• A safe, reliable way of delivering genetic changes to a human embryo, and
• Genetic modifications so compelling that large numbers of parents will want them.

Until both exist an occasional rogue attempt to clone or genetically modify a child may occur, but responsible physicians will not apply this emerging technology to humans. Interestingly, the above two developments may be much nearer than many imagine. Recent work on human artificial chromosomes³ suggests it may soon be possible to reliably insert gene cassettes into them for injection into cells, including embryonic stem cells and eggs (Figure 1).

Figure 1. To do human germline engineering, specific gene cassettes and their regulatory sequences could be loaded at preset docking sites along an artificial chromosome.⁶

Click here to view large scale version of figure.

Figure 2. The below schema shows a two-gene cassette that might be inserted in the germline for possible use in fighting prostate cancer in an adult. Both genes would be controlled by a prostate-specific transcription factor and expressed only in prostate epidermal cells. Gene 1 codes for an ecdysone-dependent transcription factor that would allow gene 2, which codes for a toxin, to be expressed only in the presence of ecdysone. Were prostate cancer ever discovered, the person would take a dose of ecdysone to turn on gene 2, thereby releasing a toxin that would kill prostate epidermal cells and eliminate the cancer.⁷

Click here for large scale version of figure.

It is critical to understand that discussion of the ethics of human germline engineering cannot be separated from the specific technology chosen to implement it. For example, Mario Capecchi has described how a crelox recombinase system could be used to prevent the inheritance of an artificial chromosome (and any inserted genes it contains) by future generations. Thus a major criticism of germline intervention – its heritability -- might be overcome by technical approaches that avoid homologous recombination.⁵

The basic discoveries that make human germline manipulations possible are likely to emerge not from controversial experiments on human embryos, but from mainstream research on mice, sheep, cows, primates, and human somatic cells. Work on human embryos will probably be needed only to refine techniques proven elsewhere. The only way to prevent our gaining the capacity to genetically manipulate human embryos would probably be to halt virtually all genetic research, so regulation should occur by controlling how this technology is applied to humans, not the type of basic research that is done.

This ATC workshop is a good place to reflect on calls for legislation designed to protect us from the possible free-market excesses that critics of human cloning and germline engineering fear these technologies will spawn. In my view, their concern is greatly overblown. There is no financial incentive for premature development of a technology like germline engineering, because until genetic modifications desirable enough to make large numbers of people eager to buy them for their future children exist, the future financial potential is too limited to motivate R&D investment. The projected market size would be too small to recover expenses much less reap a profit or face the prohibitive liability risks attending an unproven new procedure like this.

These technologies present no emergency. It is a long way from experiments on animals to viable clinical procedures in humans. And such procedures, when they emerge, will for some time remain too difficult and expensive to be used widely. A full twenty years after Louisa May Brown, the first "test-tube" baby, was born, ivf is used in less than 1% of births in the U.S.

But the time to examine and discuss the realistic benefits and challenges these new reproductive technologies embody is now, while they are still nascent. And to keep such discussion focused on realistic possibilities rather than science fiction, it is imperative that active researchers in the field participate. It would be a mistake to wait to begin these discussions until these technologies are upon us or to allow the possibilities to be viewed primarily through the distorted prism of our current ideological conflict over abortion.

¹  Director, Program on Medicine, Technology, and Society. Professor Dept. of Psychiatry and Biobehavior. UCLA School of Medicine, Los Angeles, CA. gstock@ess.ucla.edu

²  Professor, Department of Neurobiology, UCLA School of Medicine. johnc@ucla.edu

³  SATAC Artificial Chromosomes; A "Super Vector" for Multi-Function Genetic Engineering, Henry Geraedts, Chromos Corporation, Transgenics & Cloning: Commercial Opportunities, Bioconferences, Washington D.C. June 26, 1998

⁴  In Genome Race, Government Vows to Move Up Finish, Nicholas Wade, New York Times, September 14, 1998

⁵  Mario Capecchi, The Genetic Engineer's Tool Box, Engineering the Human Germline, editors Gregory Stock and John Campbell, Harvard University Press, 1999 (In Prep)

⁶   John Campbell and Gregory Stock, A Vision for Human Germline Engineering, Engineering the Human Germline, ed. Gregory Stock and John Campbell, Oxford University Press, 1999 (In Prep).