MADISON, Wis., Nov. 20 -- In a remarkable tour de force, scientists reported today they can transform ordinary adult skin cells into stem cells, a development that promises to quell the debate over the use of embryos in disease research.
These induced pluripotent stem cells appear to be identical to embryonic stem cells, according to James Thomson, D.V.M., Ph.D., of the University of Wisconsin here, who unleashed a storm of medical, religious, ethical, and political controversy when he first coaxed stem cells from human embryos in 1998.
Action Points
- Explain to interested patients that embryonic stem cells have the ability to grow into any of more than 200 tissue types in the body, making them potentially useful for a range of clinical and research applications.
- Note that research has been controversial because the cells are derived from human embryos discarded in the course of in vitro fertilization.
- Explain that these studies suggest that such cells can also be obtained by reprogramming adult skin cells, which would tone down the ethical uproar over embryonic stem cells.
The new findings, Dr. Thomson said during a press conference, should lower the temperature of the stem cell debate, although researchers will still need to make use of embryonic stem cells, which he described as "the gold standard" against which new cell lines will be measured.
He added that "these new cell lines would not have been possible without the last 10 years of human embryonic stem cell research."
Dr. Thomson and colleagues, as well as a team from Japan, reported that fully differentiated adult cells can be reprogrammed to give them the essential characteristics of embryonic stem cells.
The new cells, which have the potential to develop into any form of adult cell, could have eventual applications in clinical research, drug development, and transplant medicine, Dr. Thomson and colleagues reported online in Science.
Their findings build on previous results by Shinya Yamanaka, M.D., Ph.D., of Kyoto University, and colleagues, who showed last year they could reprogram adult mouse cells and get pluripotent cells. They have now duplicated that research using human fibroblasts, Dr. Yamanaka and colleagues reported online in Cell.
Both teams used a similar method, in which somatic cell nuclear transfer was employed to put genes from mammalian oocytes into adult cells. This caused them to revert to an undifferentiated state.
The Japanese group used the same genes they had employed in the mouse experiments -- Oct3/4, Sox2, Klf4, and c-Myc -- and were surprised to find that they worked, Dr. Yamanaka said.
Because human embryonic stem cells differ from those in mice, Dr. Yamanaka said, he and colleagues had suspected "other factors might be required to generate human-induced pluripotent stem cells.
Dr. Thomson said he and colleagues tried the Japanese formula but "couldn't make it work."
So they used another set of four genes, including two of those used by the Japanese (Oct4 and Sox2) and two different ones (NANOG and Lin28), he said.
Junying Yu, Ph.D., also of the University of Wisconsin, said the first two genes appear to be essential to the process, while the remaining two are "beneficial" -- improving the efficiency of the reprogramming.
"Four is not a magic number," she said, and further research may find a set of genes that does a better job than either of those.
The new cell lines, while possibly easing the stem cell controversy, don't have any immediate clinical value, Dr. Thomson said.
"Everything has changed and nothing has changed," he said. On one hand, the new cells are not derived from human embryos, so the ethical firestorm should die down.
On the other hand, all of the technical hurdles that have slowed clinical applications using embryonic stem cells also apply to the new cells, he said.
"The big challenges are not solved by doing this," he said, although one issue -- immune rejection of stem cell-derived transplants -- is "probably solved."
"The thing that's hard is understanding the disease you're trying to cure and putting cells in the body in a way that actually corrects that disease," he said.
He added that the new cells still need to be checked very carefully to ensure that no unsuspected danger is lurking.
The cells behave like embryonic stem cells, dividing apparently without limit and expressing the cellular markers found on natural stem cells.
But to integrate the four genes into the cell nucleus, the researchers used a lentivirus vector. In some cases, that virus might cause mutations that could lead to disease.
That wouldn't be a showstopper, Dr. Thomson said, because there are other ways to integrate genes into a cell's genome, but it could be another barrier to clinical use of the cell lines.
The Japanese approach also faces a hurdle, because one of the genes used -- c-Myc -- is a known oncogene.
On the other hand, the cells could soon be useful in drug development, Dr. Thomson said. Embryonic stem cell lines are limited in number and tend to come from a small sector of the population, so they're not representative enough to be used to test drugs.
But this method would allow researchers to generate a series of cell lines representative of the whole population, he said.
| The Wisconsin study was supported by the Charlotte Geyer Foundation and the NIH. Dr. Thomson reports financial links to Cellular Dynamics International and Stem Cell Products.
The Japanese study was supported by the National Institute of Biomedical Innovation, the Ministry of Education, Culture, Sports, Science, and Technology, the Uehara Memorial Foundation, and the Japan Society for the Promotion of Science. The researchers did not report any potential conflicts. |
Secondary Source
SciencExpress
Yu J, et al Science 2007; DOI: 10.1126/science.1151526.
Additional Source
Cell
Source Reference: Takahashi K, et al "Induction of pluripotent stem cells from adult human fibroblasts by defined factors" Cell 2007; DOI: 10.1016/j.cell.2007.11.019.