The manipulability of what? The history of G-protein coupled receptors

Abstract

This paper tells the story of G-protein coupled receptors (GPCRs), one of the most important scientific objects in contemporary biochemistry and molecular biology. By looking at how cell membrane receptors turned from a speculative concept into a central element in modern biochemistry over the past 40 years, we revisit the role of manipulability as a criterion for entity realism in wet-lab research. The central argument is that manipulability as a condition for reality becomes meaningful only once scientists have decided how to conceptually coordinate measurable effects distinctly to a specific object. We show that a scientific entity, such as GPCRs, is assigned varying degrees of reality throughout different stages of its discovery. The criteria of its reality, we further claim, cannot be made independently of the question about how this object becomes a standard by which the reality of neighbouring elements of enquiry is evaluated.

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Notes

  1. 1.

    The latter question has been addressed at a conference entitled “The History of Science and Scientific Realism” in February 2016 in Indianapolis hosted by Timothy D. Lyons, Peter Vickers, and Yafeng Shan.

  2. 2.

    Some salient exceptions are, for instance, Rheinberger (1997) on protein synthesis; Arabatzis (2006) on the electron; an edited collection by Daston (2000), involving a range of historical biographies of entities such as cytoplasmic particles; Valenstein (2006) on the controversy surrounding soups and sparks in neuroscience; and Kay (2000) on the history of the genetic code.

  3. 3.

    See Chakravartty (2007, Ch. 2), Gelfert (2003) and Morrison (1990) as examples in the literature that take up Hacking’s line of thought and discus the issue of entity realism predominantly in terms of experimental manipulability.

  4. 4.

    These Nobel Prizes are: 1967 Nobel Prize in Physiology or Medicine to Ragnar Granit, Haldan Keffer and George Wald for the physiological and chemical processes underlying photoreception; 1971 Nobel Prize in Physiology of Medicine to Sir Earl W. Sutherland Jr. for his studies on the activity of hormones; 1988 Nobel Prize in Physiology of Medicine to Sir James W. Black for the discovery of propranolol (blocking ß-adrenergic receptors) and histamin H2 receptor blocker cimetidine; 1994 Nobel Prize in Physiology of Medicine to Martin Rodbell and Alfred Gilman for heterotrimeric G-proteins; 2004 Nobel prize in Physiology or Medicine to Linda B. Buck and Richard Axel for the discovery of olfactory receptors; 2012 Nobel Prize in Chemistry to Robert Lefkowitz and Brian Kobilka for the general study of GPCRs (Snogerup-Linse 2012).

  5. 5.

    For an excellent review on the structure and function of GPCRs as well as an outlook on current and future applications see Rosenbaum et al. (2009).

  6. 6.

    See Lefkowitz (2013, p. 6367).

  7. 7.

    Today, we know that curare blocks nicotinic acetylcholine receptors.

  8. 8.

    See also Maehle et al. (2002) and Maehle (2009). For the history of the receptor concept and the mutual influences of Langley and Ehrlich see also Parascandola and Jasensky (1974), and Silverstein (2002).

  9. 9.

    In a later synthesis of his ideas in 1921, Langley is more explicit about the chemical character of the interaction between the drug and the receptive substance: “The known physical characters of drugs are insufficient to account for the effects they produce, though they account for a difference in rate of action; in consequence I consider that there is a chemical combination between the drug and a constituent of the cell—the receptive substance. On the theory of chemical combination it seems necessarily to follow that there are two broad classes of receptive substances; those which give rise to contraction, and those which give rise to inhibition” (Langley 1921, p. 44. Cited in Maehle 2004, p. 173).

  10. 10.

    In essence, affinity refers to the binding capacity of a substance to a target domain, whereas efficacy describes the degree to which a substance initiates a response when binding to the target domain.

  11. 11.

    The patch clamp technique is a tool used in electrophysiology for the study of electrochemical potentials on double-lipid membranes and in particular the currents of single ion channels. Patch clamp was first introduced by Erwin Neher and Bert Sakmann in 1976 and soon became a crucial tool for the study of cell signaling mechanism through membranes (Neher and Sakmann 1976). Neher and Sakmann were awarded the 1991 Nobel Prize in Physiology or Medicine “for their discoveries concerning the function of single ion channels in cells”.

  12. 12.

    In radioligands, one or more atoms are replaced by radioisotopes. Such radiolabeling allows targeting and tracing a receptor’s binding activity via the measurement of differences in radioactivity in bound and unbound ligands.

  13. 13.

    To avoid confusion, it should be noted that nicotinic cholinergic receptors do not belong to the GPCR family of receptors.

  14. 14.

    “The simplest model for hormone-receptor interactions which can explain and reproduce the experimental data involves the interaction of the receptor R with an additional membrane component X, leading to the agonist-promoted formation of a high affinity ternary complex HRX’’. (De Lean et al. 1980, p. 7108).

  15. 15.

    Allosteric regulation refers to the well-studied biological phenomenon that the binding of a ligand to a protein is often regulated by the binding of further compound at another site of the protein, inducing a conformational change in the protein’s structure (in this case the regulation of the extracellular binding of ligands through the binding of the G-protein to the intracellular domain of the receptor).

  16. 16.

    An obstacle for the initial design of this experiment is the fact that almost all cells contain certain amounts of adrenaline receptors. Lefkowitz and his team found an exception in the cells of the African clawed toad. Most fortunately, these cells contain the entire molecular apparatus of a second messenger process but lack adrenergic receptors.

  17. 17.

    We thank Brian Kobilka for drawing our attention to the importance of in vivo studies.

  18. 18.

    See Egg (2014, Ch. 2.2).

  19. 19.

    A similar point could be made with respect to the conflicting observations about the movement of the ether in 19th century physics. Nonetheless, an analysis of the reasons that lead to the abandonment of scientific objects must not necessarily mirror the reasons for their step-wise realization.

  20. 20.

    Similar ideas have been suggested before, though not under the term “iteration”. See for instance Wimsatt (1987) or Nickles (1997). For an overview discussion see Elliott (2012).

  21. 21.

    An example for this are silogens, which are postulates of silicon-hydrogen hybrid atoms. Winsberg (2009) analyzed these hypothetical atoms as part of the recent philosophical debate on fictionalization strategies in scientific modeling. The argument goes that, while these entities do not exist, they can still provide successful explanations and even predictions for real phenomena, in this case the calculation of molecular dynamics.

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Acknowledgements

We want to thank Robert Lefkowitz and Brian Kobilka for their interest in our manuscript and their comments. We are also grateful to Raphael Scholl for his critical remarks. Earlier versions of this paper were presented at the 2015 meeting of the European Philosophy of Science Association in Dusseldorf, The History of Science and Scientific Realism conference in Indianapolis 2016, and a workshop on realism in the philosophy of biology at the University of Sassari. We want to thank the audiences, and Anjan Chakravartty in particular, for their questions and comments. ASB’s research for this article was possible through generous funding from the Presidential Scholars in Society and Neuroscience Program at Columbia University. KB is grateful for financial support by Society in Science—The Branco Weiss Fellowship.

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Barwich, A., Bschir, K. The manipulability of what? The history of G-protein coupled receptors. Biol Philos 32, 1317–1339 (2017). https://doi.org/10.1007/s10539-017-9608-9

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Keywords

  • Scientific realism
  • Instrumental intervention
  • Cell signaling mechanism
  • Biochemistry
  • Pharmacology
  • Wet-lab research