What if the game changes again? Perfect ES models in sight

Author: Paul Krzyzanowski, 11/21/12


While the 2012 US election was in full swing, I reminded readers that despite the dominance of the world’s economic problems in this cycle, stem cell research was a political issue that hadn’t completely gone away.

Ironically, if – and this is a big IF – the iPS work plays out, every cell in our body has the potential to result in a human. Is every cell, from a symbolic perspective, now an embryo?” – Timothy Caulfield

Methods to generate induced pluripotent stem cells (iPS cells) have constantly improved over the past few years, elegantly positioning iPS cells as the ethical stem cell of choice when ES-like models are needed. Those same advances blur the line between iPS and ES cells and are making iPS cells such good models of ES cells that soon they might be indistinguishable in terms of multipotency.

As one example of this, I described live mice being generated from mouse iPS cells through a method called tetraploid complementation. In this technique, the combination of tetraploid ES cells and normal diploid iPS cells can end up producing a live mouse that is completely composed of normal diploid cells, most likely from the iPS cells. Tetraploid ES cells end up as extra-embryonic tissues like the placenta, showing that ES cells aren’t needed to form the embryo proper.

This is a great ethical solution to breeding genetic mouse models in that it generates the desired mice in a single generation instead of creating many chimeric mice, most of which aren’t used for research purposes.

Meanwhile, while iPS cell manipulation technology improves, ethical and legal conversations also unfold. I wanted to ask a few experts in this realm about their opinion on the future of iPS cells in the ELSI space.

Will iPS cells move into the same space as ES cells?

If iPS cells in tetraploid complementation studies are considered a reliable source of cells for organism development, will a debate on the moral status of human iPS cells in these experiments ensue?

I asked Tim Caulfield at the Alberta Health Law Institute whether he thought so. For the most part, he told me that science and society have moved on from the initial stages of discovery when cloning became a household word.

“The developments with iPS cells won’t have the same pop culture traction as the work with embryos and gametes,” suggests Caulfield. “There was so much hype associated with the first embryo work and it became politicized almost immediately.”

The philosophical question of iPS cell identity as it relates to human development, which I had considered when interviewed about the original article, was also raised by Caulfield: “Ironically, if – and this is a big IF – the iPS work plays out, every cell in our body has the potential to result in a human. Is every cell, from a symbolic perspective, now an embryo?”

Rosario Isasi at the Centre of Genomics and Policy at McGill University takes a more guarded approach.

“The discovery of iPS cells was considered a scientific breakthrough that would eliminate major socio-ethical and legal concerns that beset human ES cell sources,” says Isasi, who believes iPS cells remain ethically benign. “It has been argued that iPS cells do not pose significant ELSI [ethical, legal and social issues] challenges beyond those already encountered in the general ‘genetic’ research context.”

“Having said that, the possibility of reprogramming such cells back to their origins re-introduces the ’embryonic’ issues,” Isasi added.

Moira McQueen, Director of the Canadian Catholic Bioethics Institute, argues that the main problem with a human tetraploid complementation assay is still the use of hES cells in the process, and not the contribution of iPS cells.

“The ethical point wouldn’t be altering the state of the adult cell, but whether or not [human] ES cells would be used in the process,” says McQueen. “A moral problem arises every time [human] ES cells are used.”

What happens if researchers change the game yet again and devise ways to transform iPS cells from ES cell counterparts to their lab-grown alter ego?

So ethical experts more or less agree that iPS cells, in isolation, don’t pose the same ethical conundrums as their ES cell counterparts. The strongest claims preventing iPS cells from truly being considered ES cells’ equivalent is that they still require ES cells to shepherd development of an organism.

This might not always be the case: What happens if researchers change the game yet again and devise ways to transform iPS cells from ES cell counterparts to their lab-grown alter ego?

Are totipotent iPS cells within reach?

An exciting report in Nature this summer may blow current ethical positions out of the water, with claims that totipotent cells in iPS cultures can be detected.

Macfarlan et al. claim to have identified a transient cell population within mouse ES and iPS cell cultures expressing transcripts found only in two-cell (2C) embryos. The important feature of cells at this stage of development is that they are totipotent.

Tagging ES cells in this 2C-like state shows that they lack the pluripotency proteins Oct4, Sox2 and Nanog, which are normally expressed in the inner cell mass (a pluripotent state).

It’s remarkable that Macfarlan et al. show that cells in this 2C-like state have acquired the ability to contribute to both embryonic and extraembryonic tissues, which iPS cells in tetraploid complementation experiments aren’t capable of doing. The clincher of this report shows that cells in cultures of both ES and iPS cells cycle in and out of this privileged state.

The critical question of whether the 2C-like iPS cells are totipotent remains unanswered, and I’m willing to bet that multiple research groups are trying to demonstrate just that.

If iPS cells can truly be made totipotent, it will be ironic development indeed: the same techniques that solve ethical problems in mice will reopen much larger ones in humans.

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Paul Krzyzanowski

Paul is a computational biologist and writer living in Toronto. He's been a contributor to Signals for three years, writing articles for the general public about how biotechnology and biomedical research can be used to solve pressing medical problems. Alongside Paul's experience in computational biology,
 bioinformatics, and molecular genetics, he's interested in how academic research develops into real world, commercial technology, and what's needed for the Canadian biotech industry needs to grow. Paul is currently a Post-doctoral Fellow at the Ontario Institute of Cancer Research. Prior to joining the OICR, he worked at the Ottawa Hospital Research 
Institute and earned a Ph.D. from the University of Ottawa, specializing in computational biology. And finally, Paul earned an H.B.Sc. from the University of Toronto a long time ago. Paul's blog can be read at www.checkmatescientist.net
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