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Resolving Bottlenecks: Target Elimination P.52 Strategic Insights: Regulatory Compliance P.61 www.bio-itworld.com Winner of Two 2003 Neal Awards TECHNOLOGY FOR THE LIFE SCIENCES WorldAPRIL 2003 • VOL. 2, NO. 4 BioIT See Page 8 The Double Helix Turns 50 UNRAVELING Futurethe • A conversation with James Watson P.28 • Beyond the Blueprint P.38 • First Base: The Doyens of DNA P.6 • The sound of genome music P.32 KAYOMI TUKIMOTO; MIRIAM CHUA/COLD SPRING HARBOR LABORATORY (INSET) EDC SHREDS PAPER TRAILS DEBATING DNA IN MONTEREY Electronic data capture finds data capture (EDC) to improve At Time conference, top The February meeting looked increased acceptance clinical trial management. Recently, brains spin genomic future both backward at the discovery of Biogen and Dana Farber/Partners amid potshots at pharma the double helix and forward to the CancerCare (DF/PCC) have gotten benefits and havoc DNA may BY AMANDA FOX in on the action, demonstrating that wreak. Genomics, clearly, isn’t for As the pressure rises to compress the EDC applies to both settings. BY MARK D. UEHLING only scientists anymore. Ordinary time it takes to conduct clinical tri- With an increasing number of “This whole meeting has been a citizens gawked at the speakers, als, commercial and research insti- federal clinical trial and drug mixture of exhilaration and ter- begging autographs and snapshots tutions alike are adopting electronic (CONTINUED ON PAGE 24) ror,” said Francis Collins, director of uber-nerds and scientists such of the National Human Genome as Leroy Hood, Ray Kurzweil, Research Institute. If Collins were Richard Dawkins, Stewart Brand, scared, having run the public effort and E.O. Wilson. The conference to sequence the human genome, featured a baroness, an ambas- imagine the reeling minds of sador, and two Nobelists. preachers, financiers, teachers, and As Collins sketched a number other civilians attending “The Fu- of April events to celebrate the fin- ture of Life,” a conference spon- ished human genetic sequence, in- sored by Time magazine in cluding a plan to dispatch 1,000 Monterey, Calif. (CONTINUED ON PAGE 20) 50 th Anniversary of the Double Helix BEYOND the As investigators celebrate the golden anniversary of the double helix, how will the wealth of data emanating from the human genome and allied technologies impact research on health and disease? BY MALORYE BRANCA ontemplating DNA’s inner beauty from blurry X-ray images and That reality is gaining credence as the “completed” sequence of the human and oth- cardboard cutouts, James Watson and Francis Crick could hard- er genomes, transcriptomes, and proteomes ly have imagined that someday, scientists would be surfing the become publicly available, along with power- double helix from their desktops, making discoveries with the ful new tools to investigate them. To commemorate the 50th anniversary of click of a mouse. the double helix, we asked 50 experts to share Since Watson and Crick’s landmark April 1953 publication in their views about the key developments, par- ticularly since the release of the first draft CNature, molecular biology has become a mainstay of drug discovery and devel- genome sequence in 2000, as well as speculate opment, culminating in the sequencing, and public sharing, of the human on future advances. The staggering progress in genomic medicine in the past few years is genome sequence. The announcement of the “substantially complete” human just a prelude of the excitement in store. genome sequence this month, coinciding with the 50th anniversary of the double The biggest shock in the human genome is the paucity of genes. Even the earlier esti- helix, heralds a new phase in the application of genome science to improving hu- mates of 30,000 may prove too high. This man health. begs the troubling question,“Where is the hu- man complexity coming from?” The answer “There has been a remarkable transformation in the way we think about bi- shifts the spotlight from the genome to the ology,” says Eric Lander, director of MIT’s Whitehead Institute Center for proteome (and beyond). Genome Research. “We think about biology now as information.” Aravinda Chakravarti of Johns Hop- In honor of the 50th anniversary / : of Crick and Watson’s Nature kins University agrees: “Today, my students take it for 50 50 paper describing the double helix, granted they can browse the genome. Someday, we’ll Reflections Bio•IT World presents an exclusive online series of interviews with 50 do all these studies — sequence analysis, proteomics, on the Double Helix experts in genomic medicine. genotyping — from a single desktop.” bio-itworld.com/news/reflections_index.html SCIENCE MUSEUM/SCIENCE & SOCIETY PICTURE LIBRARY (TOP) 38 Bio•IT World April 2003 www.bio-itworld.com Illustration by Kayomi Tukimoto www.tukimoto.com Blueprint “This structure has novel features which are of considerable biological interest.” — J. WATSON & F. CRICK, Nature, 25 April, 1953 ERIC LANDER director, Whitehead Institute Center for Genome Research “Watson and Crick’s discovery represented the high point of the molecular biology revolution, in that they reduced biology to molecules. But that contained the seed of the next revolution, to reduce biology beyond molecules, to pure information.” The proteome — the sum of all proteins — itive DNA is being expressed,” says Affymetrix is far larger than the genome. For example, al- President Steve Fodor. “This is remarkable, be- ternative gene splicing produces multiple pro- cause the lore would be that only 1.5 to 2 percent teins from a single gene, which are then of the genome would be expressed.” chemically decorated with various moieties, Either the gene tally is wrong, or RNA serves producing a bewildering array of protein forms. many more functions than a simple messenger. Even RNA — the molecular messenger be- “Besides the standard genes that code for pro- tween genes and proteins — may play more tein, there are also genes that code for small roles than previously thought. The recent dis- RNAs,”says Adrian Krainer at Cold Spring Har- covery that RNA interference (RNAi), an excit- bor Laboratory. “There is this whole new ma- ing new tool for gene manipulation first chinery associated with RNAi and related 112. WITH PERMISSION ELSEVIER SCIENCE studied in plants, also works in mammalian processes. There appear to be hundreds of genes CELL cells has not only opened new avenues of in- coding for small RNAs that are part of this.” quiry but also may yield a new class of drugs With so much attention lavished on gene (see “The RNAi Revolution”). count, the critical issue of gene regulation — the And last year, a study by Affymetrix found role of non-coding DNA sequences, the mystery + Transcription – Transcription much more RNA than expected in a survey of all of accessing tightly bundled chromosomal DNA CHUBB, J.R. AND BICKMORE, W.A. Reading the genome: Chromosomes containing genes expressed from chromosomes 21 and 22. to switch on gene sequences — will be a fasci- active genes (red dots) loop out (left), whereas inactive “We found that 30 to 35 percent of the nonrepet- nating research vista in the coming years. chromosomes adopt a more condensed state (right). The RNAi Revolution he discovery of RNA interference (RNAi) most important new advance in biology is the to them all more quickly,” Sabatini says. could not have been more timely. RNAi approach,” says Tom Cech, president of the Early adopters of RNAi sound a cautionary T “Genomics generated a much larger uni- Howard Hughes Medical Institute and Nobel lau- note. “We’ve been using it for about five years,” verse of targets,” says Bristol-Myers Squibb’s reate for the discovery of RNA enzymes. “RNAi is says Geoffrey Duyk, president of R&D at Exelixis. Nicholas Dracopoli. “The newer targets, which vastly more powerful than anything we have “The dirty little secret of RNAi is that you are we don’t have much experience with, have had. Even people who don’t know how to spell knocking down messenger RNA to knock out pro- slowed down the industry’s success rate.” RNA can use this successfully in diverse biologi- tein. Because proteins have different turnover The standard tools to probe gene function cal systems.” rates, you have to have a good way to measure were either cumbersome, such as knockout mice, RNAi is already making an impact. Genome- protein level and activity.” or poorly informative, such as gene expression. wide knockdowns have been carried out in Even skittish venture capitalists are falling for RNAi was described in 1998 by Andy Fire and organisms including nematodes. Small interfer- RNAi and its potential therapeutic value, with Craig Mello at the Carnegie Institute in Washing- ing RNAs (siRNAs), which silence genes in mam- backing for companies such as Cenix and Alny- ton, D.C. In plants and lower organisms such as malian cells, are now being designed against as lam Pharmaceuticals. the nematode, RNAi — a process in which dou- many genes as possible. “The great thing about recombinant DNA and ble-stranded RNA fragments target and elimi- One promising approach is to spot cells monoclonal antibodies was that they gave actual nate specific messenger RNA molecules — expressing defined genes on microchips for the drugs right from the start,” says Christoph West- probably helps defend against viruses and other analysis (see Ziauddin, J. and Sabatini, D.M. phal, of Polaris Venture Partners. “With foreign molecules. Nature 411, 107-110: 2001). “The hard part is not genomics, it just wasn’t clear when it would Two years ago, a paper in Nature dramatically printing the chips or doing the experiment,” says develop a drug.” showed that RNAi also worked in mammalian David Sabatini, Whitehead Institute Center for Firms such as Polaris, which is funding Alny- cells (Elbashir, S.M.
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