Enter, the Cybrids - Printable Version

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Enter, the Cybrids - --- - 12-13-2008

Quote:Enter, the Cybrids

This week, a complex and controversial piece of legislation began to make its way through the British parliament. One of the provisions of the bill permits the creation of “savior siblings” — children created via in vitro fertilization (I.V.F.) to ensure their tissues will match those of a sick older brother or sister, in order that the new child could provide, say, a bone marrow transplant. (Conceiving a child the old-fashioned way doesn’t guarantee a tissue match.) Another is a reduction of the legal time-limit on abortion, which up to now has been 24 weeks.

A third provision — and the most controversial of all — permits the creation of human-animal hybrid embryos, or “cybrids,” for medical research. On Monday, in the first stage of passing the legislation, members of the House of Commons voted in favor. It is this third provision that I want to focus on.

Traditionally, a hybrid is the result of a mating between individuals of different species, as when a donkey and a horse mate to produce a mule. In nature, whether species form hybrids depends on many factors, including whether individuals from different species ever meet each other, whether they find each other attractive and whether they are physically able to copulate.

If mating actually takes place, several further conditions must be met. First, the sperm and egg must recognize each other, and the sperm must be able to get inside the egg. Then, the two genomes must be able to work together to build an embryo. Finally — in mammals like us with an extended pregnancy — the mother’s body needs to be able to interact correctly with the developing fetus. In these traditional hybrids half of the DNA comes from each species, and the resulting animal is a blend of the characteristics of the two.

The hybrids under discussion in the British bill are totally different. The idea is to take an animal egg — say a cow egg — and remove its nucleus. This would remove most of the cow’s DNA from the egg. Human DNA would then be introduced, and the embryo would be allowed to begin to grow. (The introduction of human DNA would normally be done by putting an entire small cell, such as a skin cell, into the animal’s egg. On being zapped with electricity, the two cells readily fuse, and the nucleus of the skin cell then becomes the nucleus of the egg.) The new nucleus thus contains only human DNA. The technical term for this procedure is interspecies somatic cell nuclear transfer, or interspecies cloning.

If the embryo were allowed to keep growing, and was then implanted into a woman, it would — presumably, and assuming nothing went wrong — grow into a baby. However, the aim is not to produce humans this way; under the new law, embryos will have to be destroyed at 14 days (the time that the embryo begins to differentiate into cells of different types). Rather, the aim is to collect stem cells from the embryos for use in medical research.

Embryonic stem cells are made in the first few days after an egg is fertilized; the reason these cells are sought after is that they have the potential to become any type of cell in the body. (There has been some progress towards reprogramming other cells to behave like embryonic stem cells; but whether these reprogrammed cells are in fact equivalent is not yet clear.) Embryonic stem cells could potentially provide treatments for diseases such as Parkinson’s and Alzheimer’s. But there is a shortage of them because the traditional way to get them comes from cultivating human eggs, and these are in short supply. Hence the interest in using animal eggs.

The idea hasn’t come out of the blue. There have been various public consultations about the procedure for well over a year: a parliamentary committee on science and technology has investigated the matter, as has the Human Fertilisation and Embryology Authority, an independent body that oversees I.V.F. and embryo research in Britain. Moreover, the general methodology — removing the nucleus of an egg and injecting a skin cell (or similar) from the same species — has already been used extensively in the cloning of cows and other animals.

Work on interspecies cloning has been also proceeding for a number of years. For example, macaque (that’s a type of monkey) DNA has been put into rabbit eggs; gaur (a kind of South Asian cow) DNA has been put into domestic cow eggs; mouflon (an exotic sheep) DNA has been put into domestic sheep eggs. Usually the experiments end before significant embryonic development takes place; in few cases have any live animals been born. (Unlike traditional hybrids, however, such animals are clearly of the species that the nucleus came from.) Most of these experiments are being done in the hopes of one day being able to rescue species that are endangered — and for which eggs are thus scarce.

Meanwhile, in several countries including China, Korea and the United States, human DNA has already been put into eggs from both rabbits and cows; in one of the experiments (with rabbit eggs), some embryonic stem cells were generated.

These results are preliminary, and it isn’t yet clear whether stem cells produced this way will behave as regular human embryonic stem cells do. The reason is that no one knows how much the animal origin of the egg is going to matter. Eggs of different species differ from one another in a number of important respects. For example, the very first stages of embryonic development are not under the control of the genome in the nucleus, but of factors in the egg. The nuclear genome does not immediately get switched on; the timing of the switching differs from one species to the next. For example, it starts at the two-cell stage in mice, the four-cell stage in humans, and the eight-cell stage in cows. In rabbits, it happens gradually. Whether such differences will cause problems remains to be seen.

And there’s something else as well. A moment ago, I said that removing the nucleus of the egg would remove “most” of the animal DNA. Importantly, it does not remove all of it. Some DNA is not stored in the nucleus, but in small entities in the cell’s cytoplasm known as mitochondria. The reason is that once upon a time, mitochondria were free-living bacteria, so they retain the remnants of their original genome.

In and of itself, the mitochondrial genome is tiny. Where the main human genome is 3 billion base pairs of DNA long, the mitochondrial genome is a mere 16,500. But that doesn’t mean it doesn’t matter: mitochondria play several crucial roles in the cell, and faulty mitochondria are linked to a large number of human diseases. Worse, mitochondria exist in many copies. A mammalian egg may contain as many as 200,000 mitochondria; each of these will have at least one copy of the mitochondrial genome.

Inserting a human cell into an animal egg does, therefore, create a kind of genetic hybrid, for most of the mitochondrial DNA will be of animal origin. (A little will be human, for the skin cell will have brought some with it. Hence the term “cybrid” — for cytoplasmic hybrid.) At least some interspecies clones have run into problems because of a failure of the DNA in the nucleus to communicate correctly with the DNA in the mitochondria; in the gaur-cow fusion, for example, problems between the mitochondria and the nucleus led to a variety of abnormalities in the embryos as they began to grow.

It may be that no human stem cell lines will be produced from such work. But even if they are not, in the course of it, we will learn an enormous amount about fundamental aspects of how embryos develop. This in itself may lead to insights about how to treat diseases, or to any number of important discoveries we cannot foresee.

So, what are the objections? Some object on religious grounds, arguing that the creation of human-animal hybrid embryos is an assault on human dignity and the sanctity of human life. I disagree: I think a tiny clump of cells in a dish does not have equal standing with a person. Moreover, if that tiny clump of cells can potentially lead to treatments that improve peoples’ lives, it seems to me that the sanctity of human life is better respected by following that potential, not preventing it.

Others object on practical grounds, arguing that it may not work. To them, I say: is it right to cut off a line of investigation because it might be unsuccessful? Whether or not this technology leads swiftly to the development of treatments, it seems to me to be worth investigating: without doing the experiments, we can’t find out if the idea is useful.

Another objection: fear that the experiments could lead to new infectious diseases. And it is true that the human genome harbors sleeping viruses — known as human endogenous retroviruses. Might these wake up on finding themselves in a new cellular surrounding? Maybe; but this can be monitored, and in any case, the risk seems remote.

When, a couple of years ago, I first imagined putting a nucleus from one animal into the egg of another, I found the idea unsettling. But that was because I was imagining something different: I had in mind the growing of animals, not the creation and swift destruction of a clump of cells. I worried that animals produced this way might not be normal. But then I learned more about the procedure and how it is done. Also, in the course of making a television program about biotechnology, I visited laboratories working with stem cells, and I was impressed by what we have already managed to achieve.

Now my discomfort has gone away. It’s been replaced by wonder. We’ve already learned a great deal about the ultimate construction of life as a result of the experiments done so far. But more than that, the fact that it’s possible at all to put one creature’s DNA into another creature’s cell and have the two work together at all is amazing — and another sign of the common evolutionary heritage of ourselves and the other beings on the planet.



For a summary of the bill, go here.

The parliamentary investigation into the pros and cons of human-animal hybrids can be read here.

This includes discussion of the shortage of human eggs, and potential objections to the work, including the three objections I raise at the end of the article.

The public consultation by the Human Fertilisation and Embryology Authority can be read about here.

For progress in making stem cells from other tissues, see Takahashi, K. et al 2007. “Induction of pluripotent stem cells from adult human fibroblasts by defined factors.” Cell 131: 861-872.

For a review of the hurdles and potential benefits of interspecies cloning, and for a list of the combinations that have been tried as well as successful live births, see Beyhan, Z., Lager, A. E., and Cibelli, J. B. 2007. “Interspecies nuclear transfer: implications for embryonic stem cell biology.” Cell Stem Cell 1: 502-512.

For human DNA being put into cow eggs in Korea, see Chang, K. H. et al 2003. “Blastocyst formation, karyotype, and mitochondrial DNA of interspecies embryos derived from nuclear transfer of human cord fibroblasts into enucleated bovine oocytes.” Fertility and Sterility 80: 1380-1387; in the USA, see for example, Illmensee, K., Levanduski, M., and Zavos, P. M. 2006. “Evaluation of the embryonic preimplantation potential of human adult somatic cells via an embryo interspecies bioassay using bovine oocytes.” Fertility and Sterilty 85 (S1): 1248-1260. For human DNA into rabbit eggs in China, and the generation of stem cells, see Chen, Y. et al 2003. “Embryonic stem cells generated by nuclear transfer of human somatic nuclei into rabbit oocytes.” Cell Research 13: 251-263.

For a review of how mitochondria may influence the outcome of interspecies cloning, for the timing of the nuclear genome being switched on in different species, and for coining of the term ‘cybrid’, see St John, J. and Lovell-Badge, R. 2007. “Human-animal cytoplasmic hybrid embryos, mitochondria, and an energetic debate.” Nature Cell Biology 9: 988-992. For the role of mitochondria in human disease, see Wallace, D. C. 1999. “Mitochondrial diseases in man and mouse.” Science 283: 1482-1488. For mitochondrial difficulties in the gaur-cow hybrid, see Mastromonaco, G. F., Favetta, L. A., Smith, L. C., Filion, F., and King, W. A. 2007. “The influence of nuclear content on developmental competence of gaur x cattle hybrid in vitro fertilized and somatic cell nuclear transfer embryos.” Biology of Reproduction 76: 514-523. For the number of mitochondria in mammalian eggs, see Reynier, P. et al 2001. “Mitochondrial DNA content affects the fertilizability of human oocytes.” Molecular Human Reproduction 7: 425-429.

I have complete faith that there is no secret dabbling with this technology going on...yes, complete faith that hugely wealthy medical and military combines under the sway of private financial interests have no interest in letting cybrid - animal human hybrids gestate until full term.

There are no experiments to create Chimeras happening. Sleep well at night, the ancients only had vivid imaginations.

Quote:Differences between Cybrids and Chimeras
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by Christopher Scott

Cybrids (cytoplasmic hybrids) are made by fusing or transferring a human nucleus into an animal egg stripped of its DNA (a process called nuclear transfer). The human embryonic stem cells made from this method could be used for research purposes. This week, the UK government approved the creation of hybrids, subject to oversight by the Human Fertilization and Embryo Authority, HFEA.

In their decision, they said:

Having looked at all the evidence the Authority has decided that there is no fundamental reason to prevent cytoplasmic hybrid research. However, public opinion is very finely divided with people generally opposed to this research unless it is tightly regulated and it is likely to lead to scientific or medical advancements.

Cybrids are distinct from chimeras, which are commonly used in biomedical research. Here are a few different types of chimeras, taken from a report by the House of Commons Committee on Science and Technology, which recommended the approval. Common kinds of chimeras include heart patients with replacement valves taken from pigs; mice made with two different kinds of mouse cells, and animals made by combining cells of different species. The Geep was one of the first of the interspecies chimeras, made at the University of California, Davis, in 1985.

sorry my mistake. Nothing to worry about