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Basic Biomedical
Research and the Public’s Health |
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In last December’s The Physiologist
Rebecca Osthus and Dale Benos reported that lawmakers were asking what
benefits came from an investment in the NIH of $30 billion/year (4). This is
a very reasonable question from those who are responsible for distributing
the nation’s financial reserves in the interest of the entire country. The
country has many priorities, but it would seem fair to say that the nation’s
health is certainly at or near the top of the list. From a political
perspective the legislator who can point to bills (s)he has introduced or
supported which related to improving the nation’s health will certainly
improve his/her political status considerably. Osthus and Benos single out three diseases—Parkinson’s disease, Cholera, Cystic Fibrosis—and show how a basic understanding of pathophysiology led to significant advances in disease treatment. They also showed the positive correlation between the increase in Life Expectancy and the billions of dollars in the NIH budget between 1990 and 2003. So just in terms of increasing life expectancy (in the face of rampant heart and lung disease, and cancer) it would seem like the NIH budget allocation is a very good investment for the public’s welfare. A different approach was taken in Raiten’s and Berman’s 1993 study entitled: “Can the Impact of Basic Biomedical Research be Measured?: A Case Study Approach” (6). This study should clearly be of value to legislators who have the responsibility of deciding how the taxpayers’ money should be allocated in addressing the nation’s needs. Do the benefits of basic biomedical research justify the costs? This was the question. The study is an economic evaluation of one very specific, limited procedure than currently in practice in terms of what it has cost and the benefits that came, are coming, and are derived from it. They traced the line from the early work in immunology (early in the 20th century) to the hybridoma technology described by Kohler and Milstein in 1975, generating the methodology for producing monoclonal antibodies (MAb). The cost of their original five year period (1971-1976) plus the current (1991) cost and the costs projected up to 1996 were estimated in total to be about $6.23 billion. Their case-study was a single application of MAb technology to the screening of blood for HIV contamination. For the screening of blood for HIV contamination they used data supplied by the NIH. They divided the benefits into primary and secondary. In their very careful and detailed analysis the primary benefits were measured in terms of (a) income losses avoided from lower production resulting from lost days of work including that due to accelerated mortality; (b) reduction in medical care costs which would otherwise have been incurred due to blood supply transmission of the HIV and subsequent development of AIDS. Secondary benefits were generated by the manufacture and use of the products, the output and employment of supporting manufacturing and services. The benefit to cost ratio for the initial investment in the development of a screening test for HIV contamination of the blood supply was estimated to be 19:1. From an economic perspective, clearly of very high importance for legislators, a 19:1 benefit/cost ratio seems to be a very desirable investment. It is important to emphasize that this is the analysis for just one single application of the investment in the development of MAb. Finally, an interesting finding in their study was the key role played in this development of non-mission directed, investigator-initiated basic biomedical research. This last finding echoed perhaps the most resounding point made in the study of Drs. Julius Comroe and Robert Dripps, a superb, monumental two volume study published in 1977 (1). Comroe was Director of the Cardiovascular Research Institute at the University of California at San Francisco and Dripps was Professor of Anesthesia at the University of Pennsylvania. In the early 1970s responding to the then debate and anecdotal testimony in Congress on the relative value of targeted versus non-targeted and basic versus applied research, they sought to determine whether the objective techniques of scientific research could be used to obtain data that could be useful in designing a national biomedical science policy. Their study was very limited in that they restricted themselves to a field they both knew exceptionally well, cardiopulmonary physiology and medicine. Their study was also very existential in that their goal was to determine why, how, and where the research and development necessary for many important clinical advances in medicine and surgery of the preceding 30 years had come about. This intensive research appeared in a two volume masterpiece (1). They wanted to avoid the anecdotal (“let-me-give-you-an-example”) approach. They focused their attention exclusively on the important clinical advances in the cardiovascular and pulmonary fields. To eliminate, or at least minimize, their own bias they asked a panel of 90 physicians and surgeons to select the “top ten” advances that had “saved lives or greatly prolonged the lives of their patients, prevented disease, or greatly decreased suffering or disability.” The panel selected: 1) Open-heart surgery; 2) Blood vessel surgery; 3) Treatment of hypertension; 4) Management of coronary artery disease; 5) Prevention of poliomyelitis; 6) Chemotherapy of TB and acute rheumatic fever; 7) Cardiac resuscitation and cardiac pacemakers; 8) Oral diuretics (for treatment of high blood pressure and congestive heart failure); 9) Intensive care units; and 10) New diagnostic tests. Comroe and Dripps screened 6,000 articles in these fields and picked more than 3,400 of them for special consideration. And with the help of a large team of consultants they carefully analyzed 663 key articles the group felt were essential for one or more of the top ten clinical advances. Comroe and Dripps go to extraordinary lengths to minimize their own bias; this is amply and persuasively documented in their study. They summarized some of their findings as follows: 1) 41.6 % of the 663 key articles reported research done by investigators whose goal at that time was unrelated to the later clinical advance. They sought knowledge for the sake of knowledge. The results were often unexpected, unpredictable, and usually greatly accelerated advance in many fields. 2) Viewed from another perspective 61.5% of the 663 key articles described “basic” research; these studies tried to determine mechanisms which account for the functions of living organisms (including man), or the mechanisms by which drugs act. 3) 20% presented descriptive clinical investigations with no experimental work on basic mechanisms. 16.5% dealt with development of new apparatus, techniques, operations, or procedures; and 2% presented review and synthesis of earlier work. 4) Better than 67% of the work was done in colleges and universities or their medical schools and associated hospitals, most of it being done in clinical or basic science departments of medical schools. But significant contributions also came from non-medical basic science units, including from agriculture, engineering, physics, plant physiology, and mathematics. 5) An interesting point made from their study is the attachment of a cure bearing the name of an individual to that individual alone by the public in general and even by scientists, when actually dozens, maybe hundreds, of investigators had participated in the discovery of the cure. A good example was the Salk vaccine for polio. 6) Of enormous importance to legislators is the issue of lag between the initial discovery and its effective clinical application. Comroe and Dripps analyzed 111 such lags. One might reasonably expect a significant lag between the initial discoveries required for a successful prognosis in the clinical advance of open-heart surgery since no less than 25 pre-, intra, and post-surgical areas had to be mastered. However, except for an unusual instance like the clinical use of x-rays, lag times were surprisingly modest: 8% of the lags came to 0.1 to1.0 year; another 18% were 1 to 10 years; 17% were 10 to 20 years; 39% were 21 to 50 years. Only 18% of the initial discoveries required more than 50 years for clinical application. And the reasons for the lags were many and sometimes somewhat humorous. For example, certain personal attributes of the scientist prevented early acceptance of his discovery. An investigator was arrogant, unpopular, aggressive, as apparently Carrel was, delaying the application of his vascular surgical feats in animals saw a delay in the application of his important work in animals to human trials. An investigator’s previous work was incorrect. The investigator was little known as was the case with Gibbon and his pump-oxygenator. Sometimes the initial discovery was regarded as good science, but there was no perceived clinical need for it. There may have been an insufficient number of properly trained clinical investigators willing to apply the discovery. From the studies considered so far it seems absolutely clear that research which is called “basic” has a critically important role to play in preserving and advancing the health of the public. To use the oft-quoted axiom: “We stand on the shoulders of giants.” We are the recipients of an indescribable treasure. We are asked to contribute to it. How should whatever funds are allocated to “basic” biomedical research be distributed? In trying to formulate the beginning of an answer to that question it would be helpful to consider briefly the highly interesting and informative article by Allen Cowley which appeared in The Physiologist (2). This article was first published in IUPS Newsletter (7: September, 2004). As President of the International Union of Physiological Sciences, Cowley had the opportunity to travel the world and consult with scientists from Europe, China, Japan, North America, and Brazil. He found an emerging recognition everywhere of the need to train a greater number of integrative systems physiologists. Our research must deepen our understanding of how the whole living organism responds. Our task is to wed functional genomics and integrative physiology. The pure reductionist approach has found itself severely limited in trying to help us understand complex functions and their interactions on the organ, system, organism levels. There is a great need to support science and the training of scientists devoted to, and the training of scientists, addressing the health of the organism on the organ, system, organism levels. This area of basic research has, perhaps, been neglected for two decades or more as we sought to advance more deeply into the molecular biology of the cell and into the genome. Perhaps the time has arrived to extend and integrate the astounding and marvelous results of these studies into the organism at higher levels of organization—tissue, organs, systems, and organism. Splendid examples of this in the field of cardiopulmonary control are the recent studies of Schultz and his colleagues (3, 5, 8). In brief, they observed in their rabbits, which suffered from pacing-induced heart failure, enhanced peripheral chemoreflex function due to decreased nitric oxide in the carotid bodies. They showed that gene transfer of adenovirus encoding nNOS (neuronal nitric oxide synthase) into the carotid bodies reversed the enhanced activity and the increased sympathetic output resulting from it. Though basic biomedical research must continue along molecular lines, it would seem integrative systems physiology must receive increasing support to stimulate clinical applications in the interests of the public’s health. Perhaps it might serve well to conclude with a quote from Professor Schmidt-Nielsen’s review of the 1993 monograph The Logic of Life: The Challenge of Integrative Physiology (7): “I have chosen what I perceive as a consistent message in this book ... that physiology will be indispensable in putting together and interpreting the masses of detailed information emanating from the revolutionary progress in molecular biology. We must detach ourselves from the infatuation with more data and more information and remember that, in the end, all the interesting molecules come from, and belong in, living organisms.” References 1. Comroe, JH.and Dripps RD. The top ten clinical advances in cardiovascular-pulmonary medicine and surgery. DHEW Publication No. (NIH) 78-1521, 1977. 2. Cowley, A. Global manpower needs for integrative systems physiologists. The Physiologist 48: 1-8, 2005. 3. Li, Y-L., Li, Y-F., Liu, D., Cornish, KG., Patel, KP., Zucker, IH., Channon, KM., Schultz, HD. Gene transfer of neuronal nitric oxide synthase to carotid body reverses enhanced chemoreceptor function in heart failure rabbits. Circ. Res. 97: 260-267, 2005. 4. Osthus, R. and Benos, D. Making a case for NIH funding: how cures are built on decades of research. The Physiologist 49: 313-321, 2006. 5. Paterson, DJ. Targeting arterial chemoreceptor over-activity in heart failure with a gas. Circ. Res. 97: 201-203, 2005. 6. Raiten, DJ., Berman, SM. Can the impact of basic biomedical research be measured?: a case study approach. Life Sciences Research Office Federation of American Societies For Experimental Biology. Pp.iii-27, 1993. 7. Schmidt-Nielsen, K. Unifying science. Nature 367: 230, 1994. 8. Schultz, HD. and Sun, S-Y. Chemoreflex function in heart failure. Heart Failure Revs. 5: 45-56, 2000. |