Germ-line gene therapy: Can we do it, do we need it, where do we start, and where might it lead?

Despite several setbacks, somatic cell gene therapy is finally beginning to record some solid clinical successes.¹ There is growing optimism that such an approach to the treatment of disease will indeed prove fruitful, and somatic gene therapies for a variety of disorders, both genetic and nongenetic, lethal and nonlethal, are at advanced stages of development. As this former frontier of genetic medicine becomes increasingly commonplace, the leading edge of novel therapeutic intent will continue to expand and challenge new boundaries. One of these, germ-line gene therapy, is already beginning to evolve, in certain quarters, from the realm of the undoable and unthinkable, to that of the possible and desirable. Indeed, it is increasingly suffused by an air of inevitability. This chapter, written during the early stages of this transition, examines whether intentional human inheritable genetic modification (IGM) is indeed scientifically possible and medically necessary, and attempts to identify clinical settings where it might be applied, both initially and ultimately. No attempt is made to address societal, moral, religious, or other nonscientific elements of IGM, which are dealt with elsewhere in this volume.