Human biology is playing an increasingly important role in guiding the early phase of therapeutic discoveries. For example, analysis of human genetics is revealing allelic series of risk and protective variants of genes across a range of diseases. These allelic series demonstrate a dose–response relationship that relates the activity of a gene to its effect on, for example, the risk of a disease. Prior to embarking on the discovery of a drug, we can establish whether perturbing a target, in the context of human physiology, has the intended effect in terms of safety and efficacy. Biochemical mechanistic investigations of variant proteins can provide a blueprint for the activities that drugs should confer on the more common versions of the target proteins in order to be safe and efficacious.

This is an amazing advance with the potential to transform medicine. We hear about this promise frequently, especially from scientists pioneering these advances. The promise of these advances has led to powerful terms such as “precision medicine” being used by President Obama at his State of the Union speech in 2015, and these terms have even entered the mainstream vernacular of the media and public. However, major hurdles exist to realize this potential, and these hurdles may not be well appreciated by the advocates of the human biology/patient based approach to drug discovery. Without recognizing these hurdles and overcoming them, we are at risk of this potential revolution in medicine being unfulfilled.

Why this pessimism? For one, the activities suggested by these experiments of nature are challenging and often unfamiliar in the context of the historical path towards drug discovery. For the most part, to date, drugs that have these suggested mechanisms of action (MoA) do not exist. In order to realize the promise of modern biology in medicine, we must innovate in the science of therapeutics.

Chemistry and chemical biology, as evidenced by this important new book High Throughput Screening Methods: Evolution and Refinement, are offering new ways to discover compounds with novel (previously unknown) MoA (nMoA). Novel methods are being developed to discover specific nMoA compounds suggested by the human biology, patient based concept. Novel methods are also being developed to identify vast collections of compounds where each member has a distinct MoA—known and novel—in anticipation of their future utility. The range of innovations presented by the authors is extraordinary and the level of creativity that underlies these advances is inspiring and makes for exciting reading. The methods described in this book and their descendants, once integrated into the therapeutics discovery efforts of laboratories worldwide, offer great promise to bridge the gap between the knowledge gained from human biology and the thus far elusive transformative medicines that we hope to derive from them.

In addition to the specific screening methods, this book also hints at cultural and organizational challenges that represent opportunities for future success. Foundational capabilities that enable the translation of insights from human biology to novel therapeutics are in general far easier to share than compounds, targets and biological insights associated with specific drug discovery projects. Innovations in the science of therapeutics can be developed effectively through collaborations involving scientists in the public and private sectors, especially when the participating not-for-profit and for-profit organizations agree to avoid restrictions in the sharing of novel innovations. Evidence of this opportunity for interaction and collaboration is seen in the contributions from the authors in this book—the chapter contributors are from both sectors and cover topics important to each (for example, the importance of novel asymmetric synthetic chemistry and small-molecule libraries, integrating new techniques into probe and drug discovery, and proper annotation and sharing of data, among many others). The individual chapters also reinforce how overcoming the new challenges of human biology based precision medicine will need the foundational capabilities to continue evolving and how researchers will need to learn from each other as part of this evolution.

Stuart L. Schreiber

Center for the Science of Therapeutics, Broad Institute, Cambridge, USA

Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University, Cambridge, USA