We are poised on the brink of a fabulous milestone in human history. Sometime late in the year 2000 or in 2001, the world's newspapers will run a banner headline proclaiming that the final base pair (chemical letter) in the human DNA sequence has been identified and placed in its proper place on one of the 23 chromosomes. We have already sequenced the first billion bases, and the pace is accelerating. Today, no gene can elude us. Indeed, shortly after the completion of the consensus sequence (the 3,000,000,000 or so bits of DNA information that make up a haploid human genome, the DNA in an egg or sperm), it will be available on CD-ROM and easily downloaded from the Net. It will take many decades to decode this wonderful molecular book, but it will be worth the effort. For in reading the text, we will learn a great deal about the evolutionary history of our species and gain insights into how individuals interact with the environment.

Think of our wonderful complexity! Each of us has about 100,000 pairs of genes, itself a number large enough to impress. Somehow, these genes are self-organized to operate and maintain our trillions of cells. At any given moment, each cell in our bodies is performing under the guidance of a particular subset of these 100,000 genes, while the rest are quiescent. Much of the beautiful mystery of human embryology lies hidden in the program by which—over just a few weeks—genes turn on and off to create our hearts, our lungs, and our brains.

Because I have been trained in law, genetics, and medicine, over the last few years I have been asked hundreds of times to talk with groups of non-scientists about human genetics. The task is formidable: In an hour or two or three, teach some basic facts about genetics, provide an accurate description of our scientific powers, pose some issues that will drive home the immensely important relevance of genetics to our lives, and critique our early, bumbling efforts to deal with those issues. Since most of the peo ple that I talk with (including physicians) have never studied genetics, and many lack confidence in their ability to learn science, I long ago realized that it is best to teach the subject in a painless way. I do this by telling stories.

There are really two books between these covers, one nested in the other. The obvious book is a collection of 24 stories about genetics arranged under six topics: history, justice, behavior, plants and animals, diseases, and ethical dilemmas. The historical figures include Abraham Lincoln, George III, and Nicholas II, the last Romanov tsar. Did Lincoln have Marfan syndrome? Should we try to find out? Does it matter? Did England lose its North American colonies because its king suffered from acute intermittent porphyria? DNA analysis has established to a certainty that a mass grave found in Yekaterinberg held the remains of Nicholas II and his family. What impact has that had on contemporary Russian society and on the Orthodox Church?

DNA evidence is having a profound impact on how we deal with crime. Today, the investigation of almost any crime assumes that there may be DNA evidence that will lead authorities to a suspect. To illustrate, I recount how a few cat hairs on a coat became the critical evidence in convicting the feline's master of murder. Impressed by the high recidivism rate among criminals, law enforcement officials have created a network of DNA databanks on convicted felons. In less than a decade, every state has set up, or has committed to set up, these banks, all of which will use a standard DNA testing technology developed by the Federal Bureau of Investigation. The public has paid little heed to this extraordinary development. How long will it be before the state routinely collects a DNA sample for identification purposes from all its citizens? Since we already conduct mandatory testing of infants for treatable genetic disease, it would be quite easy to save a drop of blood for such a databank.

Interest in using DNA evidence to solve crimes leads inevitably to the question of whether there are gene variants that predispose individuals to violent acts. This is an old fantasy. During the late 1960s, geneticists debated whether the presence of an extra Y chromosome predisposed men to violence. In the mid-1990s, researchers reported a family in which men with mutations in a gene that makes a brain chemical called monoamine oxidase were highly likely to commit violent crimes. How will our criminal justice system accommodate the discovery that certain people (albeit only a tiny fraction of all perpetrators) who commit crimes are biologically driven to do so? Will defendants someday be found to be not guilty by reason of genes? Will convicted felons undergo genetic testing as part of their evaluation for parole?

No field of science raises more troubling questions than behavioral genetics. With our new molecular tools we are already asking questions of immense societal significance: What role do genes play in predisposing a man or woman to schizophrenia or manic-depressive illness? Are there people in whom one could predict risk of such disorders? If a test were available, would you want your child tested to determine whether he carried an allele that predisposed him to schizophrenia? How would such knowledge affect how you and others perceived his potential or judged his mistakes?

If we succeed in finding genes that predispose to mental illness, can we hope to understand the role of genes in even more subtle topics such as the contours of personality? Geneticists are hard at work attempting to map genes that drive characteristic behaviors in different breeds of dogs. The results may present us with new and disconcerting insights into the impact that genes have on shaping human traits such as shyness and sociability. How might such information alter our understanding of human behavior? How might it affect theories of education? In 1994 scientists claimed that they had found a region of the X chromosome that contains a gene, a variant in which predisposes to homosexuality. Recently, similar research has refuted that finding. How strong is the evidence for a gay gene? What are the implications of the existence of such a gene variant? Should we even be investigating such questions? These are some of the issues that I explore in the chapters on behavior.

Part Four of the book looks at the impact that molecular genetics is having on our relationship with nature. Genetic engineering has given us a new dominion over the planet. Plant geneticists now transfer specific genes from one species to another almost at will. In the last few years, we have moved rapidly to end a chemical approach to controlling weeds and pests in favor of a genetic approach in which major crops are engineered to be resistant to a single powerful pesticide that eliminates the necessity for multiple sprayings. We are already growing millions of acres of genetically engineered soybeans. The yellow squash you will eat next week was probably grown from seed into which geneticists transferred a gene that confers resistance to the watermelon mosaic virus, which annually kills as much as a quarter of that crop. Many people have hailed genetically modified foods, but with growing zeal many more now vehemently oppose them. Do unknown dangers lurk in moving genes between species? Will feeding on genetically engineered corn pollen kill off the monarch butterfly? This is just one of many pressing societal questions that are exceedingly difficult to answer.

To feed 9 billion people (the projected world population in 2050), we will need to take a much greater percentage of our protein from the sea than we do today. Genetic engineering may well be the key to the "Blue Revolution." By tinkering with its gene for growth hormone, scientists have created salmon that grow to twice the usual adult weight during the first year of life. But there are unanswered questions. Have there been enough safety studies? Could we accidentally create superfish that, if they escaped their breeding pens, would forever change deep ocean ecology? I devote a chapter to discussing the advances and addressing the concerns.

Most of us readily agree that humans have failed to practice enlightened stewardship of the natural world, as is painfully obvious from the honor roll of species that we have extinguished. Genetic engineering raises exciting possibilities for repairing some of the damage by preserving endangered species, but it has raised a host of questions about the proper way to do so. Efforts to preserve the Florida panther, which I summarize in one chapter, force us to confront the ultimate preservation issue. Is it permissible to change a species to preserve it?

Nowhere is our growing power over nature more dramatically revealed than in xenotransplantation, the science of moving organs from one species to another. There is a major effort under way to genetically redesign pigs so that they can provide an inexhaustible reserve of needed hearts, livers, and kidneys. By moving human genes into pigs, we may be able to reshape the surface of their tissues so that our immune system will not recognize their organs as foreign when they are transplanted into our bodies. Ten years from now, several thousand people a year may avert kidney failure thanks to a genetically engineered organ harvested from a pig! What, if any, limits should be placed on xenotransplantation? Should we be able to do with cloned primates what we are currently trying to do with pigs? Does xenotransplantation carry a huge risk for humanity by permitting viruses that have for eons resided in pigs to take up residence in humans?

Twenty years ago, people thought that genetic diseases were rare, incurable disorders caused by mutations in genes that expressed themselves according to classic Mendelian principles of inheritance (dominant, recessive, and X-linked). Today, the term "genetic disease" is as likely to evoke thoughts about heart disease, mental illness, cancer, diabetes, or asthma, to name just a few of the many important disorders the onset of which is often influenced by a genetic predisposition. Advances in understanding the genetic component of human disease and how best to use that knowledge is a vast topic. To give the reader some sense of where we are headed, I have devoted chapters to one classic Mendelian disorder (cystic fibrosis) and two disorders for which in an important fraction of cases there is hard evidence of strong genetic liability—breast cancer and Alzheimer disease. The major focus here has been to explore the extremely difficult challenges of properly using genetic risk information.

About 1 in 25 white Americans carries a mutation in a cystic fibrosis gene. Scientists have designed extremely high quality, relatively low cost molecular tests to identify carriers. Should we provide universal premarital screening? By reviewing one's family history of breast and/or ovarian cancer one can estimate the likelihood that an individual will be positive if she undergoes DNA-based testing. Should the test be used more widely? How does one decide that question? How helpful is it to learn whether or not one is a carrier of a breast cancer gene or a gene variant that predisposes to Alzheimer disease? Should physicians or patients be in control of access to predictive testing?

Two of the questions that I have been asked most often in the last five years are (1) What is gene therapy? (2) When will it be available? People have been dreaming about somatic cell gene therapy—the correction of disease by delivering a normal gene to cells of affected individuals—for decades. Thus far, not a single cure can be claimed. Nevertheless, progress, especially in regard to developing effective ways to attach a payload of "healthy" DNA to viral rockets that will move on a biological trajectory to the nuclei of patients' cells, has been impressive. The tragic death in the autumn of 1999 of a young man after he had undergone gene therapy for a rare liver disease caused all involved in the field to reassess the status of our knowledge. I think it likely that we will develop effective gene therapies, particularly when the disease in question can be ameliorated by targeting a single, accessible tissue. For example, 10 years from now patients with cystic fibrosis might be treated effectively with "gene inhalers" (devices that spray a cloud of the normal version of the CF gene into the lungs), not unlike the way we treat asthma today.

The profound scientific and ethical questions in gene therapy arise when one contemplates germ-line genetic engineering—the alteration of germ cells to change the genetic constitution of an individual and his or her descendants. Thus far, scientists, religious leaders, and government policy wonks have all agreed that we should not undertake germ-line engineering. This is in part because they see it as a step toward genetic enhancement therapy, efforts to engineer embryos to be bigger, brighter, more musical, or whatever other dream one might have for one's kids. But interest in germ-line therapy will be impossible to contain if the technological hurdles are overcome. In 30 years or so, we will almost certainly have the capacity to genetically alter human embryos. What will this mean for society? Will it merely constitute the latest tool by which the upper tier of society maintains its economic lead over the lower quartiles? Or will it usher in deeper change?

In the last section of the book, I survey some key ethical dilemmas that have arisen and that will continue to complicate the implementation of advances in human genetics. At the moment, issues of genetic privacy are an overriding concern. State after state has enacted laws to limit the uses that health insurers may make of genetic information. Federal legislative interest is high. What is the crux of the issue? Who should have access to genetic information, and for what purposes may it be used? May a physician ever violate a patient's privacy to warn relatives about genetic risk? Under what conditions? Who decides? As genetic testing permeates medicine, will it change our ancient notion of confidentiality from one that is patient-centered to one that is family-centered?

After exploring the privacy debate, I take on two novel issues. During the 1990s there was growing concern for the moral and legal status of frozen human embryos. Throughout Europe and the United States there are tens of thousands of eight-cell human embryos suspended in tiny tubes immersed in liquid nitrogen. Although they were originally created to be implanted in an infertile couple, in many instances they are no longer wanted. What should be their fate if their "potential" parents die or divorce? Are frozen embryos people or property or something in between? Until quite recently, neither the parents nor the clinics had worked out a way to deal with such issues. How should their future be resolved when the couple from whose germ cells they were created divorce? How should the courts resolve such solomonic questions? I recount a fascinating, if painful, story about a divorce in which the only issue that divided the couple was control of seven frozen embryos.

No book about genetics could avoid discussing Dolly, the sheep created by cloning an epithelial cell from an adult sheep. How was this feat accomplished? How soon will we clone humans? What don't we know about Dolly? How old is Dolly? Although she was born in 1996, Dolly's progenitor DNA comes from an animal born in 1990. Rather than being young, she may be middle-aged! Is she fertile? Will she remain healthy? What threats, if any, does human cloning actually pose? Why is everyone so frightened by this prospect?

Throughout the last 50 years, genetics has labored under the shadow of the eugenics movement, a progressive idea that arose in late 19th-century England, took firm root in the United States, and became severely diseased in Nazi Germany. The old state-based negative eugenics programs—sterilization laws aimed at the mentally retarded, and immigration quotas targeted at those thought to be less genetically robust—have, thankfully, disappeared. But have they been replaced by a more subtle eugenics, one that is technologically enabled, physician-supported, and sought by couples as they plan their families? We now have the power to identify fetuses with birth defects in time to permit women to decide whether or not to abort them. As time passes, we will be able to assess fetuses with ever greater accuracy. What questions are the right ones to ask about human fetuses? What are the wrong ones? What does the advent of powerful screening tools that predict the future health or talents of individuals portend for how we view ourselves, our children, and fellow citizens with disabilities?

The other book, the one hidden inside the 24 stories, is a mini-genetics textbook. Every chapter contains important facts about genetics. For example, in the chapter on Abraham Lincoln I discuss a dominant disorder, Marfan syndrome, and introduce a powerful tool, the polymerase chain reaction. In the chapter on Toulouse-Lautrec I cover recessive disorders, consanguinity, and a rare genetic skeletal disorder called pyc-nodysostosis. In the material on mental illness I review the ups and downs of intense efforts to map a gene that predisposes to manic-depressive illness, research where claims of success have all too quickly given way to admissions of failure. To understand this story requires that one grasp the fundamental issues in gene mapping, a concept that is easy to master. I hope to teach some fundamental facts about genetics in a way that permits the reader to absorb them without effort.

The genetic revolution will be remembered as one of the great ascents of the human mind. We have started on a journey that will ultimately lead us to a world in which we will be able to influence our own evolution. This book, I hope, will give all who read it a deeper sense of where we are heading.

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