Biochemical Pharmacology 87 (2014) 1–3
Contents lists available at ScienceDirect
Biochemical Pharmacology journal homepage: www.elsevier.com/locate/biochempharm
Preface
Pharmacology in 21st century biomedical research The concept behind this special issue of Biochemical Pharmacology, entitled Pharmacology in 21st Century Biomedical Research, resulted from informal discussions with the editorial board members from several leading pharmacology journals who expressed concerns regarding the increased – and increasing – number of manuscripts being rejected that were perceived to lack an appreciation of basic pharmacological principles and the systematic use of the latter in the design and conduct of experiments. Examples of the most frequent shortcomings include: the use of a single, supramaximal concentration/dose of a target-selective compound as a pharmacological tool, assuming that it retains its selectivity; not assessing compound pharmacokinetics before compound dosing in a pharmacodynamic study, instead hoping that in the latter, efficacy is manifest at the usual time point when the effects of the compound are evaluated; designing an experiment without any consideration of a null hypothesis or – in some instances – any type of hypothesis at all; and the inappropriate use of statistical analyses on a trial and error basis in the hope of finding one test where the experimental data show the sought after significant effect, irrespective of whether it is appropriate to the data set analyzed. From a historical perspective, pharmacology has consistently represented the core discipline in biomedical research and drug discovery. The latter is characterized by a uniquely integrative approach that seeks to answer questions regarding the physiology and pathophysiology of cells, tissues and organisms via the use of any and all methodologies that are relevant and available. Pharmacology, in being hypothesis- rather than technology-driven, differs intrinsically from the more recent reductionistic disciplines and methodologies used in biomedical research. However, for more than two decades the teaching of pharmacology and its routine use in biomedical research have been systematically de-emphasized [1,2] in favor of more heuristically convenient reductionistic technologies. The latter are typically described in variations on the ‘omics’ theme, have their origins in the qualitative science of molecular biology [3], and have been funded in both academia and industry to the exclusion of pharmacology and the overall detriment of biomedical research [1]. The reductionistic approach to research frequently lacks a logical hierarchy for effective data generation and the integration that is inherent to a pharmacologically based approach – where the sum of the aggregate data sets derived using different experimental approaches is greater than its parts. Reductionism is further enabled by a computer-based culture, that tends to reduce the intellectual contribution to research activities, leading to a culture that has been termed ‘‘turn on the computer, turn off the brain’’ [4]. The results of this have been pithily termed ‘‘low input, high throughput, no output science’’ [5], much of which, by virtue of either quantity and/or bias, is archival [6] – often before it is even 0006-2952/$ – see front matter ß 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bcp.2013.10.018
published. Such an approach also adds little to the advancement of research resulting in a concerning disconnect with ‘‘medical reality’’ [7], which is viewed by many as a significant contributor to the current dearth of new drug approvals [8]. This has been accompanied by a decline in the quality, relevance and sustainability of biomedical research [9] where 70–80% – or more – of the published literature cannot be independently verified [10–12] – a matter of grave concern to all scientists involved in biomedical research. It is especially disconcerting in the context of experiments that follow from the original observation, that are frequently neither duplicated nor replicable such that the initial study leads to the generation of a large canon of literature that is based on an irreproducible finding [13] and, consequently, meaningless. Since the core purpose of publishing is to share information that will advance knowledge regarding human disease states and their potential treatment, the irreproducible literature results in a costly futile cycle that adds little to the goals of the research endeavor. These events have led to ‘‘an urgent need to reinvigorate academic pharmacology as a core discipline of translational medicine’’ [8], an initiative that is being captured under the rubric of systems biology and the like [2]. Like other major peer-reviewed journals in the pharmacological sciences, Biochemical Pharmacology has a manuscript rejection rate in the 70–80% range. While some of these rejections involved articles that lay outside the scope of interest of the journal, the majority fail to meet peer review standards because the data reported are inadequate to support the hypothesis being investigated, if indeed a hypothesis has even been considered. In addition to consuming the limited pro bono time of experienced peer reviewers and scarce research resources, such papers also reinforce the fundamental flaws in the biomedical research endeavor, highlighted above, which can be attributed to the previously mentioned lack of training – and mentoring – in the discipline of pharmacology. As it appears unlikely these issues will resolve themselves, members of the Biochemical Pharmacology Editorial Board decided to proactively address these from a scientific perspective in the form of the current series of review articles entitled Pharmacology in 21st Century Biomedical Research. The initiative humbly follows in the footsteps of the ‘‘bible’’ of pharmacology, Goodman and Gilman, which over 70 years after its first publication and in its 12th Edition, continues to emphasize the following core principles: ‘‘to correlate pharmacology with related medical sciences, to reinterpret the actions and uses of drugs in light of advances in medicine and the basic biomedical sciences; to emphasize the application of pharmacodynamics to therapeutics and to create a book that will be useful to students of pharmacology and physicians’’ [14]. With the de-emphasis in the teaching of the discipline of pharmacology and its replacement with reductionistic molecular
2
Preface / Biochemical Pharmacology 87 (2014) 1–3
approaches, a new generation of scientists is now involved in conducting biomedical research. This group tends to lack the necessary appreciation and knowledge to practice pharmacology as a core, integrative discipline. Additionally, many of these scientists come from cultures-geographical, cultural and institutional - that lack a significant history of data or evidence-based experimentation as part of the biomedical research endeavor, so are unable to provide appropriate mentoring. Accordingly, the articles in this special issue specifically address each topic of interest by targeting the needs of the intended audience. The authors of the 13 articles in this special issue are experts in their respective areas of pharmacological research and are thus well qualified to address the numerous core elements necessary to conduct and interpret pharmacology-based research. While the topics of the individual articles were clearly defined at the outset of the project to avoid overlap, in some instances this has occurred in order to highlight a specific topic, e.g., receptor theory, from different perspectives. The Editors have worked diligently with the authors, however, to ensure that overlap was kept to a minimum. The first of the 13 articles, The fall and rise of pharmacology-(re)defining the discipline (Winquist et al.), shares part of its title with an article published over a decade ago addressing the same issues from a purely in vivo perspective [15] and provides a history of pharmacology from its inception in the mid 1850s to current times, highlighting key periods, approaches and findings. The next three articles, Quantitative versus qualitative data–the numerical dimension in biomedical research (Bylund and Toews), Defining drug/ compound function, characterization and use (Kenakin and Williams) and Replicated, replicable and relevant–target engagement and pharmacological experimentation in the 21st Century (Kenakin et al.) focus on different, but interrelated, aspects of receptor theory together with its use in experimentation and target engagement. The Use and Misuse of Statistical Methodologies (Marino) addresses current concerns with the misuse of statistical tests by providing some appropriate guidelines. In the article entitled Pharmacokinetics (De Lannoy and Fan) the current status of this core pharmacological technology is reviewed, revisiting many of the themes in the section on receptor theory from the perspective of pharmacodynamics. The next four articles, Animal models of human disease: inflammation (Webb), Animal models of asthma: reprise or reboot? (Mullane and Williams), Animal models of CNS disorders (McGonigle) and Animal models of disease: pre-clinical animal models of cancer and their applications and utility in drug discovery (Ruggeri et al.) are focused on the relevance of animal models of disease in four distinct disease areas, inflammation, asthma, cancer and CNS, in predicting efficacy and safety in the human disease state. While each area has its own unique challenges, there are common features summarized in Animal models of human disease: challenges in enabling translation (McGonigle and Ruggeri) that, despite the many challenges, can provide useful insights in understanding the relationship of animal data to the mechanisms of human disease and facilitating selection and translation of new chemical entities (NCEs) for clinical trials. Another aspect of the translational paradigm is highlighted in Biomarkers in Pharmacology and Drug Discovery (Anderson and Kodukula). One of the key pillars of translational medicine [16], the identification and validation of biomarkers is a time consuming, expensive and technically challenging process fraught with false positives that requires aspects of a ‘‘Big Science’’ approach to obviate bias. Nonetheless, getting this part of the translational process transparently reduced to practice will be key to future success. The final article, The translational paradigm in pharmacology and drug discovery (Mullane et al.) builds to a major degree on the preceding 12 articles to provide a critical overview of the
practice and science behind translational medicine, inevitably yet correctly focusing on the seminal role of pharmacology (a.k.a. systems biology) in enabling the process. It also discusses the often less-than-useful contributions resulting from the reductionism and bias (the latter in the context of irreproducibility of findings) that are prevalent in contemporary biomedical research and that tend to further complicate the challenges in interpreting the huge data sets provided via the Genome Wide Association Studies (GWAS) and Next Generation Sequencing (NGS). In doing so, the final article provides insights into the unique contributions represented by ‘‘experiments in nature’’ [17], the re-emergence of phenotypic screening (including PheWAS – Phenome-Wide Association Studies) and the potential of pluripotent stem cells to contribute to the translational process. This brings the content of this special issue back full circle to the first article, The fall and rise of pharmacology–(re-)defining the discipline, highlighting the renaissance of the integrative, hierarchical discipline of pharmacology in providing the necessary focus and context for the relevance and much needed success of the biomedical research endeavor. The Editors thank the authors for their insightful contributions, their tireless efforts in following the maxim of Jack Bauer in 24 to ‘‘stay on task’’ and their patience in dealing with the considerable and often collegial, feedback from the Editors. In closing, we hope readers find these efforts worthwhile and thank them for their interest, which it is hoped will be maintained by the addition of future Commentaries in Biochemical Pharmacology related to the topic of Pharmacology in 21st Century Biomedical Research. Kevin Mullane* San Jose, CA, USA Michael Williams Lake Forest, IL, USA Raymond Winquist Cambridge, MA, USA *Corresponding author. E-mail address: [email protected] (K. Mullane)
References [1] Jobe PC, Adams-Curtis LE, Burks TF, Fuller RW, Peck CC, Ruffolo RR, et al. The essential role of integrative biomedical sciences in protecting and contributing to the health and well-being of our nation. Physiologist 1994;37:79–84. [2] Sorger PK, Allerheiligen SRB, Abernethy DR, Altman RB, Brouwer KLR, Califano A, et al. Quantitative and systems pharmacology in the post-genomic era: new approaches to discovering drugs and understanding therapeutic mechanism; 2011, http://isp.hms.harvard.edu/wordpress/wp-content/uploads/2011/10/ NIH-Systems-Pharma-Whitepaper-Sorger-et-al-2011.pdf. [3] Maddox J. Is molecular biology yet a science? Nature 1992;335:201. [4] Kubinyi H. Drug research: myths, hype and reality. Nat Rev Drug Discov 2003;2:665–8. [5] Brenner S. An interview with. . . Sydney Brenner, interview by Errol C. Friedberg. Nat Rev Mol Cell Biol 2008;9:8–9. [6] Mandavilli A. Peer review: trial by twitter. Nature 2011;469:286–7. [7] Horrobin DF. Modern biomedical research: an internally self-consistent universe with little contact with medical reality. Nat Rev Drug Discov 2003;2:151–4. [8] FDA. Innovation/stagnation. Challenge and opportunity on the critical path to new medical products; 2004, http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/ucm077262.htm. [9] Mullane K, Williams M. Translational semantics and infrastructure: another search for the emperor’s new clothes. Drug Discov Today 2012;17: 459–548. [10] Ioannidis JPA. Why most published research findings are false. PLoS Med 2005;e124. [11] Begley CG, Ellis LM. Drug development: raise standards for preclinical cancer research. Nature 2012;483:531–3.
Preface / Biochemical Pharmacology 87 (2014) 1–3 [12] Economist, Unreliable research. Trouble at the lab. In: The Economist; 2013 October 19th, 26–30http://www.economist.com/news/briefing/21588057scientists-think-science-self-correcting-alarming-degree-it-not-trouble. [13] Casadevall A, Fang FC. Reforming science: methodological and cultural reforms. Infect Immun 2012;80:891–6. [14] Brunton LL. Preface. In: Brunton L, Chabner B, Knollman B, editors. 12th ed., Goodman and Gilmans’ The Pharmacological Basis of Therapeutics, New York: McGraw-Hill; 2011.
3
[15] In Vivo Pharmacology Training Group. The fall and rise of in vivo pharmacology. Trends Pharmacol Sci 2002;23:13–8. [16] Wehling M. Translational medicine: can it really facilitate the transition of research ‘from bench to bedside’? Eur J Clin Pharmacol 2006;62:91–5. [17] Plenge RM, Scolnick EM, Altshuler D. Validating therapeutic targets through human genetics. Nat Rev Drug Discov 2013;12:581–94.
Contents lists available at ScienceDirect
Biochemical Pharmacology journal homepage: www.elsevier.com/locate/biochempharm
Preface
Pharmacology in 21st century biomedical research The concept behind this special issue of Biochemical Pharmacology, entitled Pharmacology in 21st Century Biomedical Research, resulted from informal discussions with the editorial board members from several leading pharmacology journals who expressed concerns regarding the increased – and increasing – number of manuscripts being rejected that were perceived to lack an appreciation of basic pharmacological principles and the systematic use of the latter in the design and conduct of experiments. Examples of the most frequent shortcomings include: the use of a single, supramaximal concentration/dose of a target-selective compound as a pharmacological tool, assuming that it retains its selectivity; not assessing compound pharmacokinetics before compound dosing in a pharmacodynamic study, instead hoping that in the latter, efficacy is manifest at the usual time point when the effects of the compound are evaluated; designing an experiment without any consideration of a null hypothesis or – in some instances – any type of hypothesis at all; and the inappropriate use of statistical analyses on a trial and error basis in the hope of finding one test where the experimental data show the sought after significant effect, irrespective of whether it is appropriate to the data set analyzed. From a historical perspective, pharmacology has consistently represented the core discipline in biomedical research and drug discovery. The latter is characterized by a uniquely integrative approach that seeks to answer questions regarding the physiology and pathophysiology of cells, tissues and organisms via the use of any and all methodologies that are relevant and available. Pharmacology, in being hypothesis- rather than technology-driven, differs intrinsically from the more recent reductionistic disciplines and methodologies used in biomedical research. However, for more than two decades the teaching of pharmacology and its routine use in biomedical research have been systematically de-emphasized [1,2] in favor of more heuristically convenient reductionistic technologies. The latter are typically described in variations on the ‘omics’ theme, have their origins in the qualitative science of molecular biology [3], and have been funded in both academia and industry to the exclusion of pharmacology and the overall detriment of biomedical research [1]. The reductionistic approach to research frequently lacks a logical hierarchy for effective data generation and the integration that is inherent to a pharmacologically based approach – where the sum of the aggregate data sets derived using different experimental approaches is greater than its parts. Reductionism is further enabled by a computer-based culture, that tends to reduce the intellectual contribution to research activities, leading to a culture that has been termed ‘‘turn on the computer, turn off the brain’’ [4]. The results of this have been pithily termed ‘‘low input, high throughput, no output science’’ [5], much of which, by virtue of either quantity and/or bias, is archival [6] – often before it is even 0006-2952/$ – see front matter ß 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bcp.2013.10.018
published. Such an approach also adds little to the advancement of research resulting in a concerning disconnect with ‘‘medical reality’’ [7], which is viewed by many as a significant contributor to the current dearth of new drug approvals [8]. This has been accompanied by a decline in the quality, relevance and sustainability of biomedical research [9] where 70–80% – or more – of the published literature cannot be independently verified [10–12] – a matter of grave concern to all scientists involved in biomedical research. It is especially disconcerting in the context of experiments that follow from the original observation, that are frequently neither duplicated nor replicable such that the initial study leads to the generation of a large canon of literature that is based on an irreproducible finding [13] and, consequently, meaningless. Since the core purpose of publishing is to share information that will advance knowledge regarding human disease states and their potential treatment, the irreproducible literature results in a costly futile cycle that adds little to the goals of the research endeavor. These events have led to ‘‘an urgent need to reinvigorate academic pharmacology as a core discipline of translational medicine’’ [8], an initiative that is being captured under the rubric of systems biology and the like [2]. Like other major peer-reviewed journals in the pharmacological sciences, Biochemical Pharmacology has a manuscript rejection rate in the 70–80% range. While some of these rejections involved articles that lay outside the scope of interest of the journal, the majority fail to meet peer review standards because the data reported are inadequate to support the hypothesis being investigated, if indeed a hypothesis has even been considered. In addition to consuming the limited pro bono time of experienced peer reviewers and scarce research resources, such papers also reinforce the fundamental flaws in the biomedical research endeavor, highlighted above, which can be attributed to the previously mentioned lack of training – and mentoring – in the discipline of pharmacology. As it appears unlikely these issues will resolve themselves, members of the Biochemical Pharmacology Editorial Board decided to proactively address these from a scientific perspective in the form of the current series of review articles entitled Pharmacology in 21st Century Biomedical Research. The initiative humbly follows in the footsteps of the ‘‘bible’’ of pharmacology, Goodman and Gilman, which over 70 years after its first publication and in its 12th Edition, continues to emphasize the following core principles: ‘‘to correlate pharmacology with related medical sciences, to reinterpret the actions and uses of drugs in light of advances in medicine and the basic biomedical sciences; to emphasize the application of pharmacodynamics to therapeutics and to create a book that will be useful to students of pharmacology and physicians’’ [14]. With the de-emphasis in the teaching of the discipline of pharmacology and its replacement with reductionistic molecular
2
Preface / Biochemical Pharmacology 87 (2014) 1–3
approaches, a new generation of scientists is now involved in conducting biomedical research. This group tends to lack the necessary appreciation and knowledge to practice pharmacology as a core, integrative discipline. Additionally, many of these scientists come from cultures-geographical, cultural and institutional - that lack a significant history of data or evidence-based experimentation as part of the biomedical research endeavor, so are unable to provide appropriate mentoring. Accordingly, the articles in this special issue specifically address each topic of interest by targeting the needs of the intended audience. The authors of the 13 articles in this special issue are experts in their respective areas of pharmacological research and are thus well qualified to address the numerous core elements necessary to conduct and interpret pharmacology-based research. While the topics of the individual articles were clearly defined at the outset of the project to avoid overlap, in some instances this has occurred in order to highlight a specific topic, e.g., receptor theory, from different perspectives. The Editors have worked diligently with the authors, however, to ensure that overlap was kept to a minimum. The first of the 13 articles, The fall and rise of pharmacology-(re)defining the discipline (Winquist et al.), shares part of its title with an article published over a decade ago addressing the same issues from a purely in vivo perspective [15] and provides a history of pharmacology from its inception in the mid 1850s to current times, highlighting key periods, approaches and findings. The next three articles, Quantitative versus qualitative data–the numerical dimension in biomedical research (Bylund and Toews), Defining drug/ compound function, characterization and use (Kenakin and Williams) and Replicated, replicable and relevant–target engagement and pharmacological experimentation in the 21st Century (Kenakin et al.) focus on different, but interrelated, aspects of receptor theory together with its use in experimentation and target engagement. The Use and Misuse of Statistical Methodologies (Marino) addresses current concerns with the misuse of statistical tests by providing some appropriate guidelines. In the article entitled Pharmacokinetics (De Lannoy and Fan) the current status of this core pharmacological technology is reviewed, revisiting many of the themes in the section on receptor theory from the perspective of pharmacodynamics. The next four articles, Animal models of human disease: inflammation (Webb), Animal models of asthma: reprise or reboot? (Mullane and Williams), Animal models of CNS disorders (McGonigle) and Animal models of disease: pre-clinical animal models of cancer and their applications and utility in drug discovery (Ruggeri et al.) are focused on the relevance of animal models of disease in four distinct disease areas, inflammation, asthma, cancer and CNS, in predicting efficacy and safety in the human disease state. While each area has its own unique challenges, there are common features summarized in Animal models of human disease: challenges in enabling translation (McGonigle and Ruggeri) that, despite the many challenges, can provide useful insights in understanding the relationship of animal data to the mechanisms of human disease and facilitating selection and translation of new chemical entities (NCEs) for clinical trials. Another aspect of the translational paradigm is highlighted in Biomarkers in Pharmacology and Drug Discovery (Anderson and Kodukula). One of the key pillars of translational medicine [16], the identification and validation of biomarkers is a time consuming, expensive and technically challenging process fraught with false positives that requires aspects of a ‘‘Big Science’’ approach to obviate bias. Nonetheless, getting this part of the translational process transparently reduced to practice will be key to future success. The final article, The translational paradigm in pharmacology and drug discovery (Mullane et al.) builds to a major degree on the preceding 12 articles to provide a critical overview of the
practice and science behind translational medicine, inevitably yet correctly focusing on the seminal role of pharmacology (a.k.a. systems biology) in enabling the process. It also discusses the often less-than-useful contributions resulting from the reductionism and bias (the latter in the context of irreproducibility of findings) that are prevalent in contemporary biomedical research and that tend to further complicate the challenges in interpreting the huge data sets provided via the Genome Wide Association Studies (GWAS) and Next Generation Sequencing (NGS). In doing so, the final article provides insights into the unique contributions represented by ‘‘experiments in nature’’ [17], the re-emergence of phenotypic screening (including PheWAS – Phenome-Wide Association Studies) and the potential of pluripotent stem cells to contribute to the translational process. This brings the content of this special issue back full circle to the first article, The fall and rise of pharmacology–(re-)defining the discipline, highlighting the renaissance of the integrative, hierarchical discipline of pharmacology in providing the necessary focus and context for the relevance and much needed success of the biomedical research endeavor. The Editors thank the authors for their insightful contributions, their tireless efforts in following the maxim of Jack Bauer in 24 to ‘‘stay on task’’ and their patience in dealing with the considerable and often collegial, feedback from the Editors. In closing, we hope readers find these efforts worthwhile and thank them for their interest, which it is hoped will be maintained by the addition of future Commentaries in Biochemical Pharmacology related to the topic of Pharmacology in 21st Century Biomedical Research. Kevin Mullane* San Jose, CA, USA Michael Williams Lake Forest, IL, USA Raymond Winquist Cambridge, MA, USA *Corresponding author. E-mail address: [email protected] (K. Mullane)
References [1] Jobe PC, Adams-Curtis LE, Burks TF, Fuller RW, Peck CC, Ruffolo RR, et al. The essential role of integrative biomedical sciences in protecting and contributing to the health and well-being of our nation. Physiologist 1994;37:79–84. [2] Sorger PK, Allerheiligen SRB, Abernethy DR, Altman RB, Brouwer KLR, Califano A, et al. Quantitative and systems pharmacology in the post-genomic era: new approaches to discovering drugs and understanding therapeutic mechanism; 2011, http://isp.hms.harvard.edu/wordpress/wp-content/uploads/2011/10/ NIH-Systems-Pharma-Whitepaper-Sorger-et-al-2011.pdf. [3] Maddox J. Is molecular biology yet a science? Nature 1992;335:201. [4] Kubinyi H. Drug research: myths, hype and reality. Nat Rev Drug Discov 2003;2:665–8. [5] Brenner S. An interview with. . . Sydney Brenner, interview by Errol C. Friedberg. Nat Rev Mol Cell Biol 2008;9:8–9. [6] Mandavilli A. Peer review: trial by twitter. Nature 2011;469:286–7. [7] Horrobin DF. Modern biomedical research: an internally self-consistent universe with little contact with medical reality. Nat Rev Drug Discov 2003;2:151–4. [8] FDA. Innovation/stagnation. Challenge and opportunity on the critical path to new medical products; 2004, http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/ucm077262.htm. [9] Mullane K, Williams M. Translational semantics and infrastructure: another search for the emperor’s new clothes. Drug Discov Today 2012;17: 459–548. [10] Ioannidis JPA. Why most published research findings are false. PLoS Med 2005;e124. [11] Begley CG, Ellis LM. Drug development: raise standards for preclinical cancer research. Nature 2012;483:531–3.
Preface / Biochemical Pharmacology 87 (2014) 1–3 [12] Economist, Unreliable research. Trouble at the lab. In: The Economist; 2013 October 19th, 26–30http://www.economist.com/news/briefing/21588057scientists-think-science-self-correcting-alarming-degree-it-not-trouble. [13] Casadevall A, Fang FC. Reforming science: methodological and cultural reforms. Infect Immun 2012;80:891–6. [14] Brunton LL. Preface. In: Brunton L, Chabner B, Knollman B, editors. 12th ed., Goodman and Gilmans’ The Pharmacological Basis of Therapeutics, New York: McGraw-Hill; 2011.
3
[15] In Vivo Pharmacology Training Group. The fall and rise of in vivo pharmacology. Trends Pharmacol Sci 2002;23:13–8. [16] Wehling M. Translational medicine: can it really facilitate the transition of research ‘from bench to bedside’? Eur J Clin Pharmacol 2006;62:91–5. [17] Plenge RM, Scolnick EM, Altshuler D. Validating therapeutic targets through human genetics. Nat Rev Drug Discov 2013;12:581–94.
