Cloning Mammals: What Does It Mean?
Researchers find that clones are often developmentally abnormal
Individuals from two mammalian species--sheep and cows--have recently been cloned. The sheep "Dolly" has been generated asexually by fusing the nucleus of an adult mammary gland cell to an enucleated sheep egg (Wilmut et al., 1997). What does this mean? Scientifically, Dolly has not told us much. The cloning of an adult mammal from the transplanted nucleus of an adult mammalian cell is direct evidence for what developmental biologists have long held to be true--that the nuclei of most cells in an individual are genetically identical. The fact that the Scottish investigators do not know the developmental state of the cell from which the nucleus came makes it even less impressive scientifically than the amphibian experiments done 20 years ago. The experiments of Gurdon and colleagues (1975) and Orr and colleagues (1986) used amphibian cells that were known to be fully differentiated. Orr and her co-workers used frog erythrocytes, while Gurdon's laboratory used cultured keratinocytes whose differentiation was demonstrated by skin-specific cytokeratins. We do not know the differentiated state of the cell whose nucleus was used to generate Dolly. It could be that the nucleus was from a stem cell population which, while committed to a particular cell fate, is relatively undifferentiated. There are some valid scientific questions that could be asked. For instance, did the nucleus become "rejuvenated" by the egg cytoplasm. That is to say, will the lifespan of the cloned sheep approximate that of a normal sheep, or will it be shortened by the amount of time the nucleus has already spent as an adult. It would be interesting to know the state of its telomeres. Society has to answer its own questions, namely: (1) Is such scientific knowledge worth the risk of inventing a technique that could clone humans? and (2) When, if ever, is the cloning of human nuclei allowable? The mechanism by which Wilmut and colleagues cloned Dolly is not very efficient. Out of the 277 mammary gland nuclei fused to enucleated unfertilized eggs, only one live lamb was born. However, the claim that our inability to clone other mammals is a technical, rather than a physiological, problem suggests that more efficient cloning techniques can be developed. There may be physiological barriers against cloning in mice and humans. Sheep, for instance, activate their nuclei relatively late--at the 16 cell stage. This might give the egg cytoplasm ample time to "reprogram" the chromatin. Mice, on the other hand, activate their nuclei at the late one-cell stage. Humans activate some genes (such as SRY) during the one-cell stage, but the global activation of the human genome does not occur until the 4-8 cell stage, shortly before compaction (occurring around the 10-cell stage in H. sapiens [Nikas et al., 1996]).II. The calves ACT3, ACT4, and ACT5
James Robl's laboratory at the University of Massachusetts (Cibelli et al., 1998) has taken cloning a step further. First, their success rate is much better. Out of 28 embryos derived from dividing bovine embryonic fibroblast nuclei, three healthy and genetically identical calves were produced. The source of the nuclei--dividing fibroblasts from a 55-day old bull fetus--was important. These fibroblasts, while mesodermal in origin, are not considered to be differentiated while they are dividing. Moreover, they have a long G1 state, a stage of the cell cycle that has been thought to be conducive to the remodeling by the oocyte. About 58% of these dividing fibroblasts are in the G1 state. The nuclei were marked by the insertion of a beta-galactosidease/neomycin resistance fusion gene. The fibroblasts were selected for the expression of this gene (by growing them in neomycin), and the nuclei from these fibroblasts were inserted into the enucleated mature oocytes. Each of the three calves had this inserted gene and had the gene in the same place in the chromosomes. Since several individuals were produced from the descendents of a single embryo and were from the same modified fibroblast cell, this is truly "cloning." Each of the calves is genetically identical to the other.III. Consequences
Commercially, the production of cloned lines of "elite" breeders has been a plan of agricultural biologists for a long time. Champion milk cows and genetically modified sheep that produce large amounts of pharmaceutically valuable human proteins are extremely rare. To breed them to others means that their special abilities might not be passed to their offspring. This technique enables the propagation of that special ability. This had formerly been the special advantage that plant breeders had, since vegetative propagation by cuttings could enable the propagation of a rarely colored flower or a genetically improved cereal.
Ecologically, this may create a bottleneck in the genetic variety of various types of livestock. It may also create a larger disparity between the "haves" and "have-nots." It also may be a mechanism for reproducing endangered animals who have already gone through a severe genetic bottleneck and whose fertility is limited.
Socially, the cloning of a "large charismatic mammal" may be very important. First, it may be a wake-up call needed to pass some laws prohibiting both medical and industrial laboratories from certain types of experimentation. Second, it calls into question the proprietary relationship that companies can have to organisms. Is Dolly "nature" or "culture"? Is she the product of natural circumstances or specifically the artifact of technology? If the latter, Dolly becomes patentable. The research to produce Dolly, after all, was done in a pharmaceutical company, not in a university or medical research center. They want returns on capital investments. Patents become more important than papers. Biotechnology has blurred the distinction between nature and culture to such a degree that "nature" is seen as a genetic engineer and transgenic and cloned organisms are seen as cultural productions (see Haraway, 1997).
Human cloning and germline manipulation may be nearer than we think. In recent months, proposals have been forthcoming saying that cloning should be legalized and that germline gene therapy and enhancement should not be stopped.
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