Technologies which may contribute to human genetic engineering and eugenics - a brief summary
Introduction
In the last two years there has been rapid progress in a range of technologies which may soon enable genetic manipulation of the human germ line (human genetic engineering). Some of these technologies are also relevant to the establishment of a 'consumer eugenics', through the use of pre-implantation genetic diagnosis of embryos. The technologies can be broadly divided into two categories: reproductive and genetic technologies.
Genetic technologies
French Anderson is proposing to begin foetal gene therapy, using vectors which will likely infect germ cells (see other symposium papers). In essence, the risk arises here because of the use of vectors which are not specific in their choice of target cell. This is a reflection of the current primitive state of somatic gene therapy, the main limitation of which is universally acknowledged to be the lack of adequate vectors. It might be possible to do foetal gene therapy in a way that did not create such risks, but Anderson proposes to proceed in a way which will impose a high risk. It would appear that this is a deliberate attempt to breach the germ line barrier.
2. Human artificial chromosomes
A major problem with current methods for creating transgenic animals is the random integration of DNA into chromosomes. This can lethally disrupt existing genes, cause problems for the expression of the transgenes, and have unpredictable effects on the expression of neighbouring genes. There is therefore a major effort to devise artificial chromosomes, which are capable of replication each time the cell divides, and can be transmitted through the germ line. So far no-one has produced a well-characterised artificial chromosome which is stable in cultured cells for long periods. However, a number of groups of scientists have come close. It is likely that this target will be reached within 3 years. Since a major component of the definition of species is the chromosome number, it might be argued that people containing artificial chromosomes were a different species.
3. In-vivo site directed mutagenesis
A group of scientists from the University of Minnesota, funded by the biotechnology company, Kimeragen, recently managed to alter chromosomal DNA sequences in rats' livers, by the administration to the animals of DNA/RNA oligonucleotides. The technique has the potential to correct certain mutations that cause genetic disorders (missense mutations), although it cannot fix large DNA sequence deletions. Gene therapists are excited by the possibility for this technique in somatic gene therapy, and there will be arguments for its use in human genetic engineering, on the grounds that it is more precise than trying to introduce a wild type gene (see above). The Roslin Institute recently announced a joint venture with Kimeragen to produce transgenic farm animals.
4. DNA testing on a chip
Companies such as Affymetrix have developed chips (not computer chips) capable of detecting differences in a hundred or more different DNA sequences at a time. This paves the way for rapid testing to create a person's 'genetic profile'. Research is rapidly uncovering genes which have a major influence on predisposition to common diseases. This may soon make it possible to genetically screen embryos prior to implantation.
Reproductive technologies
1. Nuclear transfer
The major significance of the Roslin and Hawaii cloning techniques is not, in fact, cloning but the creation of transgenic animals, and eventually humans. Roslin have already produced transgenic lambs by this route, as have Advanced Cell Technologies. The advantage over existing microinjection techniques is that it is possible to do the genetic engineering in cultured cells, prior to nuclear transfer. This removes one major problem in transgenic animal production, but introduces another: the low viability of nuclear transfer embryos, and the high rate of abnormalities. There are currently intensive efforts to address these problems. The potential market for human cloning means that many US IVF clinics are no doubt attempting to develop the technology for human cloning.
New York scientist, James Grifo has recently transferred nuclei between the eggs of different women, in order to circumvent genetic problems in the mitochondria of patients. The St Barnabas Hospital has attempted the converse experiment, the transfer of mitochondria between eggs from different women, for the same purpose. Since mitochondrial DNA is part of the germ line genome, children resulting from such experiments would be the first examples of germ line genetic changes, although not actual genetic engineering in the conventional sense. They would have three genetic parents. In fact, cloned individuals, unless they were women, cloned using eggs as well as nuclei from the same woman, would also fall into this category.
2. Embryonic stem cells
Human embryonic stem cells, which can differentiate into all the cell types of the body, including the germ line, have recently been isolated. ES cells are a major route to producing transgenic mice: they are first genetically engineered and then re-introduced into embryos, creating animals that are chimeras. This may limit their use in human genetic engineering, since it is not clear whether this would be acceptable, although a strong patient pressure might overcome resistance. This chimera problem gould be circumvented by using ES cells for nuclear transfer, as was done by the Roslin team prior to Dolly (but see the caveats on nuclear transfer).
Advanced Cell Technologies recently announced their use of bovine eggs as nuclear transfer recipients, in order to create hybrid embryos which can be used as sources of human embryonic stem cells. The point of this work is that human eggs for receiving nuclear transfers are in short supply, while cow eggs are abundant. The resulting ES cells, if proven, would contain bovine mitochondria.
3. In vitro/cross species egg maturation
Other techniques for increasing the supply of eggs include the maturation of eggs from ovary slices, either in the laboratory, or by transplant to other species' ovaries. Purdue scientists recently announced the use of mice to mature elephant eggs. Similar experiments have been performed with immature sperm cells. Once it is possible to culture such cells, an alternative route to germ line engineering is by genetically manipulating them prior to maturation. There is also intensive research aimed at allowing the maturation of many eggs from ovary slices. If successful, this would allow the development of a system of pre-implantation genetic diagnosis, which would not rely on in vitro fertilisation.
A note on the issue of safety
Scientists and bioethicists often seek to reassure us that human genetic engineering will never be tried until it can be guaranteed that it will not result in genetic damage to the individual and their descendants. However, such guarantees will never be possible, and are not being required for other safety concerns in biotechnology, eg transgenic crops, xenotransplants. Rather, we will be told that risks have been reduced to an 'acceptable' level given the 'benefits' to be gained. They are already telling us that even if genetic disability does result, they will probably be able to fix it by ... gene therapy, of course! One scientist recently argued that since many mutations occur in each meiosis, one extra mutation caused by genetic engineering should be nothing to worry about. We can be sure that by the time the scientists are ready, there will be plenty of people desperate enough to take the risks. Those people and their advocates will be telling us loudly that since it is them taking the risk, we have no right to interfere. Thus, in arguing against human genetic engineering we should not rely on the issue of safety to rule it out. Conclusion
The recent explosion of reproductive technologies suggests a general trend that we would do well to take note of. Most of these technologies are being developed mainly with farm animals in mind. The overall direction of reproductive technology is to develop a system in which animal reproduction becomes a fully industrial activity, as are most other aspects of the life of farm animals. The aim is mass production, standardisation (cloning) and quality control (genetic engineering and selection). These technologies may also be applied to human beings, although, in liberal societies, in a less overtly industrial way. Nonetheless, the underlying drive of human reproductive technology, from IVF onwards, is the overcoming of biological barriers which make reproduction discrete, particular, diverse and outside of human control. This drive is integral to industrial, post-Enlightenment Western societies, and is usually called 'progress'.
David King, December 1998