Duke University Alumni Magazine

THE GENETIC REVOLUTION THE GENE TEAM BY DENNIS MEREDITH ILLUSTRATION BY RAUL COLON "This is a complex technology that will improve the quality of human life, but will also have some real problems, and we need to sort through these with precision, common sense, and care."

he woman, a Duke undergraduate, never expected to face a decision about her own life and death at such a young age. But instead of coping with the routine, even happy, exigencies of youth, two years ago she found herself trapped at the perilous, leading edge of the genetic revolution, facing an agonizing choice. She had undergone a new genetic test produced by the rush of progress in understanding breast cancer, and it revealed that she harbored the same faulty gene that had killed her mother and other family members through a predisposition for the disease. The same science had not yet yielded a certain cure, leaving her with the excruciating choice of whether or not to gamble on a drastic measure--a double mastectomy--now in an attempt to save her life decades in the future.

Kathy Rudy, who teaches a Duke course on reproductive ethics and genetics, knows this young woman as one of a growing number who are coping with such decisions in the face of uncertainty, as new genetic knowledge floods in from laboratories. "In twenty years, we could look at this glitch in history when we were doing horrible things to women's bodies, and we will be appalled that we did them," says Rudy, assistant professor of the practice in Women's Studies. "Or, such operations could be practiced regularly. It's hard to know what's going to happen."

The Duke student finally chose to have the mastectomy, a decision supported by a newly published study showing that 90 percent of at-risk women who have the operation do avoid breast cancer. While relatively few young people will confront their own mortality in such agonizing fashion, most will face a far more complex future world of genetic choices, both positive and negative. Rudy says her students reveal in classroom discussions that, as future mothers, they already expect to make far more deliberate choices about their offspring than could their own mothers. "Many of the students at Duke are very career-oriented, and although they want children, they only want one or two," she says. "They're very clear that, if they were having three or four, they wouldn't mind if one wasn't perfect. But because they really feel like they can only have one or two, they really can't afford to have a baby who has a lot of problems."

Over the next decade most of us will join Rudy's students in coping with the new choices of the genetic revolution. After all, scientists estimate that each of us possesses an estimated five to fifty abnormal genes that predispose us to some disorder--whether an obvious genetic disease such as sickle cell anemia or a subtler inherited tendency, for example, toward asthma from a sensitivity to air pollutants. Few of us realize how extensively our health depends on our genetic makeup, says Joseph Nevins, a Howard Hughes Medical Investigator at Duke and chair of Duke Medical Center's genetics department. "It's commonly said that virtually any patient who enters a hospital--other than from being run over by a truck--is there because of his or her genetic background. Even if you have an infection, the extent or the probability of that infection is influenced by your genetic makeup. If you have hypertension, it's influenced by your genetic makeup."

To geneticist Jeffery Vance, the solution to such quandaries is to speed the advance of genetic knowledge, not to wish for a retreat to simpler times. "In the near future, we will be faced with situations in which we will have such information but are not be able to do much about it," he says. Vance heads the molecular laboratories of Duke's Center for Human Genetics, which explores the genetic basis of diseases. "This is going to be a major source of conflict for those receiving the information. The answer, of course, is to move forward as fast as we can to get by this period, because we can't cure a disease until we understand it. Life deals you choices that are sometimes not the ones you want, but they are choices."

Nevins, Vance, and their colleagues believe such advances are guaranteed by the inevitable success of the massive federal and private research effort to sequence all 100,000 human genes by the year 2003. Both the federal Human Genome Project (http://www.nhgri.nih.gov/) and its corporate competitors, such as the privately held Institute for Genomic Research (http://www.tigr.org/) and Incyte Pharmaceuticals (http://www.incyte.com/), are cranking out masses of data on human genetic sequences. Once they complete their task, they will have published the contents of the entire genetic "instruction book" of human DNA. Scientists are exploring the huge volume of data so far, comparing normal genetic instructions with the "typographic errors" in genes that cause many diseases. And as this massive research effort continues to unfurl over the next century, this basic understanding will lead to cures or treatments for a stunning list of disorders--including cancer, heart disease, Alzheimer's disease, autism, asthma, muscular dystrophies, multiple sclerosis, Parkinson's disease, arthritis, psychiatric disorders, and many, many others.

Physicians will learn to treat these diseases using revolutionary techniques of "genomic medicine," in which they will pinpoint drug treatments based on a patient's specific sensitivities, as revealed by analyses of the patient's genes. This new approach will transform drug treatment from today's chemical equivalent of a general-purpose sledgehammer--with frequent unwanted side-effects--to a molecular scalpel that a physician precisely targets to an individual patient's disease.

Such potent discoveries will certainly bring major new problems. People seeking information about their odds of having a genetic disease could leave themselves open to discrimination by employers or insurance companies. Parents who can use gene therapy to avoid the risk of genetic disease in their unborn offspring may also demand "designer babies," featuring the latest fads in intelligence, hair color, or muscles. In fact, the population may become divided into what Princeton biologist Lee Silver dubs the "gen-rich" and the "gen-poor"--with the latter citizenry overburdened by genetic disease they cannot afford to treat.

Controversy will also arise from the profit motive that drives development of these new genetic treatments. Corporations, including both the smaller gene-sequencing companies and pharmaceutical giants, have already launched their lawyers on a genetic "land rush" to patent genes that might yield lucrative new treatments or other products. It's a multi-billion-dollar grab, with the government seeking to preserve human genomic data as a scientific "public park" for all to use as the basis for new diagnostic tests and treatments. Meanwhile, corporations seek to lock up choice stretches of genetic territory for their own commercial exploitation. Privacy and profit will also drive patients to assert legal rights to their own DNA or tissues, especially if those tissues hold the profitable key to treatment of a disease.

n facing such complications, perhaps the greatest mistake will be to oversimplify one's view of the genetic future, says Elizabeth Kiss, director of Duke's Kenan Ethics Program. "Many people, including popular writers, tend either to see this revolution as the Second Coming and to overlook problems; or to focus on the worst-case scenarios and see it as a Brave New World," she says. "I emphatically think it is neither of those. This is a complex technology that will improve the quality of human life, but will also have some real problems, and we need to sort through these with precision, common sense, and care."

While Duke has not been among the centers for sequencing the human genome, it is already a leader in searching for genes that cause disease, and in developing new tests and treatments. In the last few years alone, Duke scientists have made stunning discoveries about the genetic basis of Alzheimer's disease, heart disease, breast cancer, and many other disorders. They've also begun testing genetically engineered cancer vaccines, gene therapy for sickle cell disease, and genetic approaches to strengthen failing hearts. However, such a far-reaching revolution demands even more far-reaching responses from society's brain-trusts, the universities.

Chancellor for Health Affairs Ralph Snyderman began to conceive of Duke's response when he found the medical center caught between the promise of the genetic revolution and its profound quandaries. "On the one hand, some faculty had proposed that the medical center take a lead in developing a large-scale genetic screening program for high-risk diseases," recalls Snyderman. "They were also excited by the enormous potential of the Center for Human Genetics, with its databank of DNA of tens of thousands of families, to explore the causes of genetic disease. But on the other hand, faculty such as [medical ethicist] Jeremy Sugarman pointed out that nowhere in the country was there sufficient study of the implications--legal, ethical, and policy --to guide the proper use of these data."

The university administration was at the same time seeking ideas for initiatives that would be important enough to "transform" the direction of the entire university. A natural answer to both quests, Snyderman thought, was a university-wide Institute for Human Genetics that would forge links among many disciplines--and that would include scientists, engineers, lawyers, policymakers, ethicists, and theologians--to help enhance the benefits and solve the problems presented by the genetic revolution. What's more, no other university appeared to be contemplating such a broad-range program in genetics. Snyderman discovered that when he broached the idea with leaders in the field, including Francis Collins, who directs the federal Human Genome Project.

Other senior administrators, trustees, and deans enthusiastically supported the idea for the institute. And in a dramatic signal of the university's commitment, the administration designated more than $110 million from the $1.5-billion Campaign for Duke to support it. "Certainly, there should be scholars at Duke University who are looking into the causes of war, who help us understand political influences in human's behavior, who help us think about crime, and all the other macro issues," said President Nannerl O. Keohane at an October symposium, "Letting the Gen[i]e Out of the Bottle: the Impacts of Research on Twenty-First Century Life." The symposium, held on the occasion of the campaign launch, was aimed at introducing the institute and

its goals. Keohane told the audience, "If we can understand better some of the roots of human behavior in very specific genetic ways, as these factors move through psychology to economics and political science and sociology and history, we will have a better ability to answer the larger questions."

The new institute's leader arrived in January in the person of Edward Holmes, whom Snyderman recruited as the medical center's vice chancellor for academic affairs and medical school dean. Holmes also spent twenty-one years as a Duke faculty member, his last post as Wyngaarden Professor of medicine and chief of the division of metabolism, endocrinology, and genetics. He returned to Duke from Stanford, where he was senior associate dean for research, vice president for translational medicine and clinical research, and special counsel to the president. Newly arrived back at Duke, Holmes promptly put his mark on the embryonic institute by advocating that it be renamed the Institute for Genome Sciences and Policy.

"Genomics is a new way of thinking about doing biology," he explains. "Genetics implies to some people single-gene defects that cause disorders in humans, animals, or plants. Whereas, genomics implies looking at the entire genome--in the case of humans, all 100,000 genes at one time--and trying to understand how they work as a unit." Genomics also reflects the burgeoning power of the technology, says Holmes. "With new technology, we are now capable of looking at 10,000 genes at one time, and soon we'll be able to do more."

Holmes points out that such technological power affects the very scientific questions that scientists can ask. "For example, in studying cancer, you can isolate from a pathological specimen a single cancer cell and a normal cell sitting right next to it. And you can compare 10,000 genes expressed in the cancer cell with 10,000 in the normal cell and ask what they are doing. So now, you can explore entire molecular pathways, seeing how the cancer cell functions as a whole. It allows you to think of the cancer as a different sort of process from what we could before."

This "genomic way of thinking," says Holmes, allows profound new insights into the machinery of disease that will underpin the new era of genomic medicine. "Let's say I develop high blood pressure and you develop high blood pressure. But I get renal failure from high blood pressure and I lose my eyesight, but you don't. The difference between us is partly how some of our genetic differences at an individual level modulate how we respond to a disease that is not strictly a genetic disease."

The institute's new name also emphasizes its broad reach, says Holmes. He expects the institute to benefit from Duke's established strengths, not only in the medical center, but across the intellectual spectrum. He says the new institute must be far more than a research-oriented province of the medical center, but he also believes that it will depend considerably on the new Duke Health System for the vitality of its research component. The comprehensive system enables Duke "not only to provide better health care for people in the community, but also to carry out the kind of basic and clinical research represented by genomics. In more distributed health-care system, there's certainly a great deal of intellectual power. But they don't have an integrated health system that provides patients who are the critical basis for developing new treatments."

mong the new institute's many beneficiaries will be the Center for Human Genetics, a renowned medical center "detective bureau" that uses family histories, sophisticated genetic analyses, and high-powered computers to reveal the genetic origin of a wide array of disorders. In particular, the center is advancing from exploring apparent single-gene disorders such as the muscular dystrophies, to those that are far more subtle, such as Alzheimer's disease and cardiovascular disease. "Working with collaborators, we're tackling a whole new range of complex disorders that have a high genetic component, but also have multiple other causes such as environmental factors," says center director Margaret Pericak-Vance. According to Pericak-Vance, the center has launched studies of cardiovascular disease, osteoarthritis, asthma, prostate disease, Parkinson's disease, autism, schizophrenia, and depression, to name a few. "These diseases also affect a lot of people, making them good targets for therapy, which is why we're also collaborating with Glaxo-Wellcome."

That partnership, like other Duke corporate partnerships, is mutually beneficial, she says. While the company will have a chance to license new discoveries by the center for commercial development, center researchers will gain invaluable access to advanced analytical machines. "A company will have these state-of-the-art research machines, like a $300,000 DNA sequencer, that would be difficult to get government funds to buy. This support allows us to attack major health problems, such as the cancer syndromes and cardiovascular diseases."

Pericak-Vance looks forward not only to research support through the Institute for Genome Sciences and Policy, but also to institute-fostered public education and informed-consent policies that will encourage families to participate in studies such as those ongoing in the center. "I don't think everyone has made the connection between having their relatives in the hospital with a cancer that needs to be cured and the fact that this cure is not going to happen unless they participate in research studies. This is a team effort, with families working hand-in-hand with the research community."

Besides strengthening such existing research, the genomic institute will spawn radical new research facilities. For example, the medical center is planning to create a Center for Models of Human Disease--a sort of "mouse medical center" that aims to make the mouse a much more effective surrogate for human disease. Says genetics department chair Nevins, "We're aiming to utilize the mouse in a way much like human populations are studied to try to better understand more complex diseases, like diabetes, hypertension, and asthma." According to Nevins, the center will emphasize multi-gene studies that could have a profound impact on understanding of the subtleties of disease predispositions. "Let's say you've got a mouse genetic model for a form of cancer. Then, let's say that most humans who develop this cancer do so at age forty, but some develop it at age thirty, and others never at all. To study this variation in humans is very difficult. But with a mouse, we could mutate the basic mouse cancer model in a massive number of ways and screen for animals that get the cancer at different times. Then, we could pinpoint the subtle genetic factors at work and extrapolate to humans to better understand the complexity of the disease and to eventually lead to improved cancer treatments."

The center would include two basic components, says Nevins: a new mouse facility that incorporates research labs right into the mouse holding rooms, so that scientists can easily test the enormous numbers of mice needed for genetic screening; and a sort of "mouse clinic" where physiologists can develop new ways to measure the mouse as a full-fledged organism, just as physicians examine humans in diagnosing disease. These clinical measurements will range from the physiological, such as blood pressure, to the psychological, such as hyperactivity. "In other words, we want to treat the mouse as an organism, not as a bag of cells that one is going to analyze," says Nevins. "It's not going to be easy, both because the mouse is a very small animal and, obviously, because it can't tell you what it's feeling."

Engineers are also important contributors to the genomic revolution, says biomedical engineer Ashutosh Chilkoti, who advocates an expansion of such research at Duke. Engineering is critical to the development of so-called DNA chips, which consist of fingernail-sized bits of silicon that hold tens of thousands of DNA samples, allowing rapid analysis of large numbers of genes at once. "When most people think of genetic research, they think of diagnosing and treating disease, but there is a fair amount of physics, chemistry, and engineering behind genetics," says Chilkoti. "Sure, you can slap DNA onto a chip surface, but you need a whole science of physical chemistry and surface engineering to make it work right."

Scientists and engineers are already working to create technologies to make genetic analyses faster and cheaper by inventing a whole new generation of three-dimensional "labs-on-a-chip," complete with tiny pumps and reaction chambers. These chips could be used to analyze several hundred protein samples at once, says Chilkoti. "Such analyses are going to become increasingly important because, once we sequence the genome, we will have the genetic information for a lot more proteins that these sequences encode." Since proteins make up the cell's working machinery, scientists who want to understand that machinery's function will want to analyze the function of multitudes of proteins at once.

Chilkoti believes that engineers will play an important role in computer-modeling of cellular machinery. "When you consider a tissue or organ, you go from molecular interactions at the cellular level, to cells communicating with one another, and finally ensembles of cells that make an organ," he says. "Engineers are experienced at modeling complex systems. And as we discover more about the interrelationship between different genes and molecules and start to build up our knowledge of the network that is the body, you're going to have to model things on a very, very large scale."

Finally, says Chilkoti, engineers and materials scientists can play a key role in developing genetic therapies that involve inserting genes into cells. "If you want to get a gene into a particular cell, in most cases you have to package it to maximize the chances of it getting there and being incorporated. And there are also a whole host of transport issues, because it's not like the cell is hanging free in a bath of liquid. There are intervening tissues, so, from an engineering standpoint, a gene carrier has to travel through a very heterogenous medium." Engineers can also help develop new carriers for genes, he says, such as bubble-like fatty structures called liposomes and engineered viruses.

The Nicholas School of the Environment will be another key player in the new institute. Environmental genetic studies are particularly important in fostering a more accurate understanding of the old "nature versus nurture" debate over which is more important in shaping people, Dean Norm Christensen told the October genetics symposium. Historically, he said, the debate has been framed wrongly as "environment or genetics," with philosophers asking "to what extent is our behavior, our appearance, our tendencies toward ill or good health determined by the environment; or to what extent are these tendencies predetermined. Today we know that's far too simple a question; that...the expression of our genetic code is influenced by the environment," he said.

In linking nature and nurture, the Nicholas School is exploring how trace amounts of environmental contaminants can affect genes. "We know that these things, for example, can cause cancers, and those represent genetic changes," Christensen said. "What are the mechanisms? Why are some of us more susceptible than others? How do our systems repair themselves?" The Nicholas School is developing genetic methods of "environmental diagnosis," using mutations in the genes of fish and other creatures as supersensitive detectors of trace amounts of contaminants.

Besides rapid progress in the laboratory, the genomic revolution will bring major progress in the classroom to understand the revolution's implications. The Kenan Ethics Program has already launched an educational effort to explore ethical issues raised by genomics. Elizabeth Kiss and her colleagues have organized a genetics and ethics working group that, besides Duke, includes representatives from GlaxoWellcome, the North Carolina Biotechnology Center, the National Humanities Center, North Carolina State University, and the North Carolina School of Science and Mathematics. The group's meetings, Kiss says, are producing valuable dialogues about such issues as the control and uses of genetic information, the pros and cons of commercial development of genomic discoveries, and the challenges, real or perceived, that genomics poses for conventional ideas of free will. For example, corporate involvement in university research has raised, on the one hand, thorny issues of conflict of interest when academic scientists also work with industry. On the other hand, the corporate profit motive is the major force driving development of widely available treatments based on genetic discoveries. Without that profit motive, the genetic revolution would no doubt remain only a laboratory curiosity.

Kiss says that helping society cope with the genomic revolution will require higher levels of scientific literacy and greater familiarity with tools and insights from traditional philosophy and theology. "My sense is that the moral questions being raised by genetics aren't qualitatively new. People often say that cloning raises entirely new issues, and yet we have had clones since the beginning of time--twins. Similarly, we already have many ways of shaping our offspring, although genetics will dramatically increase our ability to do so. What we face with the genetic revolution are more pronounced, and more urgent forms of perennial ethical questions."

Unfortunately, the revolution now presents far more questions than answers, says medical center professor Jeremy Sugarman, who co-directs the Program in Medical Ethics. After he and colleagues Dirk Iglehart and John Bartlett convened a broad-based working group on ethics in genetics, Sugarman concluded that "we're like most if not every institution in the country doing cutting-edge research, in that there were no clear answers to the many quandaries that arise in the context of clinical care and research involving genetics."

Sugarman says ethicists have yet to sort out the implications of a person's participation in a genetics research study for that person's family. Also, there is a need for ethical analysis of the strategic decisions involving which diseases to tackle as research priorities. "Should we concentrate on rare conditions with obvious genetic causes or common conditions where the genetic components are a bit more nebulous?" he asks.

According to Sugarman, two particularly profound moral questions looming over genetic research are how to define a "disease" and whether to allow tinkering with "germline" cells--sperm and eggs--when those changes will reverberate down through generations yet unborn. So far, he says, gene therapy has been aimed at "somatic" cells--body cells--rather than reproductive cells. "We've held two big moral lines in gene therapy. One is to concentrate only on somatic, rather than germline interventions. The other is to focus on diseases and not traits. But distinguishing between a disease and a trait can be difficult. Do we call obesity a trait or a disease? We need to address explicitly and specifically whether we're going to hold these lines."

The genomic revolution presents immense challenges to science, technology, and ethics. But the befefits will be well worth the effort, Chancellor Snyderman told the October genetics symposium. "The aggregation of technologies that are now enabling us to identify and determine the structure and function of genes is the most powerful technology, with a potential impact affecting civilization, of any technology that has come before. Genetics is going to transform medicine, from an individual having a disease seeing a doctor--and presumably having the disease treated well--to the ability not only to prevent disease, but to predict it long before it comes."

However, said Snyderman, the revolution's most important ultimate impact may well be on our understanding of our own origins. "Some of the greatest questions that have been facing us as a species are, Where did we come from? What is it that created us in this form? How did we get to be the way we are, and where are we likely to be going in the future?" Scientists will answer these questions, says Snyderman, by exploring the broad sweep of genetics, from worms to humans. Their discoveries will allow us to understand for the first time how we managed to evolve from simple molecules floating in the primordial ocean to complex creatures advanced enough to take control of our own genetic destiny.