Has the Era of Genomics as we Know it Come and Gone?

I have often described my personal misgivings surrounding the application of gene profiles for the prediction of response to therapeutics. My initial concerns regarded the oversimplification of biological processes and the attempt of analyte-driven investigators to ascribe linear pathways to non-linear events.

The complexities of human tumor biology, however vast, took a turn toward the incomprehensible with the publication of a lead article in Nature by the group from Harvard under Dr. Pier Paulo Pandolfi. (Poliseno, L., et al. 2010. A coding-independent function of gene and pseudogene mRNAs regulates tumor biology. Nature. 2010 Jun 24; 465(7301):1016-7.) I sat in as Dr. Pandolfi reviewed his work during the Pezcoler Award lecture, held Monday, April 4, 2011, in Orlando at the AACR meeting.

What Dr. Pandolfi’s group found was that gene regulation is under the control of messenger RNA (mRNA) that are made both by coding regions and non-coding regions of the DNA. By competing for small interfering RNAs (siRNA) the gene and pseudogene mRNAs regulate one another. That is to say that RNA speaks to RNA and determines what genes will be expressed.

To put this in context, Dr. Pandolfi’s findings suggest that the 2 percent of the human genome that codes for known proteins (that is, the part that everyone currently studies) represents only 1/20 of the whole story. Indeed, one of the most important cancer related genes (known as PTEN, is under the regulation of 250 separate, unrelated genes. Thus, PTEN, KRAS and, for all we know, all genes, are under the direct regulation and control of genetic elements that no one has ever studied!

This observation represents one more nail in the coffin of those unidimensional thinkers who have attempted to draw straight lines from genes to functions. This further suggests that attempts on the part of gene profilers to characterize patients likelihoods of response based on gene mutations are not only misguided but, may actually be dishonest.

The need for phenotype analyses like the EVA-PCD performed at Rational Therapeutics has never been greater. As the systems biologists point out complexity is the hallmark of biological existence. Attempts to oversimplify phenomena that cannot be simplified, have, and will continue to, lead us in the wrong direction.