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.

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