Innovation in academic chemical screening: filling the gaps in chemical biology
Introduction
Operating at the frontier of biology, drug discovery, a technologically dependent and multidisciplinary activity, will be all the more successful with an engaged academic presence. Advancements in laboratory automation and the wide availability of libraries of RNAi reagents and small molecules have allowed academic institutions to enter the arena of high-throughput screening (HTS) to evaluate its potential and problems first hand. The ability to execute thousands and even hundreds of thousands of experiments in parallel with high reproducibility appeals to academic and industrial research alike. However, the practice of drug screening has become a ubiquitous endeavor in both, yielding examples that simultaneously reinforce the technique's power [1] and tribulations [2, 3]. Whereas the goal with industrial drug screening is to identify a new therapeutic entity, the aims of academic researchers range from developing chemical tools and mechanistic explorations to translational research. Therefore, we seek to shed light on major developments arising from academic chemical screening that are enhancing the potential of chemical biology. Since the term drug screening is rather biased towards therapeutic development, chemical screening more appropriately addresses the breadth of programs conducted by academic centers.
This review focuses on the recent conceptual and technological developments emerging from academic screening centers and the exciting results they have produced. Ultimately, the field is maturing and chemical screening is becoming less defined by the industrial or academic dichotomy in the light of the increasing interconnection between biotech, pharma, and non-commercial entities (universities, governments, etc.). As the public screening initiatives sponsored by the NIH are transitioning to complement and support NIH's public health mission, the need has arisen for greater specialization and cooperation across the screening centers.
Section snippets
Recent highlights in academic HTS
Over the past several years, we have seen many successes in academic HTS and probe development efforts. Even with the myriad of skepticism waged against screening centers in the academic domain, we feel it is critical to recognize examples of the excellent progress being made. Interestingly, academic screening has embraced a wide range of assay types, each with its own strengths and weaknesses (Figure 1). One notable instance came from collaboration between researchers in the UK and Canada to
High-content and the pursuit of phenotypic screening
The rise of HTS outside the classical pharmaceutical environment, especially in cases of therapeutic discovery, has been characterized by some as lacking innovation and effectiveness [17]. However, this view is clearly misguided (many successes are highlighted here) and we regard phenotypic screening as playing to the innovative strengths of academic research. More than just an opportunity to move beyond the limitations of biochemical target-based HTS, cell-based phenotypic screening also
Evolving whole-organism technologies leads academic screening on its own path
Model systems such as Caenorhabditis elegans (nematodes) and Danio rerio (zebrafish) have gained a broad representation in basic-science research as excellent models of development in multicellular organisms. Unlike the case of HCS however, model organism screening in academia has suffered from a lack of mature technologies. Now, whole-organism chemical screens with zebrafish and nematodes are growing in popularity due to key technological advancements such as improved imaging techniques,
Academic screening as a complementary avenue to industrial pursuits
The implementation of HTS techniques by academic and government entities has on occasion been described as a futile attempt to compete with industrial programs; though as many academics anticipated, such a conflict has not materialized. Indeed, something altogether different has emerged: non-industrial chemical screening has defined a complementary path to interesting discoveries. Since academic researchers operate outside of the industrial therapeutic development paradigm, they are able to
Conclusion and future directions
With over 60% of academic drug/probe discovery centers utilizing HTS [75], it is clear that the tools are now broadly available and considered generally useful. Looking forward, we anticipate academic chemical screening to continue as a center of innovation in high-throughput biology. Recently developed technologies will also have substantial impacts on the practice of chemical screening in academic environments. For instance, the ability to perform genomic manipulations on endogenous loci with
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by the Intramural Research Program of the NIH and the Pharmacology Research Associate Program. We would like to thank the reviewers of this manuscript for their helpful and insightful suggestions.
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