Editor’s
EDITOR-IN-CHIEF
Laura L. Kiessling University of Wisconsin, Madison BOARD OF EDITORS
Jennifer A. Doudna University of California, Berkeley
LETTER Congratulations, You’ve Won. . .
Kai Johnsson Ecole Polytechnique Fe´de´rale de Lausanne
Anna K. Mapp University of Michigan, Ann Arbor
Michael A. Marletta University of California, Berkeley
Peter H. Seeberger Eidgeno¨ssische Technische Hochschule
James R. Williamson The Scripps Research Institute EDITORIAL ADVISORY BOARD
Carolyn R. Bertozzi University of California, Berkeley
Brian T. Chait Rockefeller University
Tim Clackson ARIAD Pharmaceuticals, Inc.
Jon C. Clardy Harvard Medical School
Benjamin F. Cravatt The Scripps Research Institute
Peter B. Dervan California Institute of Technology
Rebecca W. Heald University of California, Berkeley
Linda C. Hsieh-Wilson California Institute of Technology
Tony Hunter Salk Institute
Stephen C. Kowalczykowski University of California, Davis
Richard H. Kramer University of California, Berkeley
Thomas V. O’Halloran Northwestern University
Hiroyuki Osada RIKEN
Anna M. Pyle Yale University
Ronald T. Raines University of Wisconsin, Madison
Charles Sawyers University of California, Los Angeles
Stuart L. Schreiber Harvard University
Peter G. Schultz The Scripps Research Institute
Michael P. Sheetz Columbia University
H. Ulrich Stilz Sanofi-Aventis, Frankfurt
Christopher T. Walsh Harvard Medical School
T
he beginning of October was rather uneventful for most of us. We woke to the sound of alarm clocks, spouses, or children and proceeded with our daily routines. A select few, including Roger Kornberg, Andrew Fire, and Craig Mello, took an unexpected path on the crisp October morning: the Nobel Foundation informed them that they had won a Nobel Prize. In this editorial, we celebrate their achievements. We speculate on whether we have turned a corner and narrowed the perceived cultural gap between chemists and biologists so that they can appreciate the value of combining their respective tools to dissect complex processes such as transcription and RNA interference (RNAi). A picture is worth a thousand words, and this is evident in many of the images of the transcription machinery captured by Roger Kornberg (1–3), this year’s winner of the Nobel Prize in Chemistry. Kornberg’s lab, using X-ray crystallography coupled with biochemistry, systematically built molecular-level pictures of RNA polymerase, the machine responsible for copying the DNA into messenger RNA (mRNA). These images have led many scientists to dissect the details of the transcription process down to the atomic level, begun to explain how transcription factors modulate the activity of the polymerase, and opened the door for chemists to probe the mechanism by which this enzyme works. mRNA, the product of the transcription process, led Andrew Fire and Craig Mello, who shared the Nobel Prize in Physiology or Medicine, to their discovery of the process of RNAi. They were trying to affect the levels of a muscle protein in worms by modulating the levels of mRNA transcribed from the relevant gene. Injecting more mRNA or antisense RNA did not modulate the concentration of protein, but injecting specific double-stranded RNA silenced the target gene (4). This discovery opened up a whole new area of RNA biology and chemistry. It was Fire and Mello’s original work that inspired Phil Zamore—one of the scientists featured on the Ask the Expert section of the ACS Chemical Biology web site—to enter this fastpaced field of research (5). Zamore notes that RNAi, which occurs naturally in plants and animals, is “one manifestation of a broader set of RNA silencing pathways that defend cells against external threats, such as viral infection, and internal threats, such as the ‘jumping’ of transposons, and that also regulate endogenous genes, shaping gene expression during development and in response to external environmental stimuli.” Today, this reversegenetics tool is used to deliberately turn off target genes and learn more about human disease. When a graduate student asked, “Speculate for a minute: where do you think the RNAi field will be in 5 years? What do you think are the most interesting questions to ask?” Zamore predicted that Fire and Mello, along with another colleague, would receive the prize soon. “In 5 years, the number of small RNA classes will likely double or triple from the three we now know. We will understand much more about how these small RNAs are made, sorted, and function. We will begin to understand their evolutionary origins, but we will still struggle with the important ‘why’ questions . . . Craig Mello, Andy Fire, and David Baulcombe will have justly won the Nobel Prize for the discovery of RNAi [Fire and Mello] and siRNAs [Baulcombe].” (For the complete answer, see http://community.acs.org/journals/acbcct/cs/AsktheExpert/ExpertResponse/tabid/72/Default.aspx?webEditionid⫽2&qid⫽5083.) With the 10.1021/cb600426z CCC: $33.50 Published online October 20, 2006 © 2006 by American Chemical Society
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Editor’s
LETTER Nobel Prize now awarded, we should expect an exciting 5 years in which we dissect the mechanism of RNAi, explore its potential and limits as a therapeutic (6, 7), and understand the machines that bind the RNA and use it to silence genes. As we move forward, we look back over our shoulders to 1959, when Arthur Kornberg (Roger’s father) received his Nobel Prize in Physiology or Medicine. How much have the disciplines of chemistry and biology changed in the last 47 years? Twenty years ago, Arthur Kornberg felt that chemists and biologists worked in two separate cultures (8). With the rise of chemical biology, has this cultural divide narrowed? Have chemists begun to appreciate the complexity of biological systems rather than fear it? Have they seen the need to apply their chemical tools to dissecting the complex biological machines at the molecular level? Are biologists appreciating the language and tools of chemistry and exploring how they can be used to elucidate molecular details of biological processes? When this year’s Nobel Prize winners and other scientists were interviewed about the awards, they indicated that the advances made in the fields of transcription and RNAi have resulted from extensive collaborative work between chemists and biologists—perhaps we have turned a corner.
Evelyn Jabri Executive Editor REFERENCES 1. Cramer, P., Bushnell, D. A., and Kornberg, R. D. (2001) Structural basis of transcription: RNA polymerase II at 2.8 Ångstrom resolution, Science 292, 1863–1876. 2. Gnatt, A. L., Cramer, P., Fu, J., Bushnell, D. A., and Kornberg, R. D. (2001) Structural basis of transcription: an RNA polymerase II elongation complex at 3.3 Å resolution, Science 292, 1876–1882. 3. Bushnell, D. A., Westover, K. D., Davis, R. E., and Kornberg, R. D. (2004) Structural basis of transcription: an RNA polymerase II–TFIIB cocrystal at 4.5 angstroms, Science 303, 983–988. 4. Fire, A., Xu, S. Q., Montgomery, M. K., Kostas, S. A., Driver, S. E., and Mello, C. C. (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans, Nature 391, 806–811. 5. Brownlee, C. (2006) Discovering the building blocks of RNA interference, ACS Chem. Biol 1, 126–128. 6. Xia, J., Noronha, A., Toudjarska, I., Li, F., Akinc, A., Braich, R., Frank-Kamenetsky, M., Rajeev, K. G., Egli, M., and Manoharan, M. (2006) Gene silencing activity of siRNAs with a ribo-difluorotoluyl nucleotide, ACS Chem. Biol 1, 176–183. 7. Snøve, O., Jr., and Rossi, J. J. (2006) Chemical modifications rescue off-target effects of RNAi, ACS Chem. Biol. 1, 274–276. 8. Kornberg, A. (1987) The two cultures: chemistry and biology, Biochemistry 26, 6888–6891.
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