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The reductionist paradox: are the laws of chemistry and physics sufficient for the discovery of new drugs?

Journal of Computer-Aided Molecular Design volume 25, pages 699–708 (2011)Cite this article

Abstract

Reductionism is alive and well in drug-discovery research. In that tradition, we continually improve experimental and computational methods for studying smaller and smaller aspects of biological systems. Although significant improvements continue to be made, are our efforts too narrowly focused? Suppose all error could be removed from these methods, would we then understand biological systems sufficiently well to design effective drugs? Currently, almost all drug research focuses on single targets. Should the process be expanded to include multiple targets? Recent efforts in this direction have lead to the emerging field of polypharmacology. This appears to be a move in the right direction, but how much polypharmacology is enough? As the complexity of the processes underlying polypharmacology increase will we be able to understand them and their inter-relationships? Is “new” mathematics unfamiliar in much of physics and chemistry research needed to accomplish this task? A number of these questions will be addressed in this paper, which focuses on issues and questions not answers to the drug-discovery conundrum.

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Notes

  1. Note that this estimate is from the Pharmaceutical Research and Manufacturers of America (PhRMA). An estimate by the National Science Foundation put the change at slightly more than half of the PhRMA estimate. All estimates are in constant dollars, inflation being removed.

  2. An example applicable to thermodynamic systems may be appropriate here. The theoretical framework of statistical mechanics provides a means (i.e. a theory) for determining the values of macroscopic variables (e.g., enthalpy, free energy, pressure, etc.) from the microscopic variables of individual molecules.

  3. As might be expected, philosophers of science provide a much more fine-grain approach to reductionism in biology, defining three principal types of reduction—ontological, methodological, and epistemic. Methodological reductionism comes closest to that described here, although bits of all three may implicitly be included. An excellent and thorough discussion is given in the section on Reductionism in Biology in the Stanford Encyclopedia of Philosophy, which is freely accessible on the Internet—See Ref. [9].

  4. While there are many versions of the story, it basically goes as follows. The parents of six-year-old twin boys are worried that they are developing extreme personalities. One appears to be a total pessimist and the other a total optimist. So the parents take them to a psychiatrist. First, the psychiatrist treats the pessimist. He takes him into a room filled with all sorts of toys to lift his spirits, but instead of being delighted the boy begins to cry. Asked why he was crying, the boy replies “If I play with the toys I’ll probably just break them.” The psychiatrist then treats his brother, trying to dampen his outlook by taking him into a room filled with horse manure. Unlike his brother, the boy is entirely delighted and begins digging through the manure with his bare hands. Somewhat taken aback, the psychiatrist asks the boy what he is doing, to which the boy replied “With all of the manure in this room, there must be a pony in here somewhere”.

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Acknowledgments

Thanks are due to Susan Maggiora for her patient reading and editing of the original manuscript and to Andy Card for permission to use a picture of the Babbage difference engine he constructed totally from Legos™.

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Affiliations

  1. Department of Pharmacology & Toxicology, College of Pharmacy and BIO5 Institute, University of Arizona, Tucson, AZ, 85721, USA

    Gerald M. Maggiora

  2. Translational Genomics Research Institute, 445 N. Fifth Street, Suite 600, Phoenix, AZ, 85004, USA

    Gerald M. Maggiora

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Correspondence to Gerald M. Maggiora.

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Maggiora, G.M. The reductionist paradox: are the laws of chemistry and physics sufficient for the discovery of new drugs?. J Comput Aided Mol Des 25, 699–708 (2011). https://doi.org/10.1007/s10822-011-9447-8

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Keywords

  • Biological reductionism
  • Emergent properties
  • Hierarchy
  • Drugs