Anirban Mahapatra

Lung Cancer − Genomics and Personalized Medicine

Laura L. Kiessling University of Wisconsin, Madison BOARD OF EDITORS Jennifer A. Doudna University of California, Berkeley Kai Johnsson Ecole Polytechnique Fédérale de Lausanne Anna K. Mapp University of Michigan, Ann Arbor Michael A. Marletta University of California, Berkeley 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 Tony Hunter Salk Institute Richard H. Kramer University of California, Berkeley Rolf Müller Saarland University/Helmholtz Institute for Pharmaceutical Research Saarland Joseph P. Noel Howard Hughes Medical Institute, The Salk Institute for Biological Studies 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 Carsten Schultz EMBL Peter G. Schultz The Scripps Research Institute Michael P. Sheetz Columbia University H. Ulrich Stilz Sanofi-Aventis, Frankfurt Hiroaki Suga The University of Tokyo Wilfred A. van der Donk Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign Christopher T. Walsh Harvard Medical School Lung Cancer Genomics and Personalized Medicine

Screening for success.

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 Screening for Success F or almost two decades, the pharmaceutical and biotech industries have been using high-throughput screening (HTS) to obtain small-molecule hits against validated biological targets. Although these industries have amassed a wealth of data and experience on target selection, technology development, and hit validation, resources for HTS have not always been readily available to researchers in academia and in government institutions. But times are changing, thanks in part to the advent of the National Institutes of Health (NIH) Molecular Libraries Roadmap. This endeavor consisting of a network of small-molecule screening centers, the PubChem database for small-molecule and screening data, and resources for technology development has helped researchers outside of industry utilize HTS to identify chemical compounds that modulate the activities of biological targets (1). This is an important advance for the field of chemical biology. HTS in an academic environment is expanding the diversity of both chemical compounds and biological targets beyond those pursued in industrial drug discovery, where the goal is to identify drug leads for targets associated with human diseases. It is encouraging to note that more and more academic researchers are utilizing HTS to identify small molecules that modulate biological processes in their favorite organisms. HTS is also a key component in large public projects. For example, the NIH Chemical Genomics Center, the Environmental Protection Agency, and the National Toxicology Program are currently collaborating on the development of an HTS resource with biochemical and cell-based assays to assess the toxicity of chemical compounds (2). As the goal of this project is to use HTS quantitatively to generate data on toxicity, the composition of the compound library naturally varies from that used in drug discovery programs (2). Notwithstanding the enthusiasm for this powerful technology, significant challenges remain with using HTS for hit identification. Particularly vexing is that a large number of hits identified in HTS assays are found to be assay-format-dependent false leads when examined further. Studies have demonstrated that small molecules form colloidal aggregates in aqueous solution that nonspecifically inhibit enzyme activity, which may explain why testing for inhibition is particularly troublesome (3). As an example, in a recent HTS analysis, 95% of the hits resulted from compound aggregation concomitant with enzyme inhibition (4). Aggregation, however, is not the only cause of artifacts. On page 463 in this issue of ACS Chemical Biology, Auld et al. (5) provide evidence that false leads may be derived from HTS platforms using luciferase reporter-gene assays where the activity arises not from the target but from the stabilization of the luciferase enzyme. As one can envisage similar arti-

Researchers in a brave new web 2.0 world.

Laura L. Kiessling University of Wisconsin, Madison BOARD OF EDITORS Jennifer A. Doudna University of California, Berkeley Kai Johnsson Ecole Polytechnique Fédérale de Lausanne Anna K. Mapp University of Michigan, Ann Arbor Michael A. Marletta University of California, Berkeley 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 Tony Hunter Salk Institute Richard H. Kramer University of California, Berkeley Rolf Müller Saarland University/Helmholtz Institute for Pharmaceutical Research Saarland Joseph P. Noel Howard Hughes Medical Institute, The Salk Institute for Biological Studies 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 Carsten Schultz EMBL Peter G. Schultz The Scripps Research Institute Michael P. Sheetz Columbia University H. Ulrich Stilz Sanofi-Aventis, Frankfurt Hiroaki Suga The University of Tokyo Wilfred A. van der Donk Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign Christopher T. Walsh Harvard Medical School Researchers in a Brave New Web 2.0 World O ver the past two decades, the Web has revolutionized the way scientific information is disseminated, and this shift has been accompanied by an increasingly paperless and wireless landscape. Scientists now routinely submit their research to journals, search for relevant work, communicate with collaborators, and register for scientific meetings digitally. Over the past decade, a new set of Web-based tools which include blogs, user-generated video and image Web sites, and professional forums have burgeoned and are collectively dubbed Web 2.0 (1). Comprising online innovations which readily facilitate the posting of content, as well as social networking tools which allow users to interact more readily with one another, Web 2.0 has blurred the distinctions between the creators and users of content. Instead of static webpages, content in this brave new world is dynamic and often subject to revision and commentary in real time. However, a recent survey from the United Kingdom indicates that while the use of online resources in research remains important, that usage of the most common Web 2.0 tools for academic scholarly communication is currently lagging behind (2). The analysis, which was commissioned by the Research Information Network, a policy forum funded by U.K. national libraries, research councils, and higher education funding councils, surveyed approximately 1% of all full-time academics in the U.K. In addition, the analysis included in-depth interviews and case studies focusing on providers of specific online tools. The responses to the survey represented a broad distribution in terms of primary scientific discipline, academic role, and age. Only 13% of respondents admitted to using Web 2.0 tools such as blogs, wikis, and social networking Web sites for scholarly communication at a frequency of once a week or more; 45% used these tools occasionally, and 39% did not use them at all. There was variability based on discipline; for example, those working in the field of computer science and mathematics were more than twice as likely to be users of these tools for scholarly communication as those engaged in the physical sciences. Also, those engaged in collaborative research were more likely to use Web 2.0 tools than those who conducted research independently. In addition, there was variability based on gender; 65% of males surveyed used these online tools compared to 50% of females. Interestingly, however, there was no clear pattern which could be discerned from the age of respondents. Why are more researchers not making use of many of the new online tools available for scholarly dissemination? Currently, while most researchers are interested these tools, the primary reason for not adopting is a lack of clear understanding of the benefits of doing so. Another hesitation centers on the quality of content released via many existing Web 2.0 outlets. A third concern centers on credibility. Many researchers are wary of using online tools which are presently deemed less credible than the traditional modes of communication through peer-reviewed publication and presentation at professional conferences. The third concern is the easiest to alleviate. As noted in the survey, most researchers who use Web 2.0 tools see these in a supplementary role augmenting collaborative and communicative practices, not replacing current modes of scholarly communication. And while surveys indicate that few researchers think peer review in the most-common avatar

Swine flu pandemic: mission accomplished?

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 Tony Hunter Salk Institute 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 Swine flu pandemic: mission accomplished? S canning through the nationally televised evening news in the United States, one cannot help but wonder whatever happened to the swine flu. A few months ago, worries over the potential of the newly emergent infectious strain of H1N1 influenza ruled the airwaves. Scores of medical correspondents camped out in front of the United States Centers of Disease Control and Prevention (CDC), perhaps somewhat morbidly, so that their news organizations would be present to break the news of the first fatalities. On the other side of the border, battle-hardened journalists provided blow-by-blow updates from the ground in Mexico City, where non-essential activities in one of the most populous and vibrant metropolitan areas in the world had come to a paralyzing halt. A little over a month later, on June 11, the World Health Organization (WHO) declared the current influenza outbreak a pandemic and assigned it to the highest possible level (1). Yet this news did not receive the media attention it would have drawn had it been announced a month earlier. What happened in the interim? Was the threat minimized or had it abated? Considering that there are tens of millions of flu infections each year in the United States alone with an estimated 30,000 deaths, had we initially overreacted to the reports of illness from this new strain? A recent review in Nature highlights prevailing opinion on the emergence of the current influenza outbreak (2). A flu-like respiratory illness was first reported in a town in Veracruz, Mexico in mid-February. By mid-April, Mexican health authorities were warning the regional office of the WHO of a potential outbreak. In the same month, the first cases in the United States were identified by the CDC. Initially, it had been feared that those with the worst outcomes from infection were not the elderly or immuno-compromised, as is the case with the seasonal flu, but rather young and otherwise healthy adults. Further investigation indicated that the infections caused by the strain were less severe than originally thought; a report published on May 7 seemed to confirm this, since it mentioned the strain caused fewer than 50 of the 159 deaths in Mexico that had originally been attributed to it (3). Now months into the pandemic, the flu gets little, if any, media coverage. One of the most informative press briefings by the CDC on the spread of the new H1N1 strain (4) was relegated to the inner pages of most newspapers (probably because it was in the same 24-h news-cycle as the death of Michael Jackson). Some of the facts presented in the CDC briefing were particularly noteworthy. In all likelihood there have been over 1 million infections of H1N1 so far this year in the United States with this strain accounting for almost all detected cases of influenza. The CDC also confirmed the demographic trends observed a few months ago in that the highest rates of illness were for those under 25 with relatively few people above 65 showing any signs of symptomatic infection. The initial panic may have subsided, but the public needs to be aware that the risk of infection is still high. Influenza infections are not particularly prevalent in the warmer summer months. Reports from countries of the Southern Hemisphere where it is currently winter and peak flu season seem to indicate that the strain is spreading and intensifying (4). We should keep in mind that swine flu will still be around to infect healthy individuals in the

Omics in the Postgenomic Era

Laura L. Kiessling University of Wisconsin, Madison BOARD OF EDITORS Jennifer A. Doudna University of California, Berkeley Kai Johnsson Ecole Polytechnique Fédérale de Lausanne Anna K. Mapp University of Michigan, Ann Arbor Michael A. Marletta University of California, Berkeley 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 Tony Hunter Salk Institute Richard H. Kramer University of California, Berkeley Rolf Müller Saarland University/Helmholtz Institute for Pharmaceutical Research Saarland Joseph P. Noel Howard Hughes Medical Institute, The Salk Institute for Biological Studies 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 Carsten Schultz EMBL Peter G. Schultz The Scripps Research Institute Michael P. Sheetz Columbia University H. Ulrich Stilz Sanofi-Aventis, Frankfurt Hiroaki Suga The University of Tokyo Wilfred A. van der Donk Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign Christopher T. Walsh Harvard Medical School Omics in the Postgenomic Era T his year marks the 10th anniversary of the completion of the draft sequence of the human genome. Technological advances over the past decade now allow genomes to be sequenced at breathtaking speed for a fraction of the cost required even a few years ago. Side by side, the number of -omic terms signifying the study of respective -omes has exploded to the point that it is difficult to keep track of the scientific terminology. Even a cursory search of academic bibliographic databases reveals numerous examples. And indeed, there is even OMICS: A Journal of Integrative Biology dedicated to the -omes. The original -ome, the genome, was derived 90 years ago from German botanist Hans Winkler’s genom. The word genome, a portmanteau of gene and chromosome, defines the sum of genes in a particular set (1). Curiously, even though the term genome is widely accepted in scientific circles, many media outlets avoid using it, preferring to use “genetic code” instead. For example, in discussing research on somatic rearrangements in the cancer genome, the BBC erroneously declared that scientists had cracked the “entire ‘genetic code’ of cancer” (2). Nonetheless, because genomics, the study of genomes, was etymologically unrelated to other similar words (such as economics), for many years, it was in a class of its own. All that changed in the early 1990s. The proteome, a term analogous to the genome, was coined to describe the sum of proteins. Within years, scientists started talking about glycomes, lipidomes, RNomes, and metabolomes. From genomics came terms such as metagenomics, toxicogenomics, and pharmacogenomics. The study of specific proteins led to the creation of words such as kinomics, degradomics, and metalloproteomics (not to be confused with metallomics). Soon scientists were well aware of the differences between proteomics and peptidomics, and metabolomics and metabonomics. But there were less clear distinctions between other terms such as transcriptomics and expressomics. Recently, the number of -omes has increased at an astonishing pace. For example, the entire set of molecular interactions in a cell was known as the interactome: earlier this year, the term negatome was coined for proteins unlikely to interact (3). Other scientific articles published recently described -omic disciplines such as N-terminomics (4) and seromics (5). Coining new terms that end in -omics is not limited to the realm of biology, though. Other fields also have neologisms that sound somewhat biological. Take, for example Joel Waldfogel’s Scroogenomics which is a book containing insight on the economics of parsimony and holiday gift-giving (6). We have not even begun to construct a comprehensive list of all -omes here. But as a sign of the postgenomic times, just as there are repositories that store -omic data, there are also Web sites that list and define -omic fields. Even after taking a quick look through a couple of these databases, I found it hard to verify if all of the listed terms had received the blessings of the scientific community. Now, here’s a thought: perhaps, what we really need is a pseudonome containing all the bogus ones.

Responding to stimuli.

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 Responding to Stimuli I n February, the United States Congress passed the American Recovery and Reinvestment Act of 2009, which President Barack Obama signed into law. As part of this Act, the National Institutes of Health (NIH) has been provided with supplemental funds in order to stimulate the economy. This, of course, promises to translate to increased funding of biomedical research. From its budget, the NIH has already decided to set aside at least

When in Doubt, Ask!

200 million for 200 or more research grants in specific challenge areas of science and medicine. The goal of this particular initiative, called the NIH Challenge Grants in Health and Science Research, is to allocate resources to “challenge topics” that were identified as high-priority by the constituents of the NIH (1). In addition to these funds, the NIH will provide extra resources for research that compares the effectiveness of different treatment options for various medical conditions. Forget “shovel-ready”. Pipette-ready seems to be the new mantra. The idea is to jumpstart research in 15 broad challenge areas that include diverse topics such as genomics, regenerative medicine, biomarker discovery and validation, biomaterials, and translational science. Recipients of grants will receive a maximum of

Catalyzing chemical bonding--the WIKI way.

500,000 per year for up to two years to tackle a project within a chosen area of research. Because of the unique nature and time scale of the initiative, the NIH has set specific guidelines lessening the burden on applicants: scientists will not be required to submit preliminary data; the proposed Research Plan is limited to about half the page-length of a proposal for a Basic Research Grant (R01); and scientists can apply for as many grants as they want to, provided each proposal is scientifically distinct. Very few of us with a direct stake in science will argue that increased funding of research is a negative proposition. Yet, there are many unanswered questions worth considering about the details behind the NIH Challenge Grants. Is two years enough time to complete a project and publish the necessary papers to get the word out about its success? How will the outcomes of the challenge grants be assessed after two years? What criteria will be used to declare a project successful? What happens to funding levels after this time frame for successful projects? Assuming there are no renewals of grants, how will principal investigators be held accountable? And, on a philosophical level, is it at all advisible to direct research into prescribed focus areas? Does this stifle innovation or merely channel it? These are all noteworthy questions worth following but are probably not enough to discourage researchers scrambling to get their grant proposals in before the deadline. And in case you are not convinced that these grants are the way to fund your research, you may still be heartened by the fact that the NIH received approximately

Deep Impact: Scientific Evaluation by the Numbers

10 billion in federal funds, much of which will be allocated to more traditional grants. One thing is for certain: no matter how you slice it, this is a good time to be a scientist.