July 29, 2010
Two papers published online recently in Nature journals indicate that the technology to produce iPS cells (induced pluripotent stem cells) is still a work in progress, but also highlight the confusion among journalists and even some scientists about stem cells—iPS cells, embryonic stem cells (ES cells), and Adult stem cells..
iPS cells provide a relatively easy and inexpensive method for creation of ES-type cells directly from virtually any tissue source or individual. They were first developed in 2006 in mice by the Japanese scientist Shinya Yamanaka, and in November 2007 both Yamanakas lab and the lab of James Thomson in the U.S. showed that this same technique could work for human cells as well. The original technique to reprogram a normal to become an iPS cell involves adding four genes directly to a human cell such as a skin fibroblast cell, with the genes added using a viral vector.
The iPS cells behave like ES cells, but the technique does not use embryos, eggs, or cloning, making it an ethical way to produce “pluripotent” stem cells (cells that potentially might form any body tissue.) In contrast, the usual way to produce ES cells is by taking an embryo (produced by the normal process of fertilization, or by cloning, a.k.a. “somatic cell nuclear transfer”) and destroying the embryo to extract the ES cells (that’s why they’re called “embryonic” stem cells.)
[Click on the figure to enlarge]
One question that has been posed ever since iPS cells were first announced, is whether iPS cells are truly identical to ES cells. Besides looking and growing like ES cells in the lab, iPS cells have passed all the usual tests for ES cells to demonstrate their pluripotent character:
-formation of teratomas containing various cell types when injected into mice
-expression of “pluripotency” genes
-formation of chimeric mice, and even whole mice, when combined with other cells to form new mouse embryos
-differentiation in the lab to form specialized cells
Both of the new papers (Kim et al., rushed into online publication in Nature, and Polo et al. published online in Nature Biotechnology) compare mouse iPS cells against mouse ES cells on a deeper molecular level. Both groups found that iPS cells retain a sort of “memory” of their origins, at least for a while. Methylation of DNA, while not changing the DNA sequence itself, provides markers of which genes are turned on or off. These are “epigenetic” (as opposed to genetic) differences. The newly-created iPS cells retained some of these epigenetic marks from their tissue of origin, e.g., blood, skin, or muscle. When the researchers tried to make blood cells from the iPS cells, the ones whose origin was blood could make blood cells much more easily than the iPS cells from other tissues, actually easier than ES cells, but by the same token those iPS cells made from blood had a more difficult time making other tissues. Their residual “epigenetic memory” helped them return to their tissue of origin, but hindered their formation of different tissues.
Those results indicate that iPS cells do retain some memory of their original tissue. This would make it easier to study a particular disease in the lab if the iPS cells were made from that tissue, but could limit their use for other tissues or diseases (different iPS cells for different tissues or diseases might be preferable.)
Interestingly, the Kim et al. paper also went to the trouble of making cloned mouse embryos from which ES cells were harvested (“cloned” ES cells). In the comparisons, the “cloned” ES cells were more similar to traditional ES cells than were the iPS cells, though still not identical. The use of cloning (somatic cell nuclear transfer) seemed a contrived add-on to make a political point. Nature’s blog picked up on the political message, and in fact, that political message was delivered in some of the interviews. George Daley of Harvard said:
“Stem cells generated by somatic cell nuclear transfer are on average, closer to bona fide embryonic stem cells than are iPS cells. This has an important political message—we still need to study the mechanisms by which nuclear transfer reprograms cells, because the process seems to work more efficiently and faithfully. Learning the secrets of nuclear transfer may help us make better iPS cells.”
In point of fact, both papers show that the “memory” differences seen in the iPS cells gradually disappear with further time in culture, and/or with chromatin-modifying chemicals.
This was highlighted by the senior author of the Nature Biotechnology paper, Konrad Hochedlinger, who said:
“Our paper comes to a similar conclusion that a retention of memory reflects the cell of origin and affects the capacity of the iPS cell to differentiate into other cell types. When we let the cells go through a lot of cell divisions, they lose the memory.”
Daley himself (a co-author of the Nature paper that added on the cloning aspect), admitted in a less political moment that the “memory” aspect of iPS cells could be overcome for their use:
Its a challenge to be understood and overcome. We already have strategies for overcoming this.”
“This study in no way challenges the usefulness of IPS cells. They remain enormously valuable.
So the results are an interesting wrinkle in the continuing saga of iPS cells, indicating that freshly-made iPS cells need some maturing in the lab before they truly resemble ES cells.
But the media are still confused on the subject of stem cells. For years there were only ES cells (made by destroying embryos) and Adult stem cells (taken from tissues without harming the donor), then along came iPS cells. While iPS cells are made from adult cells and tissues, they behave like ES cells; they are certainly NOT adult stem cells. But some still can’t get the facts right.
For example, Newsweek had this erroneous title:
“Developments in Adult-Stem-Cell Research; Adult stem cells have memories”
Likewise, the Washington Times misleading title:
“Adult stem cells said to ‘forget’ retooling”
And ABC News got their title right but bungled the interpretation in the text, leaping from adult cells for iPS to adult stem cells that are currently used to treat diseases. They also included a quote from an embryonic stem cell scientist that indicated even he didn’t understand the topic of the story (iPS cells from adult tissues, not adult stem cells):
“The take home message is that what stem cell biologist have been arguing for years is true — that we need to continue studying both stem cells, because we don’t know which cells can be used for which applications,” said Sean Morrison, director of the Center for Stem Cell Biology at the University of Michigan.
See the figure for the differences in stem cell types.
And take this link if you want to see some real patient applications of ADULT STEM CELLS.