Author for correspondence::
Bruce G Charlton MD
Henry Wellcome Building
University of Newcastle upon Tyne
NE2 4HH
England

Tel: 0191 222 6247
bruce.charlton@ncl.ac.uk

Peter Andras PhD
School of Computing Science
University of Newcastle upon Tyne
NE1 7RU

Abstract

The continual and uninterrupted expansion of medical research funding is generally assumed to be a permanent feature of modern societies, but this expectation may turn-out to be mistaken. Sciences tend to go through boom and bust phases. Twentieth century physics is an example where huge increases in funding followed an era of scientific breakthroughs. Speculative over-expansion led to diminishing returns on investment then a collapse in funding. We predict that medicine will follow the same trajectory. After prolonged over-funding of the ‘basic-to-applied’ model of clinical innovation, and a progressive shift towards Big Science organization, medical research has become increasingly inefficient and ineffective. Although incremental improvements to existing treatment strategies continue, the rate of significant therapeutic breakthroughs has been declining for three decades. Medical science now requires rationalization and modernization. From this perspective, the current level of medical research funding looks like a bubble due to burst.

* * * * * * * * * *

On the face of it, the long-term expansion of medical research funding which has been established for several decades seems set to continue [1] but this might turn-out to be an illusion induced by overconfidence. Sciences tend to go through boom and bust phases, with over-expansion leading to a speculative bubble that inevitably bursts. The example of physics may serve as a warning of what is to come for medical science.

Physics was once the richest, most-self-confident and prestigious science; it attracted the brightest students and the bulk of funding. From the late nineteenth century through the first half of the twentieth century was the golden age of fundamental breakthroughs. The subject was thronging with ‘geniuses’: of whom Faraday, Maxwell, Curie, Thomson, Einstein, Rutherford, Bohr, Heisenberg and Dirac are only a sample [2]. After a lag, this led to the massive post-WW II expansion in funding, with physics as the first ‘Big Science’ [3]. For several decades, the continual growth of physics funding seemed inevitable and permanent; but expansion went too-far, the achievements of late twentieth century physics did not live-up to the hype, and the last couple of decades have seen a collapse in physics support and the closure of many physics departments [4]. Currently, fundamental physics research is pursued in only half a dozen UK universities.

We suggest that medical research will follow a similar trajectory to physics - with revolutionary breakthroughs leading to over-expanded funding then collapse - but with the time-course of medical science delayed by several decades compared with physics.

Clinical medical science made its most rapid progress between about 1935 and 1965 [5], overlapping a period of major conceptual advance in biology [6]. During this era were discovered the antibiotics, the glucocorticoid steroids, hormone replacement therapies, and most of the current psychiatric drugs; with similar qualitative advances in the scope and safety of surgery and anesthetics [7]. In biology there was the discovery of DNA as the gene, the structure of the double helix, and the unraveling of the genetic code and gene transcription, leading to the development of molecular biology [6].

This period of clinical and scientific revolution was followed by massive expansion in research funding [8]. But over recent decades the rate of major clinical breakthroughs has probably declined [5, 9], even as claims for the importance of medical research have grown more exaggerated. Perhaps the major deficiency of current therapy is the lack of significant progress in treating common solid cancers such as brain, lung, bowel, prostate, ovary and breast, which together make-up the main cause of mortality in developed countries. Available therapies typically offer only modest or marginal benefit, detectable only in very large clinical trials, and usually at the cost of severe side-effects [10]. In psychiatry the major classes of useful drugs all date from before 1965, excepting the selective serotonin re-uptake inhibitors (SSRIs) which (like the neuroleptics and the tricyclic anti-depressants) were synthesized in the early 1970s by chemically modifying a 1940s anti-histamine (ie. chlorpheniramine/ Piriton) [11]. In other words the developmental strategy underpinning SSRIs was not new. The phenomenon of a declining frequency of breakthroughs seems common to many medical specialties [7]. Furthermore, the output of effective new drugs for serious diseases, such as novel classes of antibiotics, seems to be drying-up [12, 13].

The problem may be that Big Science is inappropriate for generating medical progress. The dominant research paradigm has been termed the ‘basic to applied’ model, and is (roughly) the assumption that expanding ‘basic’ medical research (especially molecular biology-based approaches) leads predictably to an increasing frequency of ‘applied’ clinical breakthroughs [14]. The continuing failure to sustain therapeutic progress is making it increasingly apparent that these assumptions are, at best, only partially valid. For instance, there is a spreading disillusion with the Human Genome Project - the biggest and costliest biological venture in history. This was ‘sold’ to the public and political funders as essentially a means of generating major clinical breakthroughs, yet these have failed to materialize.

Although medical breakthroughs do sometimes results from Big Science and ‘basic’ research, when the major advances in medicine are surveyed the most striking aspect is their causal heterogeneity. Le Fanu’s selection of definitive mid-twentieth century breakthroughs [7] were: penicillin, cortisone, streptomycin for TB, discovering the causal link between smoking and lung cancer, chlorpromazine for schizophrenia, the invention of intensive care, open-heart surgery, hip-replacement surgery, kidney transplantation, preventing strokes with anti-hypertensives, and the curing of several fatal childhood cancers with chemotherapy. The selection illustrates twelve very different pathways of therapeutic discovery, many involving incalculable and unplanned elements of serendipity.

It seems that there is no single dominant model for therapeutic discovery, rather the implication is that the best results arise from simultaneously pursuing a wide range of investigative strategies [15]. We suggest that excessive monolithic funding of the basic-to-applied model may be stifling a diversity of potentially more fruitful research strategies which at present are disregarded because they are not amenable to the Big Science model. Other approaches, being small scale and cheaper, or dependent on the accidents of individual skill and clinical observation, are less prestigious and less influential. The anticipated cull of medical research funding should therefore bring benefits in terms of an increased frequency of clinical breakthoughs.

Examples of other clinical research strategies that might thrive with a reduction in the dominance of Big Science include what Nobel Laureates Goldstein and Brown have termed ‘Patient Oriented Research’ (POR) [16] – the successes of which include the delineation of AIDS by Gottleib, and the discovery of the etiological importance of Helicobacter pylori in duodenal ulcer by Marshall. As Rees points out, clinical medicine is a problem-solving activity which somewhat resembles engineering, so a wide range of sciences beyond molecular biology might potentially contribute to breakthroughs [17]. Imaging and computers are examples from the past, micro-economics may be an example for the future?

In conclusion, it is unlikely that current patterns of medical science funding will yield the hoped-for advances in therapeutics which provides the main justification for expanding the input of resources. Too much expansion, too narrowly channeled, for too long, has probably led to increasing inefficiency with diminishing returns from ever-greater spending. Linking scientific prestige with funding has created centralized selection pressures on medical science which cause a functional drift away from its proper goals – researchers now compete for funding instead of competing to cure diseases [18, 19]. All this suggests that we are indeed in a period of over-expanded medical science funding which will inevitably be followed by collapse. It also implies that collapse would be beneficial to medical science in the long term since this would allow the rationalization and modernization of medical science, with future re-growth from the best models of practice [20]. Indeed, the modernization of science in general is arguably overdue, especially in Europe [19].

If the example of physics applies, in a decade or two there will be much less funding of medical research, fundamental medical science will be pursued in much smaller number of research centres, and most medical schools and universities will be concentrating on the more practical matter of training doctors and doing 'applied' R&D. Systems of clinical practice and medical research will be more explicitly separated and more specialized. Clinical innovation will be pursued using a wide range of competing models and strategies.

When medicine reaches that point it should be more effective and efficient than at present, but we are in for a period of painful transition.

REFERENCES

1. Giles, J. Funding review set to buck up basic research. Nature. 2004; 429: 688.

2. Snow CP. The physicists. Macmillan: London, 1981.

3. Price, DJ de Solla Little science, big science-- and beyond. Columbia University Press: New York, USA, 1986.

4. Horgan J. The end of science. Little, Brown and Co.: London, 1996.

5. Horrobin, D.F. Scientific medicine - success or failure? In: Weatherall, D.J.; Ledingham, J.G.G.; Warrell, D.A. (Eds.) Oxford Textbook of Medicine, 2nd Ed. Oxford University Press, Oxford. 1987, pp 2.1-2.3.

6. Judson HF. The eighth day of creation: makers of the revolution in biology. Jonathan Cape: London, 1979.

7. Le Fanu J. The rise and fall of modern medicine. Little, Brown: London, 1999.

8. Kealy T. The economic laws of scientific research Macmillan: London, 1996.

9. Wurtman RJ, Bettiker RL. The slowing of treatment discovery, 1965-1995. Nature Medicine 1995; 1: 1122-1125.

10. Horrobin D.F. Are large clinical trials in rapidly lethal diseases usually unethical? Lancet 2003; 361: 695-7.

11. Healy D. The creation of psychopharmacology. Harvard University Press: Cambridge, MA. 2002.

12. Horrobin DF. Innovation in the pharmaceutical industry. JRSM. 2000; 93: 341-5.

13. The Economist. Fixing the drugs pipeline. The Economist - Technology Quarterly. March 11 2004.

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

15. Charlton BG. Clinical research methods for the new millennium. Journal of Evaluation in Clinical Practice 1999; 5: 251-263.

16. Goldstein, J. L. and M. S. Brown. 1997. The clinical investigator: bewitched, bothered, and bewildered - but still beloved Journal of Clinical Investigation 99, no. 12:2803-2812.

17. Rees JL. The fundamentals of clinical discovery. Perspectives in Biology and Medicine, in the press.

18. Charlton B, Andras P. The modernization imperative. Imprint Academic, Exeter, UK. 2003

19. Andras P, Charlton BG. European science must embrace modernization (Correspondence). Nature. 2004; 429: 699.

20. Charlton BG, Andras P. Modernizing UK health services: ‘Short-sharp-shock’ reform, the NHS subsistence economy, and the spectre of health care famine. Journal of Evaluation in Clinical Practice, in the press.

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