Today three papers came out, two in Nature, and one in the inaugural edition of Cell Stem Cell, that basically confirm the results from last year's landmark manuscript by Kazutoshi Takahashi and Shinya Yamanaka (for details on this paper, see this post).
Just to remind you, in that original publication Takahashi and Yamanaka describe how they reprogrammed connective tissue cells (called a fibroblasts) into stem cell like entities, by introducing four active genes (Oct3/4, Klf4, Sox2 and c-Myc). The resulting iPS cells (induced pluripotent stem cells) could differentiate into any number of cell types when injected into adult mice. At the time, the authors could not show that these cells could participate in the formation of a new organism, in other words there was no proof that the cells could become any cell type (i.e. totipotent).
Well by adjusting the protocol for generating these iPS cells, the Yamanaka lab, the Jaenisch lab and a collaborative effort between the Hochedlinger and Plath labs have been able to get totipotent version of these cells. What does that mean? Well if you were to inject these iPS cells into embryos at a time when all cells in the organism are totipotent (i.e. the blastocyst), these exogenous cells can incorporate into the developing mouse fetus. Only embryonic stem cells (i.e. totipotent cells) have this ability to participate in development. Furthermore, the Yamanaka and Jaenisch labs also demonstrate that the iPS cells incorporated into the organism's germ cell line (i.e. oocyte and sperm cells). The iPS derived germ cells can combine to form animals that were derived solely from iPS cells. In the third paper they only show that the iPS cells get into the germ cell line. Thus these iPS cells are the equivalent to embryonic stem cells.
To reiterate, somatic cells can be transformed into embryonic stem cells!
There are several incredible aspects to this cellular reprogramming:
- Only four transcription factors are needed, thus the reprogramming involves some genetic algorithm that is relatively easy to activate.
- The reprogramming process (or dedifferentiation process) takes a long time, up to three weeks!
- At this stage the reprogramming is relatively inefficient, so that only 1/1000 cells that receive the four genes make in through the reprogramming process.
- The reprogramming seems complete. In fact the authors of the third paper report that in female iPS cells, the somatically silenced X chromosome is reactivated.
And so ... the expression of these four genes is the equivalent of hitting the Ctrl + Alt + Delete buttons on a PC. Once hit, a long and complicated program is executed that eventually leads to a total reprogramming. Now we just have to understand what is the nature of this algorithm.
Here is a little clip of Marius Wernig, the co-first author on the Jaenisch paper (and a member of our Bookclub) explaining the morphological changes that accompany the reprogramming process:
Other questions:Why is the reprogramming inefficient? Does reprogramming happen
in mammalian cells naturally in mammals? Will this reprogramming work with any cell type? With human cells?
Overall, an incredible achievement.
(On a personal note, congrats Marius and Kathrin, great work!)
Marius Wernig, Alexander Meissner, Ruth Foreman, Tobias Brambrink, Manching Ku, Konrad Hochedlinger, Bradley E. Bernstein & Rudolf Jaenisch
In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state
Nature (07) Advanced Online Publication doi:10.1038/nature05944
Nimet Maherali, Rupa Sridharan, Wei Xie, Jochen Utikal, Sarah Eminli, Katrin Arnold, Matthias Stadtfeld, Robin Yachechko, Jason Tchieu, Rudolf Jaenisch, Kathrin Plath, and Konrad Hochedlinger
Directly Reprogrammed Fibroblasts Show Global Epigenetic Remodeling and Widespread Tissue Contribution
Cell Stem Cell (07) 1:55-70
For some excellent videos of Dr Jaenisch explaining the science and all its implications click here (videos are on the right).
Here is the NBC nightly news's interview on Marius and others:
Yeah I just watched it ... Marius did well.
Really amazing stuff... There was alot of excitement over this in the McIntyre today from a staggering array of people. Parkinson's researchers down the hall were jumping up and down practically.
Does the fact that they used transgenes not strike anybody? This would be more amazing iff they could reprogram cells without using transgenes.
Wow, a fantastic result! There's optimism in the air again!
Thus these iPS cells are the equivalent to embryonic stem cells.
I'm afraid I have to disagree with you Alex. These are not equivalent to ES cells. They have a problem with oncogenic transformation, and the retroviral transfer of genes is going to be problematic.
It's a big step, but it's still incomplete. Don't oversell this, it's irresponsible.
It was more of a problem with the mice in the Yamanaka paper. I'll have to read the details (or ask Marius) whether oncogenic transformation was common in the other two papers. As for the induction of the genes ... once they figure out how to boost the conversion efficiency and how long the four genes have to be on to trigger the reprogramming, then they'll devise strategies to activate the genes transiently - in fact they could inject the 4 mRNAs ...
That's what I wanted to see. But this is by no means a complete cure for the ES cell problem. It will be heralded as such by the adult stem cell hypers, I'm sure.
I would like this to be accomplished by mRNA injection, protein injection, or maybe by tet-activated transcription. Until then it suffers from obvious problems that will limit its therapeutic potential.
Does reprogramming happen in mammalian cells?
According to the rest of your post: yes, ;-).
What I find astounding is the fact that seemingly the level of transcription of the four factors doesn't matter too much. Either there are some post-transcriptional mechanisms establishing the appropriate protein level for each factor or the important parts are in trans, i.e. being defined by the presence and occupancy of the respective binding sites.
Thanks sparc, I changed that line.
Getting the "Goldielocks" level of expression may be the reason that only 1 in 1000 cells get reprogrammed. We'll have to wait and see.
It is too late. The right wing will not "wait to see". Instead they are already using this development as a talking point to further restrict research on embryonic stem cells. Soon their goons and trolls will be blasting the blogs with the news that "adult stem cells have been turned into totipotent stem cells" without regard to the details.
(Of course they won't use that terminology).
I don't think that the government would be able to restrict embryonic stem cells research easily cause there are some points that you guys commented whether naturally ES cells have a reprogramming process as do iPS cells, those iPS abilities are absolutely equal to true ES cells originated from embryos or in fact all researches on ES cells nowadays all discover the characteristics of the cells naturally have. If they cannot prove these topics clearly, I have to say we still need to support embryonic stem cell research as iPS cells in order to compare their properties and thereafter making a decision to use or not to use them for medical treatments in human. This is because I don't really think that those researches we have done so far all answer the nature of ES cells.