Poor Science; Poorly Trained Scientists; Poor Policies: Major Deterrents to the War on Cancer

There has been significant progress resulting from NIH funding of grants in support of cancer research since 1946; when it began funding extramural research grants.  Over that period, the limitation of progress in the war on cancer has been described as being due to insufficient funds for cancer research grants. Yet, even with increased funding, the contemporary progress in the war on cancer has been deterred mainly by poor NIH policies that contribute to poor science and poorly trained scientists. This is the issue that is rarely considered and discussed related to the scientific and clinical quality of the funded medical research; i.e. “the return on the investment”.

Dr. Elias Zerhouni (Director of NIH from 2002-2008) cautioned that the “Federal investment needs to be tied to the societal needs of the day. Otherwise, you risk academic isolation, or living in some theoretical realm… Patients measure, better than anybody, the value of research… Any consideration of the value of research that does not take the customer into account is doomed. You’ve lost the debate if you lose sight of the taxpayers and the patients.” (https://nihrecord.nih.gov/newsletters/2013/06_21_2013/story1.htm)

This concern arises from the development of technology that facilities molecular biology (genomics, molecular genetics, molecular regulation of cell activities) which has become a dominant requisite for the approval of drugs for cancer treatment and prevention for the past 35 years. This has been driven by the NIH extreme emphasis on molecular biology, which has been hailed as the best approach leading to diagnosis, prevention, and treatment of cancer; and which is then adopted by virtually all agencies that fund cancer research.

Dr. Zerhouni added “The problem is that it hasn’t worked, and it’s time we stopped dancing around the problem… We need to refocus and adapt new methodologies for use in humans to understand disease biology in humans.

The failure of the molecular biology dominance is also described in the 2004 article, “Why We’re Losing the War on Cancer (And How to Win it)” (Leaf C. Fortune. 2004 Mar 22;149(6):76-82).  The article reveals that “PubMed identified 1.56 million published papers; largely on this circuitry (i.e. molecular biology) and its related genes in hundreds of journals over the years. (When including articles not listed in PubMed, this number is more than 2 million.)  PubMed also identified an extraordinary 150,855 experimental studies on mice… Open any major journal and 80% of it is mice or Drosophila or nematodes… few if any having an impact on human cancer.” I would add that these numbers have probably doubled since 2004.

Despite its failure, the overwhelming funding for cancer research continues to be directed for molecular biology studies. That approach and its funding have replaced the funding for the highly successful holistic organ-systems physiological/pathophysiological understanding of cancer issues. Dr. Zerhouni acknowledged this concern in stating “What new areas of science do we need to focus on that have a lot of promise to them, but may need NIH encouragement? Systems biology is one… Solving the puzzle of complex diseases will require a holistic understanding of the interplay between factors such as genetics, diet, and infectious agents.”

This holistic approach dominated cancer research and virtually all areas of medicine over the period of the initiation of NIH extramural research grant funding in 1946 until the major development and progression of molecular biology beginning around 1980. That was a period of major advances in the cellular and organ-systems metabolic/physiological/pathophysiological relationships in cancer.

When applied appropriately, molecular biology studies become an important discipline to be integrated into the holistic understanding of the normal and dysfunctional operation of the human body.  I have employed such technology and information in many of my studies.  Unfortunately, this has not been inculcated in the thinking and research of the vast majority of molecular biologists and their studies. Instead, the molecular biology interest has become an end unto itself, the raison d’etre; and “the tail wagging the dog!”  In fact, most studies, such as genetic manipulation of cells and animals, do not represent the status and conditions that exists in the human body; thereby providing results and inappropriate translational conclusions that misrepresent the physiological and pathophysiological relationships of human cancer.

The conclusion that “few molecular biology studies having an impact on human cancer” needs to be clarified.  Instead, most molecular biology studies have had a major negative impact that leads to ineffective direction and approaches of research for the diagnosis, prevention, and treatment of cancers.  Moreover, as discussed above, the critical issue is the efficacy of a drug for cancer prevention or treatment, which does not necessitate the identification of molecular biology events associated with the action of a drug.  Thus, the extreme focus of contemporary NIH funding for molecular biology research grant projects will deter, rather than advance, the progress on the war on cancer. Dr. Zerhouni’s admonishment is correct that “Federal investment needs to be tied to the societal needs of the day… Any consideration of the value of research that does not take the customer into account is doomed. You’ve lost the debate if you lose sight of the taxpayers and the patients.”

NIH is the major agency in the world for the funding of medical research.  In 1946, NIH instituted a subdivision (now represented by the Office of Extramural Research) with the responsibility to receive, review, and fund extramural medical research grant proposals; of which “R01” grants provide the major source funding.  The 2010 report “Enhancing Peer Review at NIH” (https://enhancing-peer-review.nih.gov/index.html) describes the policies and guidelines for the dedication of RO1funds for medical research that existed for ~60 years since 1946.

The report states the importance to “Fund the best science, by the best scientist…” and that “The National Institutes of Health has a longstanding history of supporting the most promising and meritorious research”. The report further emphasizes that “The excellence of peer review is directly correlated to our ability to recruit and retain the most accomplished, broad-thinking and creative scientists to serve on study sections… Peer review must consistently identify an application’s relative merit, potential for scientific and/or public health impact, and feasibility. Peer review should fairly evaluate proposals from all scientists, regardless of their career stage or discipline” The competition under the above conditions assured that the best science from the best scientists would receive the R01 funding; which is in the best interest for achieving optimal progress in the war against cancer.

Unfortunately, beginning ~2009, NIH initiated new policies that violate the above commitment. This was based on a “concern” that, since 2003, applications from New Investigators experienced a reduced success rate in receiving new R01 grants.  In response, NIH initiated the policy that “The NIH strongly encourages New Investigators to apply for R01 grants when seeking first-time NIH funding… Beginning in 2009, NIH intends to support New Investigators at success rates comparable to those for established investigators submitting new applications.”  This is exemplified by the NIH 2017 awards for the top 18% of submitted grants for new investigators; but only for the top 11% for established investigators; “to make it easier for new investigators to get an award.”  In addition, NIH will “place greater emphasis on current NIH funding mechanisms aimed at early- and mid-career investigators… with an aim of funding most early-career investigators with applications that score in the top 25th percentile. This will be achieved by “freeing up substantial funds from NIH’s base budget, beginning this year with about $210 million, and ramping to approximately $1.1 billion per year after five years to support additional meritorious early-stage investigators, as well as mid-career investigators who are about to lose all NIH funding or are seeking a second award for highly meritorious research”.

The consequences of these policies are:  1) the funding of Early Stage Investigator scientifically-inferior grant proposals that replace the funding of better science by better established scientists; 2) the introduction of prejudicial policies in the review process, and  justification for overt and covert discrimination by the reviewers; especially targeted in favor of Early Stage Investigators; 3) the misdirected use of dedicated R01 medical research funds as a substitute for the training and development of Early Stage Investigators 4) the re-direction  and decreased R01 funds to achieve the best science by the best scientists. Such policies will deter progress in the war on cancer.

It is well recognized that the training and development of new investigators as future outstanding scientists is essential for continual progress in regard to maintaining healthy conditions for the public and in dealing with medical disorders.  To ensure this, NIH provides several training and research grant programs that are dedicated specifically for the development of Early Stage Investigators; so that they will be capable of successfully competing and receiving R01-funded grants based on scientific merit.  If these programs have failed, NIH should determine Why?  It is evident that earlier generations of new investigators (I was one of them) successfully competed for R01 grant funds without having the availability of these New Investigator programs and other special considerations.

Of all the conditions described as deterrents to progress in cancer, “poorly trained scientists” presents a major issue that must be addressed.  In this context, consider the NIH emphasis on “funding the best science by the best scientists”; and the recognition that “The excellence of peer review is directly correlated to our ability to recruit and retain the most accomplished, broad-thinking and creative scientists to serve on study sections”. The problem is that the contemporary graduate and postgraduate training programs are designed to accommodate the NIH dominant focus on molecular biology to the extent that the outcome is the training of “highly specialized researchers” and “superb technologists”; rather than “broad-thinking and creative scientists”.  Lacking is the inclusion of organ-systems and cellular physiological and pathophysiological relationships and its integration with molecular biology.  Also lacking is the description and procedure of the “scientific method”, which is essential for the conduct of biomedical research as first described in 1865 by Claude Bernard (recognized as one of the greatest scientists of all time) in his book “An Introduction to the Study of Experimental Medicine.” Bernard also describes that the conduct of the scientific method requires the elimination of the influence of bias by the scientist in the planning and interpretation of the experiment.  As stated by Bernard “The theories which embody-our scientific ideas as a whole, should serve as a basis for new ideas. But as these theories and ideas are by no means immutable-truth, one must always be ready to abandon them, to alter them or to exchange them as soon as they cease to represent the truth.  If men discuss and experiment to prove a preconceived idea in spite of everything, they no longer have freedom of mind, and they no longer search for truth.” Unfortunately, this is a major contemporary issue and must be described in the training of biomedical scientists.

In summary, progress on the war on cancer requires: the training of accomplished, broad-thinking and creative scientists; the funding of the best science by the best scientists; the holistic integration of organ-systems, cellular, and molecular relationships; and Federal investment in research that is tied to the societal needs of the day.  These represent the best approach to achieve success on the war on cancer.  NIH should return to their successful policies that are consistent with the above; and abandon those policies that deter the progress in the war on cancer.

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