to try and figure out better how the gene works. A common tactic is to see what happens when extra copies of the gene are inserted into cells, or to remove the gene and see what happens to the organism. Another option is to look at where the protein product of a gene is expressed or to determine whether the protein associates closely with other known proteins. Once more is understood on the molecular level, a researcher might turn to the mouse system to look at physiological questions more relevant to humans.

    One investigator in the Boston area isolated genes for DNA repair proteins in baker's yeast that were similar to genes associated with colon cancer in humans. "You can work with millions of individuals in some organisms and you can only work with a few in others," Martin notes. "There's obviously a lot of things you don't do using people as experimental organisms."

    Martin believes the genome project will not only make the database far more complete, but also more reliable. "The average quality in the database is hampered because you have all these new graduate students just learning how to do it and so if you look at the database there's lots of pieces of vector and things backwards and stuff. The genome project wants to get things in place for some pretty uniform quality control," he says.

    The availability of the sequence information from humans and common research organisms, researchers say, will spare individual labs the tedium and expense of locating, cloning and sequencing a gene of interest, thereby allowing scientists to really buckle down and study the interesting biology. "Now people will get their claim to fame not by cloning and sequencing a gene, but by doing functional studies to find out how it works," Myers says.

    The 7-Eleven Diagnosis

    There is little doubt that medical science will be accelerated by the genome project, but the unanswered question is how the results will be used. Even as the project uncovers clues about human diseases, new understandings may begin to emerge about complex traits--hair, eye and skin color, physical size and strength, intelligence, perhaps even sexual preference.

    While custom babies are a long way off, termination of pregnancy based on "undesirable" traits or disease risk is already a real issue--one that promises to become more prominent.

    "I think the eugenics concern is very valid, because eugenics can be used as an argument for cost containment," says Sylvia Spengler, a physicist and director of Lawrence Berkeley Lab's ELSI program--a division of the genome project dedicated to studying ethical, legal and social implications. "Individuals or society makes the decisions about what is 'good' and what is 'normal' and you can imagine, in the presence of insurer-provided medicine or universal health care, that if you knew a fetus was likely to be hit with a genetic disease early on and the recommendation was to terminate the pregnancy and the family refused, the medical provider may say, 'Then we can't provide health care, period.' "

    Discrimination in health care coverage, however, is probably a greater worry, as it has the potential to affect virtually everyone. In a recent lecture, genome researcher Ray Gesteland, chair of the University of Utah's Department of Human Genetics, publicly envisioned a future where a person might go into a 7-Eleven, donate a drop of blood, and ten minutes later receive a computer printout of his or her genetic predisposition to the top 50 human diseases.

    Once tests become available to determine whether a person carries a gene associated with any of hundreds--or even thousands--of poorly understood genetic diseases, might not this information be used against them by employers or health insurers? Unfortunately, the answer is yes. As parient advocates attest, those with family histories of genetic diseases already face discrimination, even if an individual is merely a carrier of an abnormal gene and shows no disease symptoms.

    Recognizing the potential dangers, the funding agencies for the genome project--the National Institute of Health and the Department of Energy--took the unprecedented step of setting aside 3 percent (DOE) to 5 percent (NIH) of their genome budgets to study these societal issues. With the help of social scientists, philosophers and policy experts, ELSI's goal is to get laws in place to protect privacy and prevent discrimination based on a person's DNA content. While ELSI's allocation may seem trivial, genome leaders say the expense of running a scientific laboratory full of expensive equipment and bio-chemicals dwarfs that incurred by the "softer" sociological and policy studies.

    Some social scientists, however, see ELSI's allocation as insufficient. "The assumption behind the project is that scientific discovery is 97% of the problem while dissemination and consumption is a very small issue," proclaimed UC Berkeley sociologist Troy Duster at a 1992 ELSI Working Group meeting. "But since every society is complex and stratified, the rosy picture of people receiving and responding to genetic information without regard to their strong social differences is untenable."

    A example of current misuse of this kind of information has been suggested by Sue Levi-Pearl, scientific liaison for the Tourette Syndrome Association and member of the ELSI task force on insurance, whose observations were published in a 1992 report on the genome project from Los Alamos National Laboratory. Her words underscore ELSI's importance. "Recent data suggest that the vast majority of those affected [with Tourette syndrome] have mild cases and never require medical attention," she said. "Yet the typical profile of someone with a confirmed diagnosis is an employed, healthy person in his mid-20s who takes an inexpensive generic medication--and still cannot obtain health insurance. The two-word explanation for denial of coverage is 'Tourette syndrome,' and that's it. I can testify that our organization, TSA, receives scores of such reports every day.

    "Do insurers understand the variable expression of Tourette syndrome? Absolutely not," Levi-Pearl continued. "People with poorly understood genetic conditions are often rendered uninsurable because an insurer suspects the possibility of significant medical expenses."

    An Era of Unconfidentialty

    Even with new laws on the books, however, it may be difficult to keep information about a person's genetic predisposition from eventually reaching the insurance industry, particularly with health maintenance organizations, where insurer and health-care provider are one entity. And once the industry lays hands on sensitive information that may or may not be relevant to a person's actual health status, how can society prevent companies from discriminating based on that information?

    "That's the problem," Spengler says. "Large medical databases make almost anything about any of us very unconfidential. If the genome project heightens that concern in the public, that makes me happy, because even now the amount of medical and other information people can get about you is stunning.

    "If enough people were concerned," she continues, "there would be some legislation. Right now, there are small voices here and there and it's very hard. We can make recommendations and model privacy laws and all the rest, but the reality is, the people have to support those."

    Like Utah center director Gesteland, Spengler foresees a future filled with tests for various genetic diseases, a development she says society will need to handle with care. "People won't have the vaguest idea of how to handle the information, because in reality, even if you carry the gene for a disease state, what affect that has on your own personal health can vary from almost nothing to major. We are still at the level of not knowing much about even single-gene diseases and how they are expressed."

    Misuse aside, the presence of new tests for genetic predisposition raise further ethical questions among health practitioners. "Huntington's disease is a dominant disease with no treatment," says Stanford's Myers. "People with the mutant gene have a 50 percent chance of developing it. The personal decision alone of whether you want to know that is a big deal. There's no right or wrong sometimes. I think the researchers are very aware of the issues arising, and many are working to assure the information is used properly."

    Spengler says a March of Dimes survey conducted in the early 1990s convinced her the public was naive about the dangers of the brave new world coming down the pike. "In that case, people had no qualms at all about their employers or anyone else knowing their genetic histories," Spengler says. "I think that was what raised the red flag for me about how important education was. The moment you have a history of a genetic mutation in your family, your answers change drastically."

    As the genetic code rolls into the public databases over the next decade, accelerated by the genome project, society can expect to grapple with these and other, unforeseen, social problems borne of the new biological knowledge. Consider it the price of progress.

    "My only hope is that there will be really good social scientists and philosophers that have open discussions and recommend some good public policy that Congress and society will accept," Mohandas Narla says. "It's not going to be easy, but we have no choice."

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From the Dec. 21-27, 1995 issue of Metro

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