Staff Background Paper

The prospect of "human genetic enhancement" conjures up both dreams of human improvement and nightmares of a "new eugenics"(1). But current reality is both more sober and more sobering. Fueled by the completion of the human DNA sequence, our knowledge of the number, organization, and functions of human genes is advancing rapidly. We are beginning to understand how specific human genes and gene sequences either cause or increase the probability of developing a wide variety of human diseases. Even as knowledge of "how human genes work" increases, the ethical issues and questions raised by application of this knowledge remain matters of considerable discussion and debate.

As used in this paper, "human genetic enhancement" means the use of genetic knowledge and technique to bring about improvements in the capacities of existing individuals or future generations. Human genetic enhancement might be accomplished most obviously by interventions that produce directed genetic change. But it might also be brought about through genetic screening and selection of individuals with "more desirable" genotypes.

Enhancement has become a topic of concern for several reasons. First, most of us don't know what is currently possible or likely, so we imagine all sorts of scenarios fueled by science fiction. Second, directed genetic changes (as contrasted with taking drugs, which can be stopped if adverse effects appear) are copied at each cell division and thus become a permanent feature of the cells of the treated individual. Third, to the extent that people have come to regard DNA and genes as the "secret of life," manipulation of genes for any purpose strikes them as more momentous than most other forms of biotechnical intervention. So we correctly sense that important ethical issues and public policy choices are involved here.

We should distinguish genetic screening from directed genetic change. Human genetic screening determines what gene forms are present. Performed on cells removed from an adult, child, fetus, or embryo, it uses gene analysis techniques to provide information about whether specific human gene forms (frequently those associated with genetic diseases) are present or absent. Human directed genetic change goes beyond screening and attempts to make heritable changes in the genes of human cells. These directed genetic changes could be produced at all stages of human development, from embryos in vitro to adult individuals.

Human cells can be divided into somatic (specialized, differentiated cells such as those found in muscles or liver) or germ-line (eggs and sperm) cells that can give rise to future human generations. Directed genetic change of only somatic cells would affect only the individual involved. In contrast, directed genetic change of germ-line cells has the potential to affect all the descendants of that individual. Directed genetic change applied to early stage human embryos has the potential to change both somatic and germ-line cells.

Gene therapy, the directed genetic change of human somatic cells to treat a genetic disease or defect, has already produced positive results for a few diseases (2). In reviewing protocols for proposed gene therapy, particular attention is paid to whether the protocol might affect the germ-line cells. Ongoing gene therapy projects are monitored for evidence of changes in germ-line cells. Attempts are made to design gene therapy protocols so that they have minimal risk of changing germ-line cells of the treated individuals. Human genetic enhancement would use some of the same techniques as gene therapy, but would aim at improving human capacities rather than treating disease.

In vitro fertilization (IVF) is being used to compensate for human infertility. When used by couples with a known family history of genetic disease, IVF has been combined with preimplantation genetic diagnosis (PGD) to screen embryos in vitro in order to avoid uterine transfer of embryos carrying the genetic disease gene or an abnormal chromosome. PGD uses genetic tests on DNA from a cell or cells taken from the embryo to determine whether gene forms associated with genetic disease are present or absent. Embryos remain viable during this procedure and those without evidence of the tested genetic disease (or chromosomal abnormality) are transferred to the woman's uterus to initiate pregnancy.

To make human gene therapy a reality, powerful techniques have been developed for introducing and integrating exogenous genes into human cells and getting them to continuously produce the desired gene products. Most of these techniques involve using genetically modified viruses to carry the exogenous genes into human cells and to get them stably associated with the other genes of the cell (3). This has limited the number of exogenous genes that can be introduced at one time to one or two. While this practice can be an effective treatment for a genetic disease where one mutant gene is the problem, it limits prospects for genetic enhancement. Because most desirable human traits are the result of the interactions of many genes and their products, efficient directed genetic change to enhance human traits will probably require a technique able to introduce multiple human genes at the same time.

We have learned enough about chromosome structure and function to design man-made chromosomes and to get them to replicate along with natural chromosomes inside of cells (so-called minichromosomes) (4). This raises the possibility of adding new combinations of genes to human cells. This would create future possibilities for genetic enhancement well beyond the current gene therapy vector techniques which usually add or modify one gene at a time.

While we are currently a long way from the ability to produce "designer babies," techniques are currently available to make possible some forms of somatic genetic enhancement. An example, described to the Council by Professor Lee Sweeney at the September 2002 meeting, is the introduction of the gene for IGF-1 into muscle cells with resulting great increases in muscle health, strength, and efficiency. As we have seen, these techniques are being developed in order to treat human disease (e.g., certain forms of muscular dystrophy), but the same techniques can be applied to nonmedical enhancement of human muscle capabilities as well. Strong interest in using muscle enhancing gene techniques is expected to come from athletes, the elderly, and young people interested in increasing their physical attractiveness.

Other possibilities would include genes that would enhance athletic endurance and performance (such as a gene to produce more erythropoietin to increase the number of red cells in the blood). Alternatively, a gene for additional growth hormone production could be introduced in an attempt to increase height. Farther in the future, genes that confer resistance to particular pathogens (perhaps anthrax or smallpox) might be added in an attempt to protect a population from attacks with biological weapons.

1. What are the ethically choiceworthy applications of, for example, human muscle enhancement by genetic means? On what basis would we distinguish "good" applications from "bad" applications? Are these matters best left to the decisions of individual "consumers," or should they be made (and regulated) socially?

2. Effective minichromosome techniques for modifying human cells by introducing multiple new human genes could both treat human disease and facilitate future human genetic enhancement. Can the minichromosome technique be developed for therapeutic uses without increasing the possibility of future application for human genetic enhancement?

Prenatal genetic and chromosomal screening of the unborn (using amniocentesis), followed by selective abortion of abnormal fetuses, has been practiced in the United States for more than thirty years. But thanks to the combination of IVF and PGD technologies, we now have, for the first time in human history, the ability to screen human embryos in the laboratory prior to the initiation of a pregnancy. With current technologies, it is possible to test the form of several genes present in each embryo prior to uterine transfer for development. While this is highly useful where we want information about the status of one particular gene, PGD tests alone are, at present, unable to provide a high degree of assurance that a particular transferred embryo will develop into a normal human infant. Depending upon the ways in which it is used, IVF/PGD could have an impact on the prospects for human genetic enhancement in two different ways.

First, IVF/PGD has the potential to be used not just to select against the birth of individuals with human genetic diseases, but to select for the birth of individuals with desired traits or capacities. Knowledge is growing about correlations between the presence of specific forms of human genes and the probability of developing human diseases later in life. In the future, we anticipate that correlations will be developed between the presence of specific forms of human genes and the probability of desirable human traits or capacities. If such gene forms were identified, might there not be considerable demand to use IVF/PGD to screen for non-disease traits such as height, baldness, longevity, intelligence or memory? Selective embryo transfer would then be used to promote birth of more infants with the desirable traits. If applied on a large scale, slowly over multiple generations, an increase in the number of members of the population with the "desirable traits" would take place.

Second, the availability of IVF/PGD may tempt the unwitting or the unscrupulous toward experiments on directed genetic change in human embryos because they think they know enough to test the genetically modified embryos for harmful changes prior to uterine transfer. Before the introduction of IVF, experiments to develop techniques for directed genetic change with human embryos or fetuses faced insurmountable ethical difficulties. Since a pregnancy was already underway, performing the necessary experiments to develop techniques involved unknown, potentially large risks to the early embryo and the mother, with no benefit to them. Such experiments would be impossible to justify ethically. Even after IVF was developed, experiments on directed genetic change of human embryos would be ethically highly suspect since there would be no way to assess the risk of abnormality or malformation in the genetically modified child-to-be.

At the present time, IVF/PGD is a relatively small-scale practice. As summarized in a recent review article (6), "Although a growing number of centers worldwide offer PGD, it is still not widely performed as a clinical service since it requires combined expertise in the fields of reproductive medicine and molecular genetics and/or cytogenetics. Additionally, genetic diagnosis of single cells is technically demanding and protocols have to be stringently standardized before clinical application."

What are the medical indications that, at the present time, can lead to referral of a couple to specialists capable of performing IVF/PGD? They include prior birth of a child with a genetic disease, prior spontaneous abortions, or abortions after a prenatal diagnosis of a genetic disease. For IVF/PGD screening to detect chromosome abnormalities, the medical indications include 1) maternal age over 35 years, 2) recurrent IVF failure, 3) two prior miscarriages with the parents having no detectable chromosome abnormalities. In cases where male children are at risk for inheriting a genetic disease, gender determination by PGD and a decision not to transfer male embryos prevents the birth of affected sons.

Because it is still a new and largely experimental procedure, IVF/PGD is a relatively unstudied practice. The European Society of Human Reproduction and Embryology (ESHRE) Preimplantation Genetic Diagnosis Consortium was formed in 1997 to undertake a long-term study of the efficacy and clinical outcome of IVF/PGD. In their data summary as of May 2001(7), they noted that there were 1561 referrals, 370 regular PGD cycles, and 334 PGD chromosome abnormality screening cycles in their European Consortium centers during the preceding year. This data collection provides a glimpse of why people use IVF/PGD and what the outcomes are. Importantly, this report notes the appearance of the first data for gender screening on preimplantation embryos for social reasons. Although the number of centers with the capability to perform IVF/PGD is still small, a tendency for some couples to use this technique for gender balancing of their families has thus already been documented in this European data.

Should there be ethical limits on the use of IVF/PGD to select embryos for uterine transfer that have traits appealing to parents? If so, where should such limits be located? In October 2002, the Council heard from Suzi Leather, head of the Human Fertilisation and Embryology Authority in the U.K., who reported that the HFEA was just starting a public consultation on the ethics of using IVF/PGD for sex selection. Use of IVF/PGD for gender screening for social reasons is becoming an issue in the U.S. as well, and public discussion of it is intensifying.

However, it would be a mistake to concentrate only on issues involved in using IVF/PGD for gender selection for social reasons. Spreading use of IVF/PGD raises a host of other issues and questions, including:

1. Is it correct to describe and discuss screening of human embryos for genetic disease in the framework of medical diagnosis and treatment, since no patient is treated or cured?

2. Does the power to screen our potential offspring according to their genetic characteristics change the way parents see their children-including those parents who do not "need" to use IVF for fertility or genetic disease problems?

3. Does the availability of IVF/PGD create pressure to have "more perfect" or "less imperfect" children, or to have them in the "most advanced" possible way?

4. Would the possible future use of IVF/PGD to select embryos with desirable human traits for uterine transfer undermine the attitude of "unconditional acceptance" that is so fundamental the parent-child relationship?

5. Would the possible future use of IVF/PGD to select embryos with desirable human traits for uterine transfer undermine the belief in human equality that is so central to our political institutions? How would it differ in this respect from the existing discriminations made in prenatal diagnosis and abortion for genetic defect?

6. What respect, if any, do we owe those human embryos that would be tested and discarded in IVF/PGD embryo screening and selective transfer?

Genetic techniques, that could someday make possible human genetic enhancement, are being developed and applied today to treat or prevent human genetic disease. Powerful vectors that incorporate human genes into human cells in vitro are being used for the purposes of human gene therapy. Knowledge of the human DNA sequence made possible by the Human Genome Project is leading to the identification of human gene forms associated with human disease. Initial use of IVF/PGD to select for the uterine transfer of embryos whose gender is desired by the parents has been reported. All this makes the questions surrounding human genetic enhancement especially appropriate for investigation and moral reflection.

1. Silver, L.M., Remaking Eden: How Genetic Engineering and Cloning Will Transform the American Family, Avon Books, New York (1998); Stock, G., Redesigning Humans: Our Inevitable Genetic Future, Houghton Mifflin, New York (2002); Fukuyama, F., Our Posthuman Future: Consequences of the Biotechnology Revolution, Farrar, Straus & Giroux, New York (2002); Watson, J.D., Gairdner Foundation Award Speech (Toronto, Canada, October 25, 2002), quoted in The Toronto Globe and Mail online 10/26/02 as saying about the use of genetics to make people as perfect as they can be: "Going for perfection was something I always thought you should do."

2. Hacein-Bey-Abina, S., et al., "Sustained Correction of X-linked Severe Combined Immunodeficiency by Ex Vivo Gene Therapy," New Engl J Med 346, 1185-1193 (2002).

3. VandenDriessche, T., et al., "Oncoretroviral and lentiviral vector-mediated gene therapy," Methods Enzymol 346, 573-89 (2002); Jiang, Z, et al., "Systematic delivery of a high capacity adenoviral vector expressing mouse CTLA4Ig improves skeletal muscle gene therapy," Mol Ther 6, 369-76 (2002).

4. Auriche, C., et al., (2002) "Functional human CFTR produced by a stable mini-chromosome," EMBO Rep. 3, 862-868. [This is the first example of a structurally known minichromosome made to contain an active therapeutic gene, in this case the gene for possible treatment of cystic fibrosis.]

5. Kanavakis, E. and J. Traeger-Synodinos (2002) "Preimplantation Genetic Diagnosis in clinical practice," J. Med. Genet. 39, 6-11.

6. "ESHRE Preimplantation Genetic Diagnosis Consortium: data collection III (May 2001)," Human Reproduction 17, 233-46.