Cloning: potential benefits for human medicine

Of babies, lambs, medicine and milk

MJA 1997; 167: 568-569

Recent developments in cloning of animal cells (such as the creation of the lamb "Dolly")1,2 and the consequent ban by President Clinton on cloning humans in the United States3 have stimulated much discussion of the merits and ethics of cloning. Indeed, a number of countries (e.g., Germany and Denmark) and Australian States (e.g., Victoria) ban all forms of cloning in human reproductive medicine by legislation or regulation. The most publicised advance in cloning attended the birth of Dolly, a lamb created from a ewe's mammary cell.2 This achievement showed that completely differentiated cells (both fetal and adult) may be reprogrammed to return to multipotential embryonic cells. This is done by inducing a quiescent state (G 0 phase of the cell cycle) in the somatic cell and then fusing it with the enucleated cytoplasm of a mature egg (Figure 1). The fused product then acts as an embryo and develops according to a preset maternal program rather than as the original somatic cell. At present, the procedure is relatively inefficient and confined to ruminant species (sheep and cattle).1,2,4,5 It is unsuccessful in rodents,6,7 which have been the model for understanding mammalian cell differentiation and tissue formation. It is not known if humans fit the ruminant or rodent model, although the recent births of rhesus monkeys derived from embryonic cells (Dr D Wolf, Senior Research Scientist, Oregon Regional Primate Research Center, Beaverton, Oregon, US, personal communication) suggest the former. This finding has major implications for medicine and agriculture, as it opens the way to use differentiated somatic cells as vectors for genetic engineering to produce transgenic animals and for gene therapy. Considerable research on developing such vectors has focused on embryonic stem (ES) cells. Rodent ES cells have been widely used for determining gene function, as they can be manipulated to "knock out" or upregulate genes or to introduce foreign genes. 8 ES cells combined with early embryos contribute to all body tissues during development, including gonadal germ cells. When bred, the resulting animals transmit the ES cell genotype, allowing the effects of the gene manipulations to be analysed. It would be even more efficient to genetically manipulate somatic cells of sheep or cattle in culture and to use these cells for cloning 2 (Figure 2). Offspring would probably always have the desired transgene. This could code for a human protein used to treat or prevent disease (such as factor VIII and interferon), and large quantities of the protein could be produced in the animal's milk under the control of specific promoters. As proteins can be isolated from milk relatively simply, this might be an extremely cheap and efficient way to produce large quantities of human or animal pharmaceuticals. It might also be very competitive with present methods of producing recombinant proteins (e.g., from bacterial, yeast and mammalian cell lines). When one considers the cost and problems of producing antiviral drugs as well as proteins for immunisation and therapy (e.g., for haemophilia, HIV infection and multiple sclerosis), the potential for pharmaceutical production in cattle becomes economically attractive. Australia has a unique position for developing this biotechnology as our sheep and cattle are relatively disease-free. What might be other benefits of the recent advances? The search for human multipotential cells as vectors for gene therapy and as universal transplantation cells for correcting abnormal tissue function or tissue damage in humans has also focused on ES cells. 9 These have been derived from the embryonic inner cell mass,10 undifferentiated gonadal cells (GS cells),11 and stem cells which form specific tissues.12 Progress on producing these cells has been limited, although a rhesus monkey ES cell line was recently produced.13 However, ES cells may still be recognised as foreign and be rejected by the recipient. Cloning a patient's somatic cells could be a way of producing multipotential cells that are genetically identical to those of the patient and therefore not subject to rejection (Figure 3). These cells might be ideal vectors for gene therapy, but would also need to be clonally stable and to produce the cell type needed for transplantation, which requires considerable further research. These potential benefits of cloning are often ignored in the debate about its use for human reproduction. Yet, cloning could not reproduce an individual with the same attitudes, beliefs and behaviour as the original person because of the predominant influence of non-genetic factors in human development.14 While no real objection is raised to identical twins produced by natural conception, or even as a result of in-vitro fertilisation, cloning of individuals from somatic cells has no biological or social merit and in this context is unethical. However, we should not lose the substantial benefits of other applications of cloning technology in the regulatory and legislative processes, and moratoriums should not impede progress to achieve these benefits. Alan O Trounson Professor, Institute of Reproduction and Development, Monash University Monash Medical Centre, Melbourne, Victoria Campbell NHS, McWhir J, Richie WA, et al. Sheep cloned by nuclear transfer from a cultured cell line. Nature 1996; 380: 64-66. Wilmut I, Schnieke AE, McWhir J, et al. Viable offspring derived from fetal and adult mammalian cells. Nature 1997; 385: 810-813. Gorman C. To ban or not to ban? Time 1997; June 16: 66. Willadsen SM. Nuclear transplantation in sheep embryos. Nature 1986; 320: 63-65. Tatham BG, Dowsing AT, Trounson AO. Enucleation by centrifugation of in vitro matured bovine oocytes for use in nuclear transfer. Biol Reprod 1995; 53: 1088-1094. Surani MAH, Barton SC, Norris ML. Experimental reconstruction of mouse eggs and embryos: an analysis of mammalian development. Biol Reprod 1987; 36: 1-16. McGrath J, Solter D. Nuclear transplantation in the mouse by microsurgery and cell fusion. Science 1983; 220: 1300-1302. Joyner A. Gene targeting and gene trap screens using embryonic stem cells: new approaches to mammalian development. Bioessays 1991; 13: 649-656. Trounson A. Research on the development of human embryonic stem cells. Sing J Obstet Gynaecol 1994; 25: 245. Pedersen RA. Studies on in vitro differentiation with embryonic stem cells. Reprod Fertil Develop 1994; 6: 543-552. Travis J. Human embryonic stem cells found? Science News 1997; 152: 36. PrŸmmer O, Fliedner TM. The fetal liver as an alternative stem cell source for hemolymphopoietic reconstitution. Int J Cell Cloning 1986; 4: 237-249. Thompson JA, Kalishman J, Golos TG, et al. Isolation of a primate embryonic stem cell line. Proc Natl Acad Sci USA 1995; 92: 7844-7848. Machin GA. Some causes of genotypic and phenotypic discordance in monozygotic twin pairs. Am J Med Genet 1996; 61: 216-228. Reprints: Professor A O Trounson, Institute of Reproduction and Development, Level 5, 246 Clayton Road, Clayton, VIC 3168.

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