In The Field

AAAS 2010: Different on the inside

They may look the same, and behave the same — but under the surface pluripotent stem cells are not the same. That was the message coming from a well-attended AAAS session this afternoon.

After sitting through some pretty heavy science policy sessions, it feels good to get back to some solid biology, and stem cell heavyweights including Rudy Jaenisch and George Daley of MIT provided a flavour of where the field stands some four years after induced pluripotent stem (iPS) cells swept through it.

Human iPS cells in theory offer all the advantages of embryonic stem (ES) cells — pluripotency, or the ability to give rise to virtually all cell types and hence repair damaged tissue — without the technical and ethical minefields in which ES cells are mired. The hope is that researchers can take a patient’s skin or blood cells, reprogram them into iPS cells, convert those into whatever cells are needed and voilá, medical problem solved with the patient’s own cells.

Jaenisch says that as far as he’s concerned one problem in the field — how to reprogram cells into a pluripotent state without leaving behind bits of the molecular machinery used for the reprogramming — is more or less “solved”, with studies showing less and less invasive ways to do it. Needless to say other problems are not. And one of these is that pluripotent stem cell lines are, under closely scrutiny, remarkably different.

Jaenisch talked about recent work in which his group split a population of human embryonic stem cells into two: they grew one in an environment containing 20% oxygen and one in an environment of cellular ‘stress’ containing 5% oxygen. They expected to see dramatic differences in the two cell lines: hence the “disappointment” when global gene expression was more or less the same, the fact that “we got desperate” when methylation and chromatin were pretty much the same. But the group found differences in the way that the X chromosome is inactivated. The ES cells grown in 20% oxygen had one inactive X chromosome (cells normally inactivate one X chromosome during embryonic development), whereas the stressed cells in 5% oxygen appeared to have kept both X chromosomes active.

The bottom line is that even if two ES cell lines appear by most measures of function and gene expression to be the same, the different ways in which they were derived and grown may have left profound effects on molecular aspects of the cells.

This finding is important to the iPS cell field, where one major question is whether iPS cells have the same properties as ES cells, the gold standard. The various human ES cell lines used by researchers were derived in different labs using different methods. So if various cell lines all lumped together as ES cell lines are actually molecularly different under the surface, then what exactly is the gold standard researchers are using as their reference point? “We really need to define: what is the ground state of pluripotency,” Jaenisch said.

Daley picked up the theme, talking about experiments from his lab showing that iPS cells derived from skin or blood have some lingering molecular marks of the tissue from which they were derived. “We’re starting to appreciate the degree of heterogeneity in reprogrammed cells,” he said.

So what? Does it matter if iPS cells are not identical to ES cells — arguably what’s important is whether or not scientists can use the cells to make the liver or blood cells needed to treat disease. The question came up in discussion, and Daley makes the case that researchers “need a fundamental understanding of what we’re working with”. The concern is that cells with some undefined molecular state, placed in a particular niche in the body, might be predisposed to tumour formation or some other unwanted behaviour. Researchers need to keep probing deeply into the cellular state, he says, adding, “People will argue with me on that”.

A skeptic might say that this sounds like an argument to understand everything about basic stem cell biology before scientists even go near a human therapy. This seems unlikely given how much of cell biology there is still to understand, and the push to show clinical benefit from stem cell research. Besides, how are you going to define everything that is different about two cell lines when researchers might not even know what the important differences are, or perhaps even how to measure them?

Enough biology. Now back to that science policy.


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