Article in Seminars in Cancer Biology · April 2008 doi: 10. 1016/j semcancer

Development and carcinogenesis: Taking sides over underlying premises

and research programs

As François Jacob noted, nature is not an engineer, but a tinker— a given molecule is put to

different uses during evolution [62]. Thirty years after this famous dictum was coined, the

concept of signal specificity, central to the original version of the SMT is being challenged

because of the massive experimental evidence revealing the multiple interactions of a given

protein with other proteins. Early during the molecular biology revolution, the lack of a unique

correlation between a given protein and its function was addressed by Hull as the problem of

“the many and the many” [63]. In other words, one phenotype could result from several

different molecular mechanisms, while a single gene may participate in the generation of

multiple, distinct phenotypes. A clear example of this divergence is polyphenism, i.e., a single

genotype producing several different phenotypes. That single proteins display multiple

activities and a single genotype generates diverse phenotypes argues against reductionist

explanations in multicellular organisms.

A couple of examples in the field of developmental biology also point to the difficulties

encountered by embracing the notion of specificity for each signal and for each pathway in

determining a phenotype. A compelling example stems from studies in mice generated through

cloning by nuclear transplantation; these studies showed that altered gene expression involving

as many as a staggering 4% of a set of 10,000 genes resulted in a normal phenotype at the cell,

tissue and organ levels of complexity [64]. This indicates a significant degree of tolerance of

abnormal gene expression compatible with normal development.

Another example relates to the validity of the “instructive” hypothesis of differentiation.

Hormones and cytokines are supposed to determine a specific phenotype in target cells by

inducing a lineage-specific gene-activation program. The specificity of the response was found

not to reside in the hormone, its receptor, or the signal transduction pathway [65]. The

specificity of the response appeared to be determined, instead, by an apparently unrelated

differentiation process. Again, this observation points to the lack of a unique, exclusive

correlation between a given protein and its biological functions. The promise that the specificity

of the effect of a given hormone could be understood by the study of interactions between the

receptor and the hormone, and the subsequent activation of the transduction pathway

downstream, has yet to be fulfilled. Specificity is to be found elsewhere [64].

The limitations of the reductionist, bottom-up approach in dealing with complex biological

phenomena, like carcinogenesis, stresses instead the heuristic advantage of searching for

explanations at the level of organization at which a phenomenon is observed, while gingerly

moving up and down levels of organization to account for bottom-up and top-down causation

[15,66].