An Examination of Therapeutic Cloning and Cybrids
Experimentation needs practical, ethical guidelines
The creation of interspecies human-animal embryos is the latest, extreme attempt to exit from a line of research caught in a blind alley: Somatic Cell Nuclear Transfer (SCNT), the procedure used to give birth to Dolly the sheep.
Dolly's birth in 1997 and the production of the first line of human embryonic stem cells the following year, seems to have opened wide the doors to a new therapeutic strategy that consists in the exchange of cells and tissues irreparably damaged by illness without recourse to — though not always possible — organ transplants, which avoids problems of compatibility and rejection.
Embryonic stem cells are totipotent: they can produce any type of tissue (muscular, cardiac, bone, nerve, etc.). By using embryonic stem-cell lines with the same genetic patrimony of an adult individual, therefore, it would be possible to produce and transplant every type of tissue, fully compatible with the damaged organ to be repaired by substituting it for the pathologically damaged tissues.
The SCNT cloning method seems to respond exactly to this goal: a female gamete, or an oocyte, has its nucleus removed and substituted with the adult somatic cell of an individual of the same species. The thus modified and suitably stimulated oocyte will begin to behave as a fertilized oocyte, developing until a complete individual originates, and with a genetic patrimony almost entirely identical to the somatic cell donor.
In a word, it is an exact copy of the stem-cell donor, but not its perfect clone: in fact, in the enucleated oocyte the mitochondria remain, the corpuscles responsible for the cellular energy cycle, with its own DNA belonging instead to the original oocyte donor.
Scientists' 'gold rush'
The SCNT technique applied to animals in the last 10 years has had an extremely low efficacy rate, never above 2 percent: for example, in December 2006, the fact that three puppy dogs were born from 167 cloned embryos was considered a great success.
Recent news reported in the daily newspaper "Independent" on the SCNT embryonic cloning of macaque [Old World monkeys], when compared with scientific publications, confirms, as foreseen, the scarce efficacy of the technique: 100 cloned embryos implanted in about 50 female macaque did not result in a single pregnancy.
SCNT applied to man is commonly called "therapeutic cloning", to specify that the cloning was not aimed at the birth of the human being (reproductive cloning) but to produce embryonic stem-cell lines to use for therapeutic purposes.
Hence, it the cloned embryo has reached the blastocyte stage, its stem cells in the first days of its development would be extracted from those cell lines that would then be used in future therapies. But this method kills the embryo.
The technique has proved a total failure: if for animals the efficacy is slim, for humans it is simply nil.
To date there does not exist in the world a single human embryonic stem cell extracted by "therapeutic cloning". In recompense, in these years we have witnessed a true and proper "gold rush" among researches aimed at being the first to cross the threshold of human cloning.
The most striking result was that of Korean veterinarian Hwang Woo Suk, with the largest scientific fraud of all time: the announcement in the prestigious "Science" journal of having accomplished an impressive 11 staminal embryonic lines compatible with some illnesses affected by various pathologies (diabetes, spinal marrow injuries, immune deficiency). In the following months it was discovered that the results were falsified, that no cloning had taken place and that many of the oocytes used were obtained under pressure and payment from researchers of the same research group as Hwang.
The human cloning failure
Scientific articles often discuss why this technique fails. Many hold that the difficulty arises from the fact that few oocytes are available in humans. A greater number of oocytes can be obtained through the successive hormone treatment cycles for medically assisted procreation: they are cumbersome, lengthy, invasive and dangerous procedures that some women are ready to face in order to obtain a pregnancy unobtainable by natural means, and from which it would be difficult to provide materials for scientific research, especially if the procedure proved unfruitful.
It is already evident that a sufficient quantity will never be available, even where more or less surreptitious payment for ceding one's own oocytes to research is tolerated or permitted.
From this came the idea to substitute, in the SCNT, human oocytes with animal ones, the usual rabbit or cow available in almost unlimited quantities. Animal oocytes and human somatic cells: the entity that should be obtained with "therapeutic cloning" is an interspecies human-animal embryo, precisely a cytoplasmic hybrid embryo (also called "cybrid"), whose nuclear genetic patrimony is human, and whose mitochondria are totally or partially animal.
The new organism that would be created would therefore be an entity non-existent in nature, obtained by surmounting the barrier between human and animal species. The so-called hybrid embryo would be "prevalently" human, with 99.9 percent human genetic patrimony (due to the nuclear DNA), and with 0.1 percent animal genetic patrimony (through the mitochondria) DNA).
But it is known that in genetics one cannot speak in terms of percentage: the genes are not equivalent among themselves, there exists a hierarchy and priority with many having a function that is unknown, and often even the malfunctioning of a single gene can irreparably compromise the development of an organism.
To treat the genetic patrimony in purely numerical terms is totally improper. The public debate that has developed concerning this new being has thus far shown an incapacity to define it: human, animal or something else?
Even more doubts and perplexities arise from the scientific viewpoint: regarding the feasibility of the experiment and the possibility that this type of research would be usable in some way.
To date, there is only one scientific publication that claims this is a feasible path; the journal "Cell Research". In 2003, it published the description of the first experiment of the kind. It is the work of a Chinese scientist, where cells of different individual humans were fused with rabbit oocytes until embryonic staminal lines were created.
But to date, no scientific research team has been able to repeat the experiment, not even the same team who authored the original scientific publication.
What is more: the famous embryonic stem-cell researcher Robert Lanza, of Advanced Cell Technology, declared in the "New Scientist" journal of 15 September 2007 that his team worked at length to produce this type of embryo, but in vain. At the 16-cell stage, immediately prior to the blastocyte stage, the development always stopped. According to Lanza, it was probably due to incompatibility between the genetic patrimonies belonging to the different species that ceased to "dialogue among themselves".
Furthermore, if the technique of mixing nuclear and mitochondrial DNA of individuals belonging to the same species does not work (as shown to date with "therapeutic cloning"), why should mixing the DNA of different species work?
If an improvement in efficacy is expected solely by a numerical increase of available oocytes, then someone must explain why such improvement has not happened to date in animal cloning, where there are no impediments in the availability of oocytes, much less ethical and legal ones.
Doubts and perplexities
Concerning the possibility of using mixed human-animal cell lines to study degenerative illnesses, one should remember that in many of these pathologies mitochondrial metabolism is also involved, which in this case would prove altered.
One can ask how it is possible to take a human-animal hybrid cell as a model, where the mitochondrial functionality does not correspond to any existing living model since it is altered from the beginning with respect to both animal and human models, and to consider this model valid for human illnesses that are due to a pathological alteration of its functionality.
And more generally, one asks why a future system of mixed human-animal cells, of which nothing is known, would be the more efficient model than the animal model, even if modified with the techniques whose efficacy has brought, for example, the Nobel Prize to Mario Capecchi and his colleagues.
There is then a question of safety. The English Medical Academy, in the document "Interspecies embryos: A report by the Academy of Medical Science", declares itself in favour of the creation of this type of hybrid embryo and speaks of a "highly improbable but not impossible" scenario: surmounting the inter-species barrier could mean passing retrovirus possibly contained in the animal oocytes to the human being.
On the other hand, even the supporters of this line of research recognize that future mixed stem-cell lines of this kind could not be used clinically, specifically because of contamination with biological materials of animal origin.
Therefore, the doubts and perplexities of this type of experiment are many and consist above all from the viewpoint of the feasibility of the research itself and the results it could reasonably attain, and this should be clarified even before facing the thorny bioethical problem of creating a new human-animal hybrid.
Indeed, intellectual honesty would demand that, instead of many promises of cures and possible future therapies, an explanation of the actual situation be given, without selling the skin of the bear before it is cloned.
Weekly Edition in English
28 November 2007, page 15
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