While the understanding of life at the molecular level has advanced with breathtaking speed over the last century, a practical ability to solve medical problems through molecular intervention has not developed at the same pace. The global HIV epidemic, and our inability to effectively treat cancer, both evince this basic fact. Of course, there are many reasons for this. The human body is a complex machine. We may have a list of the parts, but the function of most of them remains a mystery. Recombinant DNA technology, the scientific breakthrough that revolutionized the study of human disease, has not also provided a general prescription for treating disease. Drugs are the primary tools for this purpose, and the synthetic organic chemistry required to fashion them today is much the same as it was a century ago. Finally, the economic hurdles associated with drug discovery are daunting. This Pioneer proposal addresses a technology that can close the gap between basic research discoveries, and the application of such insights to medicine. The approach, called """"""""chemical evolution"""""""" (see below), provides the means to breed drugs out of enormous synthetic small-molecule populations. It has the potential to transform drug discovery from a process requiring hundreds of chemist-years and the infrastructure of a large pharmaceutical company, to something a graduate student with knowledge of basic molecular biology can accomplish in a month. Chemical evolution is closely related to nucleic-acid and protein evolution techniques with proven track records in academia and industry. Moreover, our recent pilot studies have definitively established the feasibility of evolving small molecules[1-3]. These studies were the subject of two Science and Technology review articles in Chemical and Engineering News over the last year, and they were named a """"""""Chemistry Highlight"""""""" for 2004 (a short annual compilation by the American Chemical Society of key advances in chemistry)[4-6]. Despite its enormous potential and the excitement it engenders, three different federal agencies have declined to fund further development of the technology on the grounds that it is too ambitious and too risky.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Study Section
Special Emphasis Panel (ZGM1-NDPA-G (P3))
Program Officer
Jones, Warren
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Stanford University
Schools of Medicine
United States
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Zettl, Thomas; Das, Rhiju; Harbury, Pehr A B et al. (2018) Recording and Analyzing Nucleic Acid Distance Distributions with X-Ray Scattering Interferometry (XSI). Curr Protoc Nucleic Acid Chem 73:e54
Shi, Xuesong; Walker, Peter; Harbury, Pehr B et al. (2017) Determination of the conformational ensemble of the TAR RNA by X-ray scattering interferometry. Nucleic Acids Res 45:e64
Zettl, Thomas; Mathew, Rebecca S; Seifert, Sönke et al. (2016) Absolute Intramolecular Distance Measurements with Angstrom-Resolution Using Anomalous Small-Angle X-ray Scattering. Nano Lett 16:5353-7
Krusemark, Casey J; Tilmans, Nicolas P; Brown, Patrick O et al. (2016) Directed Chemical Evolution with an Outsized Genetic Code. PLoS One 11:e0154765
Shi, Xuesong; Huang, Lin; Lilley, David M J et al. (2016) The solution structural ensembles of RNA kink-turn motifs and their protein complexes. Nat Chem Biol 12:146-52
Shi, Xuesong; Bonilla, Steve; Herschlag, Daniel et al. (2015) Quantifying Nucleic Acid Ensembles with X-ray Scattering Interferometry. Methods Enzymol 558:75-97
Shi, Xuesong; Beauchamp, Kyle A; Harbury, Pehr B et al. (2014) From a structural average to the conformational ensemble of a DNA bulge. Proc Natl Acad Sci U S A 111:E1473-80
Shi, Xuesong; Herschlag, Daniel; Harbury, Pehr A B (2013) Structural ensemble and microscopic elasticity of freely diffusing DNA by direct measurement of fluctuations. Proc Natl Acad Sci U S A 110:E1444-51
Weisinger, Rebecca M; Wrenn, S Jarrett; Harbury, Pehr B (2012) Highly parallel translation of DNA sequences into small molecules. PLoS One 7:e28056
Weisinger, Rebecca M; Marinelli, Robert J; Wrenn, S Jarrett et al. (2012) Mesofluidic devices for DNA-programmed combinatorial chemistry. PLoS One 7:e32299

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