20.109(F10):Jonathan Gootenberg and Arvind Thiagarajan

Stem cells have long held promise in biological and biomedical research. Through their natural ability to maintain their own population while restoring lost or damaged somatic cells, they have provided us with glimpses of possible treatments, treatments for almost any disease. After all, no matter what goes wrong in a biological system, one can imagine wiping the slate clean and restoring the system with stem cells, provided the integrity of the stem cells is maintained. For this and other reasons, control of stem cells, and in particular stem cell differentiation, has remained an important area of study in biology.

Unfortunately, the signal pathways within stem cells are fairly complex, and not easily understood. The original goal of stem cell research, i.e. to elucidate all these signal pathways and manipulate them by the addition of specified amounts of appropriate chemical species, has become more or less infeasible. There is, however, another option. Stem cells sense external signals and use these to determine when to differentiate, and in what manner. It is worthwhile to notice that the latter ability is much more relevant to biomedical applications than is the former. As such, if we can construct a mechanism by which to bypass the sensory circuits of stem cells and interface directly with their differentiation circuits, we should be able to artificially drive differentiation. It is for this reason that we are interested in the engineering of synthetic circuits in stem cells. By engineering circuits that respond to our own, synthetic inputs, we can drive differentiation in stem cells without interacting with natural intracellular processes overmuch.

Research in synthetic genetic networks that control differentiation has been conducted in the past. For example, Dr. Sairam Subramanian, a former graduate student in the laboratory of Ron Weiss, published his dissertation on such a network that he constructed in murine embryonic stem cells. In particular, he constructed a synthetic toggle switch which, in one of its steady states, acted by producing a differentiation-promoting factor. He showed that the toggle worked as expected, allowing for synthetic control of the differentiation of the mouse embryonic stem cells.

There are many different types of stem cells which we might try to engineer for our purposes. However, recent research indicates that induced pluripotent stem cells (IPSCs) are particularly promising for regenerative medicine. Unfortunately, there seems to be a close link between stem cells and tumorigenicity, and the tumorigenic potential of IPSCs is comparatively high (http://onlinelibrary.wiley.com/doi/10.1002/stem.37/pdf). This presents a potential challenge, as tumorigenic cells cannot in good conscience be used for therapy.

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Subramanian, S.. Synthetic gene networks for differentiation of mouse embryonic stem cells. Ph.D. dissertation, Princeton University, United States -- New Jersey. Retrieved November 18, 2010, from Dissertations & Theses: Full Text.(Publication No. AAT 3305309).