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

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-NDPA-G (P3))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
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

Showing the most recent 10 out of 12 publications