Stem cells from human-animal hybrids 'unlikely'
By Andy Coghlan Hopes of producing a limitless supply of embryonic stem cells from hybrid human-animal cells this week met serious challenges. Genes thought to be key to stem-cell development appear not to be switched on in the hybrids, suggesting the controversial idea will be harder to pull off than hoped – and may not work at all. Embryonic stem cells (ESCs) are prized for their ability to turn into any type of cell in the body, but at the moment they can only be obtained from donated human embryos, which are in short supply. Removing the nucleus from an animal egg cell and replacing it with a nucleus from an adult human cell has been proposed as a way to obtain a limitless supply of human ESCs. The hope is that chemical signals from the egg’s mitochondrial DNA can “reprogram” the nucleus, causing it to revert to an embryonic state and produce ESCs that have the same DNA as the adult donor. If the donor has Alzheimer’s, say, the hybrid embryos – dubbed cybrids – might one day be used to make brain cells for implantation in the donor to replace damaged tissue, without the risk of provoking an immune response. In 2001, Bob Lanza of Advanced Cell Technology in Worcester, Massachusetts cloned an endangered wild cattle species called the gaur using a cow’s egg. This proved the technology, but whether it can work if the nucleus and egg are from more distantly related species is still in question. To find out, Lanza examined the profiles of gene expression in embryos derived from cybrids, from donated human eggs containing the nucleus of an adult human cell, and from donated human embryos. To make the cybrids, his team fused nuclei from adult human ovarian cells with enucleated eggs from mice, rabbits and cows. The analysis, which used DNA microarrays to reveal which genes had been activated and which silenced, showed that the pattern of expression was virtually identical in the human cloned embryo and the natural embryo. Crucially, three genes known to be vital for reprogramming the nucleus back to the embryonic state were all activated. These genes are called nanog, Oct-4 and Sox-2. This raises the hope that human-human cells, at least, might go on to provide a viable source of personalised ESCs. In the animal-human hybrids, however, the three genes were silent. The rest of their patterns of gene expression were also very different to those of ordinary human embryos, with the rabbit-human hybrids differing in the expression of 2379 genes and the cow-human hybrid differing in 2950. The hybrids also failed to develop to the crucial blastocyst stage of about 100 cells, which must happen if stem cells are to be obtained. The mouse-human hybrids stopped development after the very first division, forming just two cells in total, while the rabbit-human and cow-human hybrids stopped dividing at the 8-to-16 cell stage. The researchers conclude that although mitochondrial DNA in the cybrid eggs can direct the initial division, it doesn’t produce the signals to fully reprogram the nucleus. As a result, Lanza is sceptical that cybrids will ever be a usable source of therapeutic ESCs. “There’s no reprogramming towards the embryonic state,” he says. “These discordant combinations of species are dead on arrival.” Others dispute this conclusion. Stephen Minger of King’s College London, and a UK researcher given approval to make cybrids, believes that Lanza’s findings are far from the last word. He says that some of the key genes may get switched on eventually, if cybrids are allowed to divide further. While Lanza’s cybrids stopped dividing before this stage, Minger takes encouragement from a paper that raises this possibility (Cloning and Stem Cells, DOI: 10.1089/clo.2007.0084). The paper comes from a team led by Sheng Huizhen of Shanghai Jiao Tong University in China. Sheng is best known for a 2003 paper claiming to have created muscle and nerve cells from rabbit-human cells, a result viewed with scepticism as no one has been able to reproduce it. Sheng now reports that some of the cybrids her team had created from human skin cells and cow eggs made it to the blastocyst stage and switched on the crucial nanog, Oct-4 and Sox-2 genes. Though less than 1% of the 3000 cybrids created did this, Sheng suggests that this fraction might be increased by adding human signalling chemicals to enhance the reprogramming process. Journal reference: Cloning and Stem Cells (DOI: 10.1089/clo.2009.0004) More on these topics: