Designing Our Descendants: The Promises and Perils of Genetic Modifications

6 Gene Repair, Genomics, and Human Germ-Line Modification

c h a p t e r s i x Gene Repair, Genomics, and Human Germ-Line Modification Kenneth W. Culver, M.D. The initiation of numerous human somatic cell gene therapy experiments, the identification of scores of human genes,the recent growth of human stem cells, and progress in animal germ-line modification—all point to the likelihood of an eventual attempt at germ-line modification in humans. Under what circumstances would the accumulation of scientific information support intentional human inheritable genetic modifications (IGM)? While these recent technological advances have forced increased discussion of this question, it is precisely the knowledge gained from these technologies that will provide the basis to proceed with human IGM. The purpose of this chapter is to review key technologies that will support the initiation of human IGM and to propose a paradigm for building a foundation of confidence that IGM in humans will be successful. Major Scientific Obstacles to Human IGM Application Traditionally, there have been two major unresolved scientific safety questions in the realm of IGM technology. First, would the gene transfer methods mutate or perturb the genome, resulting in undesired inheritable consequences? This issue is particularly important for gene transfer because in this process viral and nonviral vectors are adding DNA to the genome to achieve permanent correction. A further complication is the fact that the addition of this extra DNA in the genome may occur randomly, potentially affecting other genes. The second question is, could scientists know enough about the functions of genes before these manipulations to be certain that successful correction of the gene would not have associated though unintended detrimental genetic effects? With more than 3 billion nucleotides in the human genome, the alteration of one can result in effects ranging from no consequences to severe, life-threatening effects.Therefore,a detailed understanding of the effects of any IGM procedure on the genome is essential. Satisfactory resolution of these key scientific issues must be achieved before intentional IGM is attempted in the human germ line. Reaching this level of scientific sophistication and understanding will unquestionably require the development of new, improved technologies beyond gene transfer concurrent with open public discussion. The goal of this chapter is to outline two important advances, gene repair and genomic technologies, which have moved scientific capability substantially forward , each having the potential to address one of the two major concerns adequately . A Paradigm for Proceeding with Intentional Human IGM With our present understanding of the genetic basis of disease in the context of our current technological capabilities, it is possible to construct a process by which the two major scientific obstacles to human IGM can be resolved, thereby allowing for initiation of intentional IGM in humans. This process would consist of three requisite aspects: technological advances and considerations , preclinical studies/safety assessments, and the selection of disorders for initial clinical application. Continuing technological advances are arguably the primary driving forces behind constant progress in improving the quality of clinical medicine. Therefore , it is not surprising that recent scientific progress in gene therapy research, notably new possibilities for gene repair, may reduce scientific barriers to human germ-line intervention. These new oligonucleotide-based technologies differ from traditional gene therapy (i.e.,gene transfer) in that they“repair”the mutation instead of trying to compensate for lost gene function.No extra DNA 78 Kenneth W. Culver is expected to remain permanently in the cell beyond what is considered to be the “nonmutant” or “normal” sequence. Another advantage of the gene repair approach over gene transfer is related to the need to control gene function. If one transfers a new copy of a gene into a cell (gene transfer), it typically must be accompanied by another gene to regulate its function. However, in the case of mutation correction, the regulation of gene function is maintained by genes already present in the cell and is not dependent on newly inserted genetic material. Therefore, the newly emerging field of mutation correction, or “gene repair,” with its improved benefit and safety aspects holds promise for treatment of inherited disorders due to speci fic, limited mutations. Since most disease-causing mutations are point mutations (i.e., only one chemical base is altered), gene repair technologies have the potential for very wide applicability for both somatic and...