Designing Our Descendants: The Promises and Perils of Genetic Modifications

5 Germ-Line Modification in Clinical Medicine: Is There a Case for Intentional or Unintended Germ-Line Changes?

c h a p t e r f i v e Germ-Line Modification in Clinical Medicine Is There a Case for Intentional or Unintended Germ-Line Changes? R. Michael Blaese, M.D. During the past decade,a number of technical advances have reignited the need for thoughtful consideration of the issues surrounding human germ-line modification.The unexpectedly rapid progress by the Human Genome Project has put the sequence of the entire human genome within our grasp.1 Further, improvement in the techniques for somatic cell gene therapy2 has led inevitably to discussions of the use of this approach to treat fatal genetic conditions during intrauterine fetal life.3 In this chapter I discuss some of the technical issues facing the potential intentional application of germ-line gene modification and provide a contextual framework for discussion of the implications of germ-line changes that may occur as an unintended consequence of medical therapy. Proposed Clinical Indications for Germ-Line Modification From the perspective of potential clients requesting germ-line modification (GLM),what might they want to accomplish by using this technology? The obvious answer is to predetermine part of the genetic inheritance of their offspring.Most frequently this question is raised by potential parents who wish to produce offspring free of a particular genetic disease for which their carrier status has been confirmed. It is easy to sympathize with the desire of the parents of a child suffering from a serious genetically based deformity or disease that they not pass this same disorder along to additional children. Disorders most frequently cited as candidates for germ-line intervention are those affecting multiple body systems (e.g., cystic fibrosis) or those disorders that are widely distributed in the body (e.g., Duchenne muscular dystrophy). In addition , genetic disorders that lead to fetal death (e.g., alpha thalassemia) or lead to defects that are irreversible by the time of birth (e.g., anencephaly) would be potential candidates for this type of treatment. The issues become much more difficult when the genetic modification proposed does not involve prevention of an obviously serious medical disorder but rather would enhance physical characteristics,intelligence,or other traits that the potential parents might find desirable. Several of the other contributions to this volume discuss in detail the issues of genetic enhancement and the definition of disease. The arguments in this chapter are restricted to the use of these technologies for the treatment of lethal or seriously disabling diseases that cannot be effectively treated by traditional medical therapy. Reproductive Options Available to Carriers of Serious Genetic Disease What options are currently available for carriers of serious genetic mutations wishing to avoid having a child suffering from an inherited disease? One obvious option is for the couple not to conceive additional children. If they are determined to have additional children, there have been two options available. One involved genetic testing of the fetus followed by selective termination of the pregnancy if the fetus was found to have the disorder in question. The second more recently available option involves IVF (in vitro fertilization) with preimplantation genetic diagnosis performed on early eight-cell embryos and then selective implantation of an unaffected embryo.4 A third option has recently been proposed that would use the techniques of somatic cell gene therapy to treat an affected fetus in utero to correct the genetic disorder before fatal or irreversible defects develop.5 This type of intervention might carry with it the possibility for introducing the same genetic modification into the developing reproductive tissues of the treated fetus and thus unintentionally modify the germ line. Germ-Line Modification in Clinical Medicine 69 Another proposal would be to somehow treat the potential parents to modify their reproductive tissues (in vitro or in vivo) so that their sperm or ova would not contain the disease-causing gene of concern. This would be GLM at its most basic level and would be the only way for a couple to parent diseasefree offspring in the improbable scenario that both prospective parents were homozygous for a disease-causing recessive gene or when one was homozygous for a dominant disease-causing gene.Although this theoretical scenario has often been raised, if such gene carriers had reached the age when they were seriously contemplating having children and were sufficiently...