Accident & desire. Inadvertent germline effects in clinical research.

Gene therapy is still a very crude way of treating very complicated problems. It's hard to get new genes to go where they're needed, and hard to keep them from going where they're not wanted. The worst-case scenario is that they find their way into a patient's germ cells--eggs or sperm--and end up harming the patient's offspring. Yet this possibility is hard to study in human trials, and would be hard to deal with in the clinic. It should, instead, simply be avoided. Doing so requires fundamentally changing our approach to gene therapy. For as long as we have envisioned gene transfer, we have recognized, and sometimes hoped, that it might have effects on germ cells--eggs and sperm--that would make its effects inheritable. Intentional germline gene transfer (for brevity's sake, GT) has been deemed both controversial and technically distant. (1) The National Institutes of Health's "Points to Consider" document, which guides NIH-funded institutions and investigators in preparing and submitting proposals for gene transfer clinical trials to NIH for review by the Recombinant DNA Advisory Committee, says in its preamble that the RAC "will not at present entertain proposals for germ line alterations." (2) The phrase "not at present" shows that while intentional germline GT is not now permitted, it has not been entirely ruled out either. Moreover, a discussion later in the preamble recognizes that inadvertent germline GT is a risk of somatic cell GT, and even outlines the nature of the risks of harm. (3) But while researchers have restricted their efforts to somatic cells, inadvertent germline GT has become increasingly likely. In my view, although the possibility of inadvertent germline GT is acknowledged, it has not been adequately considered. In this paper, drawing from my experience as a former member of the RAC, I examine the discussion of inadvertent germline effects from clinical GT research and reconsider some of the ethical issues raised by this possibility. I consider it essential to examine inadvertent germline GT for two reasons. First, in my view, scientific and societal reluctance to turn completely away from germline GT has influenced the direction of somatic cell GT research and actually made inadvertent germline effects more likely. Second, the issues of design and ethics in clinical research posing a risk of inadvertent germline GT are substantially similar to the issues that would be posed by research on intentional germline GT. Because inadvertent germline GT appears possible now, we can no longer avoid addressing these issues. Humans are a species-changing species; we make changes, both intentional and inadvertent, in other species and in ourselves. Because germline GT, whether intentional or inadvertent, may well have a species-changing capacity, humans arguably have some responsibility to under stand what it would mean to make inheritable changes, and to agree about whether it is acceptable to do so. An examination of inadvertent germline GT demonstrates that fulfilling these responsibilities is particularly challenging when germline effects are a byproduct of the desired effect rather than the desired effect itself. Accident and Design Somatic cell GT attempts to introduce new genetic material (often referred to as a "transgene") into specific, targeted cells, usually by means of a carrying vehicle called a "vector." The earliest GT research employed ex vivo interventions: the cells targeted for correction (often blood cells) were genetically altered outside the body and then reinserted. Ex vivo interventions are very unlikely to result in inadvertent germline GT because the correction is delivered directly to the target cells, and only to them. However, ex vivo interventions are also very unlikely to be successful. (4) Today, therefore, in vivo interventions are much more common. In this approach, genetic material is introduced directly into the body, potentially reaching and affecting more than just the targeted cells. …