From the Origins of Pharmacogenetics to First Applications in Psychiatry.

Pharmacogenetics is the division of science addressing how genetic factors contribute to the metabolism, response, and side effects of a given medication. What was once regarded as a subdivision of genetics and pharmacology is now recognized as its own field and has its own unique story of origin. While the term "pharmacogenetics" was coined by Friedrich Vogel in 1959, the relevance of inherited genetic traits in affecting the clinical outcome to xenobiotics has been observed long before. In fact, there is much hope that pharmacogenetics can help unravel the "mysteries" as to why different people may display variable responses to the same medication as well as identify new drug targets. This article will highlight the conceptual framework for pharmacogenetics advanced by pioneer scientists Arno Motulsky and Friedrich Vogel (both human geneticists), as well as Werner Kalow (clinical pharmacologist), leading up to the creation of modern pharmacogenetics. Finally, the practical implications and first steps toward implementation for current psychiatric treatment are reviewed followed by an outlook on future studies.

Genomic research delivering on promises: From rejuvenation to vaccines and pharmacogenetics.

WHAT IS KNOWN AND OBJECTIVE: There has been astounding progress made in the treatment of disease over recent years. This progress is particularly marked in cell therapy and in the personalization of therapy based on genetic insight, an approach known as genomic medicine. Our objective is to comment on the progress made in cell and genomic medicine against an historical backcloth of the search for rejuvenation. COMMENT: In 1741, close to seven decades after Antoine van Leeuwenhoek first saw his microscopic animalcules, Abraham Trembley, a tutor in Leiden, reported on an organism that could regenerate itself. The strange organism was thought to hold the secret of life. If it does, we have yet to prise the secret out. However, the ensuing study of cell programming and induced stem cells has shed considerable light on cellular development and provided new insights on the rejuvenative capacity of organisms. Inventive scientists have provided a deeper understanding of cell replication and, from this, developed new medicines for an increasing range of diseases. Targeted therapies, oligonucleotide therapy, therapeutic monoclonal antibodies and pharmacogenetics are all new therapeutic areas originating from the improved insights. More will surely follow. WHAT IS NEW AND CONCLUSION: Immortality is for the gods, but man's search for its elusive secrets, perhaps as old as man himself, will continue. Huge leaps have been made, and effective medicines have been developed from our improved insights into the mechanism of life. However, only the foolish will predict how far this new knowledge will lead us, and more particularly, at what speed new therapies will follow.

The First 50 Years of Molecular Pharmacology.

In this Perspective, former and current editors of Molecular Pharmacology, together with the guest editors for this 50th Anniversary Issue, provide a historical overview of the journal since its founding in 1965. The substantial impact that Molecular Pharmacology has had on the field of pharmacology as well as on biomedical science is discussed, as is the broad scope of the journal. The authors conclude that, true to the original goals for the journal, Molecular Pharmacology today remains an outstanding venue for work that provides a mechanistic understanding of drugs, molecular probes, and their biologic targets.

Pharmacogenomics: history, barriers, and regulatory solutions.

Pharmacogenomics is the branch of pharmacology which looks at the influence of genetic variation on drug response, connecting particular genetic markers with the effectiveness or safety of a drug. Pharmacogenomic products promise to improve medical treatment, lower health care costs, and make the new drug pipeline for FDA approval more efficient. In the last fifteen years, the FDA has approved pharmacogenomic drugs to treat a variety of cancers, HIV-AIDS, and coronary artery disease. Yet, progress in the field of pharmacogenomics has lagged behind the optimistic predictions of many researchers and policymakers. A lack of clear regulatory guidance dealing with pharmacogenomic products has been a major barrier to progress in the field. The FDA has, however, made some headway. In a series of guidance documents released between 2005 and 2011, the FDA has clarified much of its policy with respect to the development, approval, and labeling of pharmacogenomic products. Despite these efforts, many regulatory questions remain unanswered. This paper highlights a number of these regulatory gaps and provides recommendations to address them in a way which encourages increased development and clinical uptake of pharmacogenomic products.

How personalized medicine became genetic, and racial: Werner Kalow and the formations of pharmacogenetics.

Physicians have long puzzled over a well-known phenomenon: different patients respond differently to the same treatment. Although many explanations exist, pharmacogenetics has now captured the medical imagination. While this might seem part of the broader interest in all things genetic, the early history of pharmacogenetics reveals the specific factors that contributed to the emergence of genetics within pharmacology. This paper examines the work of one pioneering pharmacologist, Werner Kalow, to trace the evolving intellectual formations of pharmacogenetics and, in particular, the focus on race. Working in the 1950s and 1960s, Kalow made three arguments to demonstrate the relevance of genetics to pharmacology, based on laboratory techniques, analogies to differences between other animal species, and appeals to the logic of natural selection. After contributing to the emergence of the field, Kalow maintained his advocacy for pharmacogenetics for four decades, collecting more evidence for its relevance, navigating controversies about race and science, and balancing genetics against other possible explanations of patient variability. Kalow's work demonstrates the deep roots of the genetic and racial preoccupations in pharmacology. Understanding this history can restore attention to other explanations of individuality in medical practice, something of increasing importance given the current interest in personalized medicine.

Pharmacogenetics and anaesthesia: the value of genetic profiling.

Approximately 50 years ago, pharmacogenetics was described as a new field of medicine that may explain human drug action. Anaesthesia played a key role in the early investigations. An understanding of how a person's DNA influences drug metabolism and effectiveness may allow individually tailored prescriptions, improving outcomes and safety. The ultimate goal of pharmacogenetic research is to offer tailored personalised medicine to improve both the efficacy of medication and patient safety by helping to predict risk of adverse outcomes. In this review, we present a selection of historical landmarks where anaesthesia has been a catalyst for pharmacogenetic development. We examine the level of evidence and cite examples of candidate genes and common polymorphisms known to alter the response to peri-operative medication. Finally, we set forth current views and potential exciting perspectives that may arise from the application of pharmacogenetics to the daily practice of anaesthesia and pain medicine.

Pharmacogenetics in heart failure: how it will shape the future.

Pharmacogenomics is a growing field of research that focuses on how an individual's genetic background influences his or her response to therapy with a drug or device. Increasing evidence from clinical trials in patients with heart failure (HF) due to systolic dysfunction suggests that genetic variations can predict the occurrence of HF, influence the effects of standard therapies, and influence outcomes of HF patients. This article reviews the underlying principles of pharmacogenomics, discusses some of the complex variables that influence the investigational approach to pharmacogenomics, demonstrates how variations in genes encoding a variety of different proteins can influence the effects of pharmacologic agents, and describes the potential impact of pharmacogenomics on the treatment of patients with HF.

From human genetics and genomics to pharmacogenetics and pharmacogenomics: past lessons, future directions.

A brief history of human genetics and genomics is provided, comparing recent progress in those fields with that in pharmacogenetics and pharmacogenomics, which are subsets of genetics and genomics, respectively. Sequencing of the entire human genome, the mapping of common haplotypes of single-nucleotide polymorphisms (SNPs), and cost-effective genotyping technologies leading to genome-wide association (GWA) studies - have combined convincingly in the past several years to demonstrate the requirements needed to separate true associations from the plethora of false positives. While research in human genetics has moved from monogenic to oligogenic to complex diseases, its pharmacogenetics branch has followed, usually a few years behind. The continuous discoveries, even today, of new surprises about our genome cause us to question reviews declaring that "personalized medicine is almost here" or that "individualized drug therapy will soon be a reality." As summarized herein, numerous reasons exist to show that an "unequivocal genotype" or even an "unequivocal phenotype" is virtually impossible to achieve in current limited-size studies of human populations. This problem (of insufficiently stringent criteria) leads to a decrease in statistical power and, consequently, equivocal interpretation of most genotype-phenotype association studies. It remains unclear whether personalized medicine or individualized drug therapy will ever be achievable by means of DNA testing alone.

Implications of pharmacogenomics for drug development.

The use of pharmacogenomics (PGx) today is almost ubiquitous in drug development and is advancing into the practice of medicine as an increasing number of drugs come to market with indications that are related to the presence or absence of a specific genetic biomarker. The authors review the history of PGx and its tools in research, in clinical trials and in clinical medicine. The economic, regulatory, and technological driving forces for adoption of PGx are then considered. Current impediments to a more robust proliferation of the benefits of these technologies are discussed-pharmaceutical companies, clinical education, required statistical methods, and intellectual property landscape.

Exploiting race in drug development: BiDil's interim model of pharmacogenomics.

This paper explores events surrounding the US Food and Drug Administration's formal approval of the heart failure drug BiDil in 2005. BiDil is the first drug ever to be approved with a race-specific indication, in this case to treat heart failure in 'self-identified black patients'. BiDil has been cast by many as a step toward the promised land of individualized pharmacogenomic therapies. This paper argues, however, that when examined in context, the approval of BiDil emerges as a new model of how a pharmaceutical company may exploit race in the marketplace by literally capitalizing on the racial identity of minority populations and leveraging the disproportionate risk of adverse health outcomes they suffer into a cheaper, more efficient way to gain the US Food and Drug Administration's approval for drugs. Discussions of BiDil in both popular media and professional journals have repeatedly elided the difference between pharmacogenomic and race-based medicine. In fact, broad-based true pharmacogenomic therapies remain years-perhaps decades-in the future. The story of BiDil's development elucidates an alternative model to developing tailored therapies that promises to fill in the gap between the promise and reality of pharmacogenomic medicine. It is a model that exploits race to gain regulatory and commercial advantage, while ignoring its power to promote a regeneticization of racial categories in society at large.

Drug metabolism and pharmacogenetics: the British contribution to fields of international significance.

The branch of pharmacology we now call 'drug metabolism', the consideration of the enzymes and procesess determining the disposition of drugs in the body, emerged in the 1840s on the continent of Europe, but British science made little or no contribution until the 1920s. From this point on, the development of the field through the 20th century was shaped to a very significant extent by a series of influential British workers, whose contributions were of global significance and who can now be seen as fathers of the subject. Since the 1950s, and gaining pace inexorably from the 1970s, the significance of drug metabolism to human therapeutics has been greatly added to by the emergence of pharmacogenetics, clinically important hereditary variation in response to drugs, which underpins the current emphasis on personalised medicine. This review examines the British contributions to both these fields through the lives of seven key contributors and attempts to place their work both in the context of its time and its lasting influence.

Pharmacogenomics: historical perspective and current status.

Pharmacogenomics is an extension of pharmacogenetics, a science described here in terms of five stages of development: 1) some clinical observations predicted genetic alterations of drug response; 2) additional case discoveries led to the term "pharmacogenetics," a concept broadened by 3) many systemic case studies, and the realization of its wide applicability; 4) came the recognition of systematic pharmacogenetic differences between human populations. Then it became clear that 5) most human drug-response differences were multifactorial, caused by many genetic alterations plus environmental factors. The recognition of these complexities, and the advance of genetics into genomics led to the broader science of pharmacogenomics. This led to plans to create "personalized medicine," that is, making drug use more effective and safer by giving drugs that fit a person's genes. Much of the science of genetics, dealing with gene structure, was changed by the realization that gene expression and thereby gene function was variable; this leads to systematic studies of drug action on genes, reversing the traditional studies of genes affecting drug action. Finally, the realization that gene-protein variations contribute to most common diseases leads to efforts of creating new drugs that act on these variants.

The promise of psychiatric pharmacogenomics.

Clinicians already face "personalized" medicine every day while experiencing the great variation in toxicities and drug efficacy among individual patients. Pharmacogenetics studies are the platform for discovering the DNA determinants of variability in drug response and tolerability. Research now focuses on the genome after its beginning with analyses of single genes. Therapeutic outcomes from several psychotropic drugs have been weakly linked to specific genetic variants without independent replication. Drug side effects show stronger associations to genetic variants, including human leukocyte antigen loci with carbamazepine-induced dermatologic outcome and MC4R with atypical antipsychotic weight gain. Clinical implementation has proven challenging, with barriers including a lack of replicable prospective evidence for clinical utility required for altering medical care. More recent studies show promising approaches for reducing these barriers to routine incorporation of pharmacogenetics data into clinical care.

Perspectives in pharmacogenetics.

The historical perspective of pharmacogenetics is presented to a large extent from a personal view, since I happened to get into this field of science at the time of its beginning, and since pharmacogenetics has remained the backbone of my scientific career. Pharmacogenetics initially emphasized observations of interpersonal variability, but the attention on interethnic differences soon followed. Technical advances led to the identification of many responsible gene alterations in both individuals and in populations. Included is a relatively extensive discussion in which the effects and the different consequences of monogenic (mendelian) and multigenic (multifactorial) variation are compared.

The drugs don't work: expectations and the shaping of pharmacogenetics.

This article examines one particular set of technologies arising from developments in human genetics, those aimed at improving the targeting, design and use of conventional small molecule drugs-pharmacogenetics. Much of the debate about the applications and consequences of pharmacogenetics has been highly speculative, since little or no working technology is yet on the market. This article provides a novel analysis of the development of pharmacogenetics, and the social and ethical issues it raises, based on the sociology of technological expectations. In particular, it outlines how two alternative visions for the development of the technology are being articulated and embedded in a range of heterogeneous discourses, artefacts, actor strategies and practices, including: competing scientific research agendas, experimental technologies, emerging industrial structures and new ethical discourses. Expectations of how pharmacogenetics might emerge in each of these arenas are actively shaping the trajectory of this nascent technology and its potential socio-economic consequences.

[Genetic and biochemical approaches to individual sensitivity to drug preparations]. / Genetiko-biokhimicheskoe razvitie problemy individual'noi chuvstvitel'nosti k lekarstvennym sredstvam.

The paper addresses evolution of the concept of individual sensitivity to drugs, based on the new pharmacogenetic and pharmacogenomic approaches. The possibility of geno- and phenotypy of the pharmacodynamic and pharmacokinetic processes, aimed at establishing the parameters ensuring reliable prediction of the individual response of a patient. The promising pharmacogenomic methods will allow to create preparations directly acting upon defective genes or the related products. Factors limiting the development of pharmacogenomic methods, related to the lack of data on the structure and physiological properties of protein products and their metabolites, are considered.

Bernard Lerer: recipient of the 2014 inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine (Pacific Rim Association for Clinical Pharmacogenetics).

This article announces the recipient of the 2014 inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine by the Pacific Rim Association for Clinical Pharmacogenetics (PRACP): Bernard Lerer, professor of psychiatry and director of the Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. The Werner Kalow Responsible Innovation Prize is given to an exceptional interdisciplinary scholar who has made highly innovative and enduring contributions to global omics science and personalized medicine, with both vertical and horizontal (transdisciplinary) impacts. The prize is established in memory of a beloved colleague, mentor, and friend, the late Professor Werner Kalow, who cultivated the idea and practice of pharmacogenetics in modern therapeutics commencing in the 1950s. PRACP, the prize's sponsor, is one of the longest standing learned societies in the Asia-Pacific region, and was founded by Kalow and colleagues more than two decades ago in the then-emerging field of pharmacogenetics. In announcing this inaugural prize and its winner, we seek to highlight the works of prize winner, Professor Lerer. Additionally, we contextualize the significance of the prize by recalling the life and works of Professor Kalow and providing a brief socio-technical history of the rise of pharmacogenetics and personalized medicine as a veritable form of 21(st) century scientific practice. The article also fills a void in previous social science analyses of pharmacogenetics, by bringing to the fore the works of Kalow from 1995 to 2008, when he presciently noted the rise of yet another field of postgenomics inquiry--pharmacoepigenetics--that railed against genetic determinism and underscored the temporal and spatial plasticity of genetic components of drug response, with invention of the repeated drug administration (RDA) method that estimates the dynamic heritabilities of drug response. The prize goes a long way to cultivate transgenerational capacity and broader cognizance of the concept and practice of responsible innovation as an important criterion of 21(st) century omics science and personalized medicine. A new call is presently in place for the 2016 PRACP Werner Kalow prize. Nominations can be made in support of an exceptional individual interdisciplinary scholar, or alternatively, an entire research team, from any region in the world with a record of highly innovative contributions to global omics science and/or personalized medicine, in the spirit of responsible innovation. The application process is straightforward, requiring a signed, 1500-word nomination letter (by the applicant or sponsor) submitted not later than May 31, 2015.