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.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

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

  1. Dr Nagourney,

    Thank you for your insight in service to humanity.

    Sadly, we have set sail toward the Brave New World of medicine for money all things are billable.

    The “surface dwellers” are willling to charge massive amounts of money for unproven medicine.

    Let’s see “unproven medicine for a profit.” Sounds like the definition of the word quackery.

  2. Rich66 says:

    There is no more applicable phrase than “The Devil is in the details.” There is a reluctant humility involved in submitting to the concept of “Whatever works.” vs “Whatever my theory suggests will work.”
    Functional profiling may not be the “perfect app”, but perhaps the least presumptive and least flawed approach available at the moment. That should be ground enough for a hearty embracing.

  3. Jackie says:

    A gentleman has been active on my online breast cancer support group promoting the concept/practice of functional profiling. He just posted this link on our Board and I thought I would post my ‘sudden’ realization:

    Function profiling can be compared to tradition Chinese medicine which used trial-and-error data that’s been proven to be effective in treating certain ailment. At first, the ‘traditional’ Western medicine thought it was nonsense (the ‘rationale’ of ‘Chi’ and other stuff). After many years, the ‘scientists’ began to analyze and conduct experiment/trials to find out the reason behind the ‘curing power’ of those practices.

    One method (function profiling, Chinese medicine) is interested in the practical side of treatment (on site experiment), the other (traditional Western method) wants to find out the why and how so it can be replicated in mass volume and potentially unlocking certain key issues in biology…

    I truly think these different methods complement each other. And I truly hope that incorperating the two will speed up the process of finding a cure.

    • My response is similar to one I provided to a later comment. I agree that we do not always understand why things work. To some degree we must be content with the knowledge that they work. As has been said in different contexts most recentty by Sam Broder, former head ofthe NCI “The search for a perfect Aids (Cancer) therapy should not prevent the search for a good AIDS (cancer) therapy” .

      Thanks

  4. Rich66 says:

    I think trial and error data (Chinese or Western) along with cancer theory (Chinese or Western) are distinct from functional profiling which is less about generalizations, more about personalization. Similarly, genomics is touted as personalized medicine when it still operates on generalizations about how cancer might behave given a certain signature. Functional profiling doesn’t much care about that. More of a proof is in the pudding concept. At least that’s my take on it.

    • The use of Chinese herbal remedies are exemplary, to some degree, of results trumping mechanisms. Many natural products are active against cancer but few of their modes of actions have been elucidated at the molecular level. We should remember that Digoxin (for heart failure-known as dropsey), Penicillin and Aspirin all worked well (for centuries) with no one having any idea why. Medicine is a science of keen observation. The tendency of modern molecular biologists to insist that we know why and how things work is only slowing down drug development. We should be more focused upon the phenomenon of cancer and less focused upon its etiology.

      Thanks for your comment.

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