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How many cofactors for inducing expression of every cell type?

Another revolution in iPSC technology announced:

"Also known as iPS cells, these cells can become virtually any cell type in the human body -- just like embryonic stem cells. Then last year, Gladstone Senior Investigator Sheng Ding, PhD, announced that he had used a combination of small molecules and genetic factors to transform skin cells directly into neural stem cells. Today, Dr. Huang takes a new tack by using one genetic factor -- Sox2 -- to directly reprogram one cell type into another without reverting to the pluripotent state."

-- So the method invented by Yamanaka is now refined to rely only 1 cofactor and b) directly generate the target cell type from the source cell type (skin to neuron) without the stem like intermediate stage. 

It also mentions that oncogenic triggering was eliminated in their testing. Now comparative methods can be used to discover other types...the question Sox2 critical for all types? It may be that skin to neuron relies on Sox2 modulation but say skin to lung or heart to kidney cell might require different numbers or combinations of factors.

It's true that parsimony is on our side (I posit that "overloading" is the default state for evolutionary selective innovation over "overriding" as a form of selective polymorphism) so there may be a few modulation channels so to speak that Sox2 uniquely controls...but there are so many known cell types that there must be crossing with other key controls.  I hypothesize, that with over 200 cell types...the minimal number of cofactors required to uniquely express all types directly should be such that variation per co factor is low multiplied by number of cofactors accounts for at least a minimum of 200 (or the number of unique cell types across the life stages of a human being). So , (3)^5 or (2)^8 or (4)^4.

Conservation of energy would be the overriding constrain that determined how one combination of factors gave rise to the evolution of new cell types by modulation of the cofactors but the question of which pattern of cofactor polymorphism was most effective. Did the cofactors get "overloaded" with functionality (exponent) more than they were "overridden" (mantissa) ?? The vagaries of selective processes in the early life forms from which the original variation in cell types I fell would hold the key.

In correlation with this theory is the fact that the cofactors thus far being used to induce pluripotency have been based on 6 gene families (myc,klf,cox,lin28,nanog,oct3/4), which could cover all cell types with only 3 exponent hops...assuming those are indeed the base variations. The fact that various combinations induced cancer formation seems to indicate that not all of them may be or that they must be modulated in complex temporal ways in order to avoid cancer formation.

Whatever the correct minimal number of cofactors involved, I suspect they go way back to the Cambrian age and thus the associated pathways are highly conserved. It will be interesting to see what the actual algorithm of pluripotency turns out to be, my bet is on overriding being more important than overloading so of the three I bias for combinations that have larger exponents as they are more likely to generate new cell lines during cross modulation with minimal effort (time/energy) during a natural selection process.


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