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Collateral efficacy in new drug discovery
Editorial
TRENDS in Pharmacological Sciences
Vol.28 No.8
Special issue: Allosterism and Collateral Efficacy
Collateral efficacy in new drug discovery Terry Kenakin Department of Biochemical Reagents and Assay Development, GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park, NC27709, USA
This issue of Trends in Pharmacological Sciences deals with the pharmacology of agonists that activate seventransmembrane receptors – also called G-proteincoupled receptors – to produce direct bias (activation of selected portions of the possible receptor signaling capability) and indirect bias (ligands that allosterically modify the signaling of the receptor to endogenous agonists to select specific behaviors of the receptor). These phenomena are discussed in terms of problems with thermodynamics, cell signaling, pharmacological conformational selection of receptor states and possible therapeutic relevance. This issue of Trends in Pharmacological Sciences is devoted to the allosteric nature of seven-transmembrane (7TM) receptors and how it might lead to drug discovery beyond paradigms that simply seek to mimic or block the effects of endogenous hormones and neurotransmitters. A case can be made for identifying 7TM receptors as nature’s prototypic allosteric proteins in that they bind information-laden molecules in one region to transmit that information, through a change in tertiary conformation, to another region to effect changes in protein–protein interaction. Thus, they are powerful biological control points at which alterations in protein conformation probably involve global changes in protein tertiary structure. This being the case, allosteric changes can interfere with the interactions between large proteins. In addition, the changes might involve distant regions to which the allosteric modulator binds, enabling several intracellular processes to be affected. In terms of ligand effect on 7TM receptors, selective affinities for various receptor conformations confer the ability to traffic information selectively to some, but not necessarily all, cellular signaling pathways – an idea referred to as ‘functional selectivity’, ‘biased agonism’, ‘stimulus trafficking’ or ‘collateral efficacy’. A corollary to this idea is the redefinition of the term ‘efficacy’ as being dependent on the methods used to view drug effect. As stated by James Black, ‘the prismatic qualities of the assay distort our view in obscure ways and degrees’ [1]. The contraction of guinea-pig ileum was the main herald of efficacy for R.P. Stephenson (who initially defined the term Corresponding author: Kenakin, T. ([email protected]). Available online 13 July 2007. www.sciencedirect.com
efficacy [2]) because the technology of the times prevented him from independently observing the numerous other behaviors that might have been imposed on muscarinic acetylcholine receptors by the alkyltrimethylammonium compounds he used. Now that this constraint has largely been removed, the rich behavior of 7TM receptors can be observed, many in isolation. This has led to the idea that there is no single efficacy for a given molecule but, instead, that what is specifically observed as efficacy in a given assay is dependent on the nature of the assay (pluridimensional efficacy [3]). There is now an abundance of evidence that some molecules have collateral efficacy and, thus, cause receptors to express only a portion of their possible behaviors to induce selective cellular effects [4]. In the past 15 years, convincing evidence has been obtained that, pharmacologically, ligands can bias receptors to do this. The next question that must be answered is: can collateral efficacy be harnessed therapeutically to alter normal physiology and pathophysiology selectively? In this issue, a fascinating array of disciplines is brought together in the discussion of these phenomena. The issue was conceived in terms of four scientific ‘problems’, and experts in these areas were polled to discuss recent data in terms of the problems. However, it would be wrong to try to categorize these articles into one of the four problems because all of them take the topic through all of the layers of discussion to give a unique perspective on this complex behavior. The various stages of stimulus trafficking (the direction of receptor activation to portions of the cell machinery) can be thought of as a journey from the extracellular space (receptor conformation), through the membrane and the cytoplasm, into the realm of clinical therapeutics. First, this can be thought of as a problem in terms of ‘protein conformation and thermodynamics’. Questions involving the molecular mechanisms that are operative in creating and controlling the various tertiary conformations of the receptor can be discussed in terms of the experimental measures of protein structure (Brian Kobilka and Xavier Deupi [5] provide an authoritative overview of this area) and the theoretical models available for describing and predicting these effects. A model of conformational selection is given in the article by Kenakin [6]. As the various pathways that can be controlled by receptors are investigated and understood, there can also now be defined a ‘cellular signaling problem’. It is known
0165-6147/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2007.06.010
360
Editorial
TRENDS in Pharmacological Sciences
that there is a rich palette of systems with which these conformations can interact in the cell and that these interactions can result in unique ligand activity in a system. The newly defined role of G-protein-independent-receptor-mediated signaling through b-arrestin [e.g. to mitogen-activated protein kinases (MAPKs)] constitutes an important new player in the cellular array of receptor partners, as discussed by Jonathan Violin and Robert Lefkowitz [7]. In their article, they discuss both the study and the possible therapeutic applications of ‘biased’ ligands in terms of G-protein-mediated versus b-arrestin-mediated cellular signaling. Of particular note are the challenges of quantifying true b-arrestin bias in signaling ligands. The article by Se´gole`ne Galandrin, Genevie`ve Oligny-Longpre´ and Michel Bouvier [8] confronts the challenge of quantifying efficacy for multiple cellular functions (pluridimensional efficacy) and discusses the inevitable further challenge of guiding medicinal chemists through multivariate space to determine structure–activity relationships. The ‘pharmacological problem’ involves ligand–receptor interaction and how chemical structure can produce ligand-induced controllable bias into these complex systems. The pharmacological problem can be divided further into one of detection (screening) and lead optimization. In terms of screening for biased activity, the article by Annette Gilchrist [9] discusses an exciting new prospect involving high-affinity native Ga C-terminal peptides to amplify weak interactions and identify functionally selective ligands. Another technology that is intimately involved with receptor signaling uses resonance energy transfer; Stefano Marullo and Michel Bouvier [10] highlight the application of this emerging technology in the study of receptors. Insights into screening and subsequent optimization of these direct and indirect (see later) allosteric effects of ligands are provided in a comprehensive discussion of 7TM receptor behavior, ranging from inverse agonism to selective agonism and antagonism, by Barbara Bosier and Emmanuel Hermans [11]. The authors discuss the inevitable future challenge of applying these selective effects in the therapeutic environment. Finally, although collateral efficacy usually concerns a ligand that produces less than the complete complement of possible receptor behaviors, Thue Schwartz and Birgitte Holst [12] offer a unique perspective on allosterism whereby allosteric agonist ligands (‘ago-allosteric’ modulators) produce effects greater than those caused by natural agonists by virtue of direct agonism and allosteric potentiation of endogenous tone. Allosteric modulation can be direct (the ligand itself induces a selective conformation that interacts with different signaling moieties in the cell) or permissive, whereby modulator binding induces selective (collateral) efficacy on other ligands, including the natural agonist. This latter idea is discussed by Jillian Baker and Stephen Hill [13], who provide an insightful survey of pathway-selective antagonism. In addition, the interaction of multiple binding sites on the receptor is discussed in terms of chemically mediated sophisticated transfer of information to cells. In the article by Katie Leach, Patrick Sexton and Arthur Christopoulos [14], the theme of modulator-induced induction of collateral efficacy of natural ligands is developed www.sciencedirect.com
Vol.28 No.8
and discussed in terms of harnessing permissive modulation for pathway-selective therapies. Finally, perhaps the most difficult question to answer at this time is the therapeutic relevance of selective signaling (the ‘therapeutic problem’). In the future, the identification of selective ligands and their subsequent clinical use will forge the link between defined efficacies and therapeutic potential. However, the article by Richard Mailman [15] describes the reverse case, in which astute identification of therapeutic behavior in ligands was the impetus for identifying and proposing unique selectivity for agonists; these ideas have important implications in the therapy of schizophrenia and Parkinson’s disease. The extensive study of these dopamine-selective drugs and ligands constitutes the most compelling association to date between 7TM receptor functional selectivity and receptormediated actions in vivo, both clinically and in laboratory animals. The example of dopamine agonist therapy for central diseases can function as a model of the application of collateral efficacy to the selective treatment of other diseases. The data collected in the past decade indicate great sophistication in the signaling capabilities of 7TM receptors. One might suppose that the evolution of the capability for such fine control of receptor function is a teleological necessity of which pharmacologists can take advantage. Intuitively, one might suppose that moreselective drugs will naturally be ‘better’ in terms of being chemical ‘scalpels’ with which to tackle disease. However, a prerequisite for such an application is sufficient knowledge of the pathophysiology that is to be interfered with. If the appropriate pharmacological assays are in place to identify functionally selective ligands, the therapeutic profiles of such compounds will hopefully be obtained in the clinic in the future, and translational medicine might help to discern the therapeutically relevant from the irrelevant processes of stimulus trafficking. In this regard, this new generation of selective drugs might be the newly forged tool with which to explore this pathophysiology to lead translational medicine back to the pharmacological and medicinal chemistry bench. The articles contained herein cover the range of these disciplines and weave a tapestry that will hopefully yield a better understanding of how to exploit these subtleties of receptor signaling to produce benefits in the clinic. References 1 Black, J.W. (1993) Drugs from emasculated hormones: principles of synoptic antagonism. In Nobel Lectures. Physiology or Medicine 1981– 1990 (Frangsmyr, J. and Linsten, J., eds), World Scientific Publishing 2 Stephenson, R.P. (1997) A modification of receptor theory. 1956. Br. J. Pharmacol. 120 (Suppl. 4), 106–120 3 Galandrin, S. and Bouvier, M. (2006) Distinct signaling profiles of b1 and b2 adrenergic receptor ligands toward adenylyl cyclase and mitogen-activated protein kinase reveals the pluridimensionality of efficacy. Mol. Pharmacol. 70, 1575–1584 4 Kenakin, T. (2005) New concepts in drug discovery: collateral efficacy and permissive antagonism. Nat. Rev. Drug Discov. 4, 919–927 5 Kobilka, B.K. and Deupi, X. (2007) Conformational complexity of G-protein-coupled receptors. Trends Pharmacol. Sci. 28, 397– 406
Editorial
TRENDS in Pharmacological Sciences
6 Kenakin, T. (2007) Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors. Trends Pharmacol. Sci. 28, 407–415 7 Violin, J.D. and Lefkowitz, R.J. (2007) b-Arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol. Sci. 28, 416– 422 8 Galandrin, S. et al. (2007) The evasive nature of drug efficacy: implications for drug discovery. Trends Pharmacol. Sci. 28, 423–430 9 Gilchrist, A. (2007) Modulating G-protein-coupled receptors: from traditional pharmacology to allosterics. Trends Pharmacol. Sci. 28, 431–437 10 Marullo, S. and Bouvier, M. (2007) Resonance energy transfer approaches in molecular pharmacology and beyond. Trends Pharmacol. Sci. 28, 362–365
Vol.28 No.8
361
11 Bosier, B. and Hermans, E. (2007) Versatility of GPCR recognition by drugs: from biological implications to therapeutic relevance. Trends Pharmacol. Sci. 28, 438–446 12 Schwartz, T.W. and Holst, B. (2007) Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act? Trends Pharmacol. Sci. 28, 366–373 13 Baker, J.G. and Hill, S.J. (2007) Multiple GPCR conformations and signalling pathways: implications for antagonist affinity estimates. Trends Pharmacol. Sci. 28, 374–381 14 Leach, K. et al. (2007) Allosteric GPCR modulators: taking advantage of permissive receptor pharmacology. Trends Pharmacol. Sci. 28, 382– 389 15 Mailman, R.B. (2007) GPCR functional selectivity has therapeutic impact. Trends Pharmacol. Sci. 28, 390–396
Endeavour The quarterly magazine for the history and philosophy of science. You can access Endeavour online on ScienceDirect, where you’ll find book reviews, editorial comment and a collection of beautifully illustrated articles on the history of science. Featuring: Information revolution: William Chambers, the publishing pioneer by A. Fyfe Does history count? by K. Anderson Waking up to shell shock: psychiatry in the US military during World War II by H. Pols Deserts on the sea floor: Edward Forbes and his azoic hypothesis for a lifeless deep ocean by T.R. Anderson and T. Rice ‘Higher, always higher’: technology, the military and aviation medicine during the age of the two world wars by C. Kehrt Bully for Apatosaurus by P. Brinkman Coming soon: Environmentalism out of the Industrial Revolution by C. Macleod Pandemic in print: the spread of influenza in the Fin de Sie`cle by J. Mussell Earthquake theories in the early modern period by F. Willmoth Science in fiction - attempts to make a science out of literary criticism by J. Adams The birth of botanical Drosophila by S. Leonelli And much, much more. . .
Endeavour is available on ScienceDirect, www.sciencedirect.com www.sciencedirect.com
TRENDS in Pharmacological Sciences
Vol.28 No.8
Special issue: Allosterism and Collateral Efficacy
Collateral efficacy in new drug discovery Terry Kenakin Department of Biochemical Reagents and Assay Development, GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park, NC27709, USA
This issue of Trends in Pharmacological Sciences deals with the pharmacology of agonists that activate seventransmembrane receptors – also called G-proteincoupled receptors – to produce direct bias (activation of selected portions of the possible receptor signaling capability) and indirect bias (ligands that allosterically modify the signaling of the receptor to endogenous agonists to select specific behaviors of the receptor). These phenomena are discussed in terms of problems with thermodynamics, cell signaling, pharmacological conformational selection of receptor states and possible therapeutic relevance. This issue of Trends in Pharmacological Sciences is devoted to the allosteric nature of seven-transmembrane (7TM) receptors and how it might lead to drug discovery beyond paradigms that simply seek to mimic or block the effects of endogenous hormones and neurotransmitters. A case can be made for identifying 7TM receptors as nature’s prototypic allosteric proteins in that they bind information-laden molecules in one region to transmit that information, through a change in tertiary conformation, to another region to effect changes in protein–protein interaction. Thus, they are powerful biological control points at which alterations in protein conformation probably involve global changes in protein tertiary structure. This being the case, allosteric changes can interfere with the interactions between large proteins. In addition, the changes might involve distant regions to which the allosteric modulator binds, enabling several intracellular processes to be affected. In terms of ligand effect on 7TM receptors, selective affinities for various receptor conformations confer the ability to traffic information selectively to some, but not necessarily all, cellular signaling pathways – an idea referred to as ‘functional selectivity’, ‘biased agonism’, ‘stimulus trafficking’ or ‘collateral efficacy’. A corollary to this idea is the redefinition of the term ‘efficacy’ as being dependent on the methods used to view drug effect. As stated by James Black, ‘the prismatic qualities of the assay distort our view in obscure ways and degrees’ [1]. The contraction of guinea-pig ileum was the main herald of efficacy for R.P. Stephenson (who initially defined the term Corresponding author: Kenakin, T. ([email protected]). Available online 13 July 2007. www.sciencedirect.com
efficacy [2]) because the technology of the times prevented him from independently observing the numerous other behaviors that might have been imposed on muscarinic acetylcholine receptors by the alkyltrimethylammonium compounds he used. Now that this constraint has largely been removed, the rich behavior of 7TM receptors can be observed, many in isolation. This has led to the idea that there is no single efficacy for a given molecule but, instead, that what is specifically observed as efficacy in a given assay is dependent on the nature of the assay (pluridimensional efficacy [3]). There is now an abundance of evidence that some molecules have collateral efficacy and, thus, cause receptors to express only a portion of their possible behaviors to induce selective cellular effects [4]. In the past 15 years, convincing evidence has been obtained that, pharmacologically, ligands can bias receptors to do this. The next question that must be answered is: can collateral efficacy be harnessed therapeutically to alter normal physiology and pathophysiology selectively? In this issue, a fascinating array of disciplines is brought together in the discussion of these phenomena. The issue was conceived in terms of four scientific ‘problems’, and experts in these areas were polled to discuss recent data in terms of the problems. However, it would be wrong to try to categorize these articles into one of the four problems because all of them take the topic through all of the layers of discussion to give a unique perspective on this complex behavior. The various stages of stimulus trafficking (the direction of receptor activation to portions of the cell machinery) can be thought of as a journey from the extracellular space (receptor conformation), through the membrane and the cytoplasm, into the realm of clinical therapeutics. First, this can be thought of as a problem in terms of ‘protein conformation and thermodynamics’. Questions involving the molecular mechanisms that are operative in creating and controlling the various tertiary conformations of the receptor can be discussed in terms of the experimental measures of protein structure (Brian Kobilka and Xavier Deupi [5] provide an authoritative overview of this area) and the theoretical models available for describing and predicting these effects. A model of conformational selection is given in the article by Kenakin [6]. As the various pathways that can be controlled by receptors are investigated and understood, there can also now be defined a ‘cellular signaling problem’. It is known
0165-6147/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2007.06.010
360
Editorial
TRENDS in Pharmacological Sciences
that there is a rich palette of systems with which these conformations can interact in the cell and that these interactions can result in unique ligand activity in a system. The newly defined role of G-protein-independent-receptor-mediated signaling through b-arrestin [e.g. to mitogen-activated protein kinases (MAPKs)] constitutes an important new player in the cellular array of receptor partners, as discussed by Jonathan Violin and Robert Lefkowitz [7]. In their article, they discuss both the study and the possible therapeutic applications of ‘biased’ ligands in terms of G-protein-mediated versus b-arrestin-mediated cellular signaling. Of particular note are the challenges of quantifying true b-arrestin bias in signaling ligands. The article by Se´gole`ne Galandrin, Genevie`ve Oligny-Longpre´ and Michel Bouvier [8] confronts the challenge of quantifying efficacy for multiple cellular functions (pluridimensional efficacy) and discusses the inevitable further challenge of guiding medicinal chemists through multivariate space to determine structure–activity relationships. The ‘pharmacological problem’ involves ligand–receptor interaction and how chemical structure can produce ligand-induced controllable bias into these complex systems. The pharmacological problem can be divided further into one of detection (screening) and lead optimization. In terms of screening for biased activity, the article by Annette Gilchrist [9] discusses an exciting new prospect involving high-affinity native Ga C-terminal peptides to amplify weak interactions and identify functionally selective ligands. Another technology that is intimately involved with receptor signaling uses resonance energy transfer; Stefano Marullo and Michel Bouvier [10] highlight the application of this emerging technology in the study of receptors. Insights into screening and subsequent optimization of these direct and indirect (see later) allosteric effects of ligands are provided in a comprehensive discussion of 7TM receptor behavior, ranging from inverse agonism to selective agonism and antagonism, by Barbara Bosier and Emmanuel Hermans [11]. The authors discuss the inevitable future challenge of applying these selective effects in the therapeutic environment. Finally, although collateral efficacy usually concerns a ligand that produces less than the complete complement of possible receptor behaviors, Thue Schwartz and Birgitte Holst [12] offer a unique perspective on allosterism whereby allosteric agonist ligands (‘ago-allosteric’ modulators) produce effects greater than those caused by natural agonists by virtue of direct agonism and allosteric potentiation of endogenous tone. Allosteric modulation can be direct (the ligand itself induces a selective conformation that interacts with different signaling moieties in the cell) or permissive, whereby modulator binding induces selective (collateral) efficacy on other ligands, including the natural agonist. This latter idea is discussed by Jillian Baker and Stephen Hill [13], who provide an insightful survey of pathway-selective antagonism. In addition, the interaction of multiple binding sites on the receptor is discussed in terms of chemically mediated sophisticated transfer of information to cells. In the article by Katie Leach, Patrick Sexton and Arthur Christopoulos [14], the theme of modulator-induced induction of collateral efficacy of natural ligands is developed www.sciencedirect.com
Vol.28 No.8
and discussed in terms of harnessing permissive modulation for pathway-selective therapies. Finally, perhaps the most difficult question to answer at this time is the therapeutic relevance of selective signaling (the ‘therapeutic problem’). In the future, the identification of selective ligands and their subsequent clinical use will forge the link between defined efficacies and therapeutic potential. However, the article by Richard Mailman [15] describes the reverse case, in which astute identification of therapeutic behavior in ligands was the impetus for identifying and proposing unique selectivity for agonists; these ideas have important implications in the therapy of schizophrenia and Parkinson’s disease. The extensive study of these dopamine-selective drugs and ligands constitutes the most compelling association to date between 7TM receptor functional selectivity and receptormediated actions in vivo, both clinically and in laboratory animals. The example of dopamine agonist therapy for central diseases can function as a model of the application of collateral efficacy to the selective treatment of other diseases. The data collected in the past decade indicate great sophistication in the signaling capabilities of 7TM receptors. One might suppose that the evolution of the capability for such fine control of receptor function is a teleological necessity of which pharmacologists can take advantage. Intuitively, one might suppose that moreselective drugs will naturally be ‘better’ in terms of being chemical ‘scalpels’ with which to tackle disease. However, a prerequisite for such an application is sufficient knowledge of the pathophysiology that is to be interfered with. If the appropriate pharmacological assays are in place to identify functionally selective ligands, the therapeutic profiles of such compounds will hopefully be obtained in the clinic in the future, and translational medicine might help to discern the therapeutically relevant from the irrelevant processes of stimulus trafficking. In this regard, this new generation of selective drugs might be the newly forged tool with which to explore this pathophysiology to lead translational medicine back to the pharmacological and medicinal chemistry bench. The articles contained herein cover the range of these disciplines and weave a tapestry that will hopefully yield a better understanding of how to exploit these subtleties of receptor signaling to produce benefits in the clinic. References 1 Black, J.W. (1993) Drugs from emasculated hormones: principles of synoptic antagonism. In Nobel Lectures. Physiology or Medicine 1981– 1990 (Frangsmyr, J. and Linsten, J., eds), World Scientific Publishing 2 Stephenson, R.P. (1997) A modification of receptor theory. 1956. Br. J. Pharmacol. 120 (Suppl. 4), 106–120 3 Galandrin, S. and Bouvier, M. (2006) Distinct signaling profiles of b1 and b2 adrenergic receptor ligands toward adenylyl cyclase and mitogen-activated protein kinase reveals the pluridimensionality of efficacy. Mol. Pharmacol. 70, 1575–1584 4 Kenakin, T. (2005) New concepts in drug discovery: collateral efficacy and permissive antagonism. Nat. Rev. Drug Discov. 4, 919–927 5 Kobilka, B.K. and Deupi, X. (2007) Conformational complexity of G-protein-coupled receptors. Trends Pharmacol. Sci. 28, 397– 406
Editorial
TRENDS in Pharmacological Sciences
6 Kenakin, T. (2007) Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors. Trends Pharmacol. Sci. 28, 407–415 7 Violin, J.D. and Lefkowitz, R.J. (2007) b-Arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol. Sci. 28, 416– 422 8 Galandrin, S. et al. (2007) The evasive nature of drug efficacy: implications for drug discovery. Trends Pharmacol. Sci. 28, 423–430 9 Gilchrist, A. (2007) Modulating G-protein-coupled receptors: from traditional pharmacology to allosterics. Trends Pharmacol. Sci. 28, 431–437 10 Marullo, S. and Bouvier, M. (2007) Resonance energy transfer approaches in molecular pharmacology and beyond. Trends Pharmacol. Sci. 28, 362–365
Vol.28 No.8
361
11 Bosier, B. and Hermans, E. (2007) Versatility of GPCR recognition by drugs: from biological implications to therapeutic relevance. Trends Pharmacol. Sci. 28, 438–446 12 Schwartz, T.W. and Holst, B. (2007) Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act? Trends Pharmacol. Sci. 28, 366–373 13 Baker, J.G. and Hill, S.J. (2007) Multiple GPCR conformations and signalling pathways: implications for antagonist affinity estimates. Trends Pharmacol. Sci. 28, 374–381 14 Leach, K. et al. (2007) Allosteric GPCR modulators: taking advantage of permissive receptor pharmacology. Trends Pharmacol. Sci. 28, 382– 389 15 Mailman, R.B. (2007) GPCR functional selectivity has therapeutic impact. Trends Pharmacol. Sci. 28, 390–396
Endeavour The quarterly magazine for the history and philosophy of science. You can access Endeavour online on ScienceDirect, where you’ll find book reviews, editorial comment and a collection of beautifully illustrated articles on the history of science. Featuring: Information revolution: William Chambers, the publishing pioneer by A. Fyfe Does history count? by K. Anderson Waking up to shell shock: psychiatry in the US military during World War II by H. Pols Deserts on the sea floor: Edward Forbes and his azoic hypothesis for a lifeless deep ocean by T.R. Anderson and T. Rice ‘Higher, always higher’: technology, the military and aviation medicine during the age of the two world wars by C. Kehrt Bully for Apatosaurus by P. Brinkman Coming soon: Environmentalism out of the Industrial Revolution by C. Macleod Pandemic in print: the spread of influenza in the Fin de Sie`cle by J. Mussell Earthquake theories in the early modern period by F. Willmoth Science in fiction - attempts to make a science out of literary criticism by J. Adams The birth of botanical Drosophila by S. Leonelli And much, much more. . .
Endeavour is available on ScienceDirect, www.sciencedirect.com www.sciencedirect.com