Sixth in a series of posts inspired by ten topics in ‘Insights of the Decade’ from the December 17, 2010 special issue of Science Magazine The topics are: Inflammation, climatology, tricks of light, alien planets, the microbiome, cell reprogramming, Martian water, the DNA time machine, cosmology and epigenetics. The original articles are now behind a paywall; they won’t be reproduced here, but their gist is present. I’ll try to put them in context and also within the Impact Areas of SciTechStory.

“Researchers are also working to understand exactly how reprogramming works.” That statement from the Science Magazine article could tell you a lot about the state-of-the-art. One way of putting it: Mostly art, not much state. When a geneticist or cell biologist ‘reprograms’ a cell, what they mean is that they change the genetic instructions, in the DNA mostly, so that the cell changes into a different kind of cell. These days, a lot of the reprogramming has one goal – creation of stem cells. Especially taking an adult cell, let’s say a skin cell, and reprogramming it so that it is a cell that can become almost any other kind of cell (a pluripotent stem cell).

Stem cells have been in and out of the mainstream news, mostly because of the controversy over their origin, which used to be exclusively from the tissue of human embryos. In particular, the culture of the United States has a remarkably large portion of the population engaged in preserving the ‘right to life’ even for non-living embryos that in the usual course of things were destined for disposal but a few of their cells were salvaged for embryonic stem cell research. For religious and ethical reasons, the use of embryos for anything remains controversial and more or less illegal in several countries.

Stem cells have enormous medical promise. Because they are unformed and undeveloped, they can be and have been used to help repair many kinds of tissue (heart, muscle, liver, skin). The number of applications is growing exponentially. Unfortunately, the controversy and consequent difficulties in working with stem cells has made research and especially clinical trials difficult. When presented with this problem, scientists immediately started to wonder about ways of circumventing it. The answer, it seems, is reprogramming.

The idea, which is much easier to express than do, is to take an ‘adult’ cell (a cell already fully committed to being, say, a skin cell) and by tweaking its DNA, turn it back into a stem cell. Specifically such a cell is called an induced Pluripotent Stem Cell or iPSC. The foundation for this work was laid by John Gurdon in the 1960s and was part of the research on cloning. Cloning is almost as controversial as stem cells, but most of the work has been to develop genetic techniques, not produce clones per se. The techniques mostly involved inserting various elements of DNA either into a ‘blank’ (enucleated) cell or into the existing DNA of a cell.

In the mid-oughties Shinya Yamanaka and his team demonstrated that by adding just four genes to an adult mouse cell, they could produce a viable iPSC. Further refinements followed quickly. These days researchers are finding multiple ways to reprogram cells of various types not only into pluripotent stem cells but, skipping the development process, into other kinds of adult cells. Put another way, this could mean doing the work of stem cells without using stem cells – the post stem cell era.

What’s important is that reprogramming cells isn’t just a way around the ethical controversy over embryonic stem cells; it is a different way of approaching genetics, cell biology, and medicine. It straddles the boundaries of permanent gene modification and therapeutic manipulation. Most of the reprogramming does not affect reproduction (cell meiosis). Scientists have mostly shied away from that. Some of the reprogramming doesn’t even carry over when the cell reproduces (mitosis). Nevertheless, this kind of genetic manipulation exposes a realm of experimentation into the why’s and wherefore’s of DNA and genetic reproduction. Most scientists envision this as a gateway to understanding the origin of many diseases (cancer always being the example).

Now let’s return to the opening point: Scientists don’t fully know how reprogramming works. This is another of those very important pieces of science and technology where we ‘just do it.’ What pops into my mind is how we ‘just did it’ with nuclear fission, but that’s an unfair comparison, I hope. In any case, there are some warning flags going up. Studies have demonstrated that some of the reprogramming approaches increase the risk of cancerous cell growth. Other studies point to problems with the quality (meaning potential for side effects) of the induced stem cells. Even the difficulty in producing reprogrammed cells (typically only very small percentage successfully reprogram) may indicate that there are fundamental issues that are not yet understood.

There is the suspicion that while reprogramming can produce obvious and useful changes in a cell, the underlying situation is more complicated. Research is discovering that while genes provide the ‘blue print’ for cell construction, there is an equally important process of transforming genetic instruction into the proteins and other materials of the cell. This includes new fields of study such as DNA configuration (the presentation of DNA elements for development), proteomics (the study of proteins), and especially epigenetics (which considers, among other things, how genetic instructions are adapted to fit the environment of the cell). This research work suggests that while genes can be tweaked and some results are obtained, the results may not be stable, predictable, or durable.

In short, what we don’t yet know about cell biology may well turn out to place limits on the effectiveness of cell reprogramming. This would not be the first time that a ‘highly promising’ development in biology and medicine turns out to be useful but not revolutionary (or whatever hyper-optimistic word). Actually this is mostly how advances in science proceed; the curve of experience over the years tends to flatten the perceived dramatic effect of a new technique or procedure.

Stem cells and cell reprogramming will continue to have a major impact on research. In fact, just getting beyond the need for embryonic stem cells would be a big improvement. We’ll track that work at SciTechStory in the areas of DNA Decoding, Genetic Modification, Stem Cells, Proteomics and Cell Biology. Occasionally there will also be clinically proven and reliable applications. However, this appears to be one of those areas of science where the betting on widely effective applications shouldn’t fall to the side of the over optimistic.