© 2004 American Thoracic Society
ConGreater Funding of Cell and Molecular Biology Has Not Delivered What Was Promised to Respiratory MedicineMeakins-Christie Laboratories McGill University Health Centre Research Institute Lansdowne, Ontario, Canada Sixteen years ago, Hurd and Lenfant outlined NHLBI's strategy for research funding of respiratory science (1, 2). They stated that "[physiology] will not alone provide answers to future needs in pulmonary medicine ... priorities for research ... must emphasize the new disciplines of molecular biology and genetic chemistry" (1). A crucial aspect of this strategy was to "bring new approaches ... for early diagnosis and treatment." "The future is bright", they said, "for ... scientific advances that will lead to better modes of early detection, treatment, and prevention ..." (2). The future research program would be "comprehensive enough to include the transfer [of new knowledge] ... to medical practice" (1). Has research in cell, molecular, and genetic biology improved the practice of respiratory medicine? This is what was promised. Has it been delivered? I think not. In fact, the practice of respirology owes little to the new biology. The discovery of CFTR, and of the dystrophin gene has not yet improved outcomes in either cystic fibrosis (3) or Duchenne's muscular dystrophy, and new therapies are only promises for the future (4, 5). The same can be said for the major respiratory public health problems. Much of the reduction in mortality rates from the respiratory distress syndrome of infancy occurred before 1987 and is due to improvements in mechanical ventilation, corticosteroids, and surfactant replacement (6). Molecular science has improved our understanding of airway inflammation in asthma, resulting in the development of antileukotrienes. However, these agents have not replaced the standard therapy of inhaled corticosteroids and ß-2 agonists, and their role in asthma treatment is not yet clear. If the new biology had penetrated clinical management of obstructive lung disease, guidelines such as GINA and GOLD would reflect its contribution. The absence of any such influence clearly indicates that promises remain unfulfilled in obstructive lung diseases. Lung cancer mortality rates are unacceptably high and are rising in women: little improvement here (7). Advances in treatment of acute respiratory failure can be attributed to development of new ventilatory modalities (8, 9). Programs to control the resurgence of tuberculosis are partly based on molecular TB epidemiology, but proof is still lacking that these programs are more effective than older ones in containing this resurgence (10). On a global scale, infant mortality rates from acute respiratory infections, arguably the world's most important public health problem (11), is not even being investigated to any significant degree by the new biology. It is only with the treatment of AIDS that molecular sciences have significantly entered the clinic (12). The impact of the new biology on the practice of respiratory medicine, an integral part of NHLBI's research strategy, has not yet happened. This is not just a problem of respirology; it applies to medicine in general. The Institute of Medicine of the National Academy of Sciences was so concerned about the failure to translate "scientific discoveries ... into tangible human benefit" that it convened a Clinical Research Roundtable (CRR). Their recently published report (13) found a "disconnection between the promises of basic science and the delivery of better health." They identified blocks in the translation from basic to human studies and of clinical studies into medical practice due to, among other factors, the regulatory burden, lack of qualified investigators, career disincentives, high research costs, and lack of funding (13). In an accompanying editorial, Rosenberg states that "There is an assumption that the ... growth of scientific information about disease ... heralds a rapid move to improve human health. This illusion is the subject of an intense analysis ... by the CRR ... [Their] report indicates that the battle for fast-tracking clinical research to the bedside is being lost ... It is a cause of great concern that ... the support for basic research far outweighs that for clinical research ... The American people need to know that the current system for bringing promising biomedical research to the bedside is operating at an obsolete level of efficiency, causing great delay, and consequently resulting in the loss of many lives ... [This] is a national crisis of major proportions ... A clarion call to action ... no less needed than the response to September 11 is required to save lives." (14). These are strong words, but they are needed. We have been seduced for too long by promises that remain unfulfilled. Even Lenfant has lamented the failure of research to influence medical practice appropriately (15). The issue is not so much whether NHLBI's strategy has delivered what was promised: it clearly has not. A more important question is whether the promises can be fulfilled if the causes of failure can be eliminated. In addition to the two impediments uncovered by the CRR, Lenfant believes that "both health providers and members of the public are not applying what we know" so that "enormous amounts of new knowledge are ... not arriving at the doorsteps of our patients." (15). However, in addition to these logistic problems, I suspect that there may be scientific impediments as well. A crucial strategy, common to all cells, tissues, organs, and systems, is homeostasis, perhaps better termed homeokinesis (16), a process controlled at many levels (17). Homeostasis requires energy supplied by ATP. Health and life depend upon it and its failure characterizes disease. The genes and molecules that are responsible for homeostasis have been likened by Polanyi (18)* to chess pieces constrained by the rules governing their various movements and the overall strategy of the player. To focus on the moves of the individual pieces without understanding the strategy misses the point. To bridge this gap, Strohman (16) has championed the study of cell dynamics controlling the output of energy and matter by approaches such as metabolic control analysis. When perturbed, homeostasis requires an alteration in the energy level of a cell, tissue, or organ. If the control of energetics is inappropriate, due to genetic polymorphisms for example, a pathologic condition is more probable. The output of energy can be either too little or too great (16, 17). Focusing on individual molecules and genes to the exclusion of strategy may be necessary, but it is insufficient if we truly wish to understand the failure of homeostasis. When NHLBI-funded research focuses on how molecules interact to control the energetics of homeostasis, perhaps the new biology will finally deliver what it promised. FOOTNOTES Conflict of Interest Statement: P.T.M. has no declared conflict of interest. REFERENCES
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