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ISIS Report 28/03/11

Unacceptable Death Rates End Cloning Trials in New Zealand

Government lab announced the end to cloning eight years after the scientist who pioneered the technique abandoned it for precisely the same reasons Dr. Mae-Wan Ho

Please circulate widely and forward to your political representatives

Final curtains on animal cloning?

“Unacceptable death rates” forced New Zealand national science agency AgResearch to end its trials on cloning animals [1]. But it will continue to create more genetically modified (GM) animals using a new research method.

The agency has issued reports – obtained by The Dominion Post under the Official Information Act - documenting chronic arthritis, pneumonia, lameness and blood poisoning among the causes of death in cattle, sheep and goats.

The reports include trials on genetically modified (GM) animals for producing “super milk” as well cloned animals. Cloning and genetic modification are closely linked (see [2] Cloned Meat & Milk Coming, Be Very Afraid, SiS 50).

Applied biotechnologies general manager Jimmy Suttie said that the decision was made after 13 years of study to find out how to prevent abnormalities in cloned animals, and “enough is enough.”

Nuclear transplant cloning causes high rates of death and abnormalities

Cloning by nuclear transplant (NT) involves transferring the nucleus of a cell from the adult or developing embryo into a mature egg that has had its nucleus removed. The reconstituted eggs are activated to develop, and the resultant embryos are implanted into surrogate mothers. The technology is highly inefficient and has been known to involve horrendous deaths and deformities in clones and surrogate mothers alike.

In 2003, Ian Wilmut, who pioneered the technology abandoned it for cloning animals [3] (Death Sentence on Cloning, SiS 19), stating that he would use NT only for creating human cells for tissue repair and for studying human diseases. However, the discovery that ordinary human cells could be induced to become stem cells had made NT completely redundant [4].

In NT cloning of normal non-GM animals, at most 10 per cent of cloned embryos selected for implantation survive the trials [1]. (In terms of total embryos made by NT, it would be about 1 percent.)  The main problems were spontaneous abortions and hydrops, where the surrogate mother’s uterus fills up with water, and the animal has to be put down.

The New Zealand Animal Ethics Committee reported 16 foetuses or calves from mid gestation onwards spontaneously aborted or died in the neonatal period in 2010. Another 10 foetuses or calves had to be euthanized along with 14 cows.

Genetic modification without cloning?

Although cloning trials have been abandoned, AgResearch would continue to develop transgenic cattle, sheep and goats. Suttie said new technology using embryonic stem cells to create transgenic animals was unlikely to cause the same death rates as cloning.

However, the research has only begun four months ago. In 2010, two out of 12 kids delivered at term in a trial to develop transgenic goats died at birth. One suffered from chronic arthritis in its front legs. Four other animals died or had to be euthanized in another trial to produce transgenic cattle.

Suttie said AgResearch’s work would benefit New Zealand. The trials include creating animals that will produce proteins with pharmaceutical benefits. One goal was to produce a drug like Herceptin more cost-effectively and make it readily available. Herceptin is a monoclonal antibody drug for treating certain breast cancers costing $100 000 a year, but is controversially associated with a high risk of death from heart disease [5].

The announcement to end cloning from AgResearch lacks credibility in view of its continuation with developing transgenic animals. All the signs are that GM and cloning go together, given that the original motivation for NT was to create ‘elite herds’ of GM animals to produce drugs in their milk [2]. It is also why NT cloning is continuing in the US.

A potential alternative route to creating cloned transgenic animals is via genetic modification of cells that could then be turned into induced pluripotent stem cells (iPS cells) [4]. The iPS cells are then injected into a tetraploid embryo made by fusing the two cells of an ordinary embryo at the two-cell stage with an electric current so that the resulting cell has four complements of chromosomes (tetraploid) instead of the usual two (diploid). Such tetraploid embryos would not develop into organisms, except when embryonic stem cells or iPS cells are implanted into them. The embryo itself would then develop from the iPS cells while the tetraploid cells give rise to extraembryonic tissues. This procedure has been carried out with some success in the mouse [6], although it is still unclear whether it would work in another species. So far, iPS cells have yet to be created from livestock.

Published studies confirm high death and failure rates in NT cloning

Cloning efficiency by nuclear transfer, measured as the proportion of selected cloned embryos transferred into surrogate mothers that survive into adulthood, is 9 percent at AgResearch, according to a study published from the agency in 2009 [7]. The proportion surviving to term is 14 percent, but further losses occur before weaning. These figures compares unfavourably with IVF where approximately 30 percent develop into healthy calves at weaning.

Poor survival of cloned embryos is generally attributed to the unpredictable nature of NT-induced reprogramming of the donor nucleus and the marked changes in epigenetic identity and transcription pattern of the hybrid egg cell. These reprogramming reactions are initiated in the cytoplasm of the egg cell immediately following the transfer of the donor nucleus. Although some of the necessary genes for reprogramming are known, it is still impossible to predict or influence cloning efficiencies in any reliable way.

Microarray analyses showed substantial differences between the transcriptomes (the totality of transcripts) of NT vs fertilized or artificially activated embryos. Over 95 percent of genes were reprogrammed, but no distinct set of consistently mis-expressed genes were found in NT embryos. Proteomes (the totally of proteins expressed), with its many low-abundance proteins and often carrying post-translational modifications, are more difficult and complex to analyse, and have not been profiled comprehensively in NT clones.

No correlation between cloning efficiency and state of differentiation of donor cell

The hypothesis that cloning efficiency is inversely correlated with the differentiated status of donor cell could not be confirmed. Once the zygote (fertilized egg) starts to develop, and divides into smaller cells called blastomeres, reprogrammability declines. In the mouse, there is a clear decline in cloning efficiency between the 4 to 8 cell stage; as consistent with the notion that individual four- but not eight-cell mouse blastomeres are still totipotent, i.e., able to give rise to all embryonic and extraembryonic cell types. Thus, using nuclei from the zygote versus cumulus cells (that surround the developing egg cell in the ovary) gives cloning efficiencies of 34 vs 3 percent, and using nuclei from a 4-cell embryo vs foetal fibroblasts  results in cloning efficiencies of 43 vs 3 percent.

According to the same hypothesis, stem cells, which are undifferentiated, and multipotent (capable of giving rise to more than one cell type), should give higher cloning efficiencies than differentiated somatic cells; but this has failed to be confirmed by extensive experimentation. Cultured ES (embryonic stem) cells are notorious for epigenetic instability and accumulation of chromosomal abnormalities, which make them unreprogrammable. Patterns of DNA methylation (a common form of gene marking) and expression of imprinted genes (genes expressed according to whether they come from mother or father) vary widely between ES cell lines and between subclones of a given ES cell line, and even individual cells in a subclone.

Stem cells and progenitor cells (arising from stem cells but before they differentiate into definite cell types) were evaluated as nuclear donors in seven different somatic lineages  -  antler, adipose tissue, blood, bone marrow, muscle, brain and skin - and four different species: mouse, cattle, pig and deer.  This represented 10 percent of the total number of different mammalian cell types. There was no substantial improvement in cloning efficiencies of stem cells over somatic cells. The researcher summed up [7]: No conclusive correlation [between cloning efficiency and state of differentiation] was found, indicating that the somatic donor cell type may not be the limiting factor for cloning success.”

Hopes pinned on new stem cells

However, considerable hope has been pinned on a new method of creating pluripotent stem cells that are capable of producing all the cells of the embryo except for the extraembryonic tissues.

Induced pluripotent stem cells (iPS cells) are obtained after somatic cells are transduced (infected) with a vector expression a set of special transcription factors. Such iPS cells are practically indistinguishable from embryonic stem (ES) cells in morphology, gene expression and pluripotency. The researcher considered such cells “the most promising candidates for future somatic NT experiments,” and stressed “the importance of deriving these cells in livestock species.”

It is not clear whether the new experiments mentioned by the Dominion Post [1] on creating transgenic animals were done with iPS cells. If so, the high rates of death and abnormalities have hardly diminished.

It is time to end all attempts to create GM animals or to clone animals by nuclear transplant. It is unacceptable in terms of animal suffering and the serious hazards to health as [2].

References

1. “Animal death toll ends cloning trials”, Kiran Chug, The Dominion Post, 21 February 2011, http://www.stuff.co.nz/national/4681283/Animal-death-toll-ends-cloning-trialshttp://www.stuff.co.nz/national/4681283/Animal-death-toll-ends-cloning-trials

2. Ho MW. Cloned meat & milk coming, be very afraid. Science in Society 50 (to appear).

3. Ho MW and Cummins J. Is FDA promoting or regulating cloned meat and milk? Science in Society 33, 24-27, 2007.

4. Okita K, ichisaka T and Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature 2007,  448, 313-8.

5. Trastuzuma b, Wikipedia, 14 February 2011, http://en.wikipedia.org/wiki/Trastuzumab#Side_effects

6. Boland MJ, Hazen JL, Nazor KL, Rodriguez AR, Gifford W, Martin G, Kupriyanov S ad Baldwin KK. Adult mice generated from induced pluripotent stem cells. Nature 2009, 461, 91-96.

7. Oback B. Cloning from stem cells: different lineages, different species, same story. Reproduction, Fertility and Development 2009, 21, 83-94.

There are 1 comments on this article so far. Add your comment
Rory Short Comment left 29th March 2011 17:05:29
Natural evolution has led to humans being able to be conscious. Thus, as we are the products of nature, not its overlords, the most beneficial use of our consciousness would be to use it to work as junior partners with nature in a genuinely cooperative fashion, not as beings functioning independently from nature, which has been how the bulk of humanity has operated up until now. To me the cloning of animals is an excellent example of the misuse of our consciousness.

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