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OCTOBER 2009

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OCTOBER 2009 Contents

“We just don’t know that much about our relationship between our human cells and our microbial cells.” Julia Segre, Page 42

Gene PGx Sequencing Expression Companion Humans as Host Diagnostics Take Off Participants are calling the New Tools in Pharma is realizing that it Human Microbiome Project Neuroscience needs to collaborate with a second Human Genome A brain atlas was once on the diagnostic companies to Project. The massive global order of a coffee table book, stratify patients and to make effort aims to get to the known for its large, glossy safer, more effective drugs. bottom of the relationship illustrations. Today’s brain But obstacles remain in the between microorganism and atlases — led largely by the path to full ﬂight. host, and disease and health. Allen Institute for Brain Sci- BY JEANENE SWANSON BY CIARA CURTIN ence — capitalize on localized gene expression and other data to truly revolutionize the ﬁeld of neuroscience. BY MEREDITH W. SALISBURY 33 38 30

On The Cover 38 The Human Microbiome 33 Companion Diagnostics 30 Gene Expression in the Brain

PHOTOGRAPH BY BOB BOSTON FOR GENOME TECHNOLOGY OCTOBER 2009 GENOME TECHNOLOGY 3

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OCTOBER 2009 Contents

10 20 53 Markers In every issue Upstream NIH ...... 10 PRIMER ...... 7 PROTEOMICS ...... 45 Collins steps into new directorship We all have our bugs Grant supports proteomics with goals at the ready; funding synchrotron work stability a priority WHERE ARE THEY NOW? ...... 9 Kathy Hudson, next-gen SEQUENCING...... 47 NANOMEDICINE...... 11 sequencing on the rise, Centers of Complete Genomics raises Jamey Marth to direct new nano Excellence in Genomic Sciences, $45 million in Series D center at UC-Santa Barbara, and more Burnham RNAI...... 49 ZEITGEIST...... 16 UMass, Whitehead fire new salvo in SEQUENCING...... 12 A blog around the world Tuschl IP suit UW group sequences exomes from 12 people, confirms gene for rare CAREERS...... 19 MICROARRAYS...... 50 disease The journal perspective Affy inks deal with Beckman for custom tools SYNTHETIC GENOMICS...... 13 LAB REUNION ...... 20 Venter Institute team demonstrates ‘A community of scholars’ BIOINFORMATICS ...... 51 successful cross-species genome Pharma calls for a pre-competitive UNDER ONE ROOF...... 22 approach METHYLATION...... 14 A grassroots institute Markowitz, Vogelstein lead development of novel detection MYTAKE...... 25 Downstream technique Project annotation PGX ...... 52 STRUCTURAL VARIATION...... 14 BRUTE FORCE...... 27 Celera hones panel for non-small New BreakDancer algorithm Personal supercomputers? cell lung cancer performs high-res mapping of Q&A...... 53 indels, more UPCOMING EVENTS...... 56 Innovation through imaging BLUNT END...... 58 PCR ...... 15 CASE STUDY...... 55 CDC evaluates rapid flu tests versus The peptide blockade rRT-PCR for detecting novel strain of H1N1 influenza

OCTOBER 2009 GENOME TECHNOLOGY 5

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FROM THE EDITOR Primer

ISSUE NO. 95 125 Maiden Lane, Second Floor New York, NY 10038 We All Have Our Bugs Tel +1 212 269 4747 Fax +1 212 269 3686 ______GENOMEWEB.COM t was several years ago that I first heard about a major study of EDITORIAL DIRECTOR the human microbiome — it was from Washington University’s Meredith W. Salisbury [email protected]______Jeff Gordon, presenting at a Marco Island conference some of SENIOR EDITOR the earliest genomics-based research into the microbial content Ciara Curtin [email protected]______SENIOR WRITERS of our bodies. At the time, many attendees were surprised to Matthew Dublin [email protected] Ihear that microbial cells outnumber human cells 10 to one in the Jeanene Swanson [email protected]______ART DIRECTOR average human. Rarely have so many scientists been sent scrambling Therese Shechter [email protected]______for hand sanitizer — but, it seems, they also scrambled to participate GENOMEWEB DAILY NEWS in the nascent microbiome field. Ed Winnick, Editorial Director [email protected]______By 2007, NHGRI launched its large-scale Human Microbiome Matt Jones, Reporter [email protected]______Project, which has so far issued grants to more than 50 PIs for vari- Andrea Anderson, Reporter ous components of the effort. For our cover story this month, Ciara [email protected] Curtin grabbed her antibiotics and dove into the world of infant GENOMEWEB NEWSLETTERS Bernadette Toner, Editorial Director guts, skin biomes, and more to report on the ongoing science and [email protected]______the findings already emerging from it. It’s Kirell Lakhman, News Editor [email protected] a great story — and one that I recom- Justin Petrone, BioArray News Editor mend you don’t read over lunch. [email protected] Vivien Marx, BioInform Editor Elsewhere in this issue, we’ve got a [email protected]______feature story on companion diagnostics. Alex Philippidis, BioRegion News Editor [email protected]______Jeanene Swanson reports on growing Ben Butkus, Biotech Transfer Week Editor [email protected]______efforts from pharmas and diagnostic Julia Karow, In Sequence Editor companies alike to find better ways of [email protected] Turna Ray, Pharmacogenomics Reporter Editor targeting and dosing therapeutics. An- [email protected]______other feature article explores how gene Tony Fong, ProteoMonitor Editor [email protected]______expression is revolutionizing neurosci- Doug Macron, RNAi News Editor ence, with a particular focus on new programs to build human brain [email protected]______CHAIRMAN AND PUBLISHER atlases with localized expression data. Dennis P. Waters, PhD This month’s Brute Force column checks in on the paradox of “per- [email protected]______ADVERTISING/SALES sonal supercomputers,” while our Under One Roof article profiles Judy Block, Associate Publisher the new Institute for Genomic Medicine at the University of Califor- [email protected]______+1 212 651 5629 nia, San Diego. Our Lab Reunion column focuses on Steve Henikoff Allan Nixon, Director of Business Development [email protected] +1 212 651 5623 at the Fred Hutchinson Cancer Research Center. And in news this month, we highlight the priorities Francis Collins laid out for NIH OPERATIONS AND FINANCE Greg Anderson, Director in his all-hands-on-deck introductory meeting in August. (Yes, he [email protected] worries about funding stability, too.) Last but not least, Sandra Por- Philip Borowiecki, Associate [email protected] ter writes a My Take column this month, with a great dissection of Maz Crotty, Finance Manager [email protected]______the debate about using students to annotate genome sequence.

Meredith W. Salisbury, Editor

No portion of this publication may be reproduced in whole or in part without written permission from GenomeWeb. What do you think of Genome Technology? Let me know how we’re doing by e-mailing me at [email protected] or by calling me at +1.212.651.5635

OCTOBER 2009 GENOME TECHNOLOGY 7

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WHERE ARE THEY NOW? Update

>GT ONLINE www.genomeweb.com COMMENTS FROM THE DAILY SCAN In Review: Kathy Hudson, Next- In response to a post on ageism in the peer-review process, readers Gen Sequencing on the Rise, Centers of wrote: Excellence in Genomic Sciences, and More “The NIH grant review process (without the young investigator athy Hudson, director of the Genetics and adjustment) actively discriminates in the reverse direction Public Policy Center at Johns Hopkins Uni- — giving preference to long versity, appeared on the cover of last year’s track record and ‘inside the October issue of Genome Technology. In the paradigm’ research.” cover story on personalized medicine’s move — cashaw Kinto the clinic, Hudson was cautiously optimistic. “I think in general the hype has exceeded the reality, but “I agree that the NIH process there is reason to be excited and optimistic,” she said actively discriminates again then. Hudson is now expected to join the National Insti- younger scientists. I even had OCTOBER 2008 a reviewer comment on a sum- tutes of Health as chief of staff to Director Francis Col- mary statement that cited the lins. Prior to founding Hopkins’ policy center in 2002, ‘Relative youth of the PIs’ as a Hudson was assistant director of the National Human weakness!” Genome Research Institute. — rogerb Also in last year’s issue, GT took a look at how the next-generation — and third-generation — sequencing platforms were faring. Roche 454 was just launching its >NEED HELP? new Titanium chemistry, Illumina’s Genome Analyzer CHANGE OF ADDRESS— had upgraded to the GAII, and ABI was looking forward To change your address or to the release of its SOLiD HT System. Currently, the manage your subscription to OCTOBER 2004 Genome Technology, the next-gen companies are gaining slightly. Roche’s Applied Daily Scan, or any GenomeWeb Science section, which includes 454, had an 8 percent publication, login to ____www. gain in sales during the first half of 2009 as compared to 2008; Illumina genomeweb.com reported a 15 percent increase in second-quarter revenue for 2009; and Life and click on My Account, Technologies says its Genetic Systems division, which includes SOLiD, saw a or email us at 5.5 percent increase in second-quarter revenues. [email protected]. FREE SUBSCRIPTION– Back in 2004, the GT cover story discussed the Centers of Excellence in Ge- Genome Technology is free nomic Sciences program. Nine institutes were given $3 million a year for five to active researchers in the years to carve out a place for themselves in integrated genomics. Since then, life sciences. To subscribe, Deirdre Meldrum, who was at the University of Washington’s CEGSTech, log on to www.genomeweb. was named a dean of engineering at Arizona State University, where she also com/subscriptions and fill out a 30-second form. directs the Center for EcoGenomics. Mike Snyder, another CEGS leader, was REPRINTS– For permission then at Yale’s Human Genome Analysis center and recently headed to Stanford to reproduce material from University to lead the Center of Genomics and Personalized Medicine. Genome Technology, or to A news story five years ago asked readers to consider the CNP, now better order offset-printed or Web- known as a CNV. Jonathan Sebat — then a postdoc in Michael Wigler’s lab ready PDF reprints, write to — and his colleagues at Cold Spring Harbor Laboratory developed a method [email protected] or call +1.212.651.5632. called representational oligonucleotide microarray analysis to measure how common CNVs are. Since then, Sebat has started his own lab at Cold Spring Harbor; this past summer, he published a paper in Genome Research on a computational approach to detect CNVs. He and his colleagues plan to apply their method to the 1,000 Genomes Project and to a large-scale schizophrenia study. — Ciara Curtin

OCTOBER 2009 GENOME TECHNOLOGY 9

Markers NEWS

NIH: Collins Steps into New >SHORT READS Directorship with Goals at the

PerkinElmer has acquired two separate companies: Ready; Funding Stability a Priority SYM-BIO Lifescience in China rancis Collins’ confirma- intramural pro- for $63.7 million in cash; tion as the new director of gram which I was and Surendra Genetic Labs the National Institutes of asked to found in in India for an undisclosed Health may have come as 1993.” amount. The acquisitions are a somewhat anticlimactic He also used expected to help PerkinElmer F Congressional aside in a summer the meeting as an expand its diagnostics and filled with stormy political debates, opportunity to genetic screening busi- but his subsequent address at an lay out five major nesses. all-hands NIH meeting was any- themes he has in thing but. mind for NIH. The EU has granted €11.3 On August 17, Collins took the floor To wit: applying million to support an inter- for the first time as NIH director, al- high-throughput national genomics research ternately praising the institutes, re- technologies to project to identify the genetic assuring people who worried about find the cause of FRANCIS COLLINS and environmental causes of his potential bias toward genomics, specific disease asthma. The studies will be co- and fretting about funding. He be- states; translation, including de- ordinated by Imperial College gan his address by saying, “Well, it’s veloping “diagnostics and preven- of Science, Technology, and great to be home again. That’s what tive strategies and therapeutics for Medicine at Imperial College, this feels like for me.” He spent some diseases we treat poorly”; “putting London in a research program time highlighting a range of promis- science to work for the benefit of called GABRIEL. ing research at NIH, which, as an in- healthcare reform,” which includes stitution, “represents everything that comparative effectiveness research Stephen Minger joined GE and more tailored ap- Healthcare’s Life Science “What is going to happen to proaches to medicine; business as head of R&D for an increased focus on Cell Technologies. He was the resource support of this global health; and se- previously at King’s College amazing organization when the curing stable, reliable London, where he was direc- funding levels. tor of the Stem Cell Biology stimulus money runs out?” On that last point, Laboratory. the man who’s known is awesome and wonderful about in the community as an incurable Complete Genomics biomedical research.” optimist acknowledged that even announced that it had One of the concerns raised about his sunny attitude is challenged sequenced and analyzed 14 Collins as NIH director was his com- by the current funding situation. human genomes for custom- fort level with large, collaborative “What is going to happen to the ers since it began a limited science. To quell those worries, he resource support of this amazing trial launch in March. The told his new employees, “The main- organization when the stimulus company said customers in- stay of NIH, both intramural and money runs out?” he asked. “The clude Pfizer; Duke University; extramural, will be the creativity of feast or famine scenario is incred- the HudsonAlpha Institute for individual investigators. Those who ibly destructive to the enterprise Biotechnology; the Ontario fear that this guy who used to direct and it places our country at a Institute for Cancer Research; the genome institute may only be disadvantage over other countries the Institute for Systems Biol- interested in supporting big science that are on very strong growth ogy; and the Broad Institute, need look no further for reassurance trajectory.” among others. than the character of the NHGRI — Meredith Salisbury

10 WWW.GENOMEWEB.COM______OCTOBER 2009

Nanomedicine: Jamey Marth to Direct New Nano Center at >SHORT READS

Thermo Fisher Scientific has UC-Santa Barbara, Burnham agreed to buy German diag- hile there is no doubt orientation of my career in an envi- nostics firm Brahms for €330 that considerable ronment that was at the envelope of million in a deal that headway has been nanotechnologies, and that’s where will complement its immuno- made in the under- Santa Barbara came in,” says Marth, assay test portfolio and standing of nucleic who joined the UCSB and Burnham expand its reagent manufac- W turing capabilities in Europe. acids and proteins, two macromo- Institute faculty in early July. “Their lecular components of the cell — expertise in those fields synergize Brahms’ flagship product is lipids and glycans — are not so completely with the Burnham’s abili- the procalcitonin biomarker easily elucidated when it comes to ties in biomedical research.” Nano- for diagnosis and treatment of their roles in disease. “They are not medicine aims to utilize nanotechnol- sepsis. made by template-driven biological ogy to develop approaches, so you can’t get at their drug delivery The UK’s Human Genetics structure or regulation by looking at nanoparticles, Commission released a set the genome. ... I don’t think there’s biosensors, and of principles for direct-to- any other way of doing it because I other medi- consumer genetic testing, believe we’re beginning to see the cal devices that focused on the information wall in biomedical research with function at the and counseling consumers a purely genomics/proteomics per- molecular scale are provided before and after spective,” says Jamey Marth, director for treating dis- taking tests and on privacy of the Center for Nanomedicine at ease and repair- considerations. They apply the University of California, Santa ing tissue. to all aspects of the industry, Barbara. “So we have to use new The biggest JAMEY MARTH including marketing and ad- technological approaches to inte- challenge ahead vertising, consumer consent, grate them and that’s where nano- for Marth and his team is not so lab analysis, and support for technologies come in.” much the development of nanoparti- consumers. It was this belief in nanotechnol- cles, but learning how best to deliver ogy that made it a no-brainer for them in the human body safely and Lab901, a Scottish DNA Marth, previously a professor of cel- effectively. “For the first time we’re analysis firm, received £2.4 lular and molecular medicine at the engineering devices that go into the million in equity funding from UC San Diego Medical Center, to body and we don’t know a lot about a group of UK investors. The accept the position of director of the them in many cases. … There are company expects to use the new Center for Nanomedicine. The over 600 nanomaterials that are on money to expand international the market right now, sales of its ScreenTape analy- “We have to use new techno- but that’s just the tip sis platform, which replaces of the iceberg,” he says. manual analysis of proteins, logical approaches to inte- “We need to understand DNA, and RNA, and to con- more about them, their tinue to develop its products. grate them and that’s where distribution, their fate, nanotechnologies come in.” how to best use them. Cell Biosciences signed an Different particles have agreement to acquire Alpha different profiles in Innotech for approximately center will be launched and operated terms of their in vivo lifetimes and $17.9 million in cash. The by both UCSB and the Burnham expectations of targeting or drug acquisition will give the Institute for Medical Research. “I delivery.” company additional protein needed to make a big change in the — Matthew Dublin analysis business.

OCTOBER 2009 GENOME TECHNOLOGY 11

Markers NEWS

Sequencing: UW Group >SHORT READS Sequences Exomes from 12 People,

Stephen Davis will be chair of the University of Maryland Confirms Gene for Rare Disease School of Medicine. Davis ay Shendure’s lab at the Then they turned was recruited to Maryland University of Washington to looking for from Vanderbilt University, has shown that exome se- MYH3, the gene where he spent 20 years and quencing can be used to behind Freeman- was director of the Division of find a gene behind a rare Sheldon, to show Diabetes, Endocrinology, and J genetic disorder. Using an array- the method’s ap- Metabolism and also direc- and next-generation sequencing- plicability to iden- tor of the General Clinical based approach, Shendure and his tifying Mendelian Research Center. colleagues sequenced the exomes of diseases. Shendure 12 people: eight individuals from says they chose to JAY SHENDURE Helicos BioSciences hired the HapMap Project and four people study this disease investment bank Thomas with Freeman-Sheldon Syndrome, because the answer was already Weisel to help evaluate stra- an autosomal dominant disorder known. “We sat down and talked tegic alternatives, such as marked by craniofacial, hand, and through what might be a challeng- financings, joint ventures, or foot abnormalities. ing disease — in the sense that it’s partnerships. In other news, “For us, the study really had two autosomal dominant, so it’s going to the company announced that goals. One was to evaluate how one be more challenging than a reces- it had sold four of its sequenc- goes about doing targeted resequenc- sive [disease],” he says. “And we had ing systems to RIKEN. ing with next-generation technolo- multiple individuals, so we could set gies and, within that larger problem, up the equivalent of what we felt was Harvard Bioscience will buy there’s the specific problem of the a real-world situation.” Denville Scientific, a private exome,” says Shendure, who led the For that search, Shendure and molecular biology company Nature study. “And the second goal his colleagues catalogued variants focused on liquid handling was to try to put this into a disease from the exomes of the people with items and based in New Jer- context, rather than just being a Freeman-Sheldon, looking for genes sey, for around $23 million. proof-of-concept around technology with non-synonymous variants or itself.” indels. They then filtered out com- Researchers from the MD To home in on the exome, Shen- mon variants from those 2,000 can- Anderson Cancer Center dure and his colleagues used array didate genes by using dbSNP. That published a proof-of-principle alone, Shendure says, was study indicating that micro- “We had multiple individu- inadequate, so they also RNAs in the blood can be used used variations from the as biomarkers for pancreatic als, so we could set up the HapMap individuals as cancer. The team studied four equivalent of what we felt an extra filter. Together, miRNAs in particular, finding those narrowed the can- that all of them were elevated was a real-world situation.” didate gene list down to in blood samples from indi- one, MYH3. “[This] pres- viduals with pancreatic cancer. capture followed by next-gener- ages what is going to happen with ation sequencing on an Illumina 1,000 Genomes and projects like Advanced Cell Diagnostics machine. Instead of working to that,” Shendure adds. raised $5.4 million in a series optimize that initial capture, the He and his lab are currently working A financing, which it says will researchers used a second array on applying this method to Mendelian be used to develop diagnostic to find data missing from the first. diseases caused by unknown genes, as tests based on its RNAscope They yielded an average of 6.4 well as more complex diseases. technology. gigabases per person. — Ciara Curtin

12 WWW.GENOMEWEB.COM______OCTOBER 2009

Synthetic Genomics: Venter Institute Team Demonstrates >SHORT READS

The National Cancer Successful Cross-Species Genome Institute’s Center for Biomedi- cal Informatics and Infor- research team at the closer to the synthetic cell.” mation Technology named J. Craig Venter Insti- The barrier that had previously Caterina Lasome as chief of its tute recently complet- prevented the installation of a informatics branch. Lasome is ed work that prom- modified genome had to do with a retired US Army Lieutenant ises to seriously ramp the restriction enzymes that act Colonel who has been chief A of healthcare informatics and up synthetic genomics and as an immune system to help bac- bring the concept of a synthetic teria defend itself against invading inpatient requirements for the cell that much closer to reality. DNA. Military Health System and So far, the scientists have dem- The researchers first devised a chair of the NATO Chiefs of onstrated a method of transferring method of removing that immune the Military Medical Services genomes between a prokaryote system from the recipient cell so Medical Communications and to a eukaryote and back again. that the incoming genome would Information Systems. Using yeast cells with an added not be chewed up. dose of yeast centromeric plasmid The second method was to use in Luminex announced that sequence, the JCVI team cloned vitro chemical modification with it has received US Food the whole bacterial genome from purified methylases that would and Drug Administration Mycoplasma mycoides, modified install a protective methyl group clearance for its second- the bacterial chro- generation cystic fibrosis test, mosome using the “We’ve overcome a barrier that which looks at 39 CF-causing yeast’s own genetic gene mutations and is used systems, and fol- we needed to deal with for the to screen potential parents to lowed that up by genome to be ‘booted up’ — this determine if they are carriers transplanting the of the mutations. new genome into allows us to get a step closer to the related species Mario Caccamo has joined Mycoplasma capri- the synthetic cell.” the Genome Analysis Centre colum. The end re- to lead its bioinformatics divi- sult was a new type of mycodies on the genome, thereby overcom- sion. Prior to this, he was at cell never before seen in nature or ing the restriction enzyme barrier the European Bioinformatics in a laboratory. from the recipient cell. Institute, where he worked “Mycoplasmas in general do not Vashee says that JCVI scientists on the European Genome- have very robust genetic tools — are currently attempting to boot Phenome Archive. or hardly any genetic tools, so you up their synthetic organism, Myco- can’t easily add or delete genes. plasma genitalium, so that they can Researchers at the Broad But we can use the nice set of tools eventually whittle away its genome Institute and the UK’s Sains- that yeast has to manipulate the to produce a “minimal cell” — a bury Laboratory led an inter- [mycoides] genome,” says Sanjay useful model system that has only national effort to sequence the Vashee, a JCVI researcher who the genes absolutely necessary for 240 million base genome of contributed to the project. “The life. Phytophthora infestans, the implications here are several-fold, They also hope that these meth- pathogenic water mold behind but one is that we’ve overcome ods can be utilized to help engi- Ireland’s 19th century potato a barrier that we needed to deal neer bioenergy sources and indus- famine. The study of what was with for the genome to be ‘booted trial chemicals. once thought to be a fungus up’ — this allows us to get a step — Matthew Dublin was published in Nature.

OCTOBER 2009 GENOME TECHNOLOGY 13

Markers NEWS

for methylated and unmethylated Methylation: Markowitz, states to the beads, and followed that up with fluorescence-activated Vogelstein Lead Development of cell sorting to count the number of molecules that were methylated. “It turns out you really do need a Novel Detection Technique method this sensitive,” Markowitz n work appearing in August in DNA fragments are attached says. When they applied the Nature Biotechnology, a group of to coated magnetic beads method to blood samples researchers developed a novel, and can be amplified by from carriers of early stage highly sensitive technique to de- submerging DNA and the disease, Markowitz and his Itect methylated DNA. Because beads in a water-oil mix- team found only one or two methylation signatures change in ture and then performing molecules of methylated cancer, they hope it will be useful PCR. This “supersensitive” DNA in two milliliters of for early detection of colon and other technique, says Markowitz, blood, which is one mol- tumors. A simple, inexpensive, nonin- allows researchers to study ecule in about 5,000 un- vasive test that could be used instead individual molecules of SANFORD methylated molecules. “We MARKOWITZ of a colonoscopy — this test isn’t fail- DNA, which is important applied this method as a co- proof — is key to saving lives. when detecting the handful of methy- lon cancer blood test and we were able “Having an alternative to colonos- lated molecules in a sample that might to pick up about 50 percent of the folks copy could make an important contri- signal early cancer. who have these early stage colon can- bution to public health, so we’ve been “BEAMing is a way to do PCR on a cers,” he says. That’s four times better interested in whether you could devel- bead starting with a single molecule than the current standard, a blood se- op a molecularly-based, noninvasive of DNA,” he says. Building off previ- rum marker used to detect recurrence. screening test for colon cancer for a ous work that showed that a region Also, the new method could detect 41 long time,” says Sanford Markowitz at of the vimentin gene is hypermeth- percent of colon cancers in the stool, the Case Western Reserve University lyated in a majority of colorectal can- as well as half of pre-cancerous polyps. School of Medicine, who led the study cer patients, the researchers wanted The researchers say their method im- alongside Johns Hopkins University’s to see whether they could use the proves standard methylation-specific Bert Vogelstein. technique to detect one molecule in PCR by 62-fold. The technique combines bisulfite thousands that might be methylated. Next up is looking for genes beyond conversion with BEAMing, a tech- After performing bisulfite conver- vimentin, as this was just the first- nology developed previously in Vo- sion, they used BEAMing to amplify generation test. “We’re already hard gelstein’s lab, to come up with methyl- the vimentin gene so that there were at work looking for additional mark- BEAMing. In BEAMing — BEAM thousands of copies of the gene at- ers that you could add to the test” to stands for beads, emulsion, amplifi- tached to each magnetic bead. They improve it, Markowitz says. cation, and magnetics — individual then hybridized fluorescent probes — Jeanene Swanson

analysis is possible and provides a Structural variation: New way to predict structural variants more accurately. Challenges to data BreakDancer Algorithm Performs analysis remain, though, including how to incorporate short inserts into current mapping algorithms and how High-Res Mapping of Indels, More to take into account varying cover- ith the cost of sequenc- everything that isn’t a SNP, including age, insert size, and read length data ing coming down, indels, copy number variants, inver- from different next-gen platforms. To looking for structural sions, and translocations — people this end, work out of Elaine Mardis’ variation genome-wide have been using array CGH, among lab led by Ken Chen has resulted in Wis getting easier. Typi- other array-based tools. Now, how- a new set of algorithms that improve cally, to ﬁnd structural variants — ever, high-throughput sequencing common variant detection and de-

14 ______WWW.GENOMEWEB.COM OCTOBER 2009

tection of somatic variants also applied BreakDancer to eliminating germline, or inherited, in tumor versus normal detecting somatic variations variants. “This is a novel application,” samples. in an AML tumor sample Chen says, because it can actually Collectively called Break- as well as detecting vari- perform a “head-to-head” comparison Dancer, the software pack- ants in the 1,000 Genomes of tumor and normal samples. age consists of two com- dataset. After running BreakDancer on the plementary algorithms. What makes BreakDancer AML genomes to predict approxi- Evaluating paired-end novel, Chen says, is that mate size and location of structural reads from an Illumina KEN CHEN the other algorithms target variants, the researchers used as- sequencer, the scientists indels longer than 100 base sembly programs Velvet and Phrap to showed that BreakDancerMax detects pairs. “What we have intended to refine their predictions. By mapping five types of structural variants, in- do is to cover the entire range, from all the reads back to their predicted cluding deletions, insertions, inver- 10 base pairs to virtually no limit,” variant loci, they were able to con- sions, and intrachromosomal and in- he says, significantly increasing the firm that the variants do exist. “We terchromosomal translocations from range of indels that can be detected. found by applying this BreakDancer pooled or individual DNA samples. Both Max and Mini support pooled detection algorithm and assembly af- BreakDancerMini detects small in- samples, or multiple samples and terwards [to tumor samples], we can dels, typically 10 to 100 base pairs, libraries. For looking at variation very efficiently discover and secure which BreakDancerMax misses. The in the AML samples, for example, those predictions,” Chen says. “[The] software was published in a paper ap- they were able to look at a pair combined approach is [more] effi- pearing in August in Nature Methods. of genomes. “We were interested in cient and accurate than using either In the study, they compared the finding somatic variations, so basi- approach in isolation.” mapping capabilities of their algo- cally we compared tumor genome Development of the tools began rithm to similar ones, specifically Evan versus the normal genome,” Chen more than a year ago, and the algo- Eichler’s VariationHunter and Michael says. Because most cancer is caused rithm has already been applied to Brudno’s MoDIL, on MAQ map files by somatic alterations in the tumor many large-scale sequencing data. of the Yoruban genome. In general, genome, it’s important to be able to Chen says it will continue to evolve Chen says, BreakDancerMini showed compare tumor to normal. In this, alongside big sequencing projects, es- higher sensitivity and specificity than BreakDancer improved the specific- pecially the 1,000 Genomes Project. either of the other algorithms. They ity of somatic variant prediction by — Jeanene Swanson

with different viral titers, as based on PCR: CDC Evaluates Rapid Flu Tests the specimens’ cycle threshold value. “They were more likely to yield a valid Versus rRT-PCR for Detecting Novel result if there was more virus there [and] that depends of course on how soon after symptom onset the sample Strain of H1N1 Influenza was taken,” he adds. esearchers from the Cen- of course, off-shot of that is wonder- Shaw points out the study was lim- ters for Disease Control and ing what the sensitivity and specificity ited to the common rapid tests and Prevention found that while would be,” says Michael Shaw, associ- not controlled for how the samples rapid influenza diagnostic ate director for laboratory science in were collected and transported. Rtest could accurately detect the CDC’s influenza division. Still, the rapid tests, when positive, the virus in high concentrations, re- The rapid tests, which are enzyme- are accurate. Negative results, howev- verse real-time PCR testing should based, were evaluated on 65 samples, er, aren’t necessarily actually negative. be done if a definitive determination 45 of which contained the novel H1N1 In that case, clinicians should base is needed. virus, five with seasonal H1N1, and 15 their treatment on what is circulating “We had gotten an increasing num- with seasonal H3N2, as determined in the area and, if a more concrete ber of inquiries from physicians want- by the CDC’s rRT-PCR assay. The result is needed, rely on the rRT-PCR ing to know if the rapid test would sensitivity of the tests was determined assay. work at all on this novel strain, and, from their accuracy in calling samples —Ciara Curtin

OCTOBER 2009 GENOME TECHNOLOGY 15

Zeitgeist BLOGOSPHERE BRIEFS

A Blog Around the World Synthetic biology is not ’80s-era computer science, a researcher maps next-generation sequencers, and more. By Ciara Curtin

Not Steve Jobs in a Garage Where in the World Is a 454?

The efforts of researchers at the J. Craig Venter In August, the Cambridge Research Institute’s James Institute to move toward creating synthetic life — Hadﬁeld created a Google Map listing facilities that they recently published a paper in Science on clon- house next-generation sequencers. He posted a link to ing a bacterial genome in yeast — have been com- the map in the SEQanswers forum and soon opened pared to the work of computer scientists during the the map up so anyone could edit it. At Pathogens: 1980s. Bloggers Ricardo Vidal and Deepak Singh Genes and Genomes, Nick Loman did an analysis of aren’t convinced by the analogy. “This comparison the early data to see which next-gen machines were just brings along a whole truck load of babble that I being adopted in the UK. Discounting the Sanger think is incorrect,” Vidal writes at My Biotech Life. Centre, which Loman says skews the data, the most At business|bytes|genes|molecules, Singh adds that common next-gen platform is the Illumina Solexa. “genetic manipulation and sequencing might become “Solexa is just in the lead with 12 machines, closely available easily and inexpensively some day, but they followed by 454 with 9 machines and with ABI will never be commodities like a computer.” SOLiD trailing with just 3,” Loman writes.

my.biotechlife.net seqanswers.com/forums

mndoci.com ______pathogenomics.bham.ac.uk/blog

Trials and Tribulations After the Hood

Georgia Tech professor Rick Trebino’s article on At her eponymous blog, Female Science Profes- how to publish a scientiﬁc comment to a journal sor wonders what the role of a PhD advisor should has gotten bloggers talking. Trebino’s arduous path be after students graduate. In her experience, she went through 123 steps, plus an addendum, and was treated “with the same benign neglect” by her never resulted in a comment. Steinn Sigurðsson at advisors as other students were, but she has problems the Dynamic of Cats posts the steps as a PDF and doing that herself. She blogs that her approach is un- assures his readers it’s a true story. At Adventures in fair as there are some students for whom all she’ll do Ethics and Science, Janet Stemwedel wades through is write a letter of recommendation, while for others the steps and is left wondering about how scientiﬁc she’ll collaborate or provide other support. Uncertain communication is supposed to occur if there are Principles’ Chad Orzel says that he came away from stumbling blocks throughout the publishing process. his old lab with an armload of equipment on a “per- “The idea that the journal here seems to be missing is manent loan.” “Obviously, this is not sustainable for that they have a duty to their readers, not just to the any research group graduating more than one student authors whose papers they publish,” she writes. every 4-5 years, but it is food for thought,” he writes.

scienceblogs.com/catdynamics science-professor.blogspot.com scienceblogs.com/ethicsandscience scienceblogs.com/principles

16 ______WWW.GENOMEWEB.COM OCTOBER 2009

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PROFESSIONAL LIFE Careers

The Journal Perspective So you’re looking to get published. What’s the best way to interact with journals and editors to help make your case? By Meredith Salisbury

ll scientists are well- another journal and that wherever acceptable to contact the editor to versed in the “pub- you’re sending it this time wasn’t say you’re not happy with the deci- lish or perish” fear your first choice. Also, pay attention sion and ask for advice or feedback. — but what about to data requirements; different jour- “We’re perfectly open to being called A when publishing a nals (especially ones that are open or emailed” when this happens, she paper is so difficult that you feel access) can have different rules about says. “If we can help authors by being like the very process may do you where data must be deposited for the as transparent as we can, then that’s in? Researchers looking to get their paper to be published. good for everyone.” results into a highly regarded jour- Once you’re familiar with the nal for all the world to see have no guidelines, it can be worthwhile to Make new friends easy task ahead of them. One way to contact an editor at the journal with a get through the process unscathed: simple note to gauge interest level. “It The time to think about publishing get familiar with the journals you’re can be good to send a pre-submission is not just when you have a manu- interested in, and make friends with inquiry,” says Clare Garvey, editor at script ready to go, though. You’ll be editors. Genome Biology, who adds that these in better shape to submit a paper or Before you do anything with that inquiries are usually answered very to ask an editor about a review deci- manuscript you’re sitting on, take a quickly. It’s a simple, fast way to see if sion if you’ve already gotten to know few minutes to peruse the websites the paper fits well with the research the editor ahead of time. Garvey says of the journals you’re thinking about scope of the journal. that conferences are a great place to submitting to. They’ll all have a page When you do send your manu- take this step — editors routinely with information for authors; this script in, be sure the cover letter attend meetings, and it’s their job can help you make sure your paper is tailored to the publication you’re to get acquainted with scientists in matches the scope of the journal, and targeting. Garvey says a common the field and get a sense of the latest it also includes helpful guidelines mistake she sees is sending let- research. about formatting and other details of ters intended for other journals that Because editors have a broad per- the submission process. Ignore these have been copied and pasted on a spective on research across many at your peril: formats are chosen for paper that was perhaps sent some- fields, Garvey says it’s important to where else first. remember that they can be “a huge Ignore guidelines at your If your manuscript is resource” to bounce research ideas sent out for review and off. Editors might “even suggest ad- peril: failing to conform to accepted, you’re in great ditional experiments that might help them can send a couple of shape — and interactions that paper get into that journal,” she with the journal should be adds. bad messages straightforward. But what And if you’re not getting out to happens if the paper is re- conferences as much as you’d like, a reason, and failing to conform to jected — or, worse, rejected without Garvey says outreach is considered them can send a couple of bad mes- review? While most scientists will so important that some journals even sages — that you simply don’t care beat themselves up or fume over send editors on lab visits when there’s enough to check guidelines, or that this, very few feel comfortable fol- enough interest in how the editorial your manuscript was formatted for lowing up on it. Garvey says it’s quite process works. N

OCTOBER 2009 GENOME TECHNOLOGY 19

Lab Reunion THE HENIKOFF LAB

‘A Community of Scholars’ Steven Henikoff has been a member of the Fred Hutchinson Cancer Research Center for nearly 30 years. When it comes to trainees, his lab is as much a study in independence as it is in nucleosome dynamics. By Meredith W. Salisbury

f Steven Henikoff has the centromere, such community of indepen- thought seriously about as how it’s maintained dent scholars,” he says. leaving the Fred Hutchin- “despite the fact that “I don’t encourage at all son Cancer Research Cen- sequence doesn’t seem team research.” Genom- Iter since he started working to matter,” he says. In ics as a field lends itself there in 1981, there’s no sign of it work just published in to the concept of team today. “I found the Hutch right from Cell, Henikoff and post- research, he says, but the start to be the ideal place to do doc Takehito Furuyama he believes a better ap- what I want to do,” he says. “There’s discovered that, while all proach is to encourage never been an incentive to change.” nucleosomes wrap DNA collaborations while en- He’s serious: Henikoff, who has a in the same direction, the suring that each scientist joint appointment at the University nucleosomes in centrom- is responsible for and in- STEVEN HENIKOFF of Washington, has never so much as eres actually wrap it in vested in his or her own taken a sabbatical since he joined. reverse. “It has some re- projects. “I think that’s But why should he? Henikoff has ally profound implications,” Henikoff the best training,” he says. “After made a stellar reputation for his lab says. “All the interaction surfaces that you leave your postdoc, you’re going — as much for the science performed are holding together that nucleosome to be out there on your own” and there as for the credit he gives to the are facing away from each other.” The he wants to make sure his trainees people who join him as grad students idea that comes out of this finding is leave the lab equipped to stand on or postdocs and the opportunities that it’s the wrapping pattern that’s their own feet. To that end, Henikoff that open up to them as Henikoff causing the centromere to be so dif- avoids any impulse to micromanage. alums. ferent from the rest of the chromo- “I’m not going to look over anyone’s The lab’s focus includes epigenom- some. shoulder,” he says. ics — including histone variants and Another element of the Henikoff DNA methylation — and centromeric Independent minds philosophy is to empower research- chromatin. His lab has also been the ers by reminding them not to rely birthplace of tools essential to the Henikoff says it was the practice on the tools at hand. Over the years, community, such as TILLING (or of his PhD advisor, Matt Meselson the lab has released a number of targeting induced local lesions in at Harvard, that showed him how tools that became commonly used genomes), a large-scale approach to important it was to let students carve by the community, and the reason reverse genetics that relies on muta- out their own paths. “He gave us a lot for that is Henikoff’s refusal to be genizing whole populations and then of independence,” Henikoff says of constrained by what’s available. If screening them for mutations. The his days studying Drosophila RNA in a scientist in his lab wants to do an approach was invented in Henikoff’s the late ‘70s. “I felt that that was great experiment but the tools don’t exist lab years ago, and while it’s no longer training to be self-reliant.” to perform it, Henikoff likes to see part of his research, his team still In his own lab, Henikoff makes that person delve into building the supports it “as a service for various clear the benefits of interacting with necessary tools rather than abandon organisms.” colleagues while emphasizing the the research path in favor of some- In a recent project, Henikoff’s team need to establish one’s own proj- thing that’s more in line with exist- helped tease apart the mystery of ects. “I try to make the lab more a ing technologies.

20 WWW.GENOMEWEB.COM______OCTOBER 2009

The original TILLING work “led to a >NAMING NAMES very nice study, a nice story, a nice Just since 2000, the Henikoff lab has been home to some 25 trainees. Here are publication,” Henikoff says. just a few of the students and postdocs who have earned their stripes there. PAULINE NG TAKEHITO FURUYAMA of genetic conflict, Henikoff says, During her years as a graduate student A current postdoc with Henikoff, adding, “I learned more from him than in Henikoff’s lab, Ng came up with the Furuyama recently published a paper he learned from me, that’s for sure.” idea that deleterious nonsynonymous in Cell demonstrating a finding that the Malik was awarded a Presidential changes in protein sequence could PI calls “the most exciting thing we’ve Early Career Award for Scientists and be predicted based on evolutionary ever done” — that is, evidence that Engineers by President Barack Obama information. That work led to an nucleosomes in the centromere wrap this year. algorithm called SIFT. After leaving the DNA in the opposite way that all other lab, Ng worked at Illumina and is now a nucleosomes do. “We basically think CLAIRE MCCALLUM senior scientist in genomic medicine at that it’s the wrapping of the DNA that McCallum was the brain behind the J. Craig Venter Institute. is responsible for all the differences TILLING, the tool that has become that we see” in how centromeres synonymous with Henikoff’s lab in the BAS VAN STEENSEL behave and function, Henikoff says. time since her graduate work there Van Steensel, a postdoc with Henikoff from 1996 to 2002. Her quest for the from 1998 to 2000, helped get the lab HARMIT MALIK mutation of a known gene helped into genome-wide profiling, Henikoff Now the PI of his own lab at the Hutch, launch the method of mutagenizing says. After his time at the Hutch, van Malik did his postdoc with Henikoff all genes and screening them; it also Steensel went on to the Netherlands from 1999 to 2003. His focus has led to a company she launched, which Cancer Institute, where he heads up been studying evolutionary signatures is now part of Arcadia Biosciences. his own lab.

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Under One Roof BASIC MEETS CLINICAL

A Grassroots Institute At the Institute for Genomic Medicine, reaching out to on-campus researchers and resources has helped it weather tough economic times. By Matthew Dublin

ometimes you have to Bruce Hamilton, director of get by with a little help the UCSD Genetics Training from your friends. Such Program. Gleeson says that is the case with the re- plans to construct a dedicated Scently established Insti- building for IGM have stalled tute for Genomic Medicine at the slightly due to the poor state University of California, San Diego, of the California economy. where a severely stricken state econ- When plans are ﬁnalized, omy and limited university budget however, the group hopes have forced the institute’s executive to break ground by the end committee to operate with the man- of this year and begin mov- RENDERING OF THE INSTITUTE tra that no man — or institute — is ing in by 2012 or early 2013. FOR GENOMIC MEDICINE an island. Currently, the researchers are To compensate for a lack of giant still distributed across the UCSD taking a genomics approach to their startup coffers, the institute’s found- campus. Until the institute has its own areas of disease research, suc- ers have focused more on securing own in-house sequencing and data cess could be just a matter of put- a brain trust from around the UCSD analysis gear, members will make ting all the pieces together in one campus to form a strong foundation use of the university’s Biomedical location. “We have outstanding re- upon which to slowly build IGM. Genomics Laboratory core. searchers in many disorders, and “We have had generous intellectual And while the institute is getting we’re all learning about genomics support from the school of medi- a certain amount of startup funding on our own and applying some tech- cine, and very broad-based support thanks to the powers that be at the nologies in our own labs or maybe from the various UCSD campuses, university, when that runs out, the outside of the university,” Gleeson the undergraduate biology depart- core membership will have to assays. “We would really like to make ment, and the school of engineer- sume operational costs with shared a central place where we could all ing,” says Joseph Gleeson, a profes- grants and private donations. deposit the new technologies and sor of neurosciences and pediatrics be able to better take advantage of at UCSD, and a Howard Hughes Medical efforts them.” Medical Institute Investigator. “UC- Its leaders hope the institute can SD is a place that builds things from Despite a grim economic land- ultimately deliver real-life solutions the grassroots up. We don’t have scape, the folks behind the new to common problems doctors and someone that guides things from the institute have not been deterred in patients face every day. “We really top down, so we haven’t identiﬁed their efforts to realize the potential want to be a part of bringing per- a big source of funding to get the of genomic medicine to change the sonalized medicine to the people initiative going.” way doctors will treat patients. IGM of San Diego and [to] the national Gleeson is also a member of IGM’s will initially focus on various forms scene. …. If we could make advanc- executive committee, which in- of cancer, AIDS, and neuropsychiat- es in some of these targeted disease cludes institute director and UCSD ric, developmental, and eye diseas- areas, we will be taken seriously professor of ophthalmology and es. With the UCSD Medical Center by the rest of the genetics com- human genetics Kang Zhang, and nearby and a slew of investigators munity, and that’s our challenge,”

22 ______WWW.GENOMEWEB.COM OCTOBER 2009

Gleeson says. For many involved, helping IGM plan for its bioinfor- the establishment of IGM is seen >THE INSTITUTE FOR matics infrastructure. as a coming-out party for the uni- GENOMIC MEDICINE In addition to creating synergy versity as a signiﬁcant genomics San Diego, Calif. among resources and researchers research site. “Unfortunately, UCSD DIRECTOR: Kang Zhang on the UCSD campus, equally es- has not really had much of a pres- ESTABLISHED: 2009 sential is the role that other in- ence in genetics. With the exception SIZE: There are currently about 16 stitutes will play, particularly the of a few people who have done some researchers that have come aboard J. Craig Venter Institute, which is important work, we haven’t had a the institute, although this number right in IGM’s backyard. Albert La department of genetics or an insti- will probably increase as more UCSD Spada, an IGM member and genet- tute or anything like that,” Gleeson faculty start contributing to its ef- ics chief in the pediatrics depart- adds. “But we have certain unique forts. ment at the UCSD Medical Center, strengths — a lot of our faculty is FUNDING: Initially, IGM will garner has high hopes for on-campus and just out of their postdoc and excited the majority of its launch funding off-campus collaborations. “I think to get something done.” from money allocated by UCSD’s at UCSD and the affiliated insti- Eventually, IGM researchers budget. Once the institute is up and tutes there is incredible expertise would like to perform genome-scale running, grants and private funding in emerging genomics technologies, sequencing on every patient that from its core members will have to including next-generation sequenc- comes through the doors of the Med- keep the institute afloat. ing and, perhaps most importantly, ical Center as well as the local chil- FOCUS: IGM is intended to be a computational biology and bioin- dren’s hospital. Some of the key areas center point for all genomics efforts formatics,” La Spada says. Breaking the institute will focus on include on the UCSD campus. It also aims to through bioinformatics bottlenecks whole exome sequencing and copy take part in collaborations with other will also be facilitated by resources number variation — especially as genomics institutes with the goal at the San Diego Supercomputer they relate to particular disease enti- of making personalized medicine a Center and the California Insti- ties where UCSD has strong patient reality. tute for Telecommunications and cohorts. “Our vision is we would Technology. “What is unique about like to perform genetic analysis on UCSD is that we’re positioned to every patient ... and then we would ever, you can apply the richness of leverage this type of program based like to work with the pharmaceutical the genetic data to your particular upon access to those resources and companies to take advantage of that problem.” infrastructure … but we’re looking information in disease drug trials to partner with all types of organi- and by helping them look for outli- Getting started zations as the program grows and ers in their various clinical trials,” evolves,” La Spada adds. Gleeson says. IGM is currently building itself He is looking forward to the institute To that end, the institute is being from the ground up with a core working to elucidate the mechanisms pitched to university scientists with team of members from across the of neurological disease — his current relevant patient cohorts as a place university. This initial group in- area of focus. La Spada would really where they might be able to get more cludes several researchers from the like to have a better handle on the out of their data. “We’re trying to get Cellular and Molecular Medicine pathways responsible for neurode- all the researchers on campus who department as well as individual re- generative processes, and it appears have unique patient cohorts together searchers with specialized skill sets, that for a number of these disorders, and say that IGM can be a place such as Trey Ideker, division chief these pathways involve alterations in where you can bring your cohorts of genetics and associate professor transcriptional function. “Being able with your phenotypic data and think in the department of medicine and to interrogate the transcriptome of of ways you get them all genotyped bioengineering at UCSD, who will neurons is an important and neces- with whatever platform would be lend his expertise in bioinformatics sary approach that this institute will most applicable, whether it’s copy and genetic network analysis. Terry better allow in the future, so there are number variation, high-density SNP Gaasterland, professor and direc- certain emerging technologies that arrays, and then let’s see what data tor of the nearby Scripps Genome could better position our group to falls out,” he says. “Whether it’s a Center, is now also spending a lot of have a leadership role in [that area],” pharmaceutical response or what- time on the medical school campus La Spada says. N

OCTOBER 2009 GENOME TECHNOLOGY 23

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Sequencing | Gene Expression Profiling | Genotyping | Biologics Evaluation and Safety Testing | Sample Management

SANDRA PORTER My Take

Project Annotation Letting students get involved in annotation projects can be great real-world experience — or it can open the doors to lots of errors entered in GenBank. What’s the best plan here?

esearchers who much less a current build. study well-docu- So what do you do? Work on some- mented creatures thing else and wait for your ’omics like fruit flies or E. collection to catch up? Or is there R coli are blessed with another answer? the most powerful tools of biology at their fingertips. Armed with data The student force from genome sequences, transcrip- tomes, ontologies, and pathways, the One strategy is to seek help. Some goal of putting pieces together in a college instructors have realized that network of interacting genes can be education and annotation can coex- addressed pretty quickly. ist. They’ve found that involving stu- But what if you study something dents can speed the data annotation SANDRA PORTER else, like corn or wheat? The outskirts process and train future biologists at of biology tell a different story. Once the same time. Rather than waiting Goodner, Daniel Rhoades, and Steve you venture away from the well- for database curators to catch up on Slater from colleges across the US annotated references in the model an ever-growing mountain of work, described a joint endeavor where organism world, the set of research researchers benefit when lots of stu- students carried out functional an- tools gets sparse. The databases look dents are added to the labor pool. notation by using bacterial mutants less and less complete. Annotations, This summer, I attended the iPlant to test whether genes can correct if you can find them, are more shady, Genomics Education conference in deficiencies in nutritional pathways. and words like “hypothetical” and St. Louis and listened to talks about Cheryl Kerfeld from the Joint Ge- “putative” appear around every cor- students’ contributions to the world nome Institute discussed a program ner. And those tools that we enjoy in of annotating ’omics databases. In- where 65 bacterial and archaeal ge- the civilized world like GO ontolo- structors spoke passionately about nomes can be adopted and annotated gies or KEGG pathways? Good luck. the results they saw from integrating by college classes. Representing in- the realms of teach- sects, Sarah Elgin of Washington Once you venture away from ing and research. University discussed a national part- We learned about nership where students assemble and the well-annotated references many kinds of an- annotate genes from different species in the model organism world, notation projects. of Drosophila. Charles Hardnet We also heard about annotation the set of research tools gets from Spelman Col- projects in plants. Brent Buckner lege showed electron from Truman State University de- sparse. The databases look less micrographs of the scribed the use of yeast mutants to and less complete. phage that his stu- identify the functions of plant genes. dents isolated and Sue Wessler and Jim Burnette from Your genome sequence, if you have annotated through their school’s the University of Georgia discussed one, probably won’t even merit a partnership with HHMI. For the bac- annotating plant transposons. Iowa track at the UCSC genome browser, terial projects, Derek Wood, Brad State’s Volker Brendl presented a

OCTOBER 2009 GENOME TECHNOLOGY 25

system where the entire community mystify the whole database business dents learn best through hands-on can use cDNA and EST evidence and make future researchers a little learning, and these students could to evaluate and correct structural more skeptical. Students would learn suffer if certain kinds of activities annotations that have been flagged that “buyer beware” and reviewing are lost. as suspicious in the Plant Genome evidence with a critical eye are good Does the possibility of a few mis- Database. And Uwe Hilgert of Cold policies to follow no matter where takes slipping by reviewers and con- Spring Harbor Laboratory presented your data originates. taminating databases mean we keep a vision of the ultimate annotation Given the number of students in students from participating in anno- pipeline. some courses and the push for cost- tation projects? Does the possibility Many iPlant attendees seemed to effective solutions, some skepticism that their learning experience might agree that the ultimate annotation from the professional researchers change — or that change might be pipeline would allow a biology class might be justified. It is difficult to hard — mean we should keep things to check out a genome, review evi- imagine that students in an under- as they are? To paraphrase Paul Farm- dence, submit corrections, and give graduate class with 200 or more stu- er: this is not the end of the conversa- students some kind of visible credit dents, five teaching assistants, and a tion. This is the beginning. so they could demonstrate their con- very tight lab schedule would be able tribution to others. to finish annotation projects or make The case for inclusion contributions that wouldn’t have to The downside be double- or triple-checked. In fact, One of the biggest drivers for in- the National Science Foundation’s cluding students in annotation proj- Although the idea of combining Vision and Change survey of under- ects comes from the students them- useful work with directed studies graduate biology students conducted selves. The NSF Vision and Change might seem rather obvious, not ev- during the past two years found one student survey found that students eryone shares the belief that engag- of the most common complaints was want more of an emphasis on applying students in real annotation work that their schedule doesn’t include ing knowledge and problem-solving. is a good thing. time for repeating labs or debugging They want more chances to do re- From the researcher perspective, mistakes. Perhaps a system could be search and learn how research is the major concern with having stu- adopted where professional curators done. They want to work with real dents annotate gene sequences is would spot-check student work and data and practice evaluating scien- quality. They anxiously point to past assign reliability ratings (behind the tific evidence. What they do not want horror stories of poor quality or mis- scenes, of course) to classes from dif- are courses full of memorization that identified sequences, like dinosaur ferent schools. feel disconnected from “real world” DNA, contaminating GenBank. This In another argument, some iPlant science. group is wary of student work and educators shared stories of peers, Although incorporating research they want the barriers high lest an criticizing them for “using their means that learning opportunities incorrect annotation lead them down students as technicians,” exploiting will change, the benefits to students a wrong research path. their students, and suggesting that can be many. These projects can give Certainly, these researchers are they were allowing their students’ students a chance to practice wet lab right to be wary, but this attitude education to suffer by having them and bioinformatics techniques and shouldn’t keep students from con- do research. Still other instructors give them better preparation should tributing. After all, many of the sus- worry about the competition for time. they pursue a career in life sciences picious entries came from other re- Research projects are time-intensive or biotechnology. Students relish the searchers and were reviewed by their endeavors and there’s considerable chance to do something more mean- peers. The dinosaur entry (U41319), pressure to pack as many topics in ingful than writing a lab report. They for example, was published in 1997 a course as possible. Would the time want to “publish” and contribute to in Molecular Biology and Evolution. required to do a real project push the community. I’m glad there are Further, many entries aren’t support- other important topics out of the instructors giving some of them a ed by experimental evidence; they’re curriculum? chance. N predicted by algorithms. The concern about time is legiti- Sandra Porter, PhD, is president of the If anything, teaching students how mate. Lab activities are often used to bioinformatics education company Digi- to review the evidence by having reinforce concepts from the lecture tal World Biology. Her blog is located at them annotate data could help de- portion of the course. Some stu- scienceblogs.com/digitalbio.

26 ______WWW.GENOMEWEB.COM OCTOBER 2009

HIGH-PERFORMANCE COMPUTING Brute Force

Personal Supercomputers? Call them whatever you like, but HPC vendors are wasting no time in using current hardware to bring more processing power to the desktop than ever before.By Matthew Dublin

ou’ve got to love puter with data processing power house up to 64 processing cores. marketing trends beyond that which is commonly The price tag starts at roughly in the world of available. “There is always going $9,500, but in July, Cray released high-performance to be a class of computing power an even cheaper version called Y computing. Un- that is much bigger than anything the CX1-LC (light configuration). less, of course, you’re stuck sift- that will physically fit on your And in an obvious effort to secure ing through the hype to discern desk because if you can buy some- a customer base of individual re- the best compute configuration for thing for $1,000 or $10,000 then searchers and small labs, both ma- your lab or institute. Sometimes there are going to be users that are chines come equipped with either these trends become particularly prepared to buy hundreds of them the Windows HPC Server 2008 or slippery when categories of tech- for a million dollars,” Jones says. the Linux-based Rocks+ operating nology are stretched to the point “And there’s always going to be systems. where their very description seems something that is orders of magni- Rico Magsipoc, chief technology to be at best a misnomer or, at tude bigger than what most people officer of the Laboratory of Neuro worst, nonsensical. Many a brow can afford but the cheap stuff gets Imaging (LONI) at the University has furrowed over a recent trend more powerful.” And that’s the of California, Los Angeles, School that has picked up considerable point: good old Moore’s Law, along of Medicine, was tempted enough momentum: “desk side” or “per- with improvements in hardware by the prospect of having a mini- sonal” supercomputing. Manu- like GPUs, make that cheap and supercomputer that he decided to facturers like Cray, Nvidia, SGI, powerful stuff easily accessible for purchase a CX1 unit for the re- and HP have all gotten on the the rest of us. searchers at his lab. Among other bandwagon of marketing HPC so- projects, LONI conducts cross- lutions geared toward the individ- Cray’s CX1 species brain function studies em- ual researcher or small laboratory, ploying complex algorithms that which begs the question: Just what Supercomputer manufacturer result in computationally heavy is “personal supercomputing”? Cray, which has since its inception jobs. These jobs not only take sev- Andrew Jones, vice president of more than 35 years ago focused eral hours to run, but researchers solely on mas- were often subjected to additional “There is always going to be a sive, high-end wait time in order to gain access supercomputers, to the lab’s larger HPC resources. class of computing power that is unveiled the Cray “We have quite an extensive HPC much bigger than anything that CX1 personal implementation in our facility here, supercomputer a but the problem is we have a large will physically fit on your desk.” year ago. Unlike pool of processors for production, anything Cray and a large pool of processors for consulting at the Numerical Al- created before, the CX1 can fit development — but for the indi- gorithms Group, a nonprofit HPC on or under a desk, draws its vidual researcher, we don’t really software and services solution power from a standard 110 volt have resources,” Magsipoc says. group, has argued that by defini- wall socket, requires no addition- “With CX1 we were able to give a tion, a supercomputer is a com- al cooling infrastructure, and can faculty member a machine with 32

OCTOBER 2009 GENOME TECHNOLOGY 27

CPUs, configured any which way, Theoretical and Computational whose form factor would fit on or and he’s now a lot more nimble Biophysics Group at the Univer- under your desk. “This is very ex- and agile with his research.” sity of Illinois, has done to facili- citing to me because I develop mo- Ultimately, eliminating the high tate the development of molecu- lecular visualization and analysis cost of failure during the test- lar visualization software without software and this software is run ing and tweaking phase of tool having to fork over development is where Magsipoc a lot of money or “I don’t think there’s anything sees the big win with personal su- deal with queuing percomputing. Before purchasing up for time at a clus- wrong with the term ‘personal their CX1, all tools had to be tested ter. Stone currently supercomputing.’” on the lab’s development cluster, uses a preconfigured so if something turned out not quad-core Linux PC to work as planned, it was costly with three Nvidia GPUs that is by a range of researchers, many of in terms of energy usage and the capable of more than a teraflop’s whom are not computer experts or time it took to queue up for access. worth of performance. “We actu- hardware guys. They are wet lab Now, users can test tools to their ally bought that from a local PC scientists, so they are not compute heart’s desire without even set- vendor, had them assemble the savvy beyond the point of using ting foot in the cluster room. “We machines for us, and we got three the software to do what they need have a number of researchers here of the Nvidia GPUs,” Stone says. to do,” Stone says. “For them, the and I can envision each of them “It was very easy and this is some- appeal is that they can very easily having their own CX1 and then thing a lot of people can do.” ask their local computer adminis- when their tools are ready, we can Stone’s personal supercomputer tration team and say ‘I need a new deploy them on our larger cluster,” serves as a very real replacement computer that has four GPUs in it Magsipoc says. for a cluster of PCs, and lets his and I will be able to run my work team of researchers avoid some 100x faster’ which means they can Nvidia’s Tesla of the operational hassles asso- do things they just couldn’t even ciated with clusters. Currently, do before.” GPU chipmaker Nvidia also has a his lab has 20 such GPU-enabled A few years back we might have desk-side supercomputer offering: PCs specifically equipped for vi- called desk-side machines that the Tesla Personal Supercomputer, sualization tool development. Ul- were way beyond PCs’ processing which is Linux 64-bit and Win- timately, he says that what the power ‘technical workstations.’ dows XP 64-bit enabled and comes personal supercomputing hoopla Whether they really count as su- loaded with a quad-core AMD or should really point to is the fact percomputers is beside the point Intel CPUs, and up to four Nvidia that for the first time ever, there — at the end of the day, mak- are commodity de- ing researchers aware of what’s “This is very exciting to me vices that are mas- out there is what really counts. sively parallel and “I don’t think there’s anything because I develop molecular have the same ag- wrong with the term ‘personal visualization and analysis gregate floating point supercomputing’ if it successfully performance that just gets a whole lot more people mak- software.” a few years ago would ing use of the compute power have required a room that’s available,” Jones says. “It’s GPU cards. Nvidia encourages us- full of typical PCs or server class marketing, but it’s perfectly valid ers to construct their own units machines. marketing, aimed at an audience the same way gamers have done for In the case of Nvidia’s products, that would normally not go any- years; still, preconfigured units are assuming you feel comfortable in where near large-scale supercom- available through affiliated resell- the GPU programming world — puters. … HPC can do so much ers, or one can just go to a local PC which by steps is getting more and for people trying to do simula- shop and have one built for you. more attainable — you can get a tions and modeling that whatever That’s exactly what John Stone, a level of performance that was not we call it to get more people to senior research programmer at the practical before with a machine using it, the better.” N

28 WWW.GENOMEWEB.COM______OCTOBER 2009

Accelerating the pace of engineering and science

Over one million people around the world speak MATLAB. Engineers and scientists in every field from aerospace and semiconductors to biotech, financial services, and earth and ocean sciences use it to express their ideas. Do you speak MATLAB?

Cells in mitosis: high-throughput microscopy for image-based screens. Provided by Roy Wollman,

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The language of technical computing

GENE EXPRESSION New Tools in Neuroscience A brain atlas was once on the order of a coffee table book, known for its large, glossy illustrations. Today’s brain atlases — led largely by the Allen Institute for Brain Science — capitalize on localized gene expression and other data to truly revolutionize the ﬁeld of neuroscience.

BY MEREDITH W. SALISBURY level of information helps his team partition patients into t’s been just three years groups based on likely treat- since the Allen Institute ment course and predicted released its mouse brain outcome. Of course, what he atlas — a free, publicly really wants is to have a brain Iavailable online tool atlas for human — and one that allows users to zoom in that would reflect the changes and out of a 3D brain, search by seen in glioblastoma patients. gene, and see expression data — Foltz is getting his wish. but in that short time, this revo- Thanks to a three-year, $2.1 lutionary look at the inner work- million grant from the Ben and ings of a brain has dramatically Catherine Ivy Foundation, Foltz changed the way neuroscientists will be teaming up with the Al- do business. len Institute on the Ivy Glioblas- Take Greg Foltz, for instance. toma Atlas Project. The atlas will A neurosurgeon at the Swed- be based on tumor samples from ish Neuroscience Institute, Foltz 32 patients and will start with studies glioblastoma mutliforme; a focus on 300 genes selected for him, the glut of new data on “because they’ve already been this particular kind of tumor A BRAIN SLAB IS PREPARED FOR SECTIONING known to have increased expres- from the Cancer Genome Atlas sion in glioblastoma,” Foltz says. project has been both an amazing brain atlas for mouse. He and his He also plans for a comparison resource and a cause of frustration. team have made extensive use of to non-tumor brain, using around The “tremendous amount of sequenc- the atlas and believe that mouse 20 samples from operations where ing data available across hundreds of brain is a fair approximation for patients with other neurological con- patients” — while a significant first what goes on in human brain, ditions, such as epilepsy, have had step, Foltz says — doesn’t address a he says. Foltz can take the gene part of their brain removed. When key issue in heterogeneous glioblas- expression levels seen in the glio- the atlas is complete, it will include toma tumors: location. In these types blastoma-specific data and com- clinical information on the patients of tumors, knowing whether a gene pare them to the mouse brain for a and the tool will be made freely is expressed at the core of the tumor sense of “what genes appear to be available. “It is going to be absolutely or the leading edge of the tumor can expressed in an increased fashion fascinating to see,” Foltz says. be critical to deciding how to treat or silenced,” he says. “That’s been a patient. really useful for us. If you think The human angle Because of that, Foltz uses the se- about it, we have no other way of quencing data and compares it to, making that comparison.” Over at the Allen Institute, mean- of all things, the Allen Institute’s Indeed, Foltz says that even that while, the glioblastoma project

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might be considered small compared to what these researchers MicroRNA Expression Sheds Light have set their minds to: developing a human brain atlas. on Schizophrenia This is no pie-in-the-sky goal. After more than a year of planning, insti- A team of scientists at the Schizophrenia tute scientists are gearing up to begin Research Institute in Australia have used studies the human brain project, which is of microRNA expression to determine that gene expected to cost around $55 mil- silencing appears to play a key role in patients lion, include two phases — the first with schizophrenia. a macro-level look and the second Murray Cairns, senior research fellow at focusing more on the cellular level the institute, worked on the project involving — and be completed in 2012, says a cohort of postmortem samples from schizo- institute COO Elaine Jones. The in- MURRAY CAIRNS phrenia patients and controls. “After doing a stitute is currently trying to raise $10 lot of gene expression profiling, we noticed that million to support the initiative from there was a general trend — more down-regulated … genes than upregulated. a variety of sources, including gov- We thought maybe this was gene silencing.” That finding led to the current study, ernment agencies, private sources, recently published in Molecular Psychiatry, in which “microRNA expression and philanthropies, she adds. seemed to be globally elevated in the schizophrenia cases compared with the As most people are reluctant to give controls,” Cairns says. up their brains, the study will be per- To follow up on that, Cairns and his colleagues looked at the primary and formed on cadavers — anywhere from precursor microRNAs of some of the differentially expressed microRNAs, finding four to 10, with a mix of males and that “the mature and precursor forms were … upregulated in schizophrenia but females, says Elaine Shen, manager the primary transcripts didn’t seem to be altered,” he says. That suggested some of the human brain atlas project. She kind of post-transcriptional alteration, which the team is currently investigating. notes that the end result will be multi- The researchers are using microarrays and next-gen sequencing in their latest modal, including magnetic resonance studies. “We’re looking at some other brain regions and we’re also trying to do and classic histology information in some laser capture and identify the actual cell types,” Cairns says. They’re adding addition to the microarray analysis some functional genomics approaches as well to get a better sense of the patho- and in situ hybridization data. “All of genesis of the disease. the gene expression data is going to be mapped back into 3D space,” Shen says. With all of that information in in adapting protocols to work with ning for this project involved reach- one place, she adds, the hope is that fresh frozen tissue. The team also ing out to the neuroscience com- the new brain atlas will be far more had to rebuild the informatics side munity. The goal was “to understand useful to clinical researchers. of the pipeline to accommodate all from them what they thought, one, The human brain is approximate- the new clinical data as well as the would be needed [by scientists in the ly 2,000 times the size of mouse microarray data. “The scale’s so field], and, two, the challenges and brain, Shen says, which in itself much larger,” Shen says. “A project expertise that would be required,” has created major challenges for of this kind of scale and scope has she says. a pipeline designed around brain not really been tried.” The choice of human brain for the slices that could easily fit on a typi- In the first phase of the atlas proj- institute’s next major project was cal laboratory slide. Other hurdles ect, researchers will collect about no accident. According to Jones, the have come from using fresh frozen 1,000 samples per brain and per- institute plans in three- to five-year tissue: “So many of the stains have form microarray analysis on them phases, based in large part on the been optimized for fixed tissue,” as a way to “systematically survey recommendations of its scientific Shen says. The brain sectioning through the brain,” Shen says. The advisory board. “We are looking at process is typically easier in fixed second phase will include the ISH what’s the next big, high-impact proj- tissue as well. As the institute has part of the study and will “very ect that we should be working on geared up for this project during likely concentrate on specific genes that will have a major effect on neu- the past year and a half or so, sci- and specific structures.” roscience … that nobody else will entists there have become experts Shen notes that a key phase in plan- touch,” Jones says. N

OCTOBER 2009 GENOME TECHNOLOGY 31

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PGX Companion Diagnostics Take Off Pharma is realizing that it needs to collaborate with diagnostic companies to stratify patients and to make safer, more effective drugs. But obstacles remain in the path to full ﬂight.

BY JEANENE SWANSON will eventually become the norm. “It’s a new field, and it’s growing,” s the saying goes, says Peter Tolias, executive director all good things of the Institute of Genomic Medicine must come to at the UMDNJ-New Jersey Medical an end. And for School. pharma, that In the last five years most of the means banking major pharmaceutical companies Aon the one-size-fits-all model of drug have adopted new programs to deal development. Companion diagnos- with companion diagnostic products. tics, a relatively new concept that’s “In the olden days they never used hitting the frontlines of drug discov- to worry about who their drug was ery and development, is promising to going to be functioning in, or who’s change the way drugs are made and going to have an adverse effect and marketed. to actually support it with a clinical With more and more biomarkers product in the marketplace,” Tolias being discovered and validated, the says. “The tide has changed now and field of companion diagnostics has pharmaceutical companies are very more than a leg to stand on. Us- “It’s going to take interested in moving products onto ing a companion test — whether [the] market where they can target it looks for genetic, proteomic, or probably a generation safer and more effective products gene expression markers — to pre- with companion diagnostics.” dict whether a drug will work in for us to see a trans- Recently, the field has really heated someone or what kind of dose that formative change.” up, and that’s due in part to increased person should take is becoming more awareness among pharma that in common and, according to experts, Peter Tolias order to be more effective and save

OCTOBER 2009 GENOME TECHNOLOGY 33

money, drugs will have to be more a drug debuted in 1998. Diagnostic be used to predict whether a patient personalized. “The very important company Dako launched HercepTest, with metastatic colorectal cancer will trend that’s emerged is the realization an immunohistochemistry assay used respond to Amgen’s drug Vectibix. by the pharmaceutical industry that to identify patients with HER2-pos- The K-RAS test is also used to predict whether they like it or not, this is just itive metastatic breast cancer, when response to ImClone System’s Erbitux, how things are going to be, and once it was discovered that patients with which only works for patients whose they realize that, that should be a re- HER2 amplification responded better tumors are not mutated. ally big impetus in terms of moving to Genentech’s breast cancer therapy, “The uptake of [the K-RAS muta- things forward,” says Stephen Little, Herceptin. In August of this year, Ge- tion diagnostic] has been really fast, CEO of UK-based pharmacogenom- nentech and Dako agreed to submit and I’m sure part of the reason for ics company DxS. for FDA approval both HercepTest that is that we don’t just have the and Dako’s HER2 FISH pharmDx diagnostic industry promoting the Taking off benefits of the assay, we have the pharmaceutical industry promoting While the anticipation in the field the benefits of the assay as well,” says is that there will be a marked in- Little at DxS. Since the whole point crease in the number of companion of these tests is to identify patients diagnostic products, it’s not going to who will do well, “you end up with happen overnight, says Tolias. “It’s better treatment for less money,” he going to take probably a generation adds. “It’s a very alluring prospect.” for us to see a transformative change Other notable collaborations are in the way that drugs are used, but in the works, too. In July, Glaxo- clearly it’s already happening and SmithKline and Abbott announced there are tangible examples on the that they would develop a companion market today,” he adds. diagnostic for GSK’s investigational The Personalized Medicine Coali- MAGE-A3 immunotherapy. In Oc- tion, a nonprofit advocacy group, CAROL BERRY tober 2008, Merck signed a two-year reports that there are currently about exclusive licensing agreement with 40 drugs in the US that have com- test for Herceptin in the treatment Celera that gave the pharma access to panion diagnostic tests associated of advanced HER2-positive stomach up to 10 cancer targets for the devel- with them — whether that means cancer. opment of RNAi-based therapeutics. as a requirement to their being pre- One leader in the field is DxS, which Effectively, Celera can develop com- scribed, a recommendation for use, has partnered with some of the big- panion diagnostics for any therapeu- or label information that lists genetic gest pharma companies to co-devel- tics that Merck develops out of the susceptibility relating to efficacy or op companion tests. In April 2007, licensed targets. In 2007, Merck inked dose. the company launched TheraScreen, a research collaboration agreement While a number of pharma compa- the first CE-marked diagnostic for with Asuragen to develop a gene-ex- nies have bought in, including Na- detecting mutations in the epidermal pression-based companion diagnostic tional Pharmaceutical Council mem- growth factor receptor gene. The kit for use in Merck’s clinical trials for an bers Abbott, Pfizer, Bristol-Myers is used to select lung cancer patients investigational cancer treatment. Squibb, Boehringer Ingelheim, and who can be treated with tyrosine ki- Use in clinical trials is one of the AstraZeneca, among others, it’s no- nase inhibitors, since recent studies reasons pharmas like to partner ticeably the diagnostics industry that have shown that some patients with with diagnostic companies. Ac- has benefited financially. According non-small cell lung cancer who have cording to Carol Berry, head of the to the PMC, the 200 companies in the mutations in this gene respond better pharmacogenomic services division diagnostics space reported $30 billion to tyrosine kinase inhibitors such as at Asuragen, “Our clients, which are in sales in 2008. There are 65 publicly Roche/OSI Pharmaceuticals’ Tarceva pharmaceutical companies, mostly traded imaging diagnostic companies, and AstraZeneca’s Iressa. In 2007, are looking at how can we develop and venture capital invested in 57 DxS launched its K-RAS mutation de- assays — in other words, gene sig- molecular diagnostic companies last tection kit, and in 2008 the company natures — and then use those gene year totaled $467 million. partnered with Amgen to develop a signatures in various phases of their The first test to be associated with K-RAS companion diagnostic that can clinical trials.” Indeed, most pharma

34 WWW.GENOMEWEB.COM______OCTOBER 2009

giants look to companies like Asura- different organizations from diag- and approved, this would be the first gen, for instance, toward the end of nostics firms to pharma companies, time a drug has been resuscitated by phase 2 or 3 trials when they are there’s a more complex set of prob- a companion diagnostic. considering FDA submission. “The lems. “The significance here is that regulatory requirements drive them the companion diagnostic can facili- Regulatory hurdles to solicit outside companies like ours tate the approval of a drug because that have the expertise and the know- it works in a large percentage of Another big hurdle, according to how and the manufacturing facilities people,” says Director Ed Abrahams. Abrahams, involves regulatory is- to be able to produce the diagnostic,” “[Pharma has] understood for quite sues. While FDA issued a draft Drug Berry says. some time that they need to enrich Test Codevelopment Concept Paper the pool — so that they understand in early 2005 to lay out the initial Working together why a drug works and for whom guidelines for the regulatory process for drugs with companion tests, While most available companion the document hasn’t been improved diagnostics — whether molecular upon much since then. In 2002, the tests like those for the EGFR mu- FDA created the Office of Combi- tation or in vitro diagnostic tests nation Products, which addresses like Oncotype DX’s test that looks companion devices and tests that for gene expression differences to don’t fit into the agency’s established measure susceptibility to breast pipelines. “Companion diagnostics cancer reoccurrence — have been don’t really fit into the current FDA developed separately from the drug paradigm of regulating diagnostic they’re used with, the trend now is kits,” says PMC’s Amy Miller, public toward developing them together. policy expert. The FDA has indi- And as more clinical trials include cated that it may turn the concept early biomarker tests for toxicity or paper into an actual guidance for efficacy screening purposes, it’s easy FELIX FRUEH industry, and the PMC is taking to springboard these into compan- responsibility for collecting sugges- ion tests, says Tolias. it works and so that they can pull tions from the community on how “It’s pretty straightforward for the plug early if they’re seeing it’s to update it. They plan to publish us to design and develop a good not working. … But now they un- those suggestions in late October, quality assay, but to actually link derstand, to get something onto the says Miller. However, she adds, “It’s that assay to drug response needs market, it can be useful to have the really unclear how these products a clinical trial, and that needs the diagnostic joined to the drug.” But are going to be regulated.” pharmaceutical industry’s buy-in,” working together is not as simple as Felix Frueh, who used to lead the says DxS’s Little. While that’s hap- it sounds. Abrahams says one of the genomics review group at FDA’s cen- pened over the last several years, the big hurdles to getting personalized ter for drugs and now heads up bigger challenge is getting pharma medicine tests up and running is research and development for per- to start planning co-development that of divergent business models, sonalized medicine at Medco, is on agreements earlier in the clinical which do “not allow for easy part- the board of PMC and has helped trials process. “I think the biggest nerships.” compile the comments. “For one, challenge is often one of lack of fore- A looming incentive for pharma the co-development draft guidance sight,” Little adds. “Oftentimes we’re companies to partner with a diag- is still only talked about, but noth- involved with a drug company who nostic manufacturer is that submit- ing has been written,” Frueh says. requires a companion diagnostic, ting a diagnostic with a drug might So far, he adds, many feel the cur- but they need it straightaway and increase the therapeutic’s chances rent concept paper is too technical they haven’t really given us time to of being approved. In the case of and doesn’t address the regulatory develop that. What would be ideal Novartis’ failed drug, Prexige, there strategies that one could actually use would be if those co-development have been whispers about the phar- in the co-development of a drug and programs were initiated earlier.” ma resubmitting the drug to FDA for companion test. “The last I heard is From the viewpoint of PMC, whose approval, but this time with a com- that the comments are going to be membership comprises a number of panion diagnostic test. If submitted written up more or less as the white

OCTOBER 2009 GENOME TECHNOLOGY 35

paper itself,” Frueh says, adding that drug therapy,” Frueh says. “Our fo- he thinks FDA should focus the cus is the translation of these tools paper on teasing out the clinical into clinical practice,” he adds. “We and strategic issues involved in the want to know how they’re going process. “But I don’t know what to perform, not just in one or two FDA is currently thinking about — highly skilled clinical settings,” but [whether they are] going to write in the broader sense. This will be a guidance, how that guidance is especially useful as more insurance going to look, and what it’s going to companies start covering the tests — say. … I know they want to do it, I it’s hard to determine whether or not just don’t know whether it’s going to a company should cover a test with- happen or not.” out a true measure of its prevention A significant incentive for drug of hospitalization, he adds. makers to co-develop a diagnostic Moreover, though uptake for re- is not only for preventing drugs that quired companion diagnostics has will ultimately fail, but also because been good, most doctors still don’t FDA approval might come more eas- know enough about the field to feel ily. “The approval of the drug is STEPHEN LITTLE comfortable ordering recommended potentially more imminent with a tests. Medco recently conducted a diagnostic because they can show people with non-mutated forms of nationwide physician survey that it’s working,” Asuragen’s Berry says. the K-RAS gene. reached about 400,000 doctors. However, matching up timelines It’s unclear, however, how use- While 98 percent agreed that ge- and understanding the separate ful updating labels with recom- netics is important for drug therapy, regulatory processes between drug mended or informational items will only about 10 percent said they felt manufacturers and diagnostic com- be. While warfarin labeling now adequately informed about it. Addi- panies could prove daunting. “All includes FDA-recommended geno- tionally, about 12 percent said that of us are navigating through these typing for mutations in two genes they’ve been ordering a genetic test various organizations and entities that cause increased susceptibility over the last six months and about at the FDA and trying to understand to bleeding, the label doesn’t require 25 percent indicated that they’re what is the best way to develop a it. Many industry insiders have said planning to order genetic test. “So diagnostic test that could go with a that stronger labeling is needed to you see there is tremendous growth drug,” Berry says. make sure the tests are actually used potential,” Frueh says. “It really all That’s not to say that FDA hasn’t to guide dosage when prescribing points to a lack of education, a lack made inroads. Changing drug la- warfarin. of penetration with respect to get- bels to include various types of ting the information about these pharmacogenetic information is Down the line tests.” becoming more prevalent. Of the Little at DxS predicts a move from 40 or so drugs that are associated While co-development strategies “cytotoxics toward targeted thera- with diagnostic tests, FDA requires and regulatory issues are big wrin- pies” when it comes to cancer drug a companion diagnostic test to be kles to be ironed out, what eventually development, while Tolias see more used for only about five. Some drugs matters is whether or not doctors use protein markers being used. Now, have updated labels that include the tests. And though development it’s mostly genetic markers — tests recommendations to use a test — has taken off in terms of proving that look for SNPs or some form of warfarin being an example — while certain tests’ efficacy in clinical trials, structural variation — but proteins the majority only have updated in- proving real-world success isn’t as could take the field much further. formation about the possible genetic cut and dry. Frueh’s work at Medco “What you ultimately want is not link to side effects and optimal dose. involves this sort of outcomes re- necessarily just something that pre- Peter Tolias says, “You’re going to search, for which the company just dicts risk but something that’s caus- see this trend increasing.” In fact, finished enrollment for two clinical ative, and a lot of these markers are in July, FDA changed the labeling trials. Research “focuses on estab- risk predictors, but they don’t actu- of colon cancer drugs Erbitux and lishing the clinical effectiveness for ally tell you that you’re sick at that Vectibix to be prescribed only to the use of biomarkers to optimize time,” says Tolias. N

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SEQUENCING Humans as Host

Participants are calling the Human Microbiome was formed to foster collaboration and data-sharing among member Project a second Human Genome Project. The countries. In the United States, the National Institutes of Health recently massive global effort aims to get to the bottom launched a five-year, $140 million Human Microbiome Project, mod- of the relationship between microorganism and eled after the Human Genome Proj- ect, to better understand how the host, and disease and health. human microbiome affects human health and disease. This project had been in the wings for a while, Weinstock says, but tech- BY CIARA CURTIN we’re right at the very, very begin- nology and tools hadn’t caught up ning of an extremely exciting era to the idea. “Then, four years ago or he exact num- where we’re going to make connec- so when next-generation sequencing ber of bacte- tions between things that we waved methods started coming and they also ria living in our hands about in the past or didn’t became highly adaptable for microbial or on humans understand or may not have even genomics, you had the development isn’t known, focused on.” of the perfect storm where there was though it is Researchers have been studying the a large microbial project just waiting estimated to flora living in and on the human body there to be done,” he says. Tbe around a trillion. In any case, the for decades. The problem, however, is number of microbial cells in the hu- that most of the bacteria that can be The known biome man body outnumbers the human seen peering through a microscope ones by a factor of 10. Those symbi- stubbornly refuse to grow on Pe- Despite the lack of funding focus on otic microbes endow humans with tri dishes in microbiology labs. Still, the human microbiome until recently, otherwise unattainable metabolic ca- scientists slogged through and man- researchers have been whittling away pabilities, but also may contribute aged to link these microorganisms to at the microbiome’s unknowns: How to human disease. What is certain, everything from cirrhosis to irritable is it established? How similar is it however, is that humans may really be bowel syndrome to autism. Recently, between individuals? How diverse is classified as super-organisms — and though, the human microbiome has it? How does it affect human health? ones that are mainly bacterial at that. been lavished with attention and “This was of great interest at least to “There’s a huge amount of gene funds. Now, genomics approaches are me and my colleagues elsewhere prior activity [in the human body] that’s being applied to identify the bacteria to the NIH Roadmap Program,” says being carried out by microbes,” says lurking in and on the human body. Stanford University’s David Relman. George Weinstock, associate director Knowledge from what is being called In 2007, Relman and his colleagues of the Genome Center at Washing- the “second Human Genome Project” followed 14 babies — including a ton University in St. Louis. “There will be able to inform clinicians pre- set of fraternal twins — as well as just has to be a very large impact of viously stymied by the cause of a dis- their mothers and most of the fa- all of that microbial genetic activ- ease or a patient’s response to a drug thers during the babies’ first year. ity on both healthy body as well as treatment. Organizations around the The researchers profiled 16S rRNA when pathological conditions set in world have poured money into this sequences from the participants’ stool different parts of the body. I think work — an international consortium samples using a specialized micro-

38 ______WWW.GENOMEWEB.COM OCTOBER 2009 PHOTOGRAPH BY BOB BOSTON FOR GENOME TECHNOLOGY

WASHINGTON UNIVERSITY’S GEORGE WEINSTOCK

array and sequencing in an effort sulfur for acetaminophen to go down to determine how the microbiome that metabolic pathway. “Even Tyle- is established. And it arises quickly. nol is affected by your gut microbe By the end of a week, Relman says, activity,” Nicholson says. there are a surprising number of Of course, some drugs are meant taxa present, and a prominent source to affect the microbiome. Antibiotics of microbiota for each baby was its act broadly on bacteria and disturb mother. At the end of a year, the ba- the microbiome. Last year, Relman bies’ microbiome is adult-like and is, and his colleagues studied the effect for the most part, distinct from each of a five-day course of Ciprofloxacin other and the adults. “The one pair of on healthy human gut communities. twins that we had in our group, they “What we saw was a return to es- were shockingly similar at any given sentially the same community after time during that first year, one to the about four weeks of time, but there other,” Relman says. DAVID RELMAN are some exceptions,” Relman says. Relman and his colleagues, includ- “The exceptions might be important.” ing the J. Craig Venter Institute’s phyla living on the skin, though most There were microorganisms that Karen Nelson, also characterized the belonged to Actinobacteria, Firmicutes, hadn’t returned by the end of four diversity of the adult microbiome. In Proteobacteria, or Bacteroidetes. Like months and others that were more 2005, they analyzed the 16S rDNA Relman and Nelson, Segre saw great- abundant than they had been. “It’s of mucosal and fecal samples from er diversity at the species level. hard to say if that’s important or what three healthy human adults, finding She also noted that some bacteria the long-term consequence might be, 244 novel bacterial phylotypes. Most prefer certain body sites, such as se- but we’re now looking at longer time of the organisms they found belonged baceous sites. “They are very different periods of follow-up,” Relman says. to one of two phyla, the Firmicutes in terms of properties, whether they As in-depth as the studies have been, or the Bacteroides. “That work also have hair, whether they have sweat they have merely skimmed the top pointed out that there was a lot of this glands, and it turns out that those layer of what’s to be found in the mi- micro-diversity within populations,” factors end up really influencing what crobiome. A deeper look is still ahead. Nelson says. It’s been described as a [is there],” Segre says. tree with thick limbs that branch into By following up on five of the vol- Sequencing the tiny twigs at the ends. unteers, Segre also found that the microbiome Then in 2006, they kicked off the skin microbiome is fairly stable. The metagenomics age of microbial stud- volunteers were significantly more One of the main tools being used ies by shotgun-sequencing the distal similar to themselves than to the in the Human Microbiome Project is gut microbiome of two healthy adults other participants. the sequencer. The first phase of that — a study affectionately known as In other research, Imperial Col- project is to develop tools to support the HuPoop Project. “Using Sanger- lege London’s Jeremy Nicholson has further research into the microbiome. based approaches, [we] could see a found that the microbiome affects For that phase, four sequencing cen- significant amount of microbial di- how people respond to drug treat- ters — Baylor College of Medicine, the versity in those two samples,” Nelson ment. “The bugs make compounds Broad Institute, JCVI, and Washing- says. “I think that everybody realized that are actually competitive with ton University — have been working from that study that there’s a tremen- drugs for metabolism,” he says. on sequencing bacteria from healthy dous amount of diversity in human Recently, in an August issue of individuals and 200 bacterial refer- that has yet to be tapped into.” PNAS, he and his colleagues found ence genomes. Naturally, studies haven’t focused that the chemical p-cresol, produced That first prong was originally to solely on the gut. The National Hu- by gut microflora, affects how people take samples from 250 healthy vol- man Genome Research Institute’s metabolize Tylenol as both p-cresol unteers between the ages of 18 and Julia Segre characterized the skin and acetaminophen undergo sulfona- 40 at various body sites — 15 sites microbiome by taking samples from tion. Some people have microflora for men and 18 for women — to try 20 different skin sites on 10 healthy that are more active in cresol produc- to get a description of the human people. Also from 16S rRNA, she tion than others, and when they take microbiome. Now, that number of and her colleagues found 19 bacterial acetaminophen, there isn’t enough volunteers has been upped to 750.

40 ______WWW.GENOMEWEB.COM OCTOBER 2009

between individuals.” According to Baylor College of Medicine’s James Is There a Core Human Microbiome? Versalovic who is coordinating the clinical efforts for this phase of the Part of the Human Microbiome Project aims to determine whether there is a project, more than 150 people have core human microbiome that all people share. Right now, whether there is one or been sampled. not is a matter of some controversy. And then, if there is, there’s the matter of reso- The 12,000 samples from the par- lution — how far down the taxonomy ladder do you have to go? What percentage of ticipants are a mixture of bacteria, people must have the group for it to be “common”? A few preliminary studies have prokaryotic microorganisms, and vi- suggested there is a core microbiome, but they are far from the full picture. ruses; the sequencing centers want JCVI’s Karen Nelson isn’t convinced there is a microbiome common to all to do a sort of census to determine people. Early studies, she points out, were limited to North Americans. “I think that what microbes are there and in what once we start to get out and do broader sampling, we will have a better feel,” she quantities. One way to do a head- says. count of the bacteria, Weinstock says, “To some extent, the question is: how big is the core group of organisms?” says is to sequence all the 16S rRNA in George Weinstock at Washington University in St. Louis. From years of medical the mixture. “[16S] is the functional microbiology, he says that “we know that for certain parts of your body, there are equivalent of a barcode for an organ- certain organisms that we’re pretty sure are going to be there.” ism,” says Doyle Ward at the Broad However, Baylor’s James Versalovic and Stanford’s David Relman add that there Institute. That barcode can then be is not even a deﬁnition of “core” just yet. analyzed and compared against ref- RIKEN’s Todd Taylor says the issue depends largely on resolution. “If you are erence genomes to determine what talking globally, at the strain level, I’d guess no. If you are talking more locally, say bacteria are present. within Japan, at the strain level, maybe, at the genus level, almost certainly,” he The centers have been working to- says. “There are many factors that need to be considered in the core microbiome gether to establish rigorous methods question, such as, one, are we talking about genes or species; two, if species, at for deeply surveying community com- what level: genus, species, or strain; or, three, if geographic, in what range: global, position by sequencing and analyzing continental, country, state, local, or some other region?” 16S sequence. In particular, Ward is Versalovic says he thinks there is a core microbiome but agrees it is a matter of developing methods to do this work resolution. “When you say there is a core, does that mean that E. coli, for example, on the 454 Titanium platform, as well is present in more than 50 percent of people or does that mean that E. coli is pres- as new analytical tools. One example ent in 80 percent of people?” he says. “I take a somewhat liberal perspective on is ChimeraSlayer, which detects chi- this. More than 50 percent is probably enough.” meras in 16S data. He is currently Now with sequencing, more species can be found than before using culture working on adapting it for 454 data. plates. “The question then becomes: is the core just a handful of organisms, and However, looking at 16S rRNA then there’s a lot of variation after that, or are there really quite a few additional doesn’t answer all the questions. organisms that are non-culturalable that are also frequently found in body sites?” Weinstock says that while 16S rRNA Weinstock says. Furthermore, he adds that there could be more than one core gives a good idea of a bacterium’s rela- group for a particular body site, based on environmental factors. tive abundance, it doesn’t take vastly Then for a particular body site, one set of people might have one group of organ- different strains of the same bacteria isms and another have a different set of organisms. “There might be more than one into account. For example, he says type of core that people can have,” Weinstock says. that through 16S sequencing, E. coli “In some way, shape, or form, it would be nice to know what, if anything, we all look the same. Some E. coli strains, share that determines the ability of our communities to promote health or be as- such as the K12, are benign but others sociated with health,” Relman says. are not — in 1993, the O157:H7 strain killed four people who ate at Jack in the Box restaurants in the western “The ﬁrst goal ought to be to have crobiome should go far beyond any- US. In their gene content, those two some description of human micro- thing that has been done so far and to strains differ by about 1,000 genes. biome that could be comparable to really help to answer some of the very “Work that we’ve done looking at the working draft of the human ref- basic questions about our different other environments has shown that erence sequence,” Weinstock says. microbiome communities in different organisms can have identical 16S se- “That description of the human mi- parts of the body and how they vary quences, but have wide variation in

OCTOBER 2009 GENOME TECHNOLOGY 41

their genome content,” Nelson adds. also in terms of pain perception,” he Shotgun analysis of the DNA sam- says. “There are some data that some ples, on the other hand, will catch bacteria that normally live within us those virulence factors and other actually affect the nervous system and genes of interest. Since assembling the ways that, for example, transmis- genomes from that mix is very hard to sion of pain and reception of pain and do, Weinstock says that each of those pain signals may be processed.” sequences is analyzed to determine The University of Michigan’s Vin- what genes are present in the commu- cent Young and his colleague, mi- nity. “That’s what allows you to detect crobial ecologist Thomas Schmidt toxins and things like that,” he says. at Michigan State, have both been This approach also allows research- studying the gut microbiome for a ers to determine whether any eu- decade; they received a $1 million karyotes or viruses are also present. grant to study ulcerative colitis, a “The metagenomic approach allows JAMES VERSALOVIC bowel disease marked by abdominal us to really delve into the question pain, gurgling, and diarrhea. of how much genetic diversity there and pilot programs, the Broad has Nelson is working with New York is in these populations,” Nelson says, sequenced 150 microbial genomes University’s Zhiheng Pei on esopha- adding that it also avoids introducing and recently received an award to geal cancer. “Our preliminary work biases inherent to other approaches. sequence at least 200 more. has suggested that you can see a cor- Data derived from those healthy Data from these large-scale projects relation with various microbial popu- volunteers then needs to be compared are continually being released and up- lation and the onset and development to something to tell just what their dated. “We actively try and release data of esophageal cancer,” Nelson says. microbiomes contain. In addition as quickly as possible,” Nelson says. She is also collaborating with NYU’s to sequencing people’s microbiome, Martin Blaser to study psoriasis, a the four sequencing centers are also Funding the condition in which skin becomes tasked with creating reference bac- smaller scale salmon-colored, scaly, and raised. terial genomes. “We are going to Another project comes out of Segre’s sequence, overall, about 1,000 mi- With the first large-scale phase of lab at NHGRI and will be studying crobial references genomes,” Nelson the Human Microbiome Project un- the relationship between the human says. Through the Human Micro- der way, the second phase — smaller- immune system and the microbiome. biome Project, JCVI has received $8.8 scale projects — is now beginning. “The NIH Clinical Center has a lot million in American Recovery and NIH has awarded $21.2 million for of patients who are immunocompro- Reinvestment Act funding to do just these demonstration projects, and mised. So we’re looking at patients that. Baylor received $3.7 million and program officially kicked off in June who are immuno-deficient and see- WashU was awarded $16.1 million. of this year. Many of these new proj- ing how specific immunodeficiencies But which lucky microorganisms ects focus on health and disease, but affect their microbiome,” Segre says. will be sequenced? “The centers in some will also look into technology “We just don’t know that much about the consortium arrived criteria that development. “Fifteen new principal our relationship between our human we tried to apply to our selections,” investigators that are from different cells and our microbial cells.” the Broad’s Ward says. Those criteria institutions in the United States are On the tool development end of the emphasize phylogenetic uniqueness now funded by NIH to pursue spe- spectrum, there is the University of and whether or not related organisms cific clinical projects,” says Baylor’s Colorado, Boulder’s Rob Knight and have been sequenced, as well as its Versalovic, who is the clinical coor- the University of Maryland’s Mihai dominance or abundance within its dinator of these projects. Pop. Knight has been given $1 mil- niche and whether it is associated For his own work, Versalovic is lion to develop computational tools. with health or disease. As the Broad studying irritable bowel syndrome in “What we have been doing is devel- has no microbiology lab, Ward says children between the ages of seven oping ways to compare communities they also rely on the clinical exper- and 12 with his $750,000 grant. and individuals with [a] large number tise of their collaborators to deter- “We think that bacteria have a role of sequences from each individual,” mine what would be interesting to to play — not only in the immune re- Knight says, as in the past few years sequence. Through the initial phase sponse, immunity inflammation, but the scale of the data has increased

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rapidly. He and his lab are developing be present in all cases of the disease, tools to make a phylogenetic tree from isolated from someone with the dis- 16S bacterial sequences and measure ease, cultured, and then cause dis- the distances between them. ease in a new host from which the Pop is working with Steven Salz- agent is then recovered. “Causation berg on a $780,000 grant to develop is a really tough nut to crack,” Rel- assembly and analysis tools for all the man says. “What has emerged so new data. “Essentially there is very far is a bunch of associations that little bioinformatics infrastructure no one can really be sure that the for metagenomics data,” Pop says. different-looking community is re- “In particular, there is I would say sponsible for, or whether it simply zero software available for assembly. is a result of, disease.” There are a lot of issues in gene find- Instead, he says, longitudinal stud- ing and binning.” ies will be needed in which people Also, Young and Schmidt will be JULIA SEGRE at risk for certain diseases, and their coming full circle and developing microbiomes, are followed over time. ways to “culture the unculturable,” of this research is for us to under- “You’re looking for an early change particularly of organisms near the stand how the meta-system — host, that predates the pathology,” Relman. mucosal lining of the intestines that microbes, viruses, other organisms, “That’s going to be tough. It’s doable, need low levels of oxygen. So far, metabolites, environment, et cetera but it’s going to take some really they have been able to grow organ- — works as a whole and to be able to smart clinicians getting together with isms that had only been identified predict how perturbations in the sys- some willing subjects and good sci- through molecular surveys. “One of tem impact the various parts,” RIK- entists and then being patient.” the reasons for doing that is that part EN’s Todd Taylor says. “This research In the long run, though, a swarm of the Human Microbiome Project, is still in its infancy. There is a long, of prebiotics and probiotics could they have a list of 600 organisms unpaved road ahead, that they want to get full genome but with persever- “The ultimate goal of this sequences, [but] they want more ance, hard work, and things to sequence,” Young says. “We innovation on the research is for us to understand thought that by doing this, we could part of the research- how the meta-system works as a generate more cultivars so that we ers involved, we will can do full-genome sequencing to discover many fasci- whole and to be able to predict understand how different members nating things along of a microbiota make their living.” the way.” how perturbations in the system With these new impact the various parts.” The practice of medicine tools, Segre says that the practice of medicine and diag- be developed to encourage a healthy The ultimate goal of diving into nosing and treating diseases will microbiome or to have an effect on a the depths of the human micro- change. “Now that we have the tools dysfunctional microbiome and bring biome is to make people healthier. to do it, we can start to look for the community into a better balance. If there is a core microbiome that disorders we previously hadn’t ex- “You might lack this important mi- most people have that keeps them pected to have microbial infections,” crobe — and there’s some evidence healthy (see sidebar, p. 41), then, Segre says. Baylor’s Versalovic adds now already that suggests there are as the story goes, perturbations to that they may be able to develop some key elements missing in pa- that community could be tracked new diagnostic test. tients with certain diseases — so we and correlated to disease. Then the However, Relman says it will be may have diagnostic tests that detect microorganisms behind the problem difficult to prove Koch’s postulates certain bacteria for human health could be targeted by therapies, or for a microbial community. Those and, when absent, indicate suscepti- prebiotics or probiotics could pre- postulates set the criteria that need bility to disease,” Versalovic says. ventively encourage the establish- to be fulfilled for an infectious agent “I really think that this is a big deal ment of a healthy microbiome. to be the cause of a disease. Namely, and I think it is going to have a very “In my opinion, the ultimate goal the agent or microorganism has to big impact,” Weinstock says. N

OCTOBER 2009 GENOME TECHNOLOGY 43

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PROTEOMICS Upstream

PROTEOMONITOR In addition to paying for the eight employees at the Proteomics Grant Supports Proteomics center and three staffers Notes who provide off-site sup- Synchrotron Work port from the university in DENATOR, a Swedish Cleveland, Ohio, the first- sample prep firm, is he Case chrotron Light Source, year allotment includes heading up a consortium Western Re- built in 1984 and operated funds for the purchase of that received $427,000 serve Univer- by the US Department of a new detector for the cen- from the EU EUROSTARS T sity School Energy, is located. ter’s X-ray spectroscopy PROGRAMME to of Medicine announced it Worldwide, there are program for investigations improve how human blood has been awarded a five- about 60 synchrotrons into metal atoms in pro- plasma samples year, $4 million grant from with hundreds of beamline teins at low concentrations are handled to help the National Institutes of facilities. The Case center and molecular structure advance the discovery Health to fund the school’s is one of six that receives around the metal, says of blood-based protein synchrotron center, where, NIH funding. Mark Chance, director of biomarkers. among other things, novel In the first year of the the center. proteomics approaches are grant, the center will re- The funding from NIBIB As part of the CHINESE being developed. ceive about $1.1 million, supports technology in HUMAN LIVER While synchrotrons have and in each of the four three technology cores PROTEOME PROJECT, historically been used in remaining years, it will at the center — the foot- researchers have identified chemistry and physics, receive about $750,000. printing core, based on the 6,788 liver proteins. In the life sciences, especially X28C footprinting beam- the Journal of Proteome protein-related studies, are line, provides facilities for Research, they also report increasingly finding value DATAPOINT the study of protein and a transcriptome data set of in the technology. The nucleic acid structure and 11,205 genes. grant, from NIH’s Nation- function, including in vivo al Institute of Biomedical studies. Mass spec-based BRUKER reports that it Imaging and Bioengineer- research, including novel has received $10 million ing, continues a history of proteomics approaches in- in orders from stimulus funding from the agency vented at the center, is also programs in the US, to the Case Center for $828 conducted at this core. Japan, and Europe, and it Synchrotron Biosciences THOUSAND The center also has a expected more NMR, stretching back to 1995. FUNDING FOR AN AUSTRA- macromolecular crystal- X-ray crystallography, The Case center is based lography core based on high-end mass LIAN PROJECT TO LOOK at Brookhaven National the X29 undulating beam- spectrometry, and other Laboratory in New York, FOR PROTEINS INVOLVED IN line. orders during the second where the National Syn- MULTIPLE SCLEROSIS — Tony Fong half of the year.

FUNDED GRANTS

$282,202/FY 2009 $365,200/FY 2009 METABOLOMIC INVESTIGATION OF BIOSIGNATURES MARKERS FOR HCV-RELATED HCC: PLASMA PROFILING, OF CHRONIC COCAINE EXPOSURE TARGETED STRATEGIES AND VALIDATION Grantee: Chi Chen, University of Minnesota, Twin Cities Grantee: Laura Beretta, Fred Hutchinson Cancer Began: Sep. 1, 2009; Ends: Aug. 31, 2011 Research Center In this work, Chen will use liquid chromatography/mass Began: May 1, 2009; Ends: Feb. 28, 2014 spectrometry-based approaches to identify small- Using her new method to quantify a complex proteome, molecule metabolites linked to chronic drug exposure Beretta and her colleagues will look for proteins and or drug addiction. Chen and his colleagues will analyze protein isoforms that differ between patients with changes to the metabolome due to chronic cocaine use hepatitis C virus-related cirrhosis that have progressed to identify biosignatures in rats. Then, they will examine to hepatocellular carcinoma and those with HCV-related how treatment affects those biosignatures. cirrhosis without HCC.

OCTOBER 2009 GENOME TECHNOLOGY 45

______

SEQUENCING Upstream

INSEQUENCE manner, he says. In April, Complete Genomics first Sequencing Complete Genomics Raises revealed that the closing Notes of its Series D round was $45 Million in Series D delayed, forcing it to cut LADATECH has filed costs. suit against ILLUMINA, n late summer, by six months, and the “Our timing could not saying that the sequencing Complete Genom- company now expects have been worse,” Reid vendor’s Genome Analyzer ics announced that to reach it by mid-2010, says. “We started this fi- and related products Iit had raised $45 says Complete Genomics nancing the day that Leh- and services infringe a million in private equity chairman, president, and man Brothers failed and patent originally assigned from a Series D fund- CEO Cliff Reid. The firm found that in Q4 and Q1, to GENELABS and now ing round, which closed is still targeting a price the private equity financ- held by LadaTech. The six months later than of $5,000 per human ge- ing world was really on patent was issued in 2000 originally planned. As nome for batches of ge- hold.” Only in early April and covers a “method a result, the company, nomes when the service did those companies start of amplifying a mixture which anticipates reach- launches. to move toward making of DNA fragments by ing profitability next year, The six-month push- new investments again, repeated linker/primer has pushed back its plans back is tied to the com- he adds. replication.” to launch its human ge- pany’s inability to raise The funding will be suf- nome sequencing service new funding in a timely ficient to launch the com- HELICOS from June 2009 to Janu- pany’s human genome BIOSCIENCES installed ary 2010. The funding sequencing service in two systems and recorded adds to the $46 million DATAPOINT January and to build and $371,000 in revenue that the company raised scale up its commercial during the second quarter, in three prior financing sequencing center, based according to its SEC rounds. in Mountain View, Calif., filings. As of Aug. 14, the The firm plans to se- over the first six months company reported having quence 10,000 human ge- of 2010 as the firm tran- $5 million in cash and nomes next year using its sitions from an R&D to equivalents. According to proprietary sequencing a services company, ac- Helicos President Steve NUMBER40 OF WORM technology. Previously, it cording to Reid. Lombardi, in late summer was aiming to sequence GENOMES RESEQUENCED Complete Genomics, the company had a total 1,000 human genomes by BY THE BEIJING GENOMICS which currently has about of seven instruments the end of this year and 120 employees, also plans installed, including four INSTITUTE TO DEVELOP A 20,000 in 2010. a “modest headcount in- “placements” by Helicos The “1,000 genome GENETIC VARIATION MAP crease.” and three systems ordered mark” has “slipped out” FOR SILKWORM. — Julia Karow by customers.

FUNDED GRANTS

$187,130/FY 2009 $232,500/FY 2009 PHYLOGENETIC BINNING OF CROSS-SPECIES MICROARRAY-BASED GENOMIC METAGENOMIC SEQUENCE DATA SELECTION: APPLICATION TO NONHUMAN PRIMATE Grantee: Eric Allen, University of California, San Diego Grantee: James Thomas, Emory University Began: Aug. 24, 2009; Ends: Jul. 31, 2011 Began: Jan. 15, 2009; Ends: Dec. 31, 2009 Allen and his team will use this grant to “develop new The plan for this grant is “to test and to demonstrate computational methods for large-scale taxonomic clas- the capability of a newly developed genomic technology, siﬁcation of metagenomic sequence data, applicable to microarray-based genomic selection” as a method to raw reads as well as assembled contigs” and “develop “use the available nonhuman primate genomic resourc- software and protocols to use taxonomic data binning es as a springboard for population-based genomic se- as a pre-treatment to increase efficiency of existing quencing in a greater diversity of species,” according to sequence assembly software,” the grant abstract says. the abstract.

OCTOBER 2009 GENOME TECHNOLOGY 47

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RNAi Upstream

RNAiNEWS to the use of siRNAs, 21 to 23 nucleotides in length, RNAi Notes UMass, Whitehead Fire New to target specific mRNA degradation in mammals. Australia-based Salvo in Tuschl IP Suit However, Tuschl-II in- BENITEC received a cludes claims on two- to notice of allowance he University Max Planck sued UMass, three-nucleotide-long 3’ from the US Patent and of Massachu- Whitehead, and the Mas- overhangs. Both are named Trademark Office for its setts and the sachusetts Institute of after former Max Planck application for the use T Whitehead Technology for allegedly researcher Thomas Tuschl, of multiple-promoter Institute for Biomedical Re- misappropriating certain an Alnylam co-founder expression cassettes search returned fire against RNAi inventions, most who is now a researcher at for simultaneous RNAi the Max Planck Institute notably the use of 3’ over- Rockefeller University. delivery. and Alnylam Pharmaceu- hangs on siRNAs, from Alnylam acquired the ex- ticals in their ongoing le- the Tuschl-II patent family clusive therapeutic rights SILENCE gal battle, counterclaiming and included them in pat- to the Tuschl-II family THERAPEUTICS that, among other things, ent applications from the from the IP’s sole owner, and DAINIPPON Max Planck inappropri- Tuschl-I IP estate. Max Planck, but shares SUMITOMO PHARMA ately sought to replace the Both Tuschl-I and therapeutic rights to the are collaborating to Whitehead-appointed law Tuschl-II generally relate Tuschl-I estate — invented work on an siRNA drug- firm overseeing prosecution at Max Planck, Whitehead, delivery system. Silence of the intellectual property MIT, and UMass — with will use its proprietary at issue in the case. DATAPOINT Merck subsidiary Sirna siRNA molecules with its UMass further argued in Therapeutics and, to a in-house AtuPlex delivery its counterclaim that a key limited degree, RXi Phar- technology. aspect of the disputed RNAi maceuticals. technology — the 3’ over- Alnylam and Max Planck SANTARIS PHARMA hangs commonly incorpo- maintained in their law- and British rated into siRNAs — was suit that if any Tuschl-II biopharmaceutical firm $ SHIRE will be using an inherent feature of the 672 inventions are included THOUSAND RNAi molecules described in Tuschl-I patents, Sirna, locked nucleic acid in a patent application filed AMOUNT A SUBSIDIARY OF RXi, and any other compa- technology to develop prior to another patent ap- NEW ZEALAND’S GENESIS nies sublicensing Tuschl-I drug candidates for rare plication from Max Planck RESEARCH AND DEVELOP- will “unfairly gain access genetic disorders. Shire that specifically claims the to the Tuschl-II property will be doing most of the MENT WILL RECEIVE TO DE- overhangs. without paying consider- development as Santaris The litigation began in VELOP SINGLE-STRANDED ation for a license.” expands its therapeutic June when Alnylam and RNAI TECHNOLOGY — Doug Macron program.

FUNDED GRANTS

$162,000/FY 2009 $282,600/FY 2009 GLYCOBIOLOGICAL ANALYSIS OF PLASMODIUM- DOUBLE-STRANDED RNA-MEDIATED SIGNALING VECTOR HOST INTERACTIONS PATHWAY AND GENE SILENCING Grantee: Rhoel David Ramos Dinglasan, Johns Grantee: Yi Liu, University of Texas Southwest Hopkins University Medical Center Began: Apr. 1, 2009; Ends: Mar. 31, 2011 Began: Apr. 1, 2009; Ends: Mar. 31, 2013 To identify protein-glycan interactions between Plasmo- With forward and reverse genetic approaches, Liu and dium ookinete and the mosquito midgut, Dinglasan and his lab plan to characterize the signaling pathway of his colleagues will use RNAi to knock down mosquito dsRNA-induced gene transcription. They will also study glycosyl- and sulfo-transferases and analyze midgut the role of DNA damage-induced small RNA. This “will glycoconjugates during Plasmodium infection. They will reveal the role and the mechanism of RNAi in DNA repair also study the knockout proteome with mass spec. and in maintaining genome stability,” says the abstract.

OCTOBER 2009 GENOME TECHNOLOGY 49

Upstream MICROARRAYS

BIOARRAYNEWS Launched last year, the Microarray GeneTitan enables users to Notes Affy Inks Deal with run expression-profiling assays in array plates de- EXIQON plans to out- Beckman for Custom Tools signed to process 16, 24, source the manufacturing or 96 samples. Now, the of all of its research-related ffymetrix and ers performing higher- chip maker plans to launch products, including its Beckman throughput studies. next-generation genotyping microRNA arrays, by the Coulter have It also comes at a time assays for use on the system beginning of next year. The A partnered when other array vendors this fall. Unlike the gene- move is part of restructur- to create an automated are looking to provide stan- expression assays which ing to cut costs and reach tool and protocol for ge- dardized target-preparation contained legacy content, profitability. nomic research that will options for their custom- Affy will enable users to pair Beckman’s liquid- ers as the size of projects survey newly generated cat- KINEXUS, a 10-year-old handling instrumentation increases. Agilent Tech- alog and customizable con- proteomics company with Affy’s menu of array- nologies, for example, tent using its genotyping based in Vancouver, BC, based assays. said recently that it plans assays as part of what both will begin offering custom- Under the terms of the to launch an automated Affy and its rivals predict ers the ability to screen deal, Affy and Beckman liquid-handling workflow will be a second round of kinases using its internally will co-develop Affy- in coming months. large genome-wide associa- developed protein kinase specific configurations tion studies. chip. The microarray will for Beckman’s Biomek FX Being able to streamline include at least 200 differ- Dual Arm Multichannel- DATAPOINT the front end of its as- ent human protein kinases. Span 8 Liquid Handler. say workflow is therefore The companies claim that “very important” for Affy, Researchers at the UNI- the combination of the according to President and VERSITY OF DUBLIN’s Biomek with Affy’s exist- CEO Kevin King. Smurfit Institute of Genet- ing array cartridge plat- “With automated target ics compared chimp and form as well its newer prep robotics in front of human protein and DNA GeneTitan instrument will $ our GeneTitan System, 6.2MILLION sequences to identify three provide a standardized our customers will benefit human genes that lack system containing all of NEW FUNDING RAISED from walk-away automa- orthologues in other spe- the components necessary BY WAFERGEN tion from prepared sam- cies. The work, published to run Affy genotyping and BIOSYSTEMS, MAKER ples all the way through in Genome Research, gene-expression assays. array processing and data OF GENE EXPRESSION suggests that the human According to Affy, the generation,” King said in a genes evolved from non- deal with Beckman will AND GENOTYPING statement. coding DNA. help fill a gap for custom- SYSTEMS. – Justin Petrone

FUNDED GRANTS

$370,800/FY 2009 $181,024/FY 2009 DEVELOPMENT OF RIP-CHIP METHODS AND TILED NONPARAMETRIC ANALYSIS OF REVERSE-PHASE ARRAYS TO IDENTIFY FUNCTIONAL ELEMENTS PROTEIN LYSATE ARRAY DATA Grantee: Michael Whitfield, Dartmouth College Grantee: Jianhua Hu, University of Texas MD Anderson Began: May 1, 2008; Ends: Apr. 30, 2011 Cancer Center Whitfield will use recombinant RIP-chip to study how Began: Aug. 1, 2009; Ends: Jul. 31, 2011 RNA-binding proteins mediate gene expression on a To enable more reliable analysis of protein lysate arrays, genome-wide scale. He will identify the cis-acting regula- Hu will use a “monotone nonparametric response curve tory sequences in mRNAs bound by specific RNA-bind- to all samples on the same array,” according to the ing proteins by using limited nuclease digestion and tiled abstract. This includes “modern shrinkage ideas in sta- mRNA arrays, and then will determine which miRNAs tistics” to improve quantification and using “wild-boot- associate with the argonaute family of proteins. strap” to assess uncertainties in protein concentrations.

50 ______WWW.GENOMEWEB.COM OCTOBER 2009

BIOINFORMATICS Upstream

BIOINFORM open up a bit, including the non-profit Sage Bionet- Bioinformatics Pharma Calls for a works, founded by former Notes Merck scientists, which Pre-competitive Approach plans to build a pre-com- SYMYX TECHNOLOGIES petitive platform for an- established a new software hile large ning to embrace this idea, notated models of human research and development pharma- and that for some firms, disease; the cross-indus- center in Bangalore, India. ceutical “the focus has moved try collaborative initiative The company plans to hire W firms from the vigorous pur- Pistoia Alliance, which is 30 to 35 staffers for the aren’t known for being suit of intellectual prop- developing standards for center. generous with their data, a erty towards exploration non-competitive aspects of small group of pharma sci- of pre-competitive cross- the drug-discovery work- CLINICAL TRIALS entists is looking to change industry collaborations flow; and the European &SURVEYS that perception with a call and engagement with the public-private Innovative CORPORATION, a for pre-competitive bioin- public domain.” Medicines Initiative, a col- privately held clinical trials formatics projects and en- The paper comes in the laborative effort in which management firm, is set to hanced data sharing in the wake of several initia- several pharmas are pool- make raw and processed industry. tives that aim to encour- ing resources in hopes of genomic data available In an opinion piece pub- age pharma scientists to lowering the overall costs to clinical researchers as lished in the September is- of drug development. part of its StudyCTMS sue of Nature Reviews Drug The borders around this database. Under the Discovery, computational DATAPOINT emerging pre-competitive program, C-TASC will biologists from AstraZen- informatics space have yet accept gene data from eca, GlaxoSmithKline, and to be defined, the authors investigators in either raw Pfizer argue that “high- of the Nature Reviews paper or processed format for quality, open and acces- wrote, but noted that a upload. sible data are the foun- first step is creating public- dation of pre-competitive $ private partnerships that Scientists at VIRGINIA research, and strong pub- 14.3 can expand on existing TECH will use a three-year, MILLION lic-private partnerships public resources to create $1.4 million grant from have considerable poten- AMOUNT THE EUROPEAN “a series of foundational the NATIONAL SCIENCE tial to enhance public data BIOINFORMATICS INSTI- informatics resources.” FOUNDATION to expand resources, which would TUTE RECEIVED FROM THE In addition, pharma GenoCAD — a user-friendly benefit everyone engaged firms need to explore new software package that UK’S BIOTECHNOLOGY AND in drug discovery.” types of IT infrastructure enables scientists to They add that many com- BIOLOGICAL SCIENCES and tool development.” design genetic constructs panies are already begin- RESEARCH COUNCIL — Vivien Marx using a genetic “parts list.”

FUNDED GRANTS

$1,063,773/FY 2008 $135,000/FY 2009 TEXT MINING INFRASTRUCTURE FOR THE ENTIRE REPLICA EXCHANGE STMD FOR CHARMM: A POTEN- BIOLOGICAL LITERATURE TIALLY LARGE ADVANCE IN BIOPHYSICAL COMPUTING Grantee: Gully Burns, University of Southern California Grantee: Thomas Keyes, Boston University Began: Sep. 1, 2009; Ends: Aug. 31, 2012 Began: Sep. 1, 2009; Ends: Aug. 31, 2011 This grant will fund the construction of SciKnowMine, This award supports continued development of the a shared computational framework that “scales up CHARMM biosimulation application. The project aims processing large datasets across different communities to add the capability to use replica exchange statistical through the automated mining of text, images, and other temperature molecular dynamics. The STMD algorithm amenable media at the scale of the entire literature.” The and its extension to replica exchange “have substantially system will support the actions of bio-curators through a outperformed competing enhanced sampling algorithms generic set of Web services that can be specialized. in all tests,” the abstract says.

OCTOBER 2009 GENOME TECHNOLOGY 51

PGx & Downstream MOLECULAR Dx

PHARMACOGENOMICSREPORTER much as one or two years. According to Celera PGx & Molecular Celera Hones Panel for spokesperson David Dx Notes Speechly, results from the Non-Small Cell Lung Cancer most recent study involving A genome-wide asso- the lung cancer diagnos- ciation study published elera has vali- it was “expediting” com- tic confirm the company’s in the Journal of the dated its mass mercialization of its mass “indirect” biomarker dis- American Medical As- spectrometry- spectrometry-based lung covery approach by look- sociation reports that the C based approach cancer test. ing at lung cancer tissue CYP2C19*2 variant of the for identifying circulating Celera estimates the from surgical resections, cytochrome P450 gene protein biomarkers that test would be launched lung tumor cell lines, and influences Plavix response detect non-small cell lung by 2012. The test would the medium that the cell and treatment outcomes. cancer at all stages and is have been launched much lines were grown in. Researchers at the UNI- currently in the process of later were it not for these “Typically, in the detec- VERSITY OF MARYLAND deciding whether to com- promising preliminary re- tion of markers that are SCHOOL OF MEDICINE mercialize a prognostic as- sults, which allowed the present at higher levels in studied more than 400 say based on a six- or a company to move up com- the serum, one would use Amish people to find genet- nine-protein marker panel. mercialization plans for mass spectrometry to in- ic variants that affect drug In collaboration with the lung cancer test by as terrogate the serum itself response. the New York University and compare the results Langone Medical Center, from serum of lung cancer NANOSPHERE has filed Celera recently announced DATAPOINT patients with serum from a 510(k) application to the that it had replicated a healthy smokers,” Speech- US FOOD AND DRUG “novel mass spectrometry- ly says. In contrast, Cel- ADMINISTRATION for based approach to identify era’s approach “provides marketing clearance of its and validate circulating much less complexity for Verigene SP Respiratory protein biomarkers that the mass spectrometry Virus Assay, which detects detect NSCLC in an inde- analysis.” influenza and respiratory pendent cohort of individ- Celera’s clinical analyses syncytial virus. GENEUITY2 CLINICAL uals with lung cancer.” have resulted in the vali- Celera presented results RESEARCH SERVICES VALI- dation of a nine-biomarker In a study of type 2 diabetes from early studies in April DATED AND LAUNCHED immunoassay on patient in central Indiana, BIO- at the American Associa- TWO ASSAYS TO SCREEN samples with Stage I SERVE will provide clinical tion for Cancer Research NSCLC, which may be biosample and other servic- PATIENTS FOR KIDNEY DAM- annual meeting. Based on able to detect disease in es to the FAIRBANKS IN- results from these studies, AGE FROM DRUGS IN CLINI- the earliest stages. STITUTE FOR HEALTHY Celera said at the time that CAL DEVELOPMENT. — Turna Ray COMMUNITIES.

FUNDED GRANTS

$390,000/FY 2009 $746,861/FY 2009 METABOLOME AND PROTEOME PROFILES OF VALIDATION AND EXTENSION OF AN EXISTING RISK EMPHYSEMA AND AIRWAY DISEASE MODEL FOR LUNG CANCER Grantee: Russell Paul Bowler, National Jewish Health Grantee: Carol Etzel, University of Texas, Began: Apr. 9, 2009; Ends: Mar. 31, 2013 MD Anderson Cancer Center NHLBI issued this grant to determine a possible molecu- Began: Aug. 12, 2009; Ends: Jul. 31, 2011 lar basis for the different smoking-related phenotypes This NCI grant will allow Etzel’s team to build on an under the umbrella of chronic obstructive pulmonary epidemiologic risk model for lung cancer by incorporat- disease. Bowler will use “proteomic and metabolomic ing a genetic biomarker and then assessing it in 1,000 approaches to identify new plasma biomarkers that cases and 1,000 controls. The assay to be studied, the are associated with COPD phenotypes” and then study cytokinesis-block micronucleus assay, measures chro- those biomarkers further, says the abstract. mosome damage and other cellular events.

52 ______WWW.GENOMEWEB.COM OCTOBER 2009

Q&A: SANJIV SAM GAMBHIR Downstream

Innovation Through Imaging Sanjiv Sam Gambhir discusses how systems biology approaches and biomarker research are shaping the way imaging is used in detecting early-stage cancer.

anjiv Sam Gambhir is the in early cancer. The ultra- plexable molecular imaging director of the Molecular sound is imaging the lo- strategies, one can really Imaging Program and the cation molecularly of new make a significant shift in Canary Center for Can- blood vessels that are feed- earlier detection of disease. Scer Early Detection, both ing the cancer. at Stanford University. GT’s Jeanene Another strategy we’re de- GT: How does molecular Swanson spoke with him about how veloping is based on pho- imaging make use of biomolecular imaging is changing the way toacoustic imaging. The marker research? disease is detected and treated. What idea here is that light goes SSG: Molecular imaging is follows are excerpts of that conversa- in, interacts with imag- SANJIV SAM a lot like the field of drug GAMBHIR tion, edited for space. ing agents, and produces development; that is, you sound. The advantage of that is you have to start with a molecular target. GENOME TECHNOLOGY: What role now can develop imaging agents that In order to build imaging agents spe- does imaging play in early disease can leave blood vessels and go and cific for that target, you [have] got to detection? interact with molecular targets on the know what target to go after. Now, SANJIV SAM GAMBHIR: We feel surface of cancer cells. we don’t need the target to be able that molecular imaging will have a A third technique is Raman mo- to control the cell because we just significant role in the early detec- lecular imaging. In Raman imaging, want to detect it — not treat it — but tion of cancer. Right now, we see it light goes to a target tumor site, sometimes the targets are the same. as the three I’s: identify, isolate, and interacts with an imaging agent that How do we go after different mo- intervene. The ‘identify’ is a low-cost scatters the light, and we detect the lecular targets? We do our own screening test that involves blood bio- Raman scatter. And that ends up biomarker discovery: we look for, markers or urine biomarkers. ‘Isolate’ being very sensitive. We can take ad- in tissues, what biomarkers are on is where imaging comes in, to isolate vantage of systems biology in that we the surface of cells [or] within cells where in the body that disease is, if, can do multiplexing, we can target that make them unique from nor- in fact, the blood test was correct. many different molecular events and mal cells. We sometimes leverage off Then you go to the third ‘I,’ which see a separate signal from each one. of biomarkers being discovered by is to ‘intervene.’ You do it at such an One of the problems with molecular the pharmaceutical industry. In each early stage you’re able to much more imaging is it’s not highly multiplexed case, the idea is that we’re able to find effectively treat the disease. — you can interrogate one thing at a biomarkers that we can build imag- time, maybe a couple things at a time. ing agents towards, and a lot of the GT: What new techniques are you With Raman, we can interrogate 20 same techniques — proteomics for working on? [or] 30 things simultaneously. In Ra- discovering biomarkers in the blood SSG: We’re developing several new man, light gets scattered inelastically. — have been also used for finding strategies that are designed to detect Inelastic light scattering can allow biomarkers in tissue. much smaller disease foci than what you to interrogate different proper- Systems biology and other pro- is currently possible. One strategy is ties of the tumor, for example. teomics techniques are helping us using ultrasound. You can inject into The hope is that by syncing the low- also to understand which biomarkers the body bubbles and the bubbles cost screening through blood test- we should target from an imaging are targeted to blood vessels growing ing to highly sensitive, highly multi- perspective. N

OCTOBER 2009 GENOME TECHNOLOGY 53

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CASE STUDY Downstream

The Peptide Blockade Scientists demonstrate that novel peptides can block HIV infection by targeting protein-protein interactions. By Jeanene Swanson

cientists have used Gellman says. “For a macromolecules like molecular engineer- number of years, we’ve proteins. Smaller pep- ing techniques and a been interested in try- tides work better, but follow-up cell-based as- ing to take inspiration they’re broken down Ssay to block HIV entry from proteins to create faster by enzymes in into cells. In their work, published new kinds of molecules, the body and so need in August in the Proceedings of the basically by using dif- to be administered of- National Academy of Sciences, they ferent kinds of build- ten and in large doses. took advantage of the fact that engi- ing blocks, in our case Gellman’s foldamers neered peptides can stably interact B-amino acids instead SAM GELLMAN are useful in that the with cell surface proteins to block of A-amino acids.” two-stage design ap- HIV infection of cells. In the future, Their synthetic peptides, which proach he employed — first creating the technique could be used as an they’ve named foldamers, make a a B-peptide and then chemically “ri- alternative to current therapies that modest tweak to the backbone of gidifying” the backbone — created rely on antibody-based drugs, says the amino acid that ends up having peptides that are more resistant to lead author Sam Gellman, a chem- a large functional effect. Instead of natural degradation. ist at the University of Wisconsin, one carbon at the heart of the mol- In a cell-based assay using one Madison. ecule, which is called an A-amino T-cell-line-adapted strain and three For many viruses — including acid and is the usual structure, they primary isolates of HIV, the Cor- HIV, influenza, Ebola, and the se- engineered the amino acid to have nell team showed that the peptides vere acute respiratory syndrome vi- two carbons. These beta amino ac- prevented infection of a TZM-bl cell rus — protein-protein interactions ids change the shape of the result- line. Although it is not clear that between viral and host proteins are ing peptide, which they then used the foldamers themselves could ever important for the virus to be able to bind to a crucial HIV membrane be used as anti-HIV drugs, Gell- enter the cell it infects. In this fusion protein, gp41, locking it into man says, their study proves that study, Gellman’s team created a set place and preventing it from letting using modified peptides to disrupt of peptide-like molecules that were the virus enter the cell. protein-protein interactions is a new then used to successfully block HIV “So essentially there’s the potential way to think about designing mol- infection in human cells in an in vit- for a parallel universe of beautifully ecules for antiviral therapies and ro cell-based assay. The assay work complex, folded molecules of either other biomedical applications. was done by Gellman’s collabora- pure B-amino acids or mixtures of He hopes that his method will both tors, John Moore and Min Lu at the A- and B-amino acids,” Gellman enlighten the field and be broadly Weill Medical College of Cornell says. applicable in the future. “Perhaps University. In the past, attempts to prevent you could create things that would “If you look at biological systems at infection by interfering with host- mimic the recognition surfaces dis- a molecular level, it’s clear that what cell protein-protein interactions played by proteins and then use nature tells us is you want big, folded have not had widespread success, he those things, as we use them in this molecules to do complicated tasks, says. Because most drugs are small [paper] — to block biomedically not the small molecules that most molecules, they’re not very effective important protein-protein interac- organic chemists tend to work with,” at disengaging interactions between tions,” Gellman says. N

OCTOBER 2009 GENOME TECHNOLOGY 55

Events MEETINGS AND DEADLINES

Conferences

DATE CONFERENCE ORGANIZER LOCATION CATEGORY Oct 4-7 AIRI Annual Meeting Association of Seattle General Independent Research Institutes Oct 5-6 Critical Assessment Northwestern University Chicago, Ill. Bioinformatics of Microarray Data Analysis Oct 5-7 Clinical Proteomic Technologies for NCI Bethesda, Md. Proteomics Cancer Annual Meeting Oct 5-8 International MGED Meeting TGen Phoenix, Ariz. Genomics Oct 6-9 NIH Research Festival NIH Bethesda, Md. General Oct 17-21 Neuroscience 2009 Society for Neuroscience Chicago Neuroscience Oct 20-24 ASHG Annual Meeting American Society of Honolulu Genetics Human Genetics Oct 27-30 Genome Informatics Cold Spring Harbor Cold Spring Bioinformatics Laboratory Harbor, NY Oct 29-31 11th International EMBL European Molecular Heidelberg, Student PhD Student Symposium Biology Laboratory Germany Nov 2-4 Discovery on Target CHI Boston Pharma Nov 9-10 Burrill Personalized Medicine Meeting Burrill & Company San Francisco Personalized medicine Nov 9-11 Northeast Regional Life Sciences Cornell University Ithaca, NY Core labs Core Directors Meeting Nov 16-17 The Science of Biobanking CHI Philadelphia Clinical Nov 18-19 Personalized Medicine Conference Harvard Partners Center Boston Personalized medicine Nov 19-22 AMP Annual Meeting Association for Molecular Kissimmee, Fla. Clinical Pathology Dec 5-9 ASCB Annual Meeting American Society San Diego Cell biology for Cell Biology

2010 Jan 4-8 Paciﬁc Symposium on Biocomputing Big Island, Hawaii Bioinformatics Jan 9-13 Plant and Animal Genome Meeting XVIII Scherago International San Diego Genomics Jan 11-15 PepTalk CHI San Diego Proteomics Feb 3-5 Molecular Medicine Tri Conference CHI San Francisco Translational Feb 18-22 AAAS Annual Meeting AAAS San Diego General Feb 24-27 Advances in Genome Gcorp Marco Island, Fla. Genomics Biology and Technology Feb 28-Mar 5 Pittcon 2010 Pittsburgh Conference on Orlando Proteomics Analytical Chemistry and Applied Spectroscopy Mar 7-10 US HUPO US HUPO Denver Proteomics Mar 18-20 AUTM 2010 Annual Meeting Association of University New Orleans, La. Tech transfer Technology Managers Mar 20-23 ABRF 2010 Association of Sacramento, Calif. Core labs Biomolecular Resource Facilities Apr 17-21 AACR 101st Annual Meeting AACR Washington, DC Cancer Apr 20-22 Bio-IT World Conference & Expo CHI Boston Bioinformatics Apr 24-28 Experimental Biology AFMR Anaheim, Calif. General

56 ______WWW.GENOMEWEB.COM OCTOBER 2009

MEETINGS AND DEADLINES Events

Deadlines

OCTOBER 1 Application the dynamics of the scien- $1,000 GENOME. The possibly transforming ap- deadline for the NIH grant, tiﬁc workforce in the US. money — for researchers, proaches to addressing ma- APPLICATION AND USE organizations, and small jor biomedical or behavioral OF TRANSFORMATIVE OCTOBER 15 Application businesses — will support challenges.” EMERGING TECHNOLO- deadline for the INSTI- the development of new GIES IN CANCER RE- TUTIONAL CLINICAL technologies for low-cost, OCTOBER 28 Application SEARCH. These funds will AND TRANSLATIONAL high-throughput DNA deadline for the grant, 2010 reward innovative, high-risk SCIENCE AWARD. These sequencing, with a goal of NIH DIRECTOR’S NEW research to evaluate the funds will support new re- sequencing a mammalian- INNOVATOR AWARD performance of emerging sources for investigators to sized genome for $1,000. PROGRAM. These funds technologies for studying further advance basic and will go to investigators who cancer. The grant is part of translational research. OCTOBER 21 Applica- propose “bold and highly NCI’s broader Innovative tion deadline for the innovative new research ap- Molecular Analysis Tech- OCTOBER 20 Applica- grant, 2010 NIH DIREC- proaches that have the po- nologies Program. tion deadline for the NIH TOR’S PIONEER AWARD tential to produce a major grant, REVOLUTIONARY PROGRAM. This grant impact on broad, important OCTOBER 2 Application GENOME SEQUENCING will support scientists who problems in biomedical and deadline for the NIH award, TECHNOLOGIES – THE propose “pioneering and behavioral research.” PILOT-SCALE LIBRARIES FOR HIGH-THROUGHPUT SCREENING. As part of the NIH Roadmap Molecu- lar Libraries Program, this money will support the generation of chemical libraries for high-throughput biological screening by the Molecular Libraries Probe Production Centers Network.

OCTOBER 7 Application deadline for the NSF grant, INTEGRATIVE, HYBRID &COMPLEX SYSTEMS, which is meant for research and development in nanosystems, among other things. Integrative devices could include system-in-a- package and system-on-a- chip technologies.

OCTOBER 9 Application deadline for the NIH grant, MODELING THE SCIEN- ______TIFIC WORKFORCE. This money will help develop computational models of

OCTOBER 2009 GENOME TECHNOLOGY 57

Blunt End HUMOR, WE HOPE

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58 WWW.GENOMEWEB.COM______OCTOBER 2009

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