Introduction

The realization of the human genome sequence has electrified the life sciences community, providing a fundamental shift in experimental design toward more global analyses of human physiology, while simultaneously providing a litany of putative novel therapeutic drug targets. For the first time, access to a list of nearly all human genes is available for scrutiny by basic researchers to applied scientists well versed in the practices and pursuit of drug discovery. Some estimate that as many as 5000-10 000 new drug targets1 may have come to light based on the realization of the full genome sequence, while more conservative estimates place the number in the thousands.2 The magnitude of the change in number of possible targets has lead to the general and not necessarily unfounded feeling within pharmaceutical companies that there are now more targets than can be dealt with effectively. While on the one hand small-molecule screening groups with industrial high-throughput screening (HTS) robots are prepared for the onslaught of targets, and may welcome the challenge, many drug discovery practitioners are threatened by the real possibility that the expansive number of targets might clog the pipeline, inflate R&D costs, and generally make drug discovery less efficient. Given the highly competitive quest for the next blockbuster compound, pharmaceutical companies must weigh the opportunity cost of delaying a new program in order to do more validation studies versus starting prematurely on an undervalidated target. The fact that the industry as a whole only delivers two to three novel target-based drugs to market per year3 may indicate an increased difficulty/decreased probability of success and/or the aggregate decision to avoid such targets.

The question and the opportunity then posed by the genome is how to optimally and rapidly translate the human genomic information into validated targets and eventually drugs without sacrificing efficiency. The human genome project has done its job to highlight in an abstract sense that there are additional drug targets 'out there,' and in doing so has effectively shifted the bottleneck from gene identification to target validation, posing a new challenge to the drug discovery industry. The types of questions that require addressing fall into two main categories: first, druggability (a primary concern of the chemist), or what is the likelihood of achieving a small-molecule binder that preferentially modulates the target? And second, validation (of primary concern to the biologist), or what is the likelihood that pharmacological modulation of the target will result in a tangible alleviation of disease or symptoms? In other words, how is the function of the putative target linked to the disease in question? Is the gene expressed in the relevant tissue type? What happens when you genetically delete the gene in physiologically relevant cellular or animal models? Is there any human genetic information correlating gene function with a disease? The target windfall begs for a framework toward understanding which 'targets' represent both 'druggable' and 'validated' targets, an important question given the associated risk involved in launching drug discovery campaigns on poorly validated targets.

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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