GENETIC ENGINEERING, HUMAN

The development of recombinant DNA techniques in the 1970s enabled scientists to create genetically engineered organisms. In 1975 molecular biologists and geneticists held a conference in Asilomar, California, to discuss the biosafety issues relating to the new technology as well as policies for regulation and oversight. In 1978 fertility specialists used in vitro fertilization (IVF) techniques to assist a British couple in conceiving Louise Brown, the world's first "test tube" baby. In the early 1980s researchers began using embryo-splitting technologies to produce desirable livestock clones for agriculture. By the end of the decade universities and biotechnology companies were manufacturing and patenting transgenic mice for use in drug testing and medical research.

During the course of those events many people expressed concern that these discoveries and innovations eventually would lead to human genetic engineering (HGE). In early discussions of HGE (circa 1965–1980) scientists, journalists, and scholars conjured up the familiar allegories of Mary Shelly's Frankenstein and Aldous Huxley's Brave New World to question the wisdom of pursuing the new technologies (Gaylin; Boone). Science fiction novels such as Mutant 59 and The Boys from Brazil depicted the disastrous effects of genetic engineering experiments gone awry. The biotechnology critic Jeremy Rifkin (1983) warned of the Faustian bargain of genetic engineering and the dangers of meddling with nature. Theologians such as Paul Ramsey (1970) and bioethicists such as Leon Kass (1972) spoke about the dangers of "playing God" and disrupting family relationships. However, scientists, such as Joshua Lederberg (1966) and James Watson (1971) and philosophers such as Jonathan Glover (1984) and Joseph Fletcher (1965) embraced the possibilities of using HGE to advance scientific and social goals.

Two Key Distinctions and Four Basic Categories

While the public debate continued, scientists, clinicians, and scholars began to envision potential medical uses of HGE as they developed a framework for justifying the application of gene transfer technologies to human beings. Two key distinctions defined this framework: the somatic versus germline distinction and the therapy versus enhancement distinction (Walters; Anderson, 1985, 1989). Those distinctions implied four types of HGE:

Somatic gene therapy (SGT)

Somatic genetic enhancement (SGE)

Germline gene therapy (GLGT)

Germline genetic enhancement (GLGE)

Anderson (1989) and others argued that SGT could be justified on the grounds that it was morally similar to other types of medical treatments, such as pharmaceutical therapy and surgery. The goal of SGT is to transfer genes into human somatic cells to enable those cells to produce functional proteins in the appropriate quantities at the appropriate time. In 1990 the first SGT clinical trial involved an attempt to transfer normal adenosine deaminase (ADA) genes into patients with ADA deficiency, a disease of the imnune system caused by mutations that prevent the patient from producing sufficient quantities of ADA (Walters and Palmer). Because SGT targets somatic cells, it probably will not transmit genetic changes to future generations as a result of the fact that genetic inheritance in human beings occurs through germ cells. However, there is a slight chance that an SGT protocol will result in an accidental gene transfer to germ cells, and that chance increases as one performs the experiment earlier in human development. For example, SGT administered to a developing fetus entails a significant risk of accidental gene transfer to germ cells (Zanjani and Anderson).

The goal of GLGT, in contrast, is to transfer genes into human germ cells to prevent the development of a genetic disease in a child who has not yet been born. A GLGT protocol for ADA deficiency would attempt to transfer normal genes into the parents' gametes or a zygote so that the progeny would have the correct gene and therefore would not develop the disease. Because GLGT targets germ cells, it is likely to transmit genetic changes to future generations; therefore, it poses far greater risks than does SGT. According to many authors and organizations, SGT can be morally justified but GLGT cannot because it is too risky. Thus, many clinician-scientists who saw the promise of SGT attempted to draw a firm moral boundary between SGT and GLGT.

After the first SGT experiments began, many writers made the case for crossing the line between somatic therapy and germline therapy (Zimmerman; Berger and Gert; Munson and Davis). Those writers argued that some germline interventions are morally justifiable because they promote medical goals such as disease prevention and the relief of suffering. Most of the approximately 5,000 known genetic diseases cause disabilities, premature death, and suffering. Although couples often can use nongenetic methods such as prenatal genetic testing and preimplantation genetic testing to give birth to children without genetic diseases, for some diseases germline therapy offers the only hope of producing a healthy child who is genetically related to the couple. For example, if a male and a female are both homozygous for a recessive genetic disease such as cystic fibrosis (CF), the only way they can produce a healthy child is to use gene transfer techniques to create embryos with normal genes (Resnik and Langer).

Therapy versus Enhancement

Many of the writers, clinicians, and scientists who defended genetic therapy also had moral qualms about genetic enhancement. In genetic enhancement the goal of the intervention is not to treat or prevent a disease but to achieve another result, such as increased height, intelligence, disease resistance, or musical ability. Thus, according to many authors, there is a moral distinction between genetic therapy, which is morally acceptable, and genetic enhancement, which is morally unacceptable or questionable (Suzuki and Knudtson; Anderson, 1989; Berger and Gert). Until society achieves a moral consensus on genetic enhancement, HGE protocols should not attempt to enhance human beings genetically.

By making these two fundamental distinctions, SGT proponents were able to obtain public approval of and funding for SGT experiments and dispel some of the fears associated with HGE. Under this twofold classification, SGT experiments were ethical and should be conducted but others types of HGE experiments were unethical or at least ethically questionable and should not be conducted.

Whereas the somatic versus germline distinction has stood the test of time, the therapy versus enhancement distinction has been criticized (Juengst, 1997; Stock and Campbell; Parens; Resnik, 2000a). Some critics of the second distinction argue that many genetic enhancements would be morally acceptable. For example, some day it may be possible to transfer disease-resistance genes to human beings. If childhood immunizations, which enhance the human immune system in order to prevent disease, are morally acceptable, what is wrong with genetic immunizations? It also may be possible some day to manipulate genes that affect the aging process. If nongenetic means of prolonging life such as organ transplants are morally acceptable, what is wrong with genetic means of prolonging life?

Other critics question the cogency of the distinction because it is founded on the concepts of health and disease (Parens). Therapy is an intervention designed to treat or prevent disease; enhancement is an intervention that serves another purpose. However, how should one define health and disease? Several decades of reflection on these concepts have not solved the problem (Caplan). According to an influential approach, disease is an objective concept that is defined as a deviation from normal human functioning that causes suffering and places limitations on a person' s range of opportunities (Boorse; Buchanan et al.).

For example, CF is a disease because patients with CF do not breath normally. As a result, they have a variety of symptoms, such as shortness of breath and a persistent cough, which cause suffering and interfere with physical activity. CF patients also usually die many years before the normal human life span of seventy-plus years. Thus, a genetic intervention designed to treat or prevent CF is therapeutic.

However, this approach has some well-known problems and limitations. First, social and cultural factors play an important role in delineating the normal range of values that define disease. For example, dyslexia is recognized as a disease in developed nations because it interferes with reading, but it does not cause that problem in a nonliterate society. An adult in the United States who is shorter than four feet tall is regarded as having a disease—dwarfism—but the same adult living in an African pygmy tribe would be regarded as normal. Modern psychiatrists recognize depression as a mental illness, but it was regarded as a lifestyle or bad mood a hundred years ago.

Second, social and political values affect the range of opportunities in society and therefore have an impact on diseases; societies choose who will be disabled (Buchanan et al. 2000). For example, if a person has an allergy to cigarette smoke, he or she would have a difficult time breathing in a society in which smoking is permitted in public places. That person may become disabled, and his or her condition therefore would be a disease. However, that person would not have those difficulties is a society that bans smoking in public. The allergy would not prevent that person from working or participating in public activities. He or she therefore would not be disabled and would not have a disease.

Third, health usually is not defined as merely the opposite of disease. According to an influential definition of health, "Health is a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity" (World Health Organization [WHO]). This definition implies that some enhancements of human functioning are necessary to promote health because health is understood not only as the absence of disease but as an ideal state of functioning and flourishing. Thus, immunizations that enhance the immune system promote health, as do exercise regimens that enhance human musculature and endurance.

As a result of these and other problems with the therapy versus enhancement distinction, several authors have argued that it does not mark any absolute moral or metaphysical boundaries. One cannot equate therapy with morally acceptable or morally required, and one cannot equate enhancement with morally unacceptable or morally forbidden. To determine the moral justifiability of a genetic intervention in a particular case, one must assess that intervention in light of the relevant facts as well as moral values and principles such as autonomy, beneficence, and justice (Resnik and Langer). Some writers who criticize the distinction nevertheless maintain that it may be useful in setting an agenda for policy discussions or for raising moral warning flags (Buchanan et al.).

Inheritable Genetic Modifications

In the early debates about germline interventions most writers viewed GLGT and GLGE as methods for transferring genes to human germs cells such as sperm, ova, and zygotes or to human germ tissues such as the testes and ovaries. A human germline intervention would be similar to a genetic engineering experiment in a mammal in that it would attempt to transfer a gene into the DNA in the chromosomes in the cell nucleus. Writers on both sides of the GLGT debate agreed that random gene insertion would be an extremely risky procedure and that targeted gene replacement (TGR) would pose the fewest risks to progeny (Resnik, Steinkraus, and Langer).

Several important scientific and technical developments in the 1990s challenged this way of thinking about genetic interventions in the germline. In 1997 the experiment that produced Dolly, the world's first cloned sheep, demonstrated that nuclear transfer (NT) techniques could be applied to human beings (Pence). In this procedure one removes the nucleus from a zygote and transfers a nucleus from another egg or a somatic cell to the enucleated egg. The resulting embryo has a donor nucleus combined with the cytoplasm of the recipient. An NT procedure, like a GLGT procedure, produces inheritable genetic changes. However, an NT procedure does not attempt to modify human chromosomes. Since the early 1990s scientists and scholars around the world have had a vigorous debate about the ethical and social issues of human cloning (Kristol and Cohen). Several European countries, including Germany and France, have outlawed all human cloning. At the time of this writing the United States was considering a ban on human cloning, although no bill has been signed into law.

While the world was debating the ethics of NT, researchers conducted a more modest form of genetic manipulation in human beings: ooplasm transfer (OT). OT already has resulted in over thirty live births (Barritt et al.). In OT one infuses ooplasm (the cytoplasm from an egg) into a zygote. The resulting embryo has its original nucleus and a modified ooplasm containing ooplasm from the donor egg. OT also produces inheritable genetic changes because it modifies DNA that resides in the mitochondria: mitochondrial DNA (mtDNA). Because the mitochondria facilitate many important metabolic processes in cells, mtDNA plays an important role in cellular metabolism. Some metabolic disorders are caused by mutations in mtDNA. Less than 1 percent of human DNA consists of mtDNA; the majority of human DNA, nuclear DNA (nDNA), resides in the nucleus.

Although OT experiments and NT experiments do not appear to be as risky as experiments that manipulate human chromosomes, they are not risk-free because they can result in a mismatch between nDNA and mtDNA known as hetereoplasmy, which can affect the expression of both nDNA and mtDNA (Resnik and Langer; Templeton).

Artificial chromosomes pose an additional challenge to the earlier paradigm because they would not modify the chromosomes but would carry genes on a separate structure that would be segregated from the chromosomes (Stock and Campbell). One reason for developing artificial chromosomes is to avoid tampering with existing chromosomes. However, because an artificial chromosome could carry dozens of genes, it would transmit genetic changes to future generations.

As these developments unfolded, scholars discussed ethical and policy issues related to NT, OT, and artificial chromosomes (McGee; Bonnickson; Pence; Robertson, 1998; Stock and Campbell; Parens and Juengst; Davis). Some writers suggested that it would be useful to develop a typology for different interventions in the human germline to allow a distinction between various techniques, procedures, and methods (Richter and Baccheta; Resnik and Langer). For example, some techniques, such as TGR, attempt to modify the nDNA in human chromosomes. Other procedures, such as OT, attempt to change the composition of mtDNA. One could classify these procedures according to the degree of risk they entail, with OT being low-risk and TGR being high-risk (Resnik and Langer).

In light of the scientific, technical, and philosophical developments that occurred after the early discussions of germline interventions, in 2001 a working group convened by the American Association for the Advancement of Science proposed that people use the term inheritable genetic modification (IGM) instead of GLGT or GLGE because it provides a more accurate description of the techniques and methods that have been the subject of so much debate. According to the working group, IGM refers to "the technologies, techniques, and interventions that are capable of modifying the set of genes that a subject has available to transmit to his or her offspring" (Frankel and Chapman, p.12). Under that definition, TGR, OT, NT, and the use of artificial chromosomes all would be classified as types of IGM. IGM could include methods that are used to treat or prevent diseases as well as methods intended to enhance human traits.

Arguments for and against IGM

There is not sufficient space in this entry for an in-depth discussion of the arguments for and against applying IGM procedures to human beings, and so the entry will provide only a quick summary of those arguments (for further discussion, see Resnik, Steinkraus, and Langer; Walters and Palmer; President' s Commission; Holtug).

ARGUMENTS FOR IGM. The following arguments have been made in favor of IGM.

1. IGM can benefit patients by preventing genetic diseases as well as the disability, pain, and suffering associated with those diseases (Zimmerman; Berger and Gert; Munson and Davis). IGM also can benefit patients who will enjoy the effects of enhancements of health, longevity, intelligence, and so on (Stock and Campbell; Glover; Silver).
2. IGM can benefit parents by enabling them to have healthy children who are genetically related to the parents (Zimmerman; Robertson, 1994).
3. IGM can benefit society by reducing the social and economic burdens of genetic disease. Society also can benefit from IGM if enhancements of human traits increase human knowledge, productivity, performance, aesthetic experience, and other social goals (Harris; Silver).
4. IGM can benefit the human gene pool by enabling society to promote "good" genes and weed out "bad" genes. For a critique of this argument, see Suzuki and Knudtson (1989).
5. Parents have a right to use IGM to prevent genetic diseases and promote the overall health and wellbeing of their children (Robertson, 1994).

ARGUMENTS AGAINST IGM. The following arguments have been made against IGM.

1. IGM can cause biological harms to patients that result from genetic defects caused by IGM procedures, such as underproduction or overproduction of important proteins, the production of a protein at the wrong time, and the production of nonfunctional proteins. Although some procedures, such as OT, are safer than other procedures, such as TGR, IGM entails many risks that scientists do not understand fully (Resnik and Langer). IGM also could cause psychological harms to patients, who may view themselves as products of their parents' desires or as mere commodities (Kass, 1985; Andrews).
2. IGM could cause harm to a mother who carries a genetically modified child. For example, IGM might carry an increased risk of preeclampsia or complications during labor and delivery.
3. IGM could harm future generations. Because some genetic defects may not manifest themselves until the second or third generation, it may be difficult to estimate the potential harm to future generations (Suzuki and Knudson).
4. IGM could harm the gene pool by reducing genetic diversity, which is important for the survival of the human species (Suzuki and Knudston). For a critique, see Resnik (2000b).
5. IGM could cause harms to society, such as the increased social and economic burden of caring for patients with genetic defects caused by IGM, increased discrimination and bias against racial and ethnic groups and people with disabilities, the breakdown of the traditional family and traditional methods of reproduction, the loss of respect for the value of human life as a result of treating children as commodities, and the loss of human diversity (Kass, 1985; Kitcher; Kimbrell; Parens and Asch; Andrews, 2000).
6. IGM could waste health-care resources that could be better spent elsewhere (Juengst, 1991).
7. IGM could violate the rights of children, including the right not to be harmed, the right to an open future, and the right not be the subject of an experiment (Kimbrell; Andrews, 2000; Davis; McGee; Kass, 1985; Resnik, Steinkraus, and Langer).
8. IGM subverts natural reproduction and the natural human form (Rifkin; Kass, 1985). See Resnik, Steinkraus, and Langer (1999) for a discussion of this argument.
9. IGM is a form of "playing God" because people do not have the wisdom or the authority to design themselves (Rifkin; Kimbrell; Ramsey). See Peters (1997) for a critique of this view.
10. IGM is the vain pursuit of human perfection (Kass, 1985). See McGee (1997) for a critique of this view.
11. IGM is nothing more than a modern version of the eugenics movement (Kevles). It will repeat all the errors of the Social Darwinists and the Nazis (Kass, 1985). See Buchanan et al. (2000) and Kitcher (1997) for a discussion of this view.
12. IGM will cause social injustice by increasing the gap between the genetic "haves" and the genetic "havenots." See Buchanan et al. (2000) and Mehlman and Botkin (1998) for further discussion of this argument.

Policy History

Many governments, regulatory agencies, and international bodies have taken a dim view of IGM. In the United States the National Institutes of Health (NIH) formed the Recombinant DNA Advisory Committee (RAC) in 1975 to regulate and oversee recombinant DNA experiments supported by NIH funds. The RAC has the authority to regulate NIH-sponsored human gene therapy experiments, including IGM experiments. The RAC will not consider proposals for germline alterations because those procedures do not involve attempts to treat individual patients but instead involve attempts to change the genes passed on to future generations (Recombinant DNA Advisory Committee 1995).

The U.S. Food and Drug Administration (FDA) has the authority to regulate human experiments supported by private funds in the United States. The FDA sets ethical standards for human experimentation related to the development of new drugs, biologics, and medical devices. If a company wants to obtain approval of and market an item governed by the FDA, that company must submit data to the FDA that conform to its ethical guidelines. The FDA has stated that it has the authority to regulate human gene therapy as well as human cloning (U.S. Food and Drug Administration 2002a, 2002b). Although the FDA has not published a statement about its authority to regulate IGM, it would appear to have the authority to regulate any IGM procedures that involve new biologics, which could include human embryos. However, an important loophole in the FDA's regulatory authority is the fact that the agency does not have the authority to regulate assisted reproduction per se; it can only regulate drugs, biologics, and medical devices used in assisted reproduction. There are no federal laws and few state laws pertaining to assisted reproduction (Annas). It is possible that fertility clinics could perform IGM procedures such as OT or even cloning without any government regulation or oversight unless new legislation is enacted (Frankel and Chapman).

Outside the United States the Council for the Organization of Medical Sciences (CIOMS), the World Health Organization (WHO), and the United Nations Educational, Scientific, and Cultural Organization (UNESCO) have stated that the safety and efficacy of germline therapy must be evaluated thoroughly before any procedure takes place (CIOMS, WHO, and UNESCO). The International Bioethics Committee (IBC), sponsored by UNESCO, issued a report on human gene therapy that opposed germline manipulation at present as well as all forms of genetic enhancement (International Bioethics Committee). A group of advisers to the European Commission issued a report in 1993 that concluded that germline gene therapy is not ethically acceptable at the present time (Group of Advisors). Several countries, including Denmark and Germany, have banned germline gene therapy (National Bioethics Advisory Committee).

In the United Kingdom the Human Fertilization and Embryology Authority (HFEA) regulates and oversees IVF and infertility clinics. In 1998 the Human Genetics Advisory Commission (HGAC) and HFEA released a consultation paper opposing germline manipulation as well as cloning for reproductive purposes (Human Genetics Advisory Commission/Human Fertilization and Embryology Authority).

Professional societies also have not embraced IGM. The Council for Responsible Genetics (CRG), a genetics watchdog group, has opposed human germline engineering since the 1990s (Council for Responsible Genetics). The American Medical Association (AMA) does not oppose germline gene therapy, but it holds that genetic interventions should be limited to SGT for the present time. The AMA endorses genetic therapy but opposes genetic enhancement (American Medical Association). The American Society for Reproduction Medicine (ASRM) has not taken an official position on IGM but has called for a moratorium on NT until ethical and safety issues can be resolved (American Society for Reproduction Medicine).

Conclusion

It is likely that societies will debate the ethical and legal aspects of IGM for many years. The field of biotechnology is advancing so rapidly that interventions that were merely conceivable at the end of the twentieth century are fast becoming a practical reality. It is to be hoped that people will develop effective and well-balanced laws and policies pertaining to IGM before the first genetically engineered baby is born.

david b. resnik

SEE ALSO: Aging and the Aged: Anti-Aging Interventions; Enhancement Uses of Medical Technology; Genetics and Human Behavior; Health and Disease: History of the Concepts; Human Nature; Medicine, Philosophy of; Neuroethics; Transhumanism and Posthumanism

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INTERNET RESOURCES

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