Strange landscapes

Is there a way to somehow connect the fields of organic chemistry and epigenetics? It seems that these are apples and oranges, but I will try to come up with an angle on this Monday night. Let’s go to the Nobel Prize awarded for Physiology or Medicine in 2012. The recipients, Shinya Yamanaka and John B. Gurdon were rewarded for their contributions to the field of stem cell biology. Here is a “Cliff’s Notes” summary of what Yamanaka did. The ES (embryonic stem) cell corresponds to the top of the “Waddington’s landscape” shown below.


Differentiation into a myriad of cell types found in various tissues is akin to the ball shown above sliding down one of the valleys. The discovery of induced pluripotent stem cells is what Yamanaka’s lab is known for. He and his students found that there is a simple combination of protein factors that can take a differentiated cell (at the bottom of the landscape) and reprogram it back into the pluripotent state on top of the diagram. This was a remarkable discovery no one wanted to believe at the time of its disclosure. It took Jaenisch’s lab to reproduce Yamanaka’s experiments for the research community to buy into induced pluripotency.

A conceptual relationship with organic chemistry would be to consider a bizarre class of reactions with bifurcated transition states. Ken Houk and colleagues published a very interesting review in Angewandte several years ago:

Bifurcated reactions are characterized by a divergence of pathways that somehow reminded me of the Waddington’s landscape today. In a particularly thought-provoking paper, Dean Tantillo recently demonstrated that the bifurcation concept is relevant to terpene biosynthesis:

While some might say that this is a rather obscure and esoteric concept, I find this whole bifurcation business to be fascinating. Just think about it: there are reactions lurking out there in which knowledge of the transition state during the rate-determining step is not predictive of the ultimate pathway. So let me ask you: how many times you were “sure” (by doing careful kinetic experiments) about the nature of the slowest step in your reaction and were utterly perplexed when the experimental selectivity was difficult to explain? It does not happen too often, but I think we can all recall some bizarre situations like this. Might we suspect bifurcation in a subset of such occurrences? Let’s face it, more often than not, we have very little clue about the mechanism (recall what George Olah likes to say: “One can never prove the mechanism of a reaction. One can only disprove it”). And now we have bifurcation on top of that? This whole business starts to remind me of Don Rumsfeld’s memorable quote about the “unknown unknowns”:

I am not a fan of this man, but there is something I can take from his statement.

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