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Mice Created From Skin Cells

Cell Stem Cell, Nature, July 23, 2009

In a stunning announcement that has elated some people while horrifying others, two independent teams of researchers in China have announced the creation of mice from reprogrammed stem cells.

Led by Drs. Qi Zhou and Fanyi Zeng of the Chinese Academy of Sciences and Shanghai Jiao Tong University, and Dr. Shaorong Gao at the National Institute of Biological Sciences in Beijing, the separate teams of researchers have each reported the successful creation of mice not from mouse embryos, but from the adult somatic (non-stem cell) skin cells of mice. The skin cells had been reprogrammed to de-differentiate into a more primitive, pluripotent state - known as iPS (induced pluripotent stem) cells - from which entire generations of mice have now been bred.

On the one hand, the announcement offers further evidence for the obsolescence of embryonic stem cell research; but on the other hand, the announcement raises new concerns about cloning and the genetic engineering of embryos. According to Dr. Robert Lanza, CEO of Advanced Cell Technology, "The implications of this are both enormously important and troublesome. It revives many of the issues raised by reproductive cloning."

Both teams of researchers employed basically the same procedure. Using retroviral vectors to deliver 4 genes, the scientists reprogrammed mouse fibroblasts to dedifferentiate into the iPS cells which were then injected into a tetraploid blastocyst - which the scientists created by fusing together 2 cells of a fertilized blastocyst. Tetraploid blastocysts contain twice the normal number of chromosomes, a peculiar feature which renders them incapable of developing normally. Instead of being able to develop into a regular embryo, tetraploids can only develop into extra-embryonic tissue such as the placenta. By choosing to inject the iPS cells into a 2-celled blastocyst, instead of into a normal blastocyst, the researchers could be certain that any resulting embryonic development would be exclusively the result of the iPS cells. Indeed, when each of the tetraploid blastocysts containing the iPS cells was transferred into the uterus of a female surrogate mouse, not only did embryonic development occur, but 20 days later live mice were born.

The first mouse to be born was black, exactly like that from which the original fibroblast had been obtained, and unlike the white mouse from which the tetraploid blastocyst had been formed. DNA tests further confirmed that the mouse - named "Xiao Xiao", or "Tiny" - was the genetic result of the iPS cells.

Dr. Zhou's team succeeded in creating 37 iPS cell lines, three of which produced 27 live offspring - one of whom was a male who at 7 weeks of age impregnated a female who gave birth to another generation of mice. In total Dr. Zhou and his colleagues have created more than 100 first-generation mice, who in turn have by now given birth to several hundred second-generation mice, all of whom are virtually genetically identical to the original mouse from which the iPS cells had been derived. According to Dr. Zeng, who worked with Dr. Zhou, "This gives us hope for the future therapeutic interventions using patients' own reprogrammed cells in the future."

The second group of scientists, led by Dr. Gao, created 5 iPS cell lines, one of which produced 4 embryos that survived until birth, although only one of the four lived to adulthood. Nevertheless, Dr. Gao states that such results are "proof that iPS cells are functionally equivalent to embryonic stem cells."

Indeed, this point is the astonishing conclusion of the experiments, namely, that iPS cells and embryonic stem cells are the function equivalent of each other. According to Dr. Konrad Hochedlinger of Harvard University, "This clearly says for the first time that iPS cells pass the most stringent test." As Dr. Robert Blelloch of the University of California at San Francisco adds, "It's been a lingering concern, why these (iPS) cells couldn't make animals." But now, he adds, "It's further evidence that these are not some bizarre cells out there, and that they are very much like normal embryonic stem cells."

Both teams of scientists encountered some abnormalities, however, as indicated by the fact that not all of the embryos survived. According to Dr. Zeng, "We are using the mouse iPS cells to find out the answers to some basic science questions. So far we haven't detected much tumor growth on a big, global scale. But we still have a lot to do, and a lot of animals to study so we are currently working on looking at the abnormalities in these offspring." Thus far, both teams of scientists collectively have produced more than 200 second-generation offspring and more than 100 third-generation offspring.

Both processes still remain inefficient, however, as Dr. Zhou's team produced one mouse from 400 blastocysts, while Dr. Zeng's team produced 22 pups from 1,500 blastocysts. But when Dr. Zeng's group compared iPS cells that were 14, 20 and 36 days old, she and her colleagues discovered that the greatest number of live pups were born from the iPS cells that were the youngest when they were injected into blastocysts, namely, those iPS cells that were 14 days old. The oldest of Dr. Zeng's mice is now 9 months old, while Dr. Gao's are 2 months old.

As exciting and revolutionary as these accomplishments might be, however, the possibility for commercial as well as scientific abuse and exploitation has raised a number of concerns.

As Dr. Lanza adds, "With just a little piece of your skin, or some blood from the hospital, anyone could have your child - even an ex-girlfriend or neighbor, and there's nothing you could do about it. Any couple could go to an IVF clinic and have a child that is half, say, Albert Einstein or perhaps Brad Pitt or Elizabeth Taylor. This isn't rocket science. With a little practice, any IVF clinic in the world could probably figure out how to get it to work." As Dr. Lanza further adds, "Genetic modification of the resulting stem cells could be carried out by a scientist tomorrow. For instance, the technology already exists to genetically increase the muscle mass in animals by knocking out a gene known as mystatin, and could be used by a couple who wants a great child athlete."

As Dr. Jonathan D. Moreno, a bioethicist at the University of Pennsylvania, adds, "The culture wars are not over. There was a lot of celebration about the end of the ethical issues with induced pluripotent stem cells. But this is the paradigm case that shows that the old debates are rapidly being transformed into something even more complicated."

The world first learned about iPS cells in 2006 when Dr. Shinya Yamanaka of Kyoto University in Japan announced the successful creation of these cells from mouse skin. Dr. James Thomson in the U.S. then created iPS cells from human skin in 2007, and again from human blood in 2009. Although Dr. Rudolf Jaenisch of the Massachusetts Institute of Technology had tried to create an entire mouse in 2007 using the same laboratory procedure as the scientists in China, he was unsuccessful in getting beyond the late-embryo stage. As he later described, "There were two possible explanations. Either iPS cells aren't pluripotent so it was impossible, or we just hadn't tried hard enough. The first would have been more interesting, but I assumed it was the second explanation." Indeed, from these two independent teams of researchers in China, each of whom produced entire generations of mice from a single mouse fibroblast, the world now knows that iPS cells have virtually the same pluripotency and generative potential as embryonic stem cells. As Richard M. Doerflinger of the U.S. Conference of Catholic Bishops points out, "Nobody has been able to find anything that embryonic stem cells can do that these (iPS) cells can't do. This was the last remaining barrier."

Actually, there is still at least one more barrier - to the newly produced hopes and fears - which remains, and that is the reproducibility of the technique with human cells. In most countries, however, tetraploid experimentation is not allowed with human cells, so a number of questions will have to remain unaswered, at least for awhile.

And there are other technical problems which are already known. Previous studies conducted earlier this month at UCLA indicated that human iPS cells differ significantly from human embryonic stem cells in gene expression, which could have enormous implications for the translatability of iPS experiments from mice to people. According to Dr. Kathrin Plath at UCLA, "iPS cells might do things better or worse than embyronic stem cells. I don't think we know the answer at this point." Her colleague, Dr. William Lowry, therefore adds that one cannot draw any certain conclusions about human iPS cells from experiments conducted on mouse iPS cells.

The news from China was published online today in two separate journals, Nature and Cell Stem Cell.

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