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Pro: Greater Funding of Cell and Molecular Biology Has Delivered What Was Promised to Respiratory Medicine

Posted on: Tuesday, 2 March 2004, 06:00 CST

Whether everyone-or anyone at all-will agree with the title of this editorial probably depends on each individual's definition of "greater funding" and his or her perception of "what was promised." The discovery and application of science to medicine is a lengthy and time-consuming process. Having had the opportunity for more than three decades to witness the evolution of respiratory medicine, I believe that many, and possibly most, of the expectations regarding the impact of cell and molecular biology on respiratory medicine have been met. The journey is not finished, and the goal has not been reached, but the field of respiratory medicine and the patients with lung disease are better off today than they were three decades ago.

A review of some of the budgetary and scientific facts may help to put this issue in perspective. The lung program of the current National Heart, Lung, and Blood Institute (NHLBI) was established in November 1969, one year after Marshall Nirenberg (of the Institute) received a Nobel Prize for deciphering the genetic code. His discovery represented a phenomenal advance in scientific knowledge without which much of what we know today about genetics/genomics would still remain to be learned!

During the initial years of the lung program, the Institute's annual budget was less than $350 million, yet it was barely possible to spend 15 percent of it on respiratory disease research, as mandated by the National Heart, Blood Vessel, Lung, and Blood Act of 1972. Contrast that with the situation in fiscal year 2002, when funding for research and training through the NHLBI Division of Lung Diseases constituted 20.9% of the entire extramural appropriation, or $491 million. Of that amount, about half was committed to either lung cell biology ($170 million) or genetic/genomic research ($75 million)-neither of which was even in the picture in 1969! Suffice it to say that over the years, the Institute's cumulative expenditures for lung cellular and molecular studies have been substantial. But, whether they have been insufficient, excessive, or "just right" depends on what was expected and what has been accomplished in terms of specific, measurable benefits to patients.

In a recent editorial (1), Peter Macklem compared the relationship between cellular/molecular biologists and clinical practitioners to a marriage-a marriage in which two very different partners are frequently pulled in opposite directions and ever tottering on the brink of divorce. If we were to stick with this comparison, I would say that not all marriages are alike and many improbable pairings turn out happily. However, in my view childrearing, not marriage, provides the better analogy. Here we have two partners with two different histories and perspectives striving to bring their individual and collective best to fruition in their offspring. Providing a child with all the skills and knowledge for a successful adulthood is an evolutionary process- and, as all of us know (or remember), that education is expensive!

Of course, parenthood has its ups and downs, but let us begin by enumerating some of the achievements of this child:

* One of the earliest and most striking success stories regarding the impact of cell and molecular biology on the practice of respiratory medicine has been that of the neonatal respiratory distress syndrome. The discoveries over a 20- to 25-year period of the biology and functioning of type II alveolar cells, the composition of surfactant, and the surfactant apo-protein gene, and the subsequent developments of synthetic and natural surfactant slashed the toll of neonatal respiratory distress syndrome from 270 deaths/100,000 live births in 1972 to approximately 20 deaths/ 100,000 in 2000.

* A large body of evidence has established the role of cytokines in the pathogenesis of both allergic and nonallergic asthma. This line of research will undoubtedly lead to the development of immune- based molecular therapies, and the public health impact will be considerable.

* The recent discovery that mutations in the 5-lipoxygenase gene influence how patients respond to antileukotriene therapy will lead to more effective utilization of the appropriate medications.

In truth, a multitude of examples can be provided of how promises from research on cell and molecular biology have been met. While the cost of this work has been significant, the important impact on patient care, and on lives saved, has made the investment worthwhile.

However, we have to acknowledge that in some cases, the expectation has not been met. An example is the discovery of the cystic fibrosis gene, which has yet to make an impact on the care of these patients. Indeed, attempts at gene therapy for several diseases have failed to yield significant positive accomplishments.

Nonetheless, I believe we should resist the tendency to focus on what has not worked rather than praising what has. Indeed, we should be positive that respiratory medicine (the child) has reached adulthood and fuller maturity. But, concerns do need to be recognized. The first is that our (still young) adult may be misbehaving to some extent. Its reactions to many astonishing basic research discoveries and successes may create some delusions, which in turn may result in over-promising. Here again, the field of gene therapy has given us a powerful example of what should not be. Gene therapy has been heralded as the one, or only, way to cure some diseases. However, so far, no lasting success has been reported. It is unavoidable that if the promises made by those in the field of gene therapy are not met, the criticisms and reactions will be severe.

The second concern regards the extent to which we are prepared to take advantage of what we have learned, and are learning, from cell and molecular biology-that is, to apply it to patient care. I believe that unless we prepare for this, the translation and application of the findings will not be realized. And then, of course, funding for these areas of research will be judged to have been too generous. In 1931, J. Howard Brown made the following remark in the Presidential Address to the Society of American Bacteriologists (2):

A man may do research for the fun of doing it but he cannot expect to be supported for the fun of doing it.

Even 70 years later, this is not a completely irrelevant admonition. Jerome Brody (3), in his response to Peter Macklem's editorial, believes that "What we've got here is a failure to communicate." That's a catchy phrase, but let's not forget the irony and understatement that made it famous! We cannot communicate effectively unless we know. And we cannot apply what we know unless we know what to apply. In the heading of a recent Science viewpoint (4), Ress said:

clinical discovery and patient-oriented research have become less common. . . . I suggest that these developments are interdependent, each represents the flip side of an inaccurate view of how clinical advance occurs.

The practice of respiratory medicine will not fully benefit from advances in cell and molecular biology until those who practice understand and appreciate when these advances are ready for application. It is time for the leaders in the respiratory field to take steps to develop appropriate education processes to ensure that practitioners know when it is time to apply new discoveries.

Am J Respir Crit Care Med Vol 169. pp 437-440, 2004

Internet address: www.atsjournals.org

References

1. Macklem PT. Is cell and molecular biology divorcing from clinical practice? Am J Respir Crit Care Med 2003;167:1164-1165.

2. Brown JH. The biological approach to bacteriology. J Bacterial 1932;23:1-10.

3. Brody JS. What we've got here is a failure to communicate. Am J Respir Crit Care Med 2003;168:415-416.

4. Rees J. Complex disease and the new clinical science. Science 2002;296:698-701.

DOI: 10.1164/rccm.2312004

Conflict of Interest Statement: C.L. has no declared conflict of interest.

CLAUDE LENFANT, M.D.

Former Director of the National Heart, Lung, and Blood Institute

Gaithersburg, Maryland

Copyright American Thoracic Society Feb 15, 2004

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