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The November 22, 1994 issue of The Washington Post carried an editorial discussing molecular biologist John Fagan's announcement that he was returning $100,000 in federal research grants. In addition to turning down federal funding of his work, Fagan called on other scientists who were involved in genetic research to alter certain cells to do the same. He urged fellow researchers to join him in calling for a 50-year moratorium on the unfettered commercialization of poorly understood genetic discoveries and to refuse to engage in further basic research until society determined what processes and goals would characterize its oversight of this burgeoning industry.
Dr. Fagan's actions highlight the continuing tensions between, on the one hand, unrestricted freedom of scientific inquiry and the associated drive towards rapid translation of scientific discoveries into effective technology, and, on the other, the need for careful analysis of social and ethical issues arising from the application of these scientific discoveries. This tension is heightened by the torrential flow of new scientific insights that have accompanied the widespread use of recombinant DNA technology. This technology, now two decades old, has allowed scientists to wrestle secrets from human genetic material at a logarithmic pace. At the same time, there are numerous new ethical issues to be confronted -- issues that are emerging more slowly than the pace of scientific progress but in many ways are even more difficult to resolve than the purely scientific problems.
A striking example is the public attention given to the publication in a recent issue of the Proceedings of the National Academy of Sciences of an apparently pathbreaking set of experiments in which Ralph Brinster of the University of Pennsylvania successfully applied germ-line manipulation in experimental animals. It was Page One news in The New York Times (coincidentally, also last November 22) when Brinster reported the successful alteration of the genetic makeup of sperm in mice and the carryover of the altered genes to offspring of the original generation. One can anticipate the rapid extension of these experiments to other animal species, with work in humans not as far in the future as once had been imagined.
Such progress, however, can also have important consequences. Once a genetic manipulation is made and passed on, the change could enter the gene pool permanently. Thus, a genetic alteration made to correct a specific genetic defect in an individual of one generation, when passed along to the next generation, could cause a host of other interactions that may not be known or cannot be anticipated.
In a hypothetical example, let's assume that a germ-line intervention involving the alteration of a single gene could prevent chronic low-back pain. Let us further hypothesize that the successful genetic alteration in the form of the "corrected" or disease-free gene is passed on with the result that the threat of low-back pain in subsequent generations is removed. That's the good news; the bad news is that we do not know the consequences of the placement of the genetic material upon insertion and what other unanticipated results the inclusion of the altered gene into the gene pool might have on the recipients and their progeny. It is in this sort of intervention that there are very legitimate concerns about unintended and unpredictable consequences. The uncertainties lead some to suggest that informed citizens would be prudent to regard the genetic revolution as potentially as beneficial and dangerous to the human race as the advances in physics earlier in this century.
In order to focus attention on the most pressing social issues, we can make some general guesses and interpretations of where the science of genetics is and where it is going. There must, to be sure, be a significant level of personal interpretation in it, and any one of the points we make may well be challenged by one expert or another. Nonetheless, taken together, we may be able to stimulate the reader to think critically about the nature of the ethical and societal issues we confront at this stage in this fast-moving field of science.
The Human Genome Project in the U.S. and an analogous international effort based in western Europe were initiated five years ago. Their objective was to create a road map of each human chromosome, identifying the location of landmarks (much as one does from an aircraft) in order to facilitate more precise positioning of specific disease-connected genes in the total of 80,000 that make up the entire human genome. In the five years of effort, there has been enormous progress. The public is reminded almost weekly by newspaper reports of new genetic discoveries which are the fruit of the nation's investment in this effort. For example, an ever increasing number of tests are being made available that can determine an individual's genetic susceptibility or predisposition to certain heritable disorders.
The success and international cooperative nature of the project were underscored in September 1994 by the publication of a detailed linkage map of the human genome, which provides researchers with the capacity to find genes and to study possible disease-causing alterations, thereby meeting one of the project's goals a full year ahead of schedule. As Francis Collins, the current director of the National Institutes of Health's National Center for Human Genome Research, observes, "We can no longer say tracking down a specific disease gene is made difficult by lack of a good map. We have a good map."
Juxtaposed to such rapid scientific advance is the far slower progress in dealing with policy issues, though there, too, progress is being made. To illustrate the heightened awareness on the part of policy makers of the potential impact of the new genetics, a briefing was recently held on Capitol Hill. It featured two leading DNA researchers discussing the technology and social implications of DNA testing and screening, including the implications for privacy, insurance, health care and discrimination. The capacity in the short term to identify the genetic determinants of an increasing number of diseases and in the longer term to produce from a drop of blood, even before birth, a full-blown genetic map detailing the medical and health risks inherent in each individual has enormous implications in the way people think about themselves and the future.
The public is seeing the benefits of its multibillion-dollar genetic investments in an ever increasing cascade of genetic diagnostic and therapeutic discoveries which are tumbling weekly from our university, pharmaceutical and biotechnology research laboratories, with the diagnostic advances far outnumbering therapeutic ones. In general, we are in an age dominated by the diagnostic discovery and identification of the genetic roots of particular conditions. For example, a genetic test now can tell an individual whether he or she has the gene that will cause them to develop Huntington's Disease when they grow older. At the same time, we will probably have to wait for some years before an effective treatment can be developed. Thus, we are entering a time of some public frustration with the much-touted genetic revolution.
There have been a number of important discoveries, however, in which diagnosis and therapy go together. For instance, we can treat diseases that are caused by a single defective gene if the disease-causing gene can be replaced with a normal gene. The normal or healthy gene is added in laboratory cell cultures to somatic (germ-line) cells taken from the patient, as happened at the National Institutes of Health in one experiment in human gene therapy.
A young girl with a severe immune disease called adenosine deaminase deficiency (the absence of the gene for adenosine deaminase) was given a new gene. Since then, she has been sufficiently free of life-threatening infections so that she is now able to attend school. But because the cells used in the gene replacement have a limited lifespan, the therapy must be repeated throughout the girl's life. This is at present an extremely expensive form of treatment. One expert who recently estimated the annual costs of a number of currently available genetic therapies aimed at treating specific genetic diseases has come up with an estimated average of $50,000 per patient per year of treatment.
An effective curative treatment is available for Gaucher's disease, a rare familial disorder of lipid metabolism that is fatal at an early age. The treatment requires ongoing applications at a current cost of about $300,000 per patient per year. Obviously, as costs of these dimensions proliferate, treatment will increasingly raise issues of equity and justice in the allocation of resources unless improvements in therapy lead to dramatic reductions in cost.
Perhaps the greatest promise of a practical payoff of genetic research to date has come from DNA-based products of great diagnostic and therapeutic value in the field of cancer and in the design of new drugs. In this instance, the gene really amounts to a new drug. A variety of gene-as-drug approaches is being studied.
One approach is either to stimulate or suppress the action of defective genes. If the disease-causing gene relates to increased cell division, as in cancer, one might attempt to suppress its action. Another approach would be to use recombinant technology to stimulate the body's immune system so that a cancer is more effectively attacked and rejected. A third approach is to create a chemical that interferes with the processes that control the ability of cells to replicate themselves. Finally, scientists are using new computer-based design methods to develop drugs that bind to certain types of cancer cells and mark them for destruction either by the immune system or by attached toxic chemicals. The gene therapy we have discussed so far involves what are known as somatic cells, normal body cells that are not involved in reproduction.
Germ-line therapy -- that is, using approaches to alter reproductive cells like eggs and sperm -- is not presently being done in humans. However, if a defective germ-cell could be successfully altered by this therapy, the offspring would not inherit the disease. This would be of great benefit to families that carry diseases such as sickle-cell anemia, cystic fibrosis or Tay Sachs. However, if the therapeutic gene were to be inserted in the wrong place in a woman's egg cells, that error could bring about unanticipated ill effects and be passed on to the next generation. Thus, there are pros and cons to germ-line therapy that require understanding. Certainly, it is not something we should attempt before the technology is fully developed.
Finally, gene therapy might be used, not to cure a defective genetic disease, but to enhance some characteristic of the individual. No consensus in society exists at the present time on the social and ethical issues involved with gene-related enhancement techniques.
One could argue that controls on scientists are unnecessary because of the conventions and unwritten codes of behavior that scientists live by. But is that sufficient? The stem cells of bone marrow, from which all blood cells are made, have been available from mice for years. Recently, James Thomson and John Hearn of the University of Wisconsin isolated embryonic stem cells from rhesus monkeys. They are attempting to use these stem cells to stimulate the formation of many kinds of body tissues and to create genetically altered monkeys. The scientific methods once developed could then be used with humans. In another project last year, two scientists cloned cells from human embryos that were obtained from surplus embryos formed during in vitro fertilization, ignoring the unwritten code of conduct regarding human experiments observed by many in the scientific community. Such cloning is a technology already in use in animal husbandry where animals with identical genetic constitutions are produced in great numbers. Obviously, the specter of multiple identical copies of human beings raises the need to pay attention to the difficult issues involved in cloning.
Where is society in its consideration of these matters? Clearly much is owed to the wisdom and foresight of James D. Watson, the first director of the Genome Project, who set aside 3 percent of the project's total budget for the active analysis and consideration of the social, legal and ethical implications of the new research. As a result, a lot of information is available and a lot of thinking has been going on.
Internationally as well, there is grave concern about these matters. Germany, Austria, Norway, Switzerland and France have established firm legislative restrictions on germ-line therapy in humans. Other nations tend to be open to ongoing analysis and research.
In our view, the U.S. should act now to clarify its processes and establish the means of managing the genetic revolution to ensure that the new technologies benefit citizens who fund the research. In particular, we think that a better mechanism than now exists must be found for societal discussion and decision making that relates what can be done by scientists to the social and ethical issues raised by the new technology. This could be accomplished by enlarging the role of the Human Genome Ethical, Legal and Social Implications Working Group to develop a national policy agenda or by the formation of a national commission to debate the issues and to recommend future courses of action. Whatever the mechanism, it should be empowered with enough prestige and respect that its recommendations will be taken seriously by the public, the media, the Congress, the executive branch, and by the scientific and health care communities.
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