Clones: Identical but Different

Who’s afraid of clones?

Within the revolution we are going through today in biology there are a number of areas (genomics, transgenesis, gene therapy, cellular reprogramming) that, despite having interesting applications from the medical, agricultural, stockbreeding, environmental and other points of view, also provoke controversy and resistance. This “resistance” is particularly strong in the case of clones, since various national and international authorities -EU, UNESCO, United Nations- have banned their application in humans, something which right now is not technically feasible. These prohibitions and precautions are based especially on ethical and social reasons, but the underlying reason may be a basic biological one, or even a prejudice: clones are considered to be genetically identical to the individuals to be cloned, and will therefore display the same phenotype. But this needs some clarifications.

Clones

Clones are usually obtained by transferring adult cell nuclei from one organism to oocytes enucleated in another one. These experiments have been carried out for many years in groups like the amphibia. But cloned mammals were only obtained in 1997 by Ian Wilmut with the sheep Dolly. In this specific case, the nucleus of an ovum-oocyte from a sheep was eliminated, keeping only its cytoplasm, in which the nucleus of a differentiated somatic cell from a different sheep was later introduced; in the case of Dolly, from the mammary gland of a dead sheep, which had been frozen.

And contrary to what was thought until then (that the nuclei of differentiated cells of mammals-vertebrates-organisms in general undergo irreversible changes during development), the factors –proteins, RNA, etc.– from the egg’s cytoplasm revert all the DNA of the somatic nucleus of the donor, once again becoming a ”zygote”, from which an embryo is originated -usually in a third different organism, a surrogate dam- that is going to develop as a new being, in this case Dolly.

Later, and using this technology, all kinds of animals have been cloned: lambs, cows, bulls, horses, mice, rats, pigs, cats, dogs… and even macaques. But in the case of humans, despite the fact that some cases of cloning have been reported, it has not been possible to confirm their likelihood, and various prohibitions have also been imposed on these experiments.

The same, but different

The great misunderstanding with clones is to assume that they are genetically identical to the organisms being cloned, and will therefore be phenotypically identical to them. First, we should stress that clones are not completely identical from the genetic point of view to the donors of the nuclei. And second, that the characteristics of living beings are not only the result of the genes, and despite having a large part of their genes in common will not display the same pheonotype.

Thus, and as regards the genetic identity between what is being cloned and the clone, they would be identical in terms of the DNA of the cell nuclei. But they would have different DNAs in the mitochondria of their cytoplasm, since the clone’s cytoplasm comes from the egg’s donor, and this donor is usually different from the mother from which it is going to be cloned. This can result in differences in characteristics and organs -muscles, heart, brain- in which there is greater mitochondrial activity, which as we know are the “factories” of cell energy.

We should also consider that in the process of de-differentiation of the donor nucleus (something which is initially achieved by culturing the donor’s cells in an atmosphere poor in nutrients before the nucleus is extracted from them) it may happen that the same epigenetic reprogramming is not done in the chromatin as the one the donor nucleus had: in methyl groups of the DNA itself, or in modifications of the histone proteins that cover it, in the telomere of the chromosomes, etc. These differences can originate significant differences in the operation of the clone’s genes with respect to the donor.

In addition, we should take into consideration that the initial development of early cygotes and embryos is governed by the proteins inherited from the egg’s ovum via cytoplasm, not by the genes of the nucleus. And subsequently, the operation of the nucleus’ genes continues to be influenced by the cytoplasm. In both cases, the cytoplasms of the organism being cloned and of the possible clone are different, and therefore their initial stages, which are crucial for development, can be very different.

Moreover, we should take into account that the development of an embryo and the expression of its genes depend on the intrauterine environment, with the ones from the clone and the nucleus donor being different.

And what is most important in the case of human beings, that the different characteristics of living beings (especially the complex ones like “attitudes” and “aptitudes”) depend on the interaction of their genes with the extrauterine environment in which they develop: nutrition, care, education, lifestyle, etc.; and this is where more epigenetic differences -especially because they develop at different times- may exist between an organism and its possible clones.

Conclusion

If clones are not completely identical from the genetic point of view to their “parent”, and if their phenotype will almost certainly be different, should the prohibitions on reproductive human cloning be reconsidered from the biological point of view? In certain situations of infertility, accidents, diseases, etc., perhaps it should be used once the technical barriers have been overcome. It would be a technique that could be combined with others such as in vitro fertilization, but on the basis that the clone will not at all be an exact replica of the being we intend to clone, and at most a quasi-twin in physical appearance, but different in “all” other aspects.

In the end, the possibility of obtaining human clones would only pose a conflict with some social-ethical principles: the right to be a result of fate, the principle that human beings are ends, and not means, etc. But as we have seen, the process for obtaining clones is very eventful, and sometimes there are very good ends the justify the means employed. The ill-named designer babies are a clear example where apparently those principles are also contravened -the embryos are “selected” and “used” to cure another brother- and, however, a great deal of “remorse” is overcome. Perhaps something similar will happen one day with clones.

Manuel Ruiz Rejón