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This month inGenome Technology

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RECENT RESULTS FROM GT POLLS

Know anybody who’s having trouble with tenure because of too much teamwork?

No way. Why would team science make itharder to get tenure? ........................... 15%

Definitely. I know a number of great scientistsstruggling to prove their case. ............. 31%

Yes - me! ............................................. 14%

No idea, sorry. .................................... 41%

Also inside this month’s Genome Technology• PROTEIN BIOMARKERS

For protein biomarkers to have areal clinical impact requiresbetter sample sets, new platformsand serious validation.

• LAB REUNIONMass spec guru John Yates standsby his convictions.

• TISSUEMICROARRAYSStill struggling withimaging andstandardization.

• IN THE CLINIC:CASE STUDYScientists show the potential for a biomarker test of Alzheimer’ssusceptibility.

Contents | Zoom in | Zoom out For navigation instructions please click here Search Issue | Next Page

Contents | Zoom in | Zoom out For navigation instructions please click here Search Issue | Next Page

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Clinical ProteomicsTissue Microarrays: The Imaging Challenge

Team Science v. Tenure

BONUS: NEXT-GEN SEQUENCING TECH GUIDE

M A R C H 2 0 0 8


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M A R C H 2 0 0 8 GENOME TECHNOLOGY 3

“We tell young scholars, ‘Wait until you have tenureto solve very cool problems.’”

Cathy Trower, page 36

TissuemicroarraysThe AwkwardAdolescence of ArraysTissue arrays have found their footing in translationalresearch — but scientists saythey’re still struggling withimaging and standardization.BY JEANENE SWANSON

29

Protein biomarkersToward ClinicalProteomicsScientists say protein biomarkers stand to have a real impact in the clinic.But getting there will requirebetter sample sets, new platform development,and serious validation.BY MEREDITH W. SALISBURY

33

TenureWorks Well With OthersLarge-scale biology led to the advent of “team science,”but tenure is still awarded for individual work. When itcomes down to better scienceor a solid career, researchersare losing out. GT investigateshow (and whether) to fix tenure.BY CIARA CURTIN

36On The Cover36 Team Science v. Tenure33 Clinical Proteomics29 Tissue Microarrays: the Imaging Challenge

MARCH 2008 Contents


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GENOME TECHNOLOGY PODCASTS: A recent edition covered genomic graffiti,bursty work, and Joshua Lederberg’s death.www.genome-technology.com

MARCH 2008 Contents

MarkersMICRO RNA....................................10MIT’s Kellis finds possible geneticswitch in dual-direction DNA

WEB BOOKMARKS..........................11Losing track of journal articles?Zotero wants to help

SEQUENCING ..................................12To solve short read problem,Danes launch network for data analysis

PROTEIN ALIGNMENT ..................13New tool allows for flexible matching to track distantly related proteins

DATABASES......................................14OpenHelix wins grant to develop search portal for open-access resources

CLINICAL RESEARCH ....................15GSK’s Roses brings a new model of drug discovery to Duke

In every issuePRIMER ..............................................7Go team!

WHERE ARE THEY NOW?................9In review: Mid-size sequencing centers, Amersham, tech transfer,and electron transfer dissociation

ZEITGEIST ........................................17The month in blogs

CAREERS ..........................................18The path less traveled

BRUTE FORCE ................................21A virtual world

MY TAKE ..........................................25Welcome to the blogosphere

UNDER ONE ROOF ........................26The legacy of Ling and Smith

UPCOMING EVENTS......................54

LAB REUNION ................................56The proteomics pedigree

BLUNT END......................................58

UpstreamMICROARRAYS................................43SeqWright, GATC in personal genomics

PROTEOMICS..................................45Proteomic biomarkers for CNS lymphoma

SEQUENCING ..................................47‘1,000 Genomes’ challenges data flow

RNA INTERFERENCE ....................49Photocaging to control RNAi

BIOINFORMATICS ..........................50EU team to coordinate Gen2Phen data

DownstreamPHARMACOGENOMICS ................51AutoGenomics’ warfarin test approved

CASE STUDY....................................52Plasma is the new risk factor

Q&A ..................................................53The biomarker black box

1815 52


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Meredith W. Salisbury, Editor

FROM THE EDITOR Primer


or all the rah-rah talk about teamwork, teams don’t always havea positive connotation. (I can attest to this as someone alwaysamong the last people chosen for dodgeball teams.)

Large-scale biology revolutionized the life sciences, shakingthe comfortable model of PIs working by themselves in their

labs. Ever since the Human Genome Project, teams have been the vehi-cle of choice for accomplishing big research programs. In science, ifyou get 20 or 50 or 100 minds focusing on the same thing, it actuallydoes get done.

But recognizing the value of this work in acade-mia has seriously lagged. Several years ago ElaineMardis treated me to a guided tour of the Wash-ington University Genome Sequencing Center. Iwas quite surprised to find that she was genuinelyconcerned about her chances of being awardedtenure. This top-notch scientist wasn’t sure thereview committee would recognize her accom-plishments, since they had mostly taken place invery large collaborations.

Elaine did indeed get tenure, but the factors atthe root of her worries persist. Tenure review committees base theirdecisions on how much a PI has accomplished solo — generally dis-missing work done with or grants awarded to teams.

GT deployed senior editor Ciara Curtin (who I believe has never beenchosen last for dodgeball) to investigate the disparity. Her cover storyreports on the problems with the tenure system, as well as a numberof novel solutions that universities and other institutions are trying outto award tenure to scientists active in collaborative research.

Also in this issue, we have feature articles on tissue microarrays —which continue to improve but still need progress in image analysis andstandardization — as well as on clinical proteomics and what it’s goingto take for protein biomarkers to have an impact on patient care.

We’ve also started a new column. My Take, on p. 25, is an opinioncolumn written by a blogger whose work we find insightful andthought-provoking. Our inaugural edition is from Keith Robison, whooffers an introduction to the blogosphere and tips for finding rele-vant and interesting blogs. Keith’s Omics! Omics! blog can be foundat omicsomics.blogspot.com — I encourage you to check it out.

Go Team!ISSUE NO. 7 9

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WHERE ARE THEY NOW? Update

Back in 2003, Genome Technology’s coverstory delved into NHGRI’s controversialdecision to ignore mid-sized sequenc-ing facilities and give most of itssequencing grants to the Big Three: Bay-

lor, Whitehead (now the Broad), and WashingtonUniversity. Left out in the cold were Harvard’s RajuKucherlapati, Stanford’s Rick Myers, CSHL’s DickMcCombie, UW’s Maynard Olson, and the Univer-sity of Oklahoma’s Bruce Roe. The fate of thesesmaller facilities, which housed between four and20 sequencers and had budgets between $2 mil-lion and $10 million, seemed to hang uncertainly.But all of those researchers found a way to survive,and are still working on various sequencing-related projects. Myers, for example, participatedin the ENCODE Project, and McCombie took partin annotating the rice genome.

That same issue included an interview withAmersham Biosciences’ Andrew Carr. Carr wasthen president of Amersham, where he was try-ing to bring the discovery side of the company’sbusinesses (including proteomics, bioassays, andinformatics) to profitability. Carr said Amersham’smantra for 2003 would be: “We’re in it for thelong term.” Two years later, Amersham was acquired by GE. Today, Carr holdsa variety of positions. He is the chairman for Teraview, deltaDot, and Aku-bio’s boards, and is also an independent consultant for SpinX Technologiesand works with SciBridge.

In last year’s March issue, GT looked at how scientists are beginning to takeadvantage of their universities’ technology transfer offices. Since the 1980Bayh-Dole Act allowed universities to patent their scientists’ technology, thenumber of patents assigned to US universities rose from fewer than 250 priorto 1980 to 11,000 between 1991 and 2004. In that cover story, Q3’s WalidQoronfleh predicted that patent pooling would become more prevalent in thelife sciences since more than one patent is usually needed for biotech com-panies to stay afloat.

Also in 2007, post-translational modification took center stage. GT spoke withJosh Coon, Akhilesh Pandey, Phil Gafken, Scott McLuckey, and Benedikt Kesslerabout electron transfer dissociation, a technique to uncover PTMs. Coon, an ETDpioneer, sang its praises while Pandey’s lab tested its capabilites — finding 80percent of the modification sites described in the literature. Others were morecautious, saying classical instruments still have much to offer. — Ciara Curtin

In Review: Mid-size SequencingCenters, Amersham, Tech Transfer, and Electron Transfer Dissociation

>GT ONLINEwww.genome-technology.com

>NEED HELP?

GT ONLINE POLL RESULTS:If you made a syntheticgenome, what would theencrypted message have said?

42%I'M A SCIENTIST. THERE WOULDNOT HAVE BEEN A MESSAGE.

20%MINE ALSO WOULD'VE BEEN MY NAME.

26%PERHAPS THE FIRST LINE OFMY FAVORITE LIMERICK.

12%I-MADE-LIFE

SUBSCRIBE — GenomeTechnology is free to activeresearchers in the life sciences.To subscribe, log on towww.genome-technology.comand fill out a 30-second form.ARCHIVE ACCESS —Subscribers can search throughthe complete GT archives byissue or keyword. Simply log in on the website.REPRINTS — For permission to reproduce material fromGenome Technology, or to order offset-printed or Web-ready PDF reprints, write [email protected] or call +1.212.651.5618.MANAGE YOUR ACCOUNT — To change your address or manage your subscription toGenome Technology, the DailyScan bulletin, or any of theGenomeWeb publications,sign in to www.genome-technology.com and click on My Account.

MARCH 2003

MARCH 2007


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Markers NEWS

10 WWW.GENOME-TECHNOLOGY.COM M A R C H 2 0 0 8

While biologists debatethe idea that mostn o n c o d i n g R N Aserves no real func-tion in the genome,

MIT’s Manolis Kellis is busy findingfunction in the most unexpectedplaces. In his latest work, he’slocated pairs of miRNAs expressedfrom the same double-strandedDNA that are both functional.“What we’ve found out now is that,in fact, for some miRNA genes, theantisense transcript gets processedinto a mature miRNA, which itselfhas distinct functions,” Kellis says.“Both directions of the DNA arecoding for distinct functions.”

Kellis’ work, published in the Jan-uary 1 issue of Genes & Develop-ment, found two such miRNA pairsin the fruit fly and eight pairs in themouse. The research is important

simply because “double dutynucleotides” have never beenobserved before in animals, Kellissays. He adds, “It’s not just thatyou’re trying to cram in additionalfunction in a little space — it’s thatantisense miRNA, sense/antisensepairs, provide a natural mechanismfor a genetic switch.”

Using a computational approach,he and his team searched sequencealignment data for evolutionarilyconserved miRNA elements, andisolated several that appeared to besense/antisense pairs. In predictingthat their targets would be several

Hox genes — thesegenes play a largerole in controllingthe positioning ofbody parts — theyran several follow-u p f u n c t i o n a lassays. First, theys u c c e s s f u l l ymatched knownsequencing reads to the in vivomiRNA transcript. Second, uponexpressing the antisense miRNA invivo, they found that the targetedHox gene was repressed. Finally, atransgenic fly built to overexpressthe antisense miRNA showedmarked homeotic transformation —the transformation of one body partto another is a hallmark of Hox generegulation gone awry. “The most sur-prising thing was that the antisensetranscript, in fact, showed a

homeotic transforma-tion that is much, muchmore pronounced thanthe sense miRNA,” saysKellis. He notes thatwhen they overex-

pressed the sense miRNA, there wasinstead a very subtle effect.

Kellis believes that the sense/anti-sense pairs in the Hox cluster maycontribute to maintaining thistightly regulated developmental cir-cuit. There could be more of thesekinds of pairs, providing in equalmeasure form and function,throughout a variety of genomes.“This is pretty exciting in the sensethat it’s not just a Drosophila-specificthing and it’s not just a Hox-specificthing,” Kellis says. “It may be a moregeneral regulatory mechanism foranimals.” — Jeanene Swanson

“Both directions of the DNAare coding for distinct functions.”

>SHORT READS

MicroRNA: MIT’s Kellis FindsPossible Genetic Switch in Dual-Direction DNAAs of January, George

Weinstock has become a professor of genetics atWashington University in St. Louis, as well as associatedirector of its GenomeSequencing Center. Formerly,Weinstock was a professor atBaylor College of Medicine,and co-director of its Human Genome Sequencing Center.

Florida promised $80 millionto the University of Miami’sInstitute for Human Genomics.The institute, which opened in November, started with aninitial $37 million in federalfunds and an undisclosedamount from the university’smedical school.

The Office of the InspectorGeneral at the US Department of Health and Human Servicesreported that the NIH didn’t do its homework. After beingqueried, the NIH couldn’t come up with the number of financial conflicts of interest its extramural grantees reported between2004 and 2006, which it is required to do.

Peter Covitz, CEO of the NCI’s Center for Bioinformaticsand prime initiator of the caBIGproject, left the NCI at the endof February. Covitz is headed to MDS Nordion as senior vice president of innovation.MDS Nordion is a mid-sizednuclear medicine biotech company based in Ottawa, Canada.

MANOLIS KELLIS


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NEWS Markers


>SHORT READS

GE Healthcare will acquireWhatman for $713 million,adding Whatman’s sample prep products to GE’s protein chro-matography platform and cellular analysis technologies.The purchase will up GEHealthcare's total staff ofroughly 46,000 by about 1,100.

454 Life Sciences and ColdSpring Harbor Laboratory have announced plans tosequence the Tasmanian devil’s genome in the hope ofidentifying which genes areresponsible for the fatal facialtumor disease that’s afflictingthe wild devil population inTasmania. Since 1996, devilnumbers have been reduced by 90 percent in some parts of the state.

The NSF doled out $50 millionfor the iPlant Collaborative, aninitiative to expand research inplant genetics. Building uponthe National Plant GenomeInitiative, the center will be ledby the University of Arizona'sBIO5 Institute, and includesresearchers at Cold SpringHarbor Laboratory, ArizonaState University, the Universityof North Carolina at Wilmington,and Purdue University.

Elisabeth Allison has joinedHelicos BioSciences’ board ofdirectors. Allison is a partner atANZI Partners, and is chiefnegotiator for ANZI Partners’publishing media and softwareventures. She was an associateprofessor in economics atHarvard University.

As users of Digg and othersocial bookmarking sitesknow, t rack ing Webpages comes in handy.Now Zotero, a Web-

based tool from George Mason Uni-versity, takes it a step further byproviding a spot for note-taking,while also storing and organizingcontent such as journal articles orWeb-based tools. Last fall, Zoterobecame compatible with all of thePLoS journals.

“Part of the birth of Zotero wasfrustration with existing tools likeEndnote and RefWorks that weren’treally cutting it for what we werewanting to do,” says Trevor Owens,a Zotero technology evangelist.

Unlike Endnote and RefWorks,Zotero is a freely available, open-source program out of GeorgeMason’s Center for History and NewMedia with approximately 400,000

users. Though originally designedwith humanities researchers inmind, Zotero also has appeal to sci-entists. “Although there is a lot ofhistory material online, you stillhave to do a significant amount ofresearch in archives, while the sci-ence community that has picked upon Zotero already has a very strongworkflow in Web-based tools, likejournals like PLoS,” Owens says.

The launch of Firefox 2.0 also

pushed the devel-opment of Zotero,since that versionallows people todeve lop ex t en -sions to increasethe browser’s func-tionality, just asZ o t e r o d o e s .When installed, itsJavaScript-based translators workquietly when the Firefox browser isopen. An icon appears in the Webaddress bar and, if clicked, savesthat page. All the saved items can beviewed in an iTunes-esque tablewhere re l a t ed i t ems can begrouped, tagged, or searched.Everything — the metadata ,images, and PDFs — is stored in theuser’s Firefox profile.

Last November, Zotero and theseven PLoS journals took a step tobecoming seamlessly integrated.

“We’ve had a significantamount of people requestingthat we have a translator forPLoS. We were more thanhappy to do it,” Owens says.Zotero can store the metadata,such as author names, issueand volume number, andDOI, as well as the full-text

articles from all of the PLoS journals.Next, the developers behind

Zotero are working on getting itsown server up and running so theycan expand its capabilities to letusers join groups, share their collec-tions, and have Zotero suggestitems for them to check out. Also, anew plug-in is in the works to allowZotero to sync with del.icio.usbookmarks.

— Ciara Curtin

Web bookmarks: Losing Trackof Journal Articles? Zotero Wants to Help

TREVOR OWENS

The science communitythat has picked up onZotero already has a very strong workflowin Web-based tools


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Markers NEWS


While next-generationsequencing technol-ogy continues to pushthe high-throughputenvelope, handling

the landslide of data remains a per-s i s tent problem. Resourcefulresearchers have no trouble develop-ing tailor-made tools to deal with thedata deluge, but the distribution ofsuch applications to the widerresearch community is oftenmarred by the fact that not all labsuse the same sequencing platforms.

In order to address this challenge,the Danish Agency for Science Tech-nology and Innovation recentlyannounced a $3 million grant to sup-port a collaborative network of Dan-ish research institutions called

Seqnet. The three-year initiativeaims to support the development ofa national, user-friendly graphicalinterface platform for the analysis ofnext-generation sequencing data.Seqnet will be a team effort amongthe University of Copenhagen, theAgricultural Sciences at Aarhus Uni-versity, Aalborg University Hospital,and the University of Southern Den-mark, with Danish bioinformaticsvendor CLC bio.

“There is a need to make a unified,next-generation sequencing plat-f o r m c a p a b l e o f a n a l y z i n gsequences for many purposes,

regardless of what-e v e r p l a t f o r m sthey are comingfrom because eachh a s t h e i r o w n software tied tot h a t p a r t i c u l a rsequencer,” saysK a r e L e h m a n nNielsen, leader ofthe Seqnet projectand an associate professor at AalborgUniversity. “We are already in theprocess of writing small scripts, butlack the capability to develop themin a user-friendly manner andmake them easily distributablebetween labs because they are com-plicated, command-line based, andvery specialized.”

The platform will bet e s t e d i n v a r i o u sresearch projects, suchas metagenome analysisof bacterial systemstaken from waste watertreatment faci l i t ies ,cancer cell typing, andtag-based expression.

“We realized very early on that youhad to develop your own applica-tions or else rely on the slow devel-opment of comprehensive tools. …There is not nearly good enoughsoftware analysis for gene expres-sion profiling,” says Nielsen, whoworks on tag-based gene expres-sion. “It is really important to do thevisualization of the data in a waythat is interpretable to regularusers.” Seqnet aims to eventuallydeploy a bioinformatics packagewith a slew of algorithms ported toCLC’s workbench platform.

— Matthew Dublin

>SHORT READS

Sequencing: To Solve ShortRead Problem, Danes LaunchNetwork for Data AnalysisA new FDA Subcommittee on

Science and Technology reportsaid that the FDA is unpreparedto keep up with genomics andpharmacogenomics advances.If the FDA is to serve the newdemands presented by today’sbiomedical advances, it’ll needmore federal resources andfunding, the report said.

Abbott Laboratories willspend $20 million for an initial 10.25 percent stake inIsis Pharmaceuticals’ sub-sidiary Ibis Biosciences, withoptions to acquire as much as 18.6 percent before July 31,and the remainder of the company before June 30,2009. Ibis sells the Ibis T5000Biosensor System, which isused for rapid identificationand characterization of infectious agents.

Genetix Group has appointedJerry Williamson to the post ofpresident of US operations, anew position. Williamson for-merly served as president ofBiacore, was president of thegenomics companyPyrosequencing, and was incommercial management atGenzyme and at RocheLaboratories.

Predictive Biosciences hasappointed Martin Madaus to itsboard of directors. Madaus ispresident, CEO, and chairmanof Millipore and he formerlywas VP of development atRoche Molecular Diagnosticsand a GM at BoehringerMannheim.

KARE LEHMANNNIELSEN

“We realized very early onthat you had to develop yourown applications or else relyon the slow development ofcomprehensive tools.”


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NEWS Markers


>SHORT READS

Janelle Hoskins has beennamed director of theMolecular Genomics Facility atthe University of North Carolinaat Chapel Hill’s Institute forPharmacogenomics andIndividualized Therapy.

Vivian Cheung has beennamed an investigator by theHoward Hughes MedicalInstitute. Cheung, who is apediatric neurologist at theChildren’s Hospital ofPhiladelphia and the Universityof Pennsylvania School ofMedicine, studies the linksbetween gene expression andindividual susceptibility to dis-ease and treatment responses.

The National Institutes ofHealth has invited ThomasKelly and Keith Yamamoto tojoin its advisory committee.Kelly is a director of the Sloan-Kettering Institute at theMemorial Sloan-KetteringCancer Center, and a professorat Weill Graduate School ofBiomedical Sciences at CornellUniversity. Yamamoto is a pro-fessor of cellular and molecularpharmacology and executivevice dean of the School ofMedicine at UCSF.

Roche has signed an agreement with VentanaMedical Systems to purchasethe company for $3.4 billion.The acquisition will provideRoche with a tissue-baseddiagnostics platform, which it sees as an important piece of the oncology diagnosticsmarket.

When it comes to simu-l a t i n g re a l - w o r l dc o n d i t i o n s , m o s tprote in al ignmentalgorithms fall short.

Three researchers from Tufts Uni-versity and MIT developed a newalignment tool that allows the pro-tein to twist or move during thealignment process, more closelymatching biological conditions.Lenore Cowen, from the Tuftscomputer science department, saysher group is interested in relatedproteins that may be evolutionarilydistant and in what those proteins’functions may be. Since no pro-gram allowed them to model pro-teins as they wanted, Cowen andMIT’s Matt Menke and BonnieBerger made their own program.“None of them did what we actuallyneeded to do quite well enough

when the structures were just evo-lutionarily a little bit too far away.We were very arrogant. We said,‘Oh well, we’ll just write ourown,’” says Cowen.

Their program, called Matt for“multiple alignment with transla-tion and twists,” is an alignmentfragment pair chaining programthat allows for local flexibility.“Most previous methods had takenthese protein crystal structures asrigid bodies and they aligned therigid bodies, but the protein is only

a rigid structurewhen you crystal-lize it. They actu-ally are somewhatflexible,” Cowensays. So instead,t h e i r p r o g r a mallows for a certainamount of rotationand translation.

After a year and half of develop-ment, Cowen and her team ranbenchmark tests of Matt ondatasets from Homstrad and SAB-mark, common standard bench-marking programs, versus otheralignment tools. Matt performed aswell as other tools on Homstad butbetter on SABmark, which includesproteins that are more distantlyrelated, as the authors reportedrecently in PLoS ComputationalBiology. “We’re able to capture sim-

ilarity even when thestructures are startingto really not be thatsimilar,” Cowen says.Matt outputs its data inFASTA or PDB format,and can also output arasmol script so users

can view the protein alignment asan animated movie. The program isopen-source and freely availablefrom the Tufts or MIT websitesunder a GPL license.

Next up for Matt is adding supportfor partial alignments so it can showonly the proteins that line up out ofa larger group. The researchers arealso adding in sequence informationto appeal to users who prefer tolook at sequence and alignmentsimultaneously.

— Ciara Curtin

Protein alignment: New ToolAllows for Flexible Matching toTrack Distantly Related Proteins

LENORE COWEN

“We were very arrogant.We said, ‘Oh well, we’ll justwrite our own,’” says Tufts’Lenore Cowen.


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Markers NEWS


If you build it, they will come.Unless they don’t know whereto find it, that is. Enter Seattle-based OpenHelix, which hasbeen offering database train-

ing courses for the past five years.With a new $1 million grant fromthe National Human GenomeResearch Institute, the team will beable to step up its offering with asearch portal for publicly accessibledatabases.

“One of the challenges with thispost-genomic era is that there’stons of data and lots of resourcesand databases that are free [and]publicly accessible,” says ScottLathe, OpenHelix CEO. “The chal-lenge is, researchers can’t find thecorrect resource because there’sjust so many out there. And thenonce they find it, they’re complexso they don’t know how to usethem.”

Initially, OpenHelix contractedwith several organizations todevelop and conduct on-site trainingcourses, including classes on how touse the three big genome browsers atEnsembl, NCBI, and UCSC. Thecompany also developed relatedonline training and Web seminars,but found the seminars to be less

valuable than the on-site and onlinetraining courses. They currentlyhave approximately 30 tutorials, butaim to expand that number to 100.

With the onslaught of moreand more publicly available data-bases — Lathe estimates thatthere are about 1,000 right now— OpenHelix has shifted its focusto creating a tool to locate them.With the new grant, the team plansto build a semantic search tool thatwould be freely accessible from thecompany’s website and that wouldallow researchers to find both data-bases and associated OpenHelixtraining courses related to specificsearch terms.

“The researcher will be pre-sented [with] a list of not only theresources but also the training onthose resources,” Lathe says.“Hopefully to tackle both thoseissues: one, to find the right

resource, and two,how to use it.”

OpenHelix plans abeta launch for nextmonth, with a fulllaunch by September2008. “Right now, [we]are focused on the lifescience researcher,”Lathe says. “One of thecritical needs is gettingthis information out

into the biomedical [field]. Andthen someday, eventually, whenpersonal genomics rea l ly dolaunch, I think we’ll be in a verygood position to [be] filling thatsame niche of being able to providetraining on these very complexissues.”

— Jeanene Swanson

>SHORT READS

Databases: OpenHelix WinsGrant to Develop Search Portal for Open-Access ResourcesJames LeVoy Sorenson,

a medical device inventor andfounder of several companiesincluding Sorenson Genomics,died of cancer at the age of 86.Sorenson developed or invent-ed the first real-time computer-ized heart monitoring systems,disposable surgical masks,non-invasive intravenouscatheters, and blood recyclingand blood infusion systems.

Researchers at Philadelphia’sMonell Chemical SensesCenter investigated the effectof gene knockouts on mousebody weight, finding that morethan 6,000 genes influencebody weight. They discovered10 times more genes associat-ed with weight gain than weightloss, among other findings thatsuggest that human obesitymay be equally complex.

The NIH officially rolled outits open-access policy at theend of 2007, which requires allpapers funded by NIH to bemade available in open accessjournals within 12 months afterinitial publication. The policyalso applies to papers writtenby investigators whose salariesare paid by NIH.

Beckman Coulter announcedit will move its existing head-quarters from Fullerton, Calif.,to the nearby city of Brea bythe end of 2009. The firm isalso cutting 158 jobs from itsPalo Alto, Calif., facility, in prepa-ration to close the site andmove its centrifuge manufactur-ing operations to Indianapolis.

“The challenge is, researcherscan’t find the correct resourcebecause there’s just so manyout there. And then once theyfind it, they’re complex so theydon’t know how to use them.”


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NEWS Markers

Allen Roses has a sense ofurgency that might comeas a surprise for someonewho has spent his careerin academia and pharma.

“I had a major heart attack in1990,” he says. “It changed the wayI live my life. I wake up in themorning, I blink twice, if I’m stillhere I go at 120 percent.”

Indeed, that’s what Roses is doingat Duke University, the institutionwhere he spent 27 years beforeheading off to head up geneticsresearch and pharmacogenetics atGlaxoSmithKline in 1997. Rosesleads the Drug Discovery Institute,which he says is a new model ofhow drug discovery could be donein a non-pharma setting.

When Roses went to GSK, he ini-tially took a three-year leave ofabsence to work on a drug forAlzheimer’s. “I was very naïveabout how long it took to make adrug,” he laughs. But what he sawin pharma discouraged him. Fre-quent changes in leadership andareas of focus — not just at GSK,but throughout the industry —

meant that successfuldrug candidates wouldbe shelved even afterpatents had been filed onthem. “A lot of stuff is lefton the table,” Roses says.

As he surveyed the dis-covery and developmentlandscape, it occurred tohim that systemic prob-lems were standing in the way ofreal progress. Pharmaceutical com-panies tend to buy late-stage mole-cules from biotechs rather thanbuild them in-house, and the aca-demics who first propose moleculesas potential drug candidates don’tpursue them beyond basicresearch stages. “If big pharma’s notmaking it, the academics aren’t

making them, the VCsthat support many ofthe biotechs want areturn in three to fiveyears, they’re not goingto be making it — sowho’s making the mol-ecules?” Roses asks.

It won’t be Roses,either, but he hopeshis so-called virtualpharma will get mole-cules to the pointwhere they’re interest-ing and relatively low-

risk for pharmas to take on. At hisnew institute, Roses has formed anexecutive committee of eight or 10people with expertise in variousstages of drug discovery. “It really isa group think,” he says.

The idea is to form partnershipswith pharmas to take over promis-ing molecules that have beenshelved, and Roses’ team will farm

out the stages of discovery andpreclinical work to get that mole-cule further along the path tobeing an approved drug. “We’regoing to be trying to become asource of proof-of-concept mole-cules,” Roses says. While the con-

cept is definitely anexperiment, he says, “onesuccess and I think thisthing becomes a model.”

While that covers late-stage molecules — thosethat have already been putthrough the paces of earlydiscovery — Roses saysthe institute will also

work with earlier-stage candidates.Those will take more time andprove more costly, so Roses hassecured funding from severaldonors — “wealthy people andsmall countries with a lot ofmoney,” he says.

Roses and the executive team arecurrently evaluating a few suchdeals, which are in various stages ofdue diligence, he says. He hopesthat the first success would come inless than three years.

Another aspect of Roses’ newplan is a separate entity that he callsCabernet Pharmaceuticals, which ishis own consultation companythat helps pharmas handle projectmanagement for compounds in thedrug development stage. Compa-nies might come to him, for exam-ple, if they “have a molecule that’sin development [and they need to]get a companion diagnostic ontime for registration with theFDA.” Roses says he started up thisventure to fulfill his interest in late-s t age pharmacogene t i c s andadverse events. “It took off likewildfire,” he says, noting that theappointments he has lined upshould keep him busy for all thetime he’s allotted to the consultancyfor its first year of business.

— Meredith Salisbury

Clinical research: GSK’s RosesBrings a New Model of DrugDiscovery to Duke

“If big pharma’s not makingit, the academics aren’t mak-ing them, the VCs that sup-port many of the biotechswant a return in three to fiveyears, they’re not going to bemaking it — so who’s makingthe molecules?”

ALLEN ROSES


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1,000 Genomes Project

In January, a consortium led by NHGRI, Sanger, andthe Beijing Genomics Institute announced the 1,000genomes project, a next-gen sequencing initiative.The news was a bit confusing, but the blogospherecleared that up. At Genetic Future, DanielMacArthur noted that the project will only besequencing about 200 complete genomes, and thenperforming exon sequencing on portions of the rest.Ultimately, the goal is to catalog variants at as little asone percent frequency across the genome. AdaptiveComplexity’s Michael White responded to the news,saying that while it’s a great start, creating useful,high-res catalogs of rare genetic variants mightnecessitate sequencing a lot more than 1,000genomes.genetic-future.comadaptivecomplexity.blogspot.com

Learning to Share

The blogosphere was chattering about everythingopen access and open notebook. Scientific American hada long piece about the pros and cons of collaborativescientific research and blogger Pedro Beltraoannounced he’d be leading an open notebook study,the data for which he’s depositing at Google Code. Inthe New York Times, an opinion piece wonderedwhether cancer researchers shouldn’t be required toopen their data archives for other investigators’ bene-fit. Moreover, with the Protocol for ImplementingOpen Access Data announced at Science Commons inDecember, blogger Deepak Singh wondered how thiswill change the way scientific information is distributed.pbeltrao.blogspot.commndoci.com/blog

Venter Builds a Synthetic Genome

Not surprisingly, Craig Venter and his colleagueswere all over the news for creating the longest syn-thetic genome. In response to the media coverage ofwhat some people considered a non-event, the blogos-phere couldn’t hold its tongue. Carl Zimmer at TheLoom acknowledged the technical challenge of creat-ing a synthetic Mycobacteria genitalium genome, butnotes that scientists have yet to boot it up in a live cell.As an added twist, Venter’s team encoded severalwatermarks in the genome, which a Wired blogreported to be the names of the scientists themselves.MIT synthetic biologist Drew Endy commented thatthe watermarks would likely disappear through ran-dom mutations, making them more like graffiti thandistinguishing engravings.scienceblogs.com/loomblog.wired.com

Impact Factors Take a Hit

Impact factors definitely got a bad rap this pastmonth, as did the analysts behind them at ThomsonScientific. Rockefeller University scientists wrote anopinion piece in the Journal of Cell Biology, slammingthe process that Thomson uses to rank publicationsas well as the lack of transparency in the ratingprocess. In turn, Thomson replied with an editorialdefending its methods and saying that the Rocke-feller crew based its stance on misinterpreted infor-mation. Blogger Neil Saunders opined that impactfactors are outmoded, while a Nature Network blogencouraged alternatives such as the SCImago Jour-nal Rank indicator.network.nature.com/blogs/user/mfennernsaunders.wordpress.com

In the past month, bloggers have been abuzz about the 1,000genomes project, Venter’s latest foray in synthetic biology, the value of impact factors, and collaborative science. By Jeanene Swanson

The Month in Blogs

BLOGOSPHERE BRIEFS Zeitgeist


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http://adaptivecomplexity.blogspot.com

http://pbeltrao.blogspot.com

http://www.mndoci.com/blog

http://www.scienceblogs.com/loom

http://blog.wired.com

http://network.nature.com/blogs/user/mfenner

http://nsaunders.wordpress.com






Denise Bouvrette, afourth-year gradu-ate student at theUniversity of Mis-souri, thinks that

after she completes her degree shemight like to become a sciencewriter or a liaison between a bio-medical company and the public.

Funny thing is, a year ago Bou-vrette didn’t even know there weresuch positions — and she certainlywouldn’t have known where to findone. After coming to terms withthe idea that a career in academiadidn’t appeal to her, she realizedthat her knowledge of alternativescientific career options was woe-

fully lacking. “I spent a lot of timeonline” looking into other paths,she says. “I realized that I couldspend the next year trying to get allthis information for myself.”

There are a number of studentsand postdocs in the same situation— and, frustratingly, just as manyscientists who are enjoying suc-cessful careers outside of academiaand have plenty of expertise toshare. The trouble is connectingthese people.

Bouvrette and her labmates,including Emily Stagner, tooktheir curiosity about alternativecareers a step further than moststudents do. Bouvrette wrote a

proposal for a training programthat would bring in speakers totalk about their jobs and got “an

In Missouri, a couple of grad students showed their university athing or two about career training. Now the school underwrites a program to help students learn about scientific jobs outside of academia. By Meredith Salisbury

The Path Less Traveled

DENISE BOUVRETTE

Careers PROFESSIONAL LIFE

Whether you’re a student, postdoc, or established facul-ty member at a university, you too might find it valuable tohelp set up a career exploration program at your institu-tion. Denise Bouvrette offers advice from her experience.

What do you want to get out of it? Bouvrette says thefirst step is to decide exactly what you’re looking to gainfrom such a program, and devise a plan based on that.For the kind of glimpse-of-alternative-careers series shehad in mind, seminars seemed like the best way toaccomplish her goal. But other goals might be betterserved through other means, so be flexible and creative.Don’t forget to identify your target audience and makesure you’re serving their needs. A quick survey could helpyou stay on track.

Communicate like a champion. If you’re a student, the

grad school may be your best bet for an ally; if you’re faculty,hit up your collaborators and fellow researchers to helpstart up a program. Let everyone know what you’re tryingto do and identify your assets — who’s willing to help andwhat they can offer.

Check the university’s mission statement. Bouvrettesays a good break came in the university’s mission state-ment, which included a section about promoting trainingfor graduate students and promotion of economic develop-ment for the state. In her proposal and other programmaterials, Bouvrette used those items to her advantage,arguing that good career counseling for grad students wasnecessary to the university’s mission and would encouragestudents to get jobs in the state. Showing the school how itwill benefit never hurts, she advises.

How to Start Your Own Program


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overwhelming response” when shecirculated it among other studentsand postdocs.

Stagner, who helped Bouvrettelaunch the program, says that “asgrad students here in the academicculture, we’re pretty well aware ofwhat a professor goes through,” butthat when it comes to looking for acareer beyond the university set-ting, “we’re doing that blindly.”

Next, Bouvrette did what any uni-versity member would: she formeda committee. Through a pilot proj-ect for the training program, Bou-vrette approached people whowere scheduled to speak on campusfor other reasons and asked if theycould give another hour for acareer seminar. Speakers haveincluded an employee from a smallgenotyping company, a patentattorney, and a genetic counselor.

Students get to hear about a day inthe life of these people, as well ashow to search for that kind of job.The seminars have attracted asmany as 50 students, and benefitswere immediate: after the patentattorney’s talk, for instance, a cou-ple of students reported switchingto a joint PhD/JD program to pursuescience in a legal setting, accordingto Bouvrette.

Bouvrette and her committee fol-lowed up each seminar with a ques-tionnaire for attendees; the positiveresponses from those provided evenmore ammunition to support theprogram, which they then shoppedaround to a number of sciencedepartments. The group neededfunding to pay for the events andreimburse speakers for their travelexpenses; several science depart-ments have contributed.

With funding in hand, Bouvrettehopes that the program — nowknown as ACES, for AlternativeCareer Exploration in the Sciences— will be active long after she’sgone. She remembers that early inher research into non-academicjobs, she was flummoxed even byjob titles she saw in job listings.“What does that mean, director ofscientific affairs?” she rememberswondering. “What’s ‘Scientist I’?”

Today, the program has seminarsevery other month; each seminar ispaired with an informal networkingsession as well. That helps students“work on their networking skills,which a lot of us are not very goodat,” Bouvrette says. The events alsogive students contacts for futureemployment or even just to getmore information about certaintypes of careers.


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The language of technical computing.

Over one million people aroundthe world speak MATLAB.Engineers and scientists in everyfield from aerospace and semiconductors to biotech,financial services, and earth andocean sciences use it to expresstheir ideas.Do you speak MATLAB?

Parlez-vous MATLAB?

Quantitative high-throughput gene expressionimaging using data from FlyEx Database.

This example available atmathworks.com/ltc

Image from

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sed by permission. http://flyex.am

s.sunysb.edu/flyex and http://urchin.spbcas.ru/flyex

®

©2007 The M

athWorks, Inc.

Accelerating the pace of engineering and science


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Linux on your Windows machine? Migrating flocks of computers? Virtual machine technology is steadily opening up new possibilities for genomics data management and bioinformatics tools. By Matthew Dublin

A Virtual World

Brute ForceHIGH-PERFORMANCECOMPUTING

Last month we lookedat cloud computing,a compute architec-ture that providesusers with access to

large amounts of on-demand com-puting power through an Internetconnection. Amazon, Google, IBM,and a growing number of other ven-dors are hosting compute cloudswhere users can go online, open anaccount, and for mere cents anhour, create virtual compute clus-ters complete with the desired CPUtype and speed, RAM, and memorycapacity.

Compute clouds are made possi-ble through virtual machine, orVM, software, which allows users tocreate multiple virtual computersthat function completely independ-ently on one physical machine.There are many benefits to employ-ing VMs, and in the case of cloudcomputing, it gives the cloudprovider more bang for the buckbecause a single server can hostnumerous virtual compute nodessimultaneously, thereby increasingoptimization of resources and sav-ing energy and maintenance costs.

VM software also has a very prac-tical and increasingly popularapplication for desktop users whodesire the ability to run whatwould normally be incompatiblesoftware in their preferred operatingsystem environment. For example,Windows users can run a Linux dis-tribution simply by installing it on

their virtual machine software plat-form of choice, and run Linuxapplications seamlessly alongsidetheir native Windows OS. In mostcases, the VM appears as any otheropen application, but in reality, it isan independent, virtual computerwith its own operating system run-ning next to the host computer’soperating system.

But VMs are not only useful forthose looking to reach across thecompatibility divide. In addition tocross-operating system applicationaccess, this technology also comesin handy if there are certain pro-grams that may only run on olderversions — or, in the case of Linux,different distributions — of yourcurrent operating system. This isespecially the case when you comeacross a must-have application butyou’re not ready to install anentirely new operating system justto complete a few tasks.

Biofx on the bandwagon

In addition to VM-savvy desktopusers, this technology is also find-ing favor with bioinformatics soft-ware developers, says MichaelBrudno, an assistant professor ofcomputational biology at the Uni-v e r s i t y o f To ro n t o . B r u d n obelieves that it may actually bemore reliable and cheaper to bringthe computers to these ballooningdatabases, rather than the otherway around; operating systems,

after all, are smaller and thereforeeasier to move over a network con-nection than enormous datasets.Following this logic, the machinesshould be in a location where itmakes the most sense to do thecomputation, says Brudno. “A vir-tual machine is just like a laptop —you can suspend and resume it,just like when you close or openyour laptop,” he says. “But insteadof carrying it with you, you sendyour VM to another site, where itpopula tes to other computenodes.”

The concept of moving a virtualcomputer from one physical pieceof hardware to another is calledmigration. “The way it works is thatyou have a running VM on yourhome machine and then youm i g r a t e t h e w h o l e r u n n i n gmachine from your own site to aremote site, so the result is that youstill have network connections to

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the original place where it camefrom,” Brudno says.

The trick with genomics data hasalways been processing in parallel,so merely migrating a single VMdoesn’t cut the compute mustard.Brudno’s solution is Snowflock, aVM software implementat ionspecifically geared toward parallelcomputation over a cluster. Likeother VM software solutions,Snowflock allows users to migrate asingle VM over a network connec-tion. Its usefulness to bioinformat-ics resides in its ability to clone auser’s VM over an entire cluster.This is achieved through an almostinstantaneous cloning mechanismthat creates exact replicas of theoriginal VM sent by the remote userand then populates each clonethroughout the cluster.

“We are also looking at this as asolution to multiple laboratorieswith different needs sharing onecompute cluster,” Brudno says.VMs can allow for secure, sharedusage of a cluster or server farmbecause access by the systemadministrator need only be grantedto the user for an allotted virtualmachine account. For example, if

one biological research groupwants to share its cluster resourcesand datasets with another, theguest would merely be granted apassword to migra te v i r tua lmachines onto the cluster instead ofgranting direct access to the cluster.If security is breached and pass-words are compromised, the

hacker only has access to the guestVMs and not the entire cluster.

VM apps

VMs are also good for those intim-idated by the world of Linux, orthose still in the learning stage withbioinformatics applications. A suiteof bioinformatics tools packaged ina virtual machine distributioncalled DNALinux Virtual DesktopEdition offers Windows users thechance to have at their favoriteapplications, such as HMMER,Bioperl, NCBI Blast, and manyothers, all contained within a pre-packaged virtual machine distri-bution based on Xubuntu, analternative version of the UbuntuLinux distribution. DNALinuxuses a virtual machine platform byVMWare, currently one of the morepopular VM vendors. DNALinuxdeveloper Sebastian Bassi, projectleader at the National University ofQuilmes in Buenos Aires, says thatwhile there are many live CD bioin-formatics software packages avail-able, a VM implementation allowsusers to save their settings and data.Bassi also says that the target

audience forDNALinux isthe greenhornbioinformaticssoftware userwho is eitherno t f am i l i a rwith Linux ordoes not wantto install Linuxon his or her

own desktop. Users can downloadDNALinux for free from VMWare’sofficial site.

VMs also allow users to put themachine and data together in oneself-contained package. Such is thecase with WormBase, the centraldatabase for C. elegans and othernematodes hosted by Cold Spring

Harbor Laboratory. According toTodd Harris, project manager ofWormbase, virtual machines solveproblems associated with the cre-ation of efficient backups, referentialaccess, and most importantly, easydistribution. Databases like Worm-Base usually consist of multipledatabase backends, complicatedvisual display layers, and a slew ofthird-party software libraries, alljoining together to create the end-user experience. “Any backup strat-egy needs to capture the underlyingdatabases but also the presentationlayer and hosting environment, sosimply mirroring the resource ontoadditional hardware is prohibitivelyexpensive and a maintenanceheadache,” Harris says. “Virtualmachines overcome backup chal-lenges by encapsulating all softwareand databases along with a pre-configured operating system in asingle convenient package.”

The reason for creating a VM dis-tribution of a Web-based database isthat many users like the option ofrunning the resource on their ownmachine, free of network congestionor server load, or even the need tobe online, says Harris. For biotechcompanies and pharmas involved inexpensive R&D projects, VM distri-bution allows for a certain level ofprivacy when browsing the data-base. Harris acknowledges thatwhile there was a small amount ofsalesmanship involved in gettingbiologists and other researcherscomfortable with the idea of down-loading a VM implementation ofWormBase onto their desktops, theresults have been positive, with a lotof interest coming from users whowant to set up their own clusters tosupport their labs. “A lot people inthe bioinformatics world were noteven aware of virtualization, but allyou have to do is tell them it’s justlike opening up a Word documentand they get it,” Harris says.


“Virtual machines overcome backupchallenges by encapsulating all software and databases along with a pre-configured operating system in a single convenient package.”


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It is a problem nearly as oldas the written word: Givena text that is found usefulor enjoyable, how doesone find others like it? In

the days of Gutenberg, the limitednumber of authors and slowprocess of producing texts miti-gated the problem, but in the mod-ern age the problem simply growsexponentially.

Blogs are websites consisting of aseries of written posts by one ormore authors. Their general tonecan range from personal diaries toonline columns to running journalclubs and, in most, readers areencouraged to comment on theentries.

Why do people blog — or morespecifically, why do scientists blog?Certainly each scientific bloggerhas her or his own reasons, but inmy case it was a mix. I started myblog during a difficult professionaltransition, having been forciblysevered from what had been my sci-entific home of a decade. I wantedto continue to think about some ofthe topics I had been working onand to expose my thoughts to theglare of professional criticism. I alsoliked the idea of writing somethingmore rewarding than terse Power-Points and hurried e-mails.

The rewards have been numerous.I do get to write something I can tryto be proud of. I do get critical feed-back that helps refine my thinking.And on a very personal note, I get

to connect with old friends whofind me through the blog and makenew ones through those who com-ment there.

From the point of view of a pro-fessional scientist, there are manyblogs that may be useful and inter-esting. But how do you find theright ones, and keep up with thenew ones that wink into existence?

A first approach is to find recom-mendations from back in theprinted world or from a friend orcolleague. This might identify abunch of sites, and after browsingthem you are likely to find a few thatreally click — perhaps you enjoy thecommentary, or find the authors aregood at pulling hidden gems out ofthe literature. Most blogs include ablogroll, or a list of other sites theblog author finds interesting; thiscan be a rich hunting ground forother sources. There are also serv-ices that aggregate multiple blogs onrelated themes, such as the DNANetwork, which is like a newswireservice for blogs related to geneticsand genomics that you can sub-scribe to through an RSS feed.

But if you’re looking for anoverview of some of the recent blogtraffic in a given subject area, checkout the species known as a blog car-nival. They don’t have rides orbarkers, but they’re a good way tosurvey the field of scientific blog-ging. The general scheme is muchlike a floating poker game: a set ofblogs takes turns hosting the carni-

val. At a given time, the host of thecarnival collects recent blog entriesof interest and writes a post men-tioning all of them with short com-mentary and links back to the orig-inal articles.

A number of active carnivals existthat may be of interest to GT read-ers. Three that I’ve contributed to inthe past are Mendel’s Garden,which celebrates the full spectrumof genetics; Gene Genie, which hasthe ambitious goal of eventuallyhaving at least one post coveringevery gene in the human genome;and the Cancer Blog Carnival,which covers a wide spectrum ofcancer research.

Keith Robison’s Omics! Omics! blogfrequently covers issues on the inter-section of large-scale biology researchwith the biotechnology industry. Hisblog can be found at http://omicsomics.blogspot.com

Keith Robison introduces you to why scientists blog, how to find relevant and useful sites, and a phenomenon called the blog carnival.

Welcome to the Blogosphere

KEITH ROBISON

KEITH ROBISON My Take


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The Legacy of Ling and Smith

Under One Roof BASIC MEETS CLINICAL

In 1997, Michael Smith andVictor Ling founded theGenome Sciences Centre, ahigh-throughput genomicscenter with a sharp focus

on cancer. “Here you have two ofCanada’s most widely respected andwell-known scientists, Victor Lingand Michae l Smi th , comingtogether and saying that they weredevoted to the concept of agenomics presence in Canada,” saysMarco Marra, director of what isnow the Michael Smith Genome Sci-ences Centre. Smith won the 1993Nobel Prize in Chemistry for site-directed mutagenesis, sharing itwith Kary Mullis, who was recog-nized for his PCR work.

In the late ’90s, Ling was the vicepresident of research at the BritishColumbia Cancer Agency, whichwas instrumental in getting thenew genomics center up and run-ning. The British Columbia CancerFoundation gave Ling and Smith$25 million to launch the center.“At the time, this was the singlelargest investment put into thefield in Canada,” says Marra. “Thecancer foundation was persuadedto back the enterprise basedlargely on the belief that cancerand cancer genomics would be thenext big thing.”

The GSC cut its teeth on its firstbig project, generating a BAC finger-print map of the mouse genome inconjunction with Washington Uni-versity and the Sanger Institute.

Since then, Marrasays, the center hashad a string ofgrants and contractfunding, totalinga p p r o x i m a t e l y$250 million. Ithas expanded to230 staff members,with 10 principalinvestigators whofocus on a range ofprojects from pro-teomics to map-ping.

“We’re all collab-orating at a very highly integratedlevel. I’m working with the cancergenomics people and the geneexpression people,” says StevenJones, head of bioinformatics at thecenter. “When we write large appli-cations, we are writing themtogether as a team. That’s really howwe’re running the center.”

The center hasn’t lost its cancergenomics focus. Of the 60 or soongoing projects, a whole host ofthem are looking into the geneticsand genomics behind cancer,including studying the follicularlymphoma genome in deep detailas well as analyzing which geneskeep people healthy by looking atoctagenarians who have neverdeveloped cancer, cardiovasculardisease, or pulmonary disease. “Atthe time [the center was founded],it seemed like a focus on cancergenomics was exactly where this

field would head. And in hindsight,it looks like Victor and Michaelwere right,” says Marra. The GSC,through Genome British Columbia,also takes on projects unrelated tocancer.

Cancer and aging

The two big projects going onright now in the cancer genetics labat the center are population-basedSNP studies of non-Hodgkin’slymphoma and of healthy aging.The GSC functions under the aus-pices of the BC Cancer Agency,which is responsible for all of thecancer patients in British Colum-bia. Angela Brooks-Wilson, whoruns the cancer genetics lab, triesto keep that in mind. “What I liketo do is take into account, or baseour studies around, the BC CancerAgency’s mandate for cancer care

MICHAEL SMITH GENOME SCIENCES CENTRE

With $250 million in funding, Marco Marra’s genome centeraims to deploy the latest technology in the battle against cancer —but it hasn’t forgotten the mountain pine beetle. By Ciara Curtin



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and research for the whole BC pop-ulation,” she says. In conjunctionwith researchers at the canceragency, her lab is conducting aSNP and haplotype-based case-controlled study to uncover geneticsusceptibilities to non-Hodgkin’slymphoma.

Brooks-Wilson is also lookinginto what it takes to grow old grace-fully — that is, without developingcancer, cardiovascular disease,pulmonary disease, or diabetes.This study takes a twist on a case-control study since the cases hereare people 85 years or older whohave never developed any of thosediseases or conditions, while thecontrols are middle-aged peoplerecruited randomly from the popu-lation, regardless of their health.“The study has a genetics, ratherthan lifestyle, focus, and we want tofind genetic factors that contributeto healthy aging,” says Brooks-Wilson. In particular, her team,which includes GSC investigatorsMarra and Jones as well as outsideclinicians, is using a SNP approachto the research.

Next-gen at the fore

Naturally, technology has a criti-cal role at the GSC, which contin-ues to build up its instrumentation.“Right now, perhaps not surpris-ingly, we’re quite heavily focusedon developing applications fornext-generation sequencing and,i n p a r t i c u l a r, t h e I l l u m i n asequencer,” says Marra. GSC scien-tists have made approximately 500Illumina sequencing libraries andare ramping up their core instru-mentation.

“The big thing is we [can] nowstart to attack cancer genomesfairly robustly with these newdevices,” adds Jones.

Marra’s already got one experi-ment in mind to try out their new

next-gen sequencers. As a continu-ation of their BAC fingerprintmapping projects, GSC researchersare making whole-genome, deeplyredundant BAC libraries of cancergenomes that they are then finger-printing to look for cancer muta-tions. Working from a library ofapproximately 150,000 BACs andusing a combination of restrictionenzymes to generate a pattern,they compare the cancer genomepattern to one predicted computa-tionally from reference genomes.Any difference between the pre-dicted pattern and the fingerprintgets marked as a candidate muta-tion to be further validated.

When they made a BAC fingerprintmap of the follicular lymphomagenome and analyzed it, they foundthat the genome has hundreds orthousands of tiny deletions with amedian size of about 5 kilobases. “Itturns out that many of these itty-bitty, tiny deletions are associatedwith repeats,” says Marra. “We

think this is a fantastic structuralgenomics project, and we’re quitekeen now to take that samegenomic material and analyze iton our Illumina sequencers to seewhat the overlap and the pickup rateis. It could be that the BAC finger-printing gives us better detectionsensitivity in these regions than theIllumina because these regions areenriched in repeat sequences and, ofcourse, sequencing repeats withshort reads is tough work.”

The forestry branch

Another part of the GSC’s mandateis to take on projects important toBritish Columbia as a whole. “Withfunding from Genome BritishColumbia, we are essentially aprovincial platform for certaintypes of genomic activity, includingDNA sequencing and bioinformat-ics,” says Marra.

With the surrounding forestrycommunity, GSC’s team is workingon the genome of the mountainpine beetle and the blue stain fun-gus it carries. This bug and its fun-gus have decimated about two-thirds of British Columbia’sforests. Due to warmer winters, themountain pine beetle populationhas exploded, says Marra. Thebeetle chews on the bark of thetrees, weakens them, and leavesthe fungus behind — which fur-ther harms the trees by interferingwith water uptake and movement.At the genome center, scientists arelooking for vulnerabilities in thebeetle and fungus to control theirspread throughout the province.“The idea is now to figure out howcan we restrict spread by perhapsusing genomics to study the beetleand fungus to find targets or sus-ceptibility to agents — perhapseven biological agents that wouldallow us to control the infestation,”says Marra.

>MICHAEL SMITH GENOMESCIENCES CENTREVancouver,British ColumbiaHOST: British Columbia CancerAgencyDIRECTOR: Marco MarraESTABLISHED: 1997, by MichaelSmith and Victor LingSIZE: 50,000 square feet of lab,occupying two floors of two buildingsSTAFF: About 230, with 10 principalinvestigatorsFUNDING: About $250 million from25 sources, including BritishColumbia Cancer Agency, GenomeCanada, Genome British Columbia,the National Institutes of HealthFOCUS: Cancer research’OMICS TOOLS: New Illuminasequencers, BAC fingerprinting, SNPanalysis, as well as bioinformaticsand proteomics


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TISSUE MICROARRAYS

The AwkwardAdolescence of Arrays

As far as microarraysgo, gene chips mightas well be consid-ered the new kid onthe block. All sorts

of samples can be put down on aslide in an array format, and thelongstanding tissue microarray isamong the most useful to the fieldof clinical pathology. While thesearrays are primarily used to probelarge numbers of tissue samples forcancer biomarkers, many patholo-gists still haven’t made the jump totruly high-throughput biology —they eyeball each sample individually.

The first tissue array was createdmore than 20 years ago, but it’staken until the last decade for auto-mated arraying and imaging to pro-pel the technique into the realm oflarge-scale biology. Still, automationhas yet to be widely adopted, leav-ing many pathologists looking formore objective analysis. Few ven-dors offer such standardized, quan-titative readouts, and in manycases, the automated platforms arejust not affordable.

Most labs create their own tissuemicroarrays using archived patient

microarray is labor-intensive,whether one has automated arrayerson hand or not. Using a hollow nee-dle, tissue cores as small as 0.6 mmin diameter are extracted fromparaffin-embedded clinical biopsysamples, and then deposited into amaster block in an evenly spacedarray pattern. From this masterblock, sections are cut andmounted on a slide. Most often,researchers use immunohistochem-istry to see which protein is beingexpressed, how much is there, andits specific location within the sec-tion. These arrays can also be usedto visualize nucleic acids throughfluorescent in situ hybridization.

Tissue arrays have found a strongfooting in clinical research labs,whether for biomarker discoveryand validation or for drug develop-ment studies. “Users are looking attissue biomarkers, or looking at try-ing to understand protein functionbetter. So they purified a new pro-tein X from some gene screen andnow they want to know, is itexpressed predominantly in pri-mary tumors or in metastases? Or isit expressed only in low-gradetumors or low-grade and high-grade? Or is it expressed in prostatecancer but not in breast cancer?”says Rimm. “Those are the kinds ofquestions they can ask.”

In clinical trials, associating patientdrug information with gene expres-sion patterns is critical to making asuccessful drug, so the arrays areoften put to use in dosage and toxi-cology studies. “It’s condensedpathology,” says Stephen Hewitt,who runs the National Cancer Insti-tute’s tissue core facility and producesarrays for both NCI and externalresearchers. “Instead of screening afew cases, you’re screening largenumbers of cases.” His team tends tofocus on validating biomarkers, bothprognostic (Will a patient’s tumorspread?) and predictive (Will the

Tissue arrays have found their footing in translational

research — but scientists say they’re still struggling

with imaging and standardization.

BY JEANENE SWANSON

samples. There are at least 20 ven-dors that sell prefabricated arrays;however, most of these aren’t thatuseful because they lack archivalclinical annotation. “There’s a verywide range of tissue and questionsand possibilities with formalin-fixed, paraffin-embedded mate-rial,” says David Rimm, director ofYale’s tissue array core facility. “Infact, one of the great resources thatI think many institutions have … isthe pathology archives. [They] rep-resent our oil well, so to speak.”

Building blocks

The process of creating a tissue

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patient’s tumor respond to ther-apy?). While much published workhas focused on localizing specificmarkers for disease mechanism ofaction, Hewitt notes that arrayshave been a boon for molecular epi-demiologists studying risk factors inlarge populations. Though the fieldis currently being driven by SNPs,he says, “people really do want tolook at environment and proteininteractions. … This is a platformwhere you can look at those ques-tions — the questions you just can’tanswer at the DNA level.”

Translational research

As a translational research tool or,as Hewitt says, “the translationpoint from basic science towardsclinical medicine through pathol-ogy,” tissue microarrays put broadpopulation samplings to good use.NCI’s Mark Sherman uses tissuearrays to classify tumors accordingto expressed protein biomarkers. Hecan then go back to find which fac-tors impose more of a risk than oth-ers, and whether or not these can berelated to all tumors. “Eventually wewant to develop a risk model forbreast cancer where we have factorsthat relate,” Sherman says, in orderto track how breast cancer develops,how it might be prevented, and howit could be detected more effectively.

His studies typically includethousands of patients. In one proj-ect, he is investigating 2,500 Polishwomen with breast cancer to corre-late risk with different factors,including low penetrance genes. “Ifwe had to look at one slide perpatient, it would cost us a prohibi-tive amount of money,” Shermansays. Not only do tissue arrays makethese studies affordable, but theyalso increase reproducibility andaccuracy, especially in light of thefact that staining many individualslides by hand can introduce error.“For efficiency, speed, standardiza-tion — very large studies have triedout this approach,” he adds.

Enabling much of this research arestandard assays, like IHC and FISH.For accreditation purposes, manyclinical labs make use of the high-throughput na ture o f t i s suemicroarrays for internal validation.At the Cleveland Clinic, Ziad Peer-wani, a third-year resident in thedepartment of pathology, is workingon a project with the College ofAmerican Pathologists to standard-ize their IHC runs across the clinic— and thereby maintain its CAPaccreditation — with specially cre-ated tissue arrays. Moreover, pre-fabricated arrays can also be used asinternal experimental controls “forpositive staining control to ensurethat your techniques are workingproperly,” Peerwani says.

With such widespread clinicaluse, it’s hard not to wonder if tissuemicroarrays have potential diag-nostic value. Most experts say thatthey predict little use as a diagnos-tic tool, simply because clinicaldiagnoses can’t wait for hundreds ofpatient samples to come in beforean IHC stain is run. Yale’s Rimmsees it as basically a high-through-put research tool. However, echoingPeerwani, he’s already seeing clini-cal use for control tissue. “Instead ofputting on a single control tissue,

you can now put on 20 or 30 or 50control tissues with every slide,” hesays. “I expect that we’ll see anincrease in usage in that context.”

Images and standards

Technological advances duringthe last decade have producedplatforms for automatically array-ing and digitally visualizing arrays,which has cut down on time andsubjective error. However, mostexperts interviewed still create andvisualize their arrays manually.

“The big 800-pound gorilla in theroom is not so much applying thesematerials, but actually trying to doit in a very validated, standardizedfashion and then reading them,”says Sherman. Most of the analysisis still done by eye, as IHC itself isdifficult to standardize. IHC is notvery reproducible and is very quan-titative. Additionally, pathologistscontinue to struggle against tissueheterogeneity — trying to create anarray that accurately and com-pletely represents protein expressionpatterns that might differ across atumor mass.

Rimm and colleagues have con-fronted these problems head-on.While automating the arrayingprocess hasn’t been that successful— tissues vary not only in proteinexpression patterns but also in


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thickness and amount of fat content— building out a platform to readthe arrays in a more standard fash-ion has. In 2000, Rimm beganworking on a measurement toolthat reads absolute protein concen-tration from an IHC stain, and it’snow licensed exclusively to HistoRxunder the name of Aqua. “Thebiggest limitation in my own mind,which is what we started working onin 2000 and now have overcome, isthe reading of them,” he says. “Backwhen they were invented, the onlyway to read them was to have apathologist look at them and issuean opinion. While I am a pathologistand I respect pathologists’ opinions,they will never be objective.”

When using IHC to visualize pro-tein concentration, pathologists use asubjective approach, estimatingwhat they think might be the inten-sity of the spot and then grading it ona gross range. HistoRx’s Aqua tech-nology measures absolute quantityand assigns each spot a standardizedscore. While a much less subjectiveroute than eyeballing, it’s still difficultto get statistically relevant informa-tion from an IHC stain. “I think the

biggest hurdle is capturing the truestatistical power that comes fromanalyzing large populations on a tis-sue microarray,” says John Tonkin-son, VP of business development atHistoRx. With IHC, “you’re using avery subjective, qualitative way ofsaying, there’s a little bit there,there’s a lot there — and now you’retrying to apply that in a quantitativefashion to generate statistical value.The two are not compatible.”

While HistoRx’s is the only systemthat does absolute concentration,Rimm says, a number of other ven-dors offer digital scoring tools.However, Tonkinson notes, despitea move toward digital pathology,most people are still “doing it byeye.” The equipment is, for the mostpart, only available to drug develop-ment companies or researcherswith deep pockets.

Says Hewitt at NCI, “The imageanalysis field is something that iscontinuing to evolve. There’s notgoing to be a winner; there’s going tobe a number of high-quality solu-tions.” He’s used several differentsystems, and acknowledges that thetechnology is not only expensive,

but also a work in progress. “It’s stilla challenge. Only recently have Ibeen willing to take my bigger proj-ects into full, automated analysis,”he says.

A major roadblock is databaseinfrastructure. For example, Hewittsays that for each tissue array, thereare 400 to 500 cores, with up to 20gigs in images for each core. Withsuch immense data sets, the analysispart tends to lag behind, simplybecause the data has more complex-ity and depth, he says. “It’s not triv-ial bioinformatics.”

Peerwani at the Cleveland Clinicknows that automation won’t takeaway the need for pathologicalanalysis — when it comes to howtumors act in living tissue and howthey interact with surroundingstructures, looking at tissue sampleson a slide probably won’t cut it. Butfor now, he says, “I think that thenewer technologies are a very bigboon to the research itself and to theart and science of using tissuemicroarrays.” He adds, “I think theproblem is their expense. As thosecome down, it will be more practi-cal to utilize it.”

Most pathologists are pessimistic about tissuearrays ever being used as a diagnostic tool, but trytelling that to the British Columbia CancerAgency’s David Huntsman. An associate professorat the University of British Columbia, Huntsmanrecently finished a pilot study that tested whetherarrays could be used in actual breast cancerpatients to determine risk subgroups. “We consid-ered whether we could use tissue arrays for thedelivery of breast cancer biomarkers,” Huntsmansays. “We’ve done a pilot study which showed that the tissuearrays gave results which were basically similar to whole sec-tion data.” While it would work in a clinical environment, hesays, it would only work for laboratories where there’s a very

high throughput of samples being analyzed. “Inthe US, where the regulatory bodies are quite dif-ferent, the use is likely to remain in quality assur-ance,” he says.

Huntsman sees more immediate challenges tothe field. He thinks miRNAs and other noncodingRNAs have a lot of potential as biomarkers, “butto my knowledge there isn’t an effective way ofstudying these using tissue arrays. And that’sgoing to be a challenge.” Another challenge is not

just identifying and localizing proteins, but determiningwhether they’re active post-translation. For this task, “thereare real issues with looking at phospho-specific antibodiesin archival specimens,” he says.

Hunting for Diagnostic Uses

DAVID HUNTSMAN


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You’ve got to wonderabout scientists whofocus on protein bio-markers. While thereare plenty of far

more stable types of markers, suchas DNA, these people have deliber-ately chosen one of the most finickyanalytes out there. As if that weren’tenough, they’re trying to wrap upmultiple proteins into an assaypanel and somehow ship them off toa clinical setting.

But these scientists contend that ifthey can get protein biomarkers towork, their virtues will far outweighthe pains it took to usher them intothe clinic. For starters, says ShawnComella, CEO of Monarch Life Sci-ences, proteins provide a moredirect measure of what’s going on inthe body than other molecules do.“Just because you have a genemutation doesn’t mean you’regoing to see a disease,” he says. “Bymeasuring the proteins and reallycorrelating it with other data you geta much better picture of what’sgoing on with the patient or withthe disease.”

Proteins can also be detectablelong before other changes — forinstance, the DNA changes charac-teristic of cancer cells — make

themselves known, says DrakeZhang at ProtTech. “A protein givesyou the best chance for early detec-tion of cancer,” he adds, noting thathis service company has seenincreased demand for work withthese kinds of biomarkers.

Early detection is just one goal ofidentifying and validating proteinbiomarkers. Potential uses for thesekinds of markers include determin-ing drug efficacy, risk stratification,prognosis and diagnosis of patients,classifying patient populations, andtoxicology, says Comella.

Current challenges

There’s no shortage of hurdles toovercome in the quest to turn pro-tein biomarkers into a clinicalmainstay. Perhaps above all else,though, proper validation proce-dures loom over the field.

The challenge is not about discov-ering biomarkers, experts say.“Everyone’s drowning in candi-dates,” says Emanuel Petricoin atGeorge Mason University. “Every labhas a series of candidate markersthat they think are great.”

That’s in part because proteins arecontinually changing, so if you’relooking for changes in proteins, you

PROTEIN BIOMARKERS

Scientists say protein biomarkers could have a

real impact in the clinic. But getting there will

require better sample sets, new platform

development, and serious validation.

Toward ClinicalProteomics

BY MEREDITH W. SALISBURY

won’t be disappointed. “I’ve neverseen anybody do a biomarker dis-covery project that didn’t come upwith an answer,” says Martin McIn-tosh at the Fred Hutchinson CancerResearch Center. Whether thatanswer will hold up through valida-tion studies is another issue entirely.

Validation — the step of takinghundreds or thousands of candi-date biomarkers and putting themthrough their paces to find thehandful that are really indicative ofthe disease or condition you’retrying to predict or diagnose — isthe real trick. “What all of us arelacking is a facile way of validatingthese multiple markers in a high-throughput system rapidly so thatyou can really separate the con-tenders from the pretenders with alarge number of samples,” Petri-coin says.

While the discovery process hap-pens in a massively parallel way,validation is still slowed by theneed for high sensitivity and goodreagents. “Right now, most peopleapproach biomarker evaluation bygenerating an antibody [and run-ning] an immunoassay or aradioimmunoassay,” Comella says.“It generally takes a long time togenerate an antibody, or you can’tget a good antibody. It’s alsoexpensive.”

At Monarch, Comella and histeam use a mass spec-based systemto eliminate the need for antibod-ies, but of course that meansthey’re using a platform that isknown to be less sensitive than itsimmunoassay counterpart. “Wehave some pretty elegant methodsof getting around that by depletingproteins, by fractionating orenriching,” he says. “Most of thetime we can develop an assay that’sas sensitive as it needs to be.”

Gordon Kapke, senior director ofbiomarker services at Covance,says that the technology for looking


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at biomarkers has a way to gobefore it reaches the necessarypoint for clinical utility. “ModernLC-MS techniques have appropriateprecision and reasonably good sen-sitivity,” he says, “but you still arelooking at only a small fraction ofthe human proteome.” He estimatesthat to look at all of the proteinsand truly evaluate their biologicalrelevance “improving the sensitivityof the assays by 10- to 100-fold ormore.”

Another issue facing clinical pro-teomics is complexity — some-thing the genomics field is justbeginning to iron out itself. Goingforward, Petricoin says, it’s unlikelythat protein biomarker tests will bebased on a single analyte; instead,panels of analytes will be studied inconcert to diagnose a patient orstudy drug response. “A lot of peo-ple in the last decade have beensearching for that elusive single-analyte marker,” Petricoin says,using PSA as an example of onethat’s currently used in the clinic.“The sea change has been towarddiscovering and measuring multiplemarkers at once.”

Which is, of course, its own can ofworms. Investigators have long

been familiar with the concept thateach protein has its own “sweetspot” of ideal temperature andother conditions. Imagine trying toaccommodate a 20-marker panelwith 20 different sets of conditions,and you can see what the field is upagainst. “The platform that youdevelop to measure those has to beunlike platforms in the past,” saysPetricoin. “That is not like yourfather’s PSA test.”

A final hurdle for all of this workis to have good sample sets to usein validation and other studies.Most b iorepos i tor ies haven ’trequired sample collection underthe conditions necessary to studyproteins, Petricoin says — forinstance, samples may have sat outfor several hours before beingstored, rendering them useless toproteomics researchers. McIntoshrecommends that scientists try toestablish partnerships with clinicalcollaborators who have access togood samples and whose ownwork could be furthered with goodprotein biomarkers.

Life in the clinic

As intimidating as those chal-

lenges are, scientists are makingprogress on all of those fronts,thanks to hard work and fundinginitiatives from agencies like theNational Cancer Institute. Expertssay a few key events will help cata-pult protein biomarkers beyondthe research lab.

For starters, Petricoin says thatadvances in mass spectrometrycould go a long way to helping getthese biomarkers validated. Hybridand other novel platforms —including immuno mass spectrom-etry, multiple reaction monitoring,and the triple quad mass spec — areall progress toward clinical utility,he says.

But scientists have to realize thatmass specs will never be a clinician’stool of choice, says Monarch’sComella. Once biomarkers arefound and well validated, clinicianswill have to be given an easier-to-useassay for them, he says.

Overall, optimism reigns in thisfield. Comella contends that it’ll takejust one big success to make theconcept truly viable. “The big thingthat will probably move it forward isto have a protein biomarker used ina clinical trial,” he says. “I don’tthink we’re very far [from that.]”

While everyone else debates the possibilitiesfor protein biomarkers, the folks at Power3Medical think they’ve got it worked out. Late lastyear, the Texas-based company launched abreast cancer test in 12 Middle Eastern coun-tries, where the incidence of breast cancer isthree to four times greater than it is in the US.The $500 test consists of a panel of 22 proteinbiomarkers. Steve Rash, the CEO of Power3,says the company hopes to launch the test in theUS as well after it completes an ongoing 100-patient study.

The company is also validating multi-marker tests for Alzheimer’s and Parkinson’s.“These would be the first known proteomicstests to be commercialized,” Rash says. Thebreast cancer test has demonstrated sensitivityand specificity of 80 percent or more, Power3says, compared to about 40 percent for thecurrent mammography standard.

Because Power3 performs all of its testing inits own CLIA-certified laboratory, these tests

do not require FDA approval, Rash says.

Power3’s Protein Biomarker Play

STEVE RASH


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WorksWell WithOthersLarge-scale biology led to the advent of

“team science,” but tenure is still awarded

for individual work. When it comes down to

better science or a solid career, researchers

are losing out. GT investigates how

(and whether) to fix tenure.

In two years or so,Narayanan Perumalwill go up for tenure.An assistant professorat the University ofIndiana/Purdue Uni-versity School of Infor-

matics, Perumal researches generegulation and immune systemdevelopment and collaborates withresearchers at the medical school.Though the informatics school val-ues working with others — really,it’s the only way to be a successfulbioinformaticist — Perumal stillhas some concerns about how thetenure review committee willassess his work.

“Informatics is a bridge betweencomputer science and biology orcomputer science and healthcare,”says Perumal, who has spoken tohis associate dean to figure out howto make sure his contributions tothe projects are recognized. “Ourtenure committee has been tellingus to clearly [say] what exactly ismy part and what exactly was donefrom my collaborators’ side, so theyknow how much credit to give me,”he says.

When junior faculty members goup for tenure around their sixthyear at a university, they are judgedon their scholarship, the grantmoney they brought in, and com-

munity service and teaching. Forscientists in large-scale biologywho spend a lot of time collaborat-ing or working in a consortium ona big project, it becomes difficult forreview committees to parse outtheir individual scholarship andfundraising abilities. As one personin a large group, a particularresearcher’s name may not appear inthat coveted first or last author posi-tion on the paper and may not belisted as a PI or co-PI on the grant.The culture of much of academia,and tenure review committees inparticular, is tied to looking at a fac-ulty member’s independent work;so if researchers rarely or never

BY CIARA CURTIN

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work alone, they may miss out ongetting tenure.

There’s the rub. Groups and con-sortiums get the big questions inbiology answered, but tenure com-mittees don’t evaluate groups —they evaluate individuals.

“In genomics … you do have to getout there and collaborate with peo-ple. It’s really the only way to get itdone. The datasets needed and theskill sets needed are too broad now.One person can’t sit down and do itall themselves,” says John McPher-son, a platform leader at the OntarioInstitute for Cancer Research. Point-ing to the Human Genome Project,he adds, “Consortiums work. Con-

sortiums get things done.”The funding is there, too, for

team science. In the US, theNational Institutes of Health andthe National Science Foundationare giving money to collaborativegroups. NIH’s Roadmap Initiativeincludes support for collaborativeteam research projects and, accord-ing to a National Academies Pressreport on interdisciplinary research,there has been a steady upwardtrend in the number of PIs on grantsawarded by NSF. “They are pouringmillions and millions of dollarsinto interdisciplinary science,” saysCathy Trower, a research associatewho studies young faculty and

tenure issues at Harvard University’sGraduate School of Education.

The funding agencies havechanged to accommodate teams ofscientists working on one problem,but the tenure system has yet tocatch up, clinging to a review sys-tem that may be outdated.

“We’re training students that teamscience is the way to do it. It seemsarchaic to then attempt to judgethem by a system that doesn’tacknowledge that,” says HuntWillard, director of Duke Univer-sity’s Institute for Genome Sciencesand Policy.

In fact, some junior faculty mem-bers are dissuaded from collaborat-

NARAYANAN PERUMALAT IUPUI

PHOTO: JOHN GENTRY, IUPUI M A R C H 2 0 0 8 GENOME TECHNOLOGY 37


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ing right from the get-go. “We tellyoung scholars, ‘Wait until youhave tenure to solve very coolproblems,’” Trower says.

Gerry Rubin, the director ofJanelia Farm, says this is a systemicproblem. “They are told that at thebest research universities explicitlyby deans, by department chairs, bysenior colleagues. But then [univer-sities] want to have collaboration.They are not being internally self-consistent, in my view,” he says.

By the time junior faculty receivetenure, they may no longer beinterested in teamwork. “My con-cern is what happens [after] sixyears or seven years or eight yearsin some cases on a tenure track,which becomes a tenure rut. It getsbeaten out of them and theybecome entrenched. … By the timethey get [tenure], they go, ‘Hmm, Idon’t remember what got me soexcited,’” Trower says.

How many authors?

Collaboration is relatively new tothe biomedical sciences, and the cul-ture of academia hasn’t changed tokeep up. Other academic areas,such as physics, have long beeninvolved in large collaborativeefforts, and junior faculty in thosedisciplines still receive tenure, saysMary Lidstrom, vice provost ofresearch at the University of Wash-ington. She says the difference is thatin those disciplines, the academicculture places value on teamwork.

Unlike physics departments,many biology and related depart-ments have yet to internalize theirvalue of collaboration, stickingwith tenure review metrics and cri-teria that focus on independentscholarship. At many places, if ajunior faculty member is not thefirst or senior author on a paper, itcounts less or not at all toward hisor her publication record. Here, the

problem isn’t with tenure, says Lid-strom, but with the values of thepromotion and tenure committee.

“Universities are extremely conser-vative and are self-defeating,” saysRubin, whose own institutiondoesn’t offer tenure. Universitieswant to promote collaborative sci-ence, he adds, but when those sci-entists are reviewed for tenure,universities say they cannot tellwhich researcher did what andwho should be promoted. Rubinsays he can envision review com-mittees questioning whether togive James Watson tenure since heworked with Francis Crick on thedouble helix. “Maybe the doublehelix was just really Francis Crick’sidea?” he says he would expect atenure committee to ask.

Changing a university’s tenure

policy won’t necessarily translate toa change in how people on thereview committee think. “We tendto focus on structure because wetend to think that maybe changingstructure, having policies that sup-port the structure or support differ-ent types of work, will help. I saythey help, but they don’t fix it. Theydon’t fix the culture,” Trower says.

To the faculty undergoing review,the issue boils down to credit, saysPerumal. If you are one of manyauthors on paper, you might not getrecognition for the role you playedin that project from your home aca-demic department. This is espe-cially worrying to junior facultywho are trying to amass publica-tions and grants for their tenuredossiers, because they have learnedthat their names must appear firstor last on the list of authors or asthe PI on the grants. Otherwise, thereview committee will likely dis-miss that paper or grant out of handsince no one can tell who con-tributed what to the research.

“There are two positions thatmatter, no matter the size of theauthor list, and that’s the firstauthor and the last author,” saysElaine Mardis, co-director of theGenome Sequencing Center atWashington University. Those largeauthor lists, she says, are one of thedifficulties with doing big science.

There are now numbers to back upthose concerns. Jonathan Wren, anassistant member at the OklahomaMedical Research Foundation, andhis collaborators surveyed promotionand tenure committee members atmedical schools in the United States,Puerto Rico, and Canada about howthey perceived an author’s contribu-tion to a paper based on where thename appeared on the author list. Onpapers with three or five authors, therespondents gave the first author themost credit for performing the workand the last author credit for conceiv-

“We’re training students that team science is the way to do it. It seems archaicto then attempt tojudge them by a system that doesn’tacknowledge that.”

HUNT WILLARDDUKE UNIVERSITY


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ing of and supervising the project.Half of the people who respondedalso thought that the more authorson the paper, the harder it is to tell if“a candidate merits promotion.”

“It’s a cautionary tale to people whothink of co-authorship as being anequal contribution because, by oursurvey, it is widely recognized bypeople on promotion and tenurecommittees that positions are notequal,” Wren says.

The same problem seems to applyto grants. Junior faculty membersmust show review committees thatthey can support themselvesthrough the grants they receive. “Inmy case, I was awarded tenure notbecause I collaborate with people,but because I brought in one NIHR01. That was at the time thebiggest R01 that the school had.They had to be nice to me,” saysGeorge Plopper, an associate profes-sor at Rensselaer Polytechnic Insti-tute. Other researchers, like Indi-ana’s Perumal, will share theirgrants with collaborators, again

bringing up the question of credit. Mardis points to getting recogni-

tion for writing sections of grants asthe biggest concern she had aboutgetting tenure. She was often a co-PIor responsible for a concept orvision of the technology portion of agrant, but she was not the main PI.Even though she played a key role,there was little recognition. “To methat was the most daunting chal-lenge,” she says. (Mardis did indeedreceive tenure when the time came.)

Tenure reform

There are no shortages of ideasabout how the tenure review systemcould be altered. First of all, thereview metrics could be changed tosupport collaboration or innovation,perhaps by a simple addition to thereview criteria. How review occurs —currently, with stacks of papers —could be replaced by, or at leastinclude, an interview with the can-didate to allow that person to pres-

ent his case andanswer the commit-t e e ’s q u e s t i o n s .Another possibility:review committeescould give moreimportance to let-ters of support fromthe candidate’s col-

laborators. More drastically, thewhole system could be replaced witha rolling tenure or contract system.

The tenure review process, con-tends Antoine Danchin, the directorof the genomes and genetics depart-ment at the Pasteur Institute, is notset up to reward creativity or inno-vation, particularly if reviewers lookmainly at past journal articles. “Cre-ativity is very important. This can bemeasured, but not … by the biblio-metrics approach,” says Danchin.

Ontario’s McPherson agrees. “Ithink it’s more of an attitudeadjustment. People have to do a lit-

tle bit more work on the committeesto read the letters and look at thepapers and the contribution totease it out more. You can’t justcount up the number of papers asfirst and last author; you actuallyhave to think about what thepapers are. Some people aren’t will-ing to do that,” he says.

Danchin suggests that site visits byoutside experts could replace muchof the paper-based review. AtJanelia Farm, the review process —which is not for tenure but tosecure a new contract — will bebased in part on site visits. Expertswill come in, meet the scientistunder review, and discuss the sci-ence and thought processes behindthe experiments to understandwhat that researcher did and why.

Another avenue for change couldbe the metrics the review commit-tee uses to judge tenure candidates.Rubin predicts that after adding acollaboration criterion to thereview process, “team sciencewould blossom tremendously.”

That’s what Lidstrom’s University ofWashington engineering center did.“The dean’s office worked with ourappointments and promotions com-mittee to specifically add a criterionthat valued this collaborative work,”Lidstrom says. Assistant professorscame through, she says, collaboratedand did individual work, and came

ELAINE MARDISJONATHAN WREN

“There are two positions thatmatter, no matter the size of the author list, and that’s the first author and the last author,”says Elaine Mardis.


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away with tenure. Lidstrom pointsout, though, that no one had onlycollaborative work, so the system hasyet to be put to the real test.

Even if no changes are made tooverhaul the process, junior facultycan still use letters of support tohelp review committees under-stand that a middle author’s contri-bution can be critical to the successof an experiment or grant. “Somepeople who don’t work in thatenvironment feel that there’s no wayto determine your contribution. Ithink letters of support are impor-tant,” McPherson says. He addsthat if they come from more seniormembers of the consortium —people like Eric Lander or BobWaterston — those letters shouldbe weighted very heavily.

Mardis gives an example of whatsuch a letter could say. “You might

have someone like Francis Collins,or someone who’s chief in charge ofthe genome centers, providing youa letter of support saying, ‘I realizethat Elaine was one of 58 authors onthe human genome paper, but herseminal work in high-throughputproduction of sequencing made itpossible for us to generate the mul-titude of data.’”

That’s just the policy that DukeUniversity’s Institute for GenomeSciences and Policy has in place forits junior faculty. In setting up theinstitute about five years ago, HuntWillard negotiated with the dean andprovost of Duke to ensure that team-work and collaboration are expresslyvalued during the review process. Onthese tenure committees, peoplefrom other interdisciplinary centersserve to provide a positive view ofcollaborative efforts to the commit-

tee, and the person up for tenure pro-vides letters of support from peoplelike Willard explaining how essentialtheir role was in the collaborativeprojects. “In genomics, we have afairly young crowd of people andthey grew up working together. Tothem, that’s the style of doing sci-ence,” Willard says.

However, no one has tried out theDuke system yet — the first crop ofjunior faculty at the institute willcome up for tenure in a year or two.“In principle, it will count here, butwe have to see how that goes,”Willard says. “I’ve got my reputa-tion on the line.”

A worthwhile system?

As people go into contortions try-ing to make the review systemwork for these scientists, it begs the

In the 1950s, when Francis Crick and James Watson pub-lished their Nature paper on the structure of DNA, the aver-age number of authors on biomedical papers was low — itheld at 2.3 authors per paper between 1934 and 1963.Since then, there has been a rise in how many authors areon a paper. Today, papers in Nature or Science can haveupwards of 100 authors. The Human Genome ProjectConsortium, perhaps the most famous example of megas-cale science, had 1,100 members.

“The number of authors per paper has been rising prettymuch steadily since 1970 and it’s not a phenomenon that’sgoing away,” says Jonathan Wren, an assistant member atthe Oklahoma Medical Research Foundation. Two main fac-tors drive that rise, he says: pressure to publish and theincreasingly specialized skills needed to complete big proj-ects quickly. With more authors appearing on journal arti-cles, some journals are providing ways for joint first or sen-ior authors to be recognized for the work they did.

Along with his collaborators, Wren studied how anincrease in number of authors has affected how people per-ceive each author’s contribution to the project. “The fact

that the first and last authors get most of the credit … thatwasn’t surprising,” Wren says. “These two anchor positionsseem to get the lion’s share of glory, and the people in themiddle are really perceived to contribute very little — com-paratively little to everybody else.”

Journals have been adopting ways for authors to indi-cate who should get how much credit. In 1999, Natureadded a feature to its articles allowing authors to list theircontribution to the project in the acknowledgments sec-tion. Science soon followed suit. The journals also allowpeople to share the different spots on a paper’s authorlist. Both Nature and Science put an asterisk next to theauthors’ names and the footnote reads: “These authorscontributed equally to this work.”

“Science and Nature have done this for a very long time,but more and more journals are moving to this,” says MaryLidstrom, vice provost for research at the University ofWashington. The Public Library of Science journals alsoinclude author contributions in their articles, and theProceedings of the National Academy of Sciences requiresauthors to list their contributions.

The Rise of the Multi-Author Paper


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question: is tenure worth fixing?The arguments in favor of tenure

are well known but worth consider-ing. The professional securityafforded by tenure protects facultymembers from lean funding budg-ets and allows them to take intellec-tual risks. “I think [tenure] doesgive you a sense of security, to stickyour neck out and not just writegrants that you think will getfunded,” McPherson says. “Ifyou’ve got your back covered a lit-tle bit, and you don’t get that grant,at least you’ve still got a job.”

Rensselaer’s Plopper also says thatprofessors are not as mobile asother professionals, and the stabil-ity that tenure provides helps makeup for that lack of mobility. “I feelthat [if] people spend enough

energy and they make enough sac-rifices in their careers to pursue anacademic career, that there shouldbe something that gives it a corre-sponding amount of both financialas well as professional security,”says Plopper.

At the same time, tenure is a voteof confidence in a faculty member’swork and capabilities. “You askyourself all the time, how am I doingrelative to my peers?” Plopper says.

WashU’s Mardis adds, “To me, itwas a very important milestone andit’s certainly gratifying to have thatacknowledgment from the faculty.”

Tenure does, naturally, have itsdownside, namely the “deadwood”effect — those tenured professorswho hang around but contribute lit-tle to the university. To avoid that, a

common suggestion is to institute arolling tenure or contract system inwhich researchers would have tomaintain certain standards to keeptheir position. “I think that in orderto be employed by any institution,doing anything, you have to be pro-ductive,” Plopper adds.

“I’m a bigger fan of the rollingwindow where it protects you fromlean times or allows you to stickyour neck out but also it doesn’tlock them into supporting you for-ever,” says McPherson.

In essence, that’s what theHoward Hughes Medical Institute’sJanelia Farm has in place. WhenGerry Rubin set up Janelia Farm, hemade a conscious decision to abol-ish tenure. He argues that there isan inverse correlation between

If you’re aiming to become a professor butyour interests in biology mean that you’ll bespending a lot of time collaborating, there are afew things to keep in mind as you fight your wayup the academic ladder to land tenure.

First, says Gerry Rubin, director of JaneliaFarm, when you’re looking for a job, ask if theinstitution supports collaborative research.Some places are more encouraging of this thanothers, though he suspects that may change forthe better over time.

Cathy Trower, who studies tenure at HarvardUniversity, urges job candidates to get every-thing in writing, especially if you are looking ata joint appointment between two departments.“Ensure through a memorandum of under-standing [your] responsibilities and expecta-tions for both departments are spelled out asclearly as possible so that [you] understandwho [your] boss is in both departments,” shesays. She adds that besides the memo, youshould sit down with both department heads to go over allthe expectations and chart out a path to tenure — before

you agree to sign anything.Once you join a department, find a good men-

tor, says the University of Washington’s MaryLidstrom. Mentors can help, especially if yourun into difficulties with collaborators who aremore senior than you. “If you get into a bad sit-uation, you need help to get out of it,” she says.“Getting advice from more senior people is theway to go.”

As for your work, pursue what interests you,though you may want to have a balance of col-laborative and independent work. “Everyoneshould be driven by their intellectual questionsthat excite them, regardless of what it means interms of team research,” Lidstrom says. “It’soften a very good thing to have a mix with collab-orative research and a more focused [project].”

Finally, work hard, says Elaine Mardis atWashington University’s genome center. “Don’tbe afraid if you think you have a good idea. Getout there and promote them and find ways to

turn your ideas into reality,” she says. “Work hard and don’tbe afraid to speak up.”

What’s a Junior Faculty Member to Do?

CATHY TROWER

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tenure and the productivity of aninstitution. Sure, tenure’s great at anindividual level, he says, but not atthe institutional level. Rubin pointsto Bell Laboratories, Cold SpringHarbor Laboratory, and the MedicalResearch Council Laboratory ofMolecular Biology as evidence.These institution either had no orlimited tenure during their heydays— when they did their most inno-vative, cutting-edge research.

When Janelia Farm hires aresearcher, whether it’s someonefresh out of a postdoc or someonecoming out of an endowed chair, itis for a six-year contract. At the endof six years, the scientist undergoesa review — but not, Rubin stresses,just based on publications. If some-one does not do well on that review,Janelia Farm provides two years ofphase-out funding while the person

finds a new position. If it does gowell, then the researcher can staywith a five-year renewal, afterwhich there will be another review.The first review at Janelia Farm willtake place in about four years.

Not having tenure hasn’t been aproblem in terms of recruiting for

Janelia Farm, Rubin says. “There’s agood correlation between the peo-ple who are willing to do theresearch we want to do and peoplewho have the attitude, ‘I know I’mgood. Just give me the resources Ineed, I think I can prove myself. …Tenure’s not relevant. I’ll always beable to find another job,’” he says.

Having tenure at cross purposeswith collaborative science couldturn scientists away from academia,Rubin adds. “[The problem with theacademic] system is it tends todrive people who like more a team-work approach and a collaborativeapproach from academics intoindustry or other modes of doing it.Because it’s a turnoff for them.”

He says the choice for institutionsis a simple one. “You decide youdon’t want team science, or youchange the review system.”

GERRY RUBIN

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MICROARRAYS Upstream

To improve copy numberanalyses, GOLDEN HELIXwill collaborate with sixacademic centers, includingUCLA, ZUCKER HILLSIDEHOSPITAL, MONTREALHEART INSTITUTE,EMORY INSTITUTE, CASEWESTERN RESERVEUNIVERSITY, and theUNIVERSITY LUBECK.

LABORATORYCORPORATION OFAMERICA will use Affychips in a molecular cyto-genetic-testing service thataims to correlate structuralgenetic variation and chro-mosomal rearrangementswith pediatric autism, men-tal retardation, and devel-opmental delay.

ERASMUS MEDICALCENTER in Rotterdam willuse ILLUMINA’s InfiniumHD Human610-QuadBeadChips for a 10,000-subject study aimed atidentifying early environ-mental and genetic causesof abnormal growth in fetaldevelopment.

Fu e l e d b y ab e l i e f t h a tw i d e s p r e a dp u b l i c d e -

mand for access to per-sonal genomic informationwill grow in coming years,two firms entered the nas-cent consumer genomicsspace this month, bothusing microarrays in theirservices.

E a r l i e r t h i s y e a r ,SeqWright, a Houston,Texas -based cont rac tgenomics firm and certi-fied Affymetrix serviceprovider, launched itsGenomic Profiling Service,which uses an Affymetrixarray to provide customerswith their own personalgenomic database to helpinfer the risk of developingspecific diseases as well asaccess to genealogicalinformation.

Also, Konstanz, Ger-many-based GATC Biotechformed a subsidiary calledLifeCode to provide a sim-ilar service to European

Union residents. Accord-ing to the firm, the Life-Code service, which alsouses microarrays, will beavailable in the EU in threelanguages — German,English, and French — byApril.

The launch of these serv-ices follows the debut lastyear of three similar ones.November saw the launch

of personal genetics serv-ices by Navigenics, whichuses an Affy platform;23andMe, which is work-ing with Illumina; andDeCode Genetics, whichhas not divulged the nameof its platform provider.

All five of the firms differon how much they chargefor their service, whatdegree of counseling theyoffer their clients, and fromwhat regional markets theywill accept orders. How-ever, they are all chasing thesame idea that the marketfor genotyping includeseverybody.

“It’s still very much spec-ulative, so it’s hard to sayhow big the market is,”says SeqWright spokesper-son Marc Dantone. “But Ido be l i eve [per sona lgenomics] has a lot ofmovement behind it andwe do believe it’s a benefi-cial service.”

D a n t o n e s a y s t h a tSeqWright decided to enterthe market because as anAffy service provider, italready was equipped toposition itself for earlyentry into the consumergenomics space.

— Justin Petrone

SeqWright, GATC inPersonal Genomics

F U N D E D G R A N T S

BILLION

VALUE THAT RESEARCH

FIRM KALORAMA

INFORMATION ESTIMATES

THE GENE EXPRESSION

PROFILING MARKET

TO BE BY 2012.

$2.5D A T A P O I N T


MicroarrayNotes

BIOARRAYNEWS

DNA METHYLATION IN CANCER GENOMESGrantee: Gerd Pfeifer, City of Hope, Beckman Research InstituteBegan: Aug. 10, 2007; Ends: June 30, 2009 A small number of genes have been found to be methy-lated at high frequency in early stage lung cancer. In thisstudy, they plan to identify genome-wide DNA methyla-tion differences between normal lung tissue and earlystage lung tumors using a combination of microarraysand methylated-CpG island recovery assay.

$1,438,644/FY 2007$253,500/FY 2007INTERROGATING EPIGENETIC CHANGES IN CANCERGENOMESGrantee: Tim Huang, Ohio State UniversityBegan: Sep. 30, 2004; Ends: Aug. 31, 2009Researchers will study complex epigenetic interactionsin order to better understand neoplasms and humanfemale cancers. They will use various microarray plat-forms to investigate DNA methylation, histone modifica-tions, loss of heterozygosity, and transcription factorbinding in cancer cell lines and neoplastic epithelium andthe surrounding stroma. This data will also be used tobuild and refine data models.


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If you are interested in emerging gene-based diagnostics and therapeutics—and the intersection ofthese medical disciplines—plan to join us for AACC’s 21st San Diego Conference. As the conferenceenters into its third decade, this year will examine how molecular and genetic tools can be the catalyst of synergy in the combined field of diagnostics and therapeutics/drug discovery.

FIVE CONFERENCE SESSIONS• Sequencing and Haplotyping• Epigenetics and Cancer• Applications• Multivariate Analysis and Genetic Testing• Infectious Disease Testing

Each session features presentations covering a number ofemerging technologies and diagnostic tools, offered by recognized experts in the field. In addition, the OrganizingCommittee has built in more time for networking, posters and exhibits.

KEYNOTE PRESENTATIONRNAi, Other Mechanisms by Which Cells and Organisms Respond to Genetic Change, and the Implication of These Mechanisms on Human Disease and Health CareAndrew Fire, PhD, Stanford University(Nobel Prize in Physiology or Medicine, 2006)

SPECIAL PRESENTATIONUpdate on Infectious Disease Testing in Emerging NationsDeborah Burgess, PhD, The Bill & Melinda Gates Foundation

WHY YOU SHOULD ATTEND THIS CONFERENCEOur expert faculty includes a Nobel Prize-winner and leading researchers who will show you:

• Implications of RNAi on human disease and health care• Advanced tools for characterizing and sequencing DNA• Novel applications of molecular tools in diagnostics

and therapeutics• The FDA perspective on regulation of multivariate

index assays

GENOMIC TECHNOLOGIES AT THE INTERFACEOF DIAGNOSTICS AND THERAPEUTICS

MARCH 25-26, 2008 | LOEWS CORONADO BAY RESORT & SPA

For additional information or to register, visitwww.aacc.org/AACC/events/meeting/SanDiegoConf2008.htm


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http://www.aacc.org/AACC/events/meeting/SanDiegoConf2008.htm






PROTEOMICS Upstream

PLEXERA has exclusiveaccess to AUGURONBIOSCIENCES’ NucleicAcid Programmable ProteinArray technology for oneyear, with an option for aone-year extension. Plexerawill be testing and develop-ing NAPPA as a contentsource for its own label-free Kx Array platform.

FLUOROTECHNICS,an Australian biotech firm, announced a partner-ship with Japan’s WAKOPURE CHEMICALINDUSTRIES. Under their agreement, Wako will sell Fluorotechnics’fluorescence-based kits as well as its protease monitoring and live-cellintracellular imaging technologies.

NACALAI TESQUEand NACALAI USA will distribute OLINKBIOSCIENCE’s Duolinkproducts in Japan. Duolinkuses Olink’s in situProximity Ligation Assay technology.

Re s e a r c h e r sfrom the Uni-versity of Cal-ifornia, San

Francisco, and biomarker-discovery firm PPD haveused a liquid chromatogra-phy-mass spectrometrybased method to identify abattery of proteins differen-tially expressed in cere-brospinal fluid, in whatthey say is the first study inwhich a proteomic analysisof CSF yielded biomarkerswith greater sensitivitythan cytology.

The researchers com-bined high-resolutionLC/MS data for profilingdifferential quantificationwithout isotope labelingwith LC/MS/MS for proteinidentification, and found76 proteins in CSF associ-ated with central nervoussystem lymphoma, includ-ing a majority that had notbeen previously identified.

The study, which appearsin the Jan. 1 edition of theJournal of Clinical Oncology,

demonstrates that “the CSFpro teome conta ins awealth of potential diagnos-tic and prognostic informa-tion,” the authors report.

The researchers say tryingto pinpoint the cause offocal brain lesions inpatients with unexplainedneurological symptoms is aclinical challenge. Diag-nostic methods for CNSlymphoma include flowcytometry and, in some

cases, measuring beta-human chorionic gonado-tropin or alpha-fetoproteinlevels.

James Rubenstein, seniorauthor of the study and anassistant professor ofhematology and oncologyat UCSF, says that amongapproaches using CSF,cytology is the “gold stan-dard” in diagnosing braincancer. However, the sensi-tivity of the method todiagnose lymphoma andother cancers is less than50 percent.

The diagnostic method oflast resort is brain biopsy,but in addition to a risk forbrain hemorrhaging, themethod carriers a failurerate as high as 35 percent.

Earlier research suggeststhat the elevation of totalCSF proteins may be asso-ciated with adverse progno-sis in CNS lymphoma,although the identity ofspecific proteins and pep-tides had not been known.In addition, mass spec-trometry has been shown tobe able to detect such pro-teins to help diagnose cer-tain cancers early in theirdevelopment.

— Tony Fong

Proteomic Biomarkers For CNS Lymphoma


MILLION

CS-KEYS, A PROTEOMICS

FIRM THAT IS DEVELOPING

TECHNOLOGY FOR CANCER

BIOMARKER DETECTION,

RAISED $6.25 MILLION IN

SERIES A FINANCING.



ProteomicsNotes

PROTEOMONITOR

A PROTEOMICS APPROACH TO STUDY THE MECHANISMS OF FAS-INDUCED LUNG FIBROSISGrantee: Dong Chang, University of WashingtonBegan: Aug. 3, 2007; Ends: Aug. 8, 2008To study acute respiratory distress syndrome and the Fas pathway involved in lung injury, the researcherswill use mice with Fas on their myeloid or non-myeloidcells to study how alveolar epithelium and alveolarmacrophages contribute to lung fibrosis. Through pro-teomic analysis, they will look at mouse bronchoalveolarlavage fluid and determine how MMP-12 modifies profi-brotic proteins.

PLASMA PROTEOME PROFILING OF INSULINRESISTANCEGrantee: Nana Gletsu, Emory UniversityBegan: Apr. 1, 2007; Ends: Mar. 31, 2009Under this grant, researchers will perform a proteomicanalysis of insulin resistance to find biomarkers. Theywill study intravenous glucose tolerance tests and oxida-tive stress and inflammation of patients as they undergoa gastric bypass or are on a low-calorie, liquid formuladiet. Also, using LC/MS/MS, they will identify proteinsassociated with differences in insulin resistance in obesepatients who lose weight.

$229,500/FY2007$58,886/FY2007


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http://www.SelectBiosciences.com


http://www.lab-on-a-chip.net

http://www.microarraytechnology.biz

http://www.biodefensetechnology.net





SEQUENCING Upstream


Ma n a g i n gand ana-lyzing thedata from

the recently announced1,000 Genomes Projectwill pose a number ofchallenges, some relatedto the nature of the next-generation sequencingplatforms, but organizerssay the results will boostboth medical research andscientists’ understandingof human evolutionaryhistory.

The study consortium,which aims to sequence atleast 1,000 and up to2,000 human genomesw i t h i n t h r e e y e a r s ,includes two data-relatedworking groups. A dataflow group will be respon-sible for collecting andarchiving the sequencereads, helping map them toa reference genome, andmaking the data availableto the research communityin different formats andlevels of detail. Meantime,

an analysis group willfocus on aligning thereads, reconstructing the1,000 genomes from thedata, calling genetic vari-ants, and interpreting theresults.

A major challenge will bethe “sheer volume of data,”according to Gil McVean, aprofessor of statisticalgenetics at the University ofOxford, who co-chairs theanalysis group. The consor-

tium expects the study toproduce on the order of 6terabases of data, or 60times the sequence datathat has been deposited inpublic DNA databases overthe last 25 years.

According to McVean,the analytical tasks fallinto three broad areas:technology-related tasksthat focus on translatingthe raw data into DNAsequence and mappingthe sequence reads to a ref-erence genome; callinggenetic variants such asSNPs and structural varia-tions and reconstructingindividual genomes; andusing the results to helpdisease studies and otherresearch projects.

On the technology side,data analysis experts haveto grapple with the factthat the nature of the dataproduced by existing next-generation sequencers isstill in flux. “The data thatcomes out of the machinesis changing pretty muchmonth by month as theengineering improves,”McVean said.

— Julia Karow

‘1,000 Genomes’Challenges Data Flow


MILLION

NHLBI AND NHGRI SET

ASIDE $12 MILLION IN

GRANTS FOR DEVELOPING

CHEAPER METHODS OF

EXON SEQUENCING.

$12D A T A P O I N T


SequencingNotes

INSEQUENCE

SEQUENCING DNA BY TRANSVERSE ELECTRICALMEASUREMENTS IN NANOCHANNELS Grantee: Robert Riehn, North Carolina State UniversityBegan: Aug. 1, 2007; Ends: July 31, 2009With this exploratory grant, Riehn and his team plan tobuild a sequencing technology using stretched and lin-earized DNA in nanofluidic channels, and detectionusing nanoelectrodes, according to the grant abstract.Riehn says this kind of technology would enable ultra-long read frames of more than 100 kilobases.

EXON SPECIFIC SEQUENCING OF WHOLE GENOMIC DNAGrantee: Darren Link, RainDance TechnologiesBegan: July 1, 2007; Ends: June 30, 2009Link says his long-term goal is to build a way to simulta-neously sequence thousands of different exons from agenomic DNA sample with 30 to 50 times coverage ofeach exon. The technology will be based on RainDance'smicrofluidics platform and 454 Life Sciences sequenc-ing, according to the abstract.

$140,625/FY2007$219,331/FY2007

KNOME, a personal whole genome sequencingstartup, lined up its firsttwo customers andannounced a partnershipwith the BEIJINGGENOMICS INSTITUTE.Based in Cambridge, Mass.,Knome offers whole-genome sequencing and genomic analysis for $350,000.

DNA sequencing technolo-gy startup GENOMECORP. raised $250,000 inventure funding to continuework on its massively paral-lel Sanger sequencing tool.It also named three found-ing members of its scientif-ic advisory board: NORMDOVICHI, ANNELISEBARRON, and PATRICKDOYLE.

PACIFIC BIOSCIENCESsaid it expects to commer-cialize a next-gen sequencerby 2010 that could eventu-ally generate 100 gigabasesof sequence per hour, or10x coverage of a humangenome in 15 minutes.


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RNAi Upstream


Wh i l e anumber oftechnolo-g i e s a re

being developed to turnthe RNAi process on andoff, these typically requireintroducing small mole-cules or other compoundsinto the cell. But aresearcher from LouisianaState University thinks thata photoactivation tech-nique developed threedecades ago may offer abetter solution.

The approach, calledphotocaging, involvesc o v a l e n t l y a t t a c h i n gblocking groups onto an u c l e i c a c i d . T h e s egroups keep the nucleicacid inert — an siRNA, forinstance — while protect-ing it from enzymaticdegradation until it isexposed to light, at whichpoint the nucleic acid’sa c t i v i t y i s r e s t o r e d ,according to Todd Mon-roe, an assistant professorin LSU’s department of

biological and agriculturalengineering.

“There are a lot of smallmolecules that can drivegene expression or generepression, but those mole-cules, if they are notalready inherent in sometype of pathway, have to bedelivered” and can be diffi-cult to regulate, he says.

With photocaging, on the

other hand, researcherscan control when andwhere in a cell a nucleicacid is activated, he says. “Ifwe’re working with anorganism instead of a cul-ture dish, we can deliver [acaged nucleic acid] in aselect spot,” such as theretina.

According to Monroe,photocaging was devel-oped in the 1970s to inac-tivate and reactivate ATP tostudy the kinetics of musclecontraction. “We’d like totake those same principles[used with ATP] and applythem in cells and tissues togovern nucleic acid bioac-tivity,” he says.

Monroe and his col-leagues have been workingon this concept for sometime and have conductedexperiments in which theyattached nitro benzyl-likecage compounds to thephosphate backbone ofDNA. This caging process“disrupts transcriptionalenzyme machinery [and]blocks [the DNA’s] degra-dation by nucleases,” heexplains. When exposedto light, the moleculesreactivated.

— Doug Macron

Photocaging to Control RNAi


MILLION

INTROGEN THERAPEUTICS,

WHICH DEVELOPS TUMOR

SUPPRESSOR DRUGS, SOLD

ITS APPROXIMATELY 7.5

MILLION SHARES OF

SILENCE THERAPEUTICS,

NETTING $7.5 MILLION.



RNAi NotesRNAiNEWS

DEVELOPING RNA INTERFERENCE FOR GENE SPECIFICSILENCING IN APLYSIA NEURONSGrantee: Kelsey Martin, UCLABegan: Apr. 1, 2007; Ends: Mar. 31, 2009With this grant, the researchers want to develop RNAifor use in Aplysia neurons. To determine if the silencingwill work, they will target four endogenous Aplysia genesand exogenously overexpressed destabilized eGFP. Theresearchers say that the ability to use RNAi in Aplysiawill also yield information about molecular mechanismsunderlying synapse formation, synaptic transmission,and synaptic plasticity.

$131,200/FY2007TITLE: NOVEL TUMOR SUPPRESSOR GENE DISCOVERYIN PANCREATIC CANCERGrantee: James Eshleman, Johns Hopkins UniversitySchool of MedicineBegan: Sep. 1, 2007; Ends: Aug. 31, 2009In this grant, the researchers propose to use RNAi touncover novel pancreatic cancer tumor suppressorgenes. First, they plan to construct cell lines by trans-ducing non-tumorigenic and weakly tumorigenic pan-creas cell lines with whole-genome libraries. Then, theywill select tumorigenic cell clones and perform sequencing.

$131,200/FY2007$171,881/FY2007

INTRADIGM licensed the rights to theMASSACHUSETTSINSTITUTE OFTECHNOLOGY’s nucleicacid delivery patent. Thiscovers a range ofbiodegradable polymerstructures used to deliverRNAi-based therapeutics.

In a filing with the USSecurities and ExchangeCommission, ARROWHEADRESEARCH said its sub-sidiaries, CALANDOPHARMACEUTICALS,an RNAi drug firm andINSERT THERAPEUTICS,a nanobiotech company,will merge.

ALNYLAMPHARMACEUTICALSannounced that a double-blind, placebo-controlled,randomized study showedthat its siRNA-based respi-ratory syncytial virus drugALN-RSV01 is safe andwell-tolerated. The resultsare to be presented at theInternational Symposiumon Respiratory ViralInfections meeting.


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F U N D E D G R A N T SF U N D E D G R A N T S

SHOTGUN LIPIDOMICS AND ALTERATIONS INSPHINGOLIPIDOMES IN ALZHEIMER’S DISEASESGrantee: Xianlin Han, Washington UniversityBegan: Sep. 1, 2007; Ends: July 31, 2012Han and his colleagues are developing a bioinformaticsapproach to yield high-throughput processing of com-plex lipidomics data, including the identification ofaltered lipid molecular species induced by a diseasestate and the construction of a lipid metabolic networkmap. This project will also attempt to identify the alteredpathways of the sphingolipidome networks present invery mild Alzheimer’s disease.

$529,887/FY2007$386,400/FY2007

Upstream BIOINFORMATICS

50 WWW.GENOMETECHNOLOGY.COM M A R C H 2 0 0 8

The NATIONAL LIBRARYOF MEDICINE will give $5 million over a three-yearperiod to fund severalresearch groups aiming toadvance biomedical infor-matics. The grant will sup-port between 12 and 15research programs in areasof public health, complexmodeling, and clinicaltranslational research.

The US ENVIRONMENTALPROTECTION AGENCY’sNational Center forComputational Toxicologywill license GENE LOGIC’sbioinformatics platform.The EPA will use the com-pany’s Genesis EnterpriseSystem, GXR Connect soft-ware, and parts of itsToxExpress and BioExpresssystems for use in theagency’s ToxCast program.

The CDC extended anexisting deal for a multi-sitelicense to DNASTAR’ssequence analysis softwarefor use at its facilities inColorado, Alaska, andPuerto Rico.

Aconsortium ofE u r o p e a nr e s e a r c hg ro u p s a n d

bioinformatics firms haskicked off an effort tointegrate the growingbody of information onhuman genotype-to-phe-no t ype re l a t i on sh ip senabled by the rise oflow-cost genotyping tech-nologies.

The five-year project,ca l led Gen2Phen, forGenotype-to-Phenotype,began earlier this monthwith €11.9 million infunding from the EuropeanUnion’s Seventh Frame-work Program. The goal ofthe project is to createtools and standards thatwill seamlessly integratenumerous genetic varia-tion databases and providea unified view of these dis-parate data sources.

“This is not a database,”says Anthony Brookes, aprofessor in the depart-ment of genetics at the UK’s

University of Leicester andthe coordinator of the proj-ect. “It’s trying to helporganize, orchestrate, andcoordinate the general fieldof genotype-to-phenotypedatabasing.”

Brookes says that theproject is a response to the“tidal wave of information”that is now coming onlinefrom low-cost genome-

EU Team to CoordinateGen2Phen Data

$50D A T A P O I N T

BioinformaticsNotes

BIOINFORM

MILLION

AMOUNT THE

NATIONAL SCIENCE

FOUNDATION HAS DOLED

OUT TO ESTABLISH A

CYBERINFRASTRUCTURE

CENTER FOR PLANT

BIOLOGY.

wide association studiesthat link genotypic datawith phenotypic informa-tion.

Brookes says that theinformatics communityhas not yet developed stan-dardized database infra-structures, data standards,or data models for the riseof so-called G2P data.Unlike genomic data,which is “unidimensional,so it’s very easy to designdatabases, and very easy tomanage and handle,”Brookes notes that “thereare a lot more complexchallenges involved inhandling phenotype databecause it’s an infinite uni-verse of information.”

As a result, different data-bases have chosen to han-dle and represent thisinformation in very differ-ent ways, which has madeit difficult for researchers toaccess data from multiplestudies and compare it.Current efforts to solve theproblem are “nowhere nearenough for the absolutetor ren t o f genotype-phenotype informationthat’s now flowing and willcontinue to flow,” he says.

— Bernadette Toner

SP BASE: A SEA URCHIN GENOME DATABASEGrantee: Robert Andrew Cameron, California Instituteof TechnologyBegan: Sep.1, 2007; Ends: Jun.30, 2012 Through this grant, Cameron will continue to expand andextend SpBase, a genome database for sea urchins thatcollects data produced by the Sea Urchin GenomeSequencing Project, composed of the Baylor College ofMedicine Human Genome Sequencing Center and theSea Urchin Genome Annotation team. SpBase is beingdeveloped to include a user interface that allows for easyupdating, editing, and installation of additional features.


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Downstream


Three soon-to-be publishedstudies suggest that a poly-morphism in KIF6, a geneencoding a kinesin-like pro-tein in the molecular motorfamily, increases the risk ofcoronary heart disease.CELERA subsidiaryBERKELEY HEARTLAB isdeveloping a laboratory test,which it expects to launchsoon, for the gene variant.

Four papers on lupusgenetics, including twolarge genome-wide SNPstudies, one investigatingSNPs that specifically pre-dict amino acid changesand one focusing on a par-ticular candidate gene,shed light on the molecularpathways implicated in thedisease. The papersappeared in NatureGenetics and the NewEngland Journal ofMedicine.

The Canadian governmentlicensed CEPHEID’s testfor methicillin-resistantStaphylococcus aureusfor use in hospitals.

AutoGenomicsa n n o u n c e dthat the USFood and Drug

Administration approvedits Infiniti Warfarin XPdose-response assay foridentifying patients withCYP450 2C9 and VKORC1genetic variants.

The company, based inCarlsbad, Calif., submit-ted the assay to the FDAfor 510(k) approval lastDecember. The test runson its Infiniti platform,which the FDA cleared formultiplex testing earlierthis year.

AutoGenomics is enter-ing a crowded market.Four months ago, the FDAapproved Nanosphere’sVerigene Warfarin Metabo-lism Nucleic Acid Test,which runs on the com-pany’s Verigene platform.There are also several com-panies, such as ClinicalData, LabCorp, Genelex,and Nanogen that markethomebrew tests for this

indication.But Autogenomics’ test

has several points that differ-entiate it from these rivals,the company says. For one,its warfarin panel was vali-dated by the Harvard Med-ical School-Partners Health-Care Center for Geneticsand Genomics. HPCGGalso used AutoGenomics’assay in the “CReating anOptimal Warfarin Nomo-gram,” or CROWN, trial, a

AutoGenomics’ WarfarinTest Approved


MILLION

VALUE OF NIH GRANT

FUNDING AN INITIATIVE

PAIRING THE CANCER

INSTITUTE OF NEW JERSEY

AND IBM TO DEVELOP

DIAGNOSTIC TOOLS.



PGx & MolecularDx Notes

PHARMACOGENOMICSREPORTER

MOLECULAR TARGETED IMAGING IN COLON CANCERGrantee: Joseph Backer, SibTechBegan: Sep. 28, 2007; Ends: Mar. 31, 2008According to the abstract, Backer and his colleaguesplan to optimize detection of colorectal lesions viaVEGFR-mediated fluorescent imaging and establish thefeasibility of early detection of colorectal lesions withscVEGF/Cy tracer. If all goes well, this work could lead tothe clinical development of a new imaging tracer forearly diagnosis of prostate cancer.

BIOMARKER SIGNATURES OF BIOLOGICAL, CHEMICAL,OR PSYCHOLOGICAL STRESSGrantee: David Lawrence, Wadsworth CenterBegan: Aug. 15, 2007; Ends: May 31, 2011Lawrence will study patients with sepsis or rheumatoidarthritis as a prototype of stressed individuals to identifyand quantify the presence of serum proteins that haveincreased, decreased, or which display epitope-modifiedexpression, according to the abstract. These molecularfeatures will form the basis of specific biomarker signa-tures characteristic of people under stress.

$471,753/FY2007$162,918/FY2007

PGx & MOLECULAR Dx

prospective study that usedgenetic tests to determineoptimal warfarin dosing.

According to AutoGe-nomics, there can be morethan a 10-fold dosing vari-ability among patients onwarfarin. The Infiniti 2C9-VKORC1 panel “has thepotential to optimize war-farin dosing and lower therisk of bleeding complica-tions,” Raju Kucherlapati,HPCGG scientific director,has said of the assay.

In addition to being vali-dated by independentresearchers, the assay isable to test for variants thatno other marketed test canassess. Most marketed war-f a r in a s s ay s t e s t f o rCYP239*2 and *3 variants,and VKORC1 variant 3673(-1639G>A).

The Infiniti assay tests forthose variants plus CYP239*4, *5, *6, and *11, as wellas VKORC1 variants 5808,6009, 6484 (1173C>T),6853, 7566, 8773, and9041(3730G>A). Clinicalstudies have linked some ofthese variants to warfarinsensitivity in certain ethnicpopulations, such as Japan-ese and African-American.

— Turna Ray


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Downstream CASE STUDY


It may not be right aroundthe corner, but a biomarkertest for increased suscepti-bility to Alzheimer’s dis-ease might be waiting

down the road. In a recent study,researchers at the Mayo ClinicJacksonville found that blood levelsof amyloid beta proteins werehigher in young relatives ofpatients with late onset Alzheimer’sdisease than in non-relative con-trols, which suggests that geneticfactors controlling the Aβ proteins— including the APOE4 geneticvariant, a well known risk factor —are related to higher risk of develop-ing the disease. The team’s researchwas published in the journal Neu-rology last month.

In comparing control groups tof i r s t - d e g re e re l a t i v e s o f 2 5extended multigenerational fami-lies with a history of late onsetAlzheimer’s disease, and an addi-tional approximately 100 first-degree relatives of patients withAlzheimer’s, they found elevatedlevels of both Aβ40 and Aβ42compared to non-related controlgroups. To find out whether theseelevations were caused by any ofthe genes known to contribute tolate onset Alzheimer’s, the scien-tists sequenced the Aβ proteinsand found no mutations. Theythen genotyped the participantsfor the APOE4 allele, hypothesiz-ing that having this risk factormight have something to do with

their higher Aβ levels. “We foundthat, in fact, it was those individ-uals with lower amyloid beta lev-els that had the APOE4 allele,”says Nilufer Ertekin-Taner, thestudy’s lead author. “What wepostulate … might be going onthere, possibly APOE4 might bepromoting deposition of amyloidbeta in the brain, and with thedeposition of amyloid beta in thebrain, the plasma levels drop.That’s one postulate — but cer-tainly it tells us that the elevationsare not due to the E4, leading us toconclude that it must be someother genetic variant or variantsleading to that.”

Taner likens plasma amyloid betaprotein to cholesterol, in that it’s aquantitative trait that varies in thegeneral population. While it’s not agiven that someone with a highblood cholesterol level will end upwith heart disease, it’s a good pre-dictor. In many cases, Tanerbelieves, a test to track the levels ofplasma Aβ in people with a familyhistory of Alzheimer’s diseasemight help with early diagnosis andtreatment of the disease. “Whenyou compare the young first-degree relatives to the control pop-ulation, you see that the youngfirst-degree relatives have higherlevels,” Taner says. “[That] tells usthat there must be genetic factorsunderlying elevations in amyloidbeta levels that you can detectyears before people deve lop

Alzheimer’s disease.”Taner sees the possibility for a

clinical biomarker test that wouldtrack plasma Aβ levels and use thatinformation to determine theprobability of getting Alzheimer’sdisease, but not before classic lon-gitudinal tests are performed tomeasure these levels through gen-erations of large populations. “Ithink that there may come a daywhen we follow the amyloid betalevels in individuals and be able tosay that if you have a family historyof Alzheimer’s disease, if you havehigher amyloid beta levels at earlierages — and perhaps we might beeven able to say if you havegenetic risk factor A, B, or C —then your likelihood of gettingAlzheimer’s disease is higher com-pared to if you didn’t have thoserisk factors.”

With a new protein study, Mayo Clinic scientists demonstratethe potential for a biomarker test of Alzheimer’s susceptibility.By Jeanene Swanson

Plasma Is the New Risk Factor

NILUFER ERTEKIN-TANER


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Q&A: LAWRENCE JENNINGS Downstream


Lawrence Jennings just wrapped up a study on biomarker validation. He shares some of his newfound insight into molecular diagnostics, testing assays, and more.

The Biomarker Black Box

Lawrence Jennings,director of molecularpathology and diag-nostics at Northwest-ern University’s Chil-

dren’s Memorial Hospital, is justputting the finishing touches to astudy on validating molecular assaysin diagnostic laboratories. How peo-ple find biomarkers and bring themto use in a clinical setting is of greatinterest to him, and it’s why GT’sMeredith Salisbury caught up withhim for a conversation about bestpractices and common mistakes invalidation.

GENOME TECHNOLOGY: Arethere some best practice guidelinesyou’d offer readers?

LAWRENCE JENNINGS: I don’tknow if there’s anything that’s per-fect. The things that we referencemost often are the FDA websitesthemselves — they have specificrecommendations. Usually it’sdirected toward industry, but forclinical laboratories that are devel-oping tests they also fall under thepurview of FDA to some degree.The FDA has jurisdiction over clin-ical laboratories and the resultsthat come out of them; however,they have not really enforced theirauthority for a couple of reasons.One of them is that clinical labora-tories are overseen by CLIA, andthey also regulate the reagents —the ASRs and other reagents that gointo the clinical laboratory.

In addition to the FDA, there arepublished guidelines — manu-scripts that talk about bringingassays into a clinical laboratory. Ithink the problem is that with theFDA and with the people whowrite these standards, they vieweverybody who’s developing a testand offering a test in the sameregard. And for the smaller labs [theresource requirements] may beoverwhelming. [They’ll ask,] whatdo I need to do? Can I do fewersamples? Ultimately it’s up to thedirector of the clinical laboratory todetermine whether it meets therequirements for validation.

GT: What are some of the mostcommon mistakes you see labsmake?

LJ: I think the biggest mistake thatmost people have is distinguishingbetween analytical validation andclinical validation. It’s really theclinical validation that matters.Analytical validation is of courserequired — but without getting tothe clinical validation aspects, itmeans nothing. For example, ana-lytical validation pertains to havingan assay that identifies whateveranalyte it’s intended to identify anddoes that reproducibly and accu-rately — whereas clinical valida-tion would take that result and giveit clinical meaning. A lot of the lab-oratory tests that we see in our owninstitution began in a research lab-oratory where they might’ve done

a research study that might haveshown that this biomarker hassome value. They might evendecide this is clinically valuable —and it might be valuable withinthat laboratory under very specificcircumstances. As long as theydefine those circumstances andthey stay within that range then it’sprobably OK. But the problemcomes when they start extrapolat-ing to other patients or other ana-lytes or when it’s done in anotherinstitution that might not be doingit the same way.

GT: More recent tests look at severalanalytes in a panel. Is this provingto be more complex?

LJ: The challenge is on the clinicalinterpretation side. The technol-ogy and the techniques areadvancing where that’s not goingto be the issue at all — whetherpeople can do it. The FDA [state-ment on IVDMIAs] is meant toaddress specifically this point,that it’s dangerous when peoplebegin to offer tests that cannot bevalidated simply because they’reoperating in some kind of a blackbox. We brought this up within acommittee meeting: at what pointdoes this have to be an FDA-approved test? Among our com-mittee members the feeling wasthat if the methods and clinicalvalidation data are not publiclyavailable — well, then, that’s notacceptable.


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Events MEETINGS AND DEADLINES


ConferencesDATE CONFERENCE ORGANIZER LOCATION CATEGORYMar 1-7 59th Pittsburgh Conference on Analytical PITTCON New Orleans Proteomics

Chemistry and Applied SpectroscopyMar 6-7 Advances in Synthetic Biology Select Biosciences Cambridge, UK Synthetic

biologyMar 10-11 MicroRNA in Human Disease and CHI Cambridge, Mass. RNAi

DevelopmentMar 10-12 2008 AMIA Summit on Translational AMIA San Francisco Bioinformatics

BioinformaticsMar 16-19 Fourth Annual US HUPO US HUPO Bethesda, Md. ProteomicsMar 17-19 Genomes to Systems 2008 Consortium for Manchester, UK Genomics

Post-Genome ScienceMar 25-26 Genomic Technologies at the Interface of AACC San Diego Clinical

Diagnostics and TherapeuticsMar 25-28 Molecular Medicine Tri Conference CHI San Francisco GenomicsMar 25-30 RNAi, MicroRNA, and Non-Coding RNA Keystone Symposia Whistler, RNAi

British ColumbiaMar 27-30 Systems Biology: Global Regulation Cold Spring Harbor Cold Spring Systems

of Gene Expression Laboratory Harbor, NY biologyMar 30 - Apr 2 RECOMB Singapore BioinformaticsApr 2 From Genome to Proteome and BioSapiens Network Brussels Functional

Biological Function of Excellence genomicsApr 5-9 Experimental Biology FASEB San Diego GeneralApr 6-10 235th National Meeting of the ACS New Orleans Chemistry

American Chemical SocietyApr 6-10 Society for Biomolecular Sciences SBS St. Louis, MO Screening

Annual MeetingApr 7-8 GenBank 25th Anniversary Celebration NCBI Bethesda, Md. BioinformaticsApr 7-12 Molecular Basis for Chromatin Keystone Symposia Snowmass, Colo. Epigenetics

Modifications and Epigenetic PhenomenaApr 12-16 AACR AACR San Diego CancerApr 20-23 Quantitative PCR CHI San Diego PCRApr 23-24 Next-Generation Sequencing CHI San Diego SequencingMay 1-2 RNAi World Congress Select Biosciences Boston RNAiMay 6-10 The Biology of Genomes Cold Spring Harbor Cold Spring Genomics

Laboratory Harbor, NYMay 7-8 Advances in Microarray Technology Select Biosciences Barcelona MicroarraysMay 19-21 Biomarker World Congress CHI Philadelphia BiomarkersMay 19-21 GOT Summit CHI Boston GenomicsMay 28 - Jun 1 American Society of Gene Therapy ASGT Boston Gene therapyJun 1-5 56th ASMS Conference on ASMS Denver, CO Proteomics

Mass SpectrometryJun 1-5 American Society for Microbiology ASM Boston General

General MeetingJun 9-11 Beyond Genome CHI San Francisco GenomicsJun 16-21 Pathways, Networks and Systems Aegean Conferences Chania, Crete, Systems

Medicine Conference Greece biologyJun 18-21 BIO Annual Meeting BIO San Diego GeneralJun 22-26 Drug Information Association DIA Boston Clinical

Annual MeetingJun 23-25 caBIG Annual Meeting caBIG Washington, DC BioinformaticsJun 27 - Jul 2 Pharmacogenetics and Pharmaco- European Science Sant Feliu de Clinical

genomics: Adverse Drug Reactions Foundation Guixols, SpainJul 11-13 Genetic Alliance Annual Conference Genetic Alliance Bethesda, Md. ClinicalJul 19-23 Symposium of the Protein Society Protein Society San Diego ProteomicsJul 19-23 International Conference on Intelligent ISCB Toronto Bioinformatics

Systems for Molecular BiologyAug 4-7 Drug Discovery and Development of IBC Boston Clinical

Innovative TherapeuticsAug 17-21 Meeting of the American Chemical Society ACS Philadelphia Chemistry


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MEETINGS AND DEADLINES EventsDeadlinesMARCH 6Application deadline for theNIH Deep Sequencing andHaplotype Profiling ofMental Disorders grant.This grant will supportlarge-scale research thatuses in-depth sequencingand candidate gene studiesto examine the genetic riskfactors of seven majormental disorders: anorexia,ADHD, autism and relatedautism spectrum disorders,depression, bipolar disor-der, obsessive compulsivedisorder, and schizophrenia.MARCH 8Application deadline for thegrant, Reference EpigenomeMapping Centers. The NIH

will support applicants todevelop comprehensive reference epigenomes from human embryonicstem cells, human differentiating and differentiated cells,cell lines, and tissues.MARCH 14Application deadline for the Non-coding RNAs andOther Post-transcriptionalRegulatory Mechanisms in Neuroplasticity andAddiction grant. The pur-pose of this NIH grant is to promote research onnoncoding RNAs pertainingto addictive processes.MARCH 14Application deadline for

Assembling the Tree of Life grant. This NSF grantwill support projects in data acquisition, analysis,algorithm development,and dissemination in com-putational phylogeneticsand phyloinformatics.MARCH 17Abstract deadline for thesecond annual RNAi WorldCongress meeting.MARCH 19Application deadline for the Protein Data BankManagement grant. TheseNSF funds will support aplan to lead, administer,and coordinate communitydatasets for the ProteinData Bank.

MARCH 19Application deadline for theNIH grant, Drug Dockingand Screening DataResource. This grant aimsto increase the amount ofhigh-quality drug targetdata for the development of ligand docking andscreening software.MARCH 28Application deadline for the HIV-1 and HostGenetics in Drug UsingPopulations and ModelOrganisms grant. This NIHgrant will fund research intomolecular mechanisms ofHIV-1 infection.


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Lab Reunion THE YATES LAB


When MichaelM a c C o s ss t a r t e d h i sproteomics labat the Univer-

sity of Washington a few years ago,he discovered that he had beenassigned his postdoc advisor’s oldlab space. “[It] was actually prettyintimidating,” he says.

Small wonder: MacCoss’ former PIwas proteomics great John Yates,who ran a lab at Washington foreight years before heading to theScripps Research Institute.

Yates, who began his careerstudying “protein sequencing usingtandem mass spectrometry,” didhis own postdoc at Caltech with ahigh-profile PI: Lee Hood. WhenHood moved to the University ofWashington and started the molec-ular biotechnology department, heoffered Yates a faculty position.

Yates recalls that being a newbie inHood’s star-studded departmentmeant not being a top pick for stu-dents. The department had “fairlyfamous faculty,” he says, “and if thestudents had half a brain they wentto work with those guys.” He beganhis lab with several postdocs and asingle student, a pattern that hascontinued throughout his career. “Ionly ever had one student at atime,” he says. “I’ve come to call itJedi knight training.”

If that’s a reflection of quality overquantity, Yates’ postdocs say they’regrateful for the high-quality lessons

they learned during their time in hislab. Ashok Dongre, now an associ-ate director at Br is tol-MyersSquibb, remembers that Yates was a“hands off” manager. “He gave abroad idea of what he wanted,”Dongre says, “and he gave us thelatitude to go ahead and try differ-ent things.” He adds that he foundthe environment so rewarding thathe’s fostered the same atmospherein his own lab ever since.

In fact, Yates says that this traitwas an inheritance for him as well.He remembers his PhD advisor

being “really good about … lettingme explore ideas in the lab,” hesays. “That’s something that Ibrought to my lab.” Yates says aquality he really values in his labmembers is being vocal and willingto speak their minds.

Dongre says what impressed himmost about Yates was his refusal tofollow the path that most peoplewere taking if it didn’t make senseto him; he was known among hisstaff as someone who carved out hisown path. When he had an idea thatdidn’t match up with what most

John Yates is known for being a mass spec guru — and in his lab, he’s known as the guy who stands by his scientific convictions. By Meredith Salisbury

The Proteomics Pedigree

As one of Lee Hood’s postdocs, JohnYates is no stranger to a high-profilepedigree. The students and postdocswho have gone through his lab havealso parlayed their experience intosuccessful careers. To name just afew:ASHOK DONGRE

After his postdoc with Yates, Dongrepacked up for Bristol-Myers Squibb,where he is currently an associatedirector.LAURENCE FLORENS

As managing director of proteomicsat the Stowers Institute, Florens wasawarded the Hudson Prize in recogni-tion of innovative research in 2006.MICHAEL MACCOSS

MacCoss runs a mass spectrometrylab at the University of Washington,and was named one of the up-and-

coming scientists in GenomeTechnology’s 2006 Tomorrow’s PIsissue.MICHAEL WASHBURN

Washburn continues his work inquantitative proteomics, and servesas proteomics director at the StowersInstitute. Along with Florens, he wonthe Hudson Prize in 2006.CHRISTINE WU

An assistant professor of pharma-cology at the University of Colorado,Wu works with membrane proteinsand biomarker profiling, as well asimprovements of proteomics methods.FUQUAN YANG

Yang works on quantitative pro-teomics and protein dynamics as aprofessor at the Chinese Academy ofSciences’ Institute of Biophysics.

>NAMING NAMES


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other proteomic scientists weredoing, Dongre says, Yates wouldanalyze “the pros and cons of whathe was proposing and say, ‘There’s agood chance that we’ll fail at this,but that shouldn’t stop us from try-ing it out.’”

MacCoss remembers that Yates“always really liked those aggres-sive, high-risk ideas” — a character-istic that encouraged his students toconduct research as innovative andunique as his own. “[What] youlearn from being in John Yates’ labis thinking big,” MacCoss says.

But it’s not all blue-sky science.Yates says he’s a stickler for makingsure his students learn the instru-mentation inside and out. “The keyfor them is to learn as much aboutthe technology as they can,” he says.In his lab, everyone’s required to“run their own samples and main-

tain the instruments.”MacCoss says that for him, one of

the major lessons he learned earlyon was the importance of softwarefor processing proteomics data —no one going through the Yates labwas going to emerge without a realappreciation for, and grasp of,good analysis procedures. “That’ssomething you learn right off thebat — you’re not going to be able tosit there and process all your databy hand,” he says.

Both MacCoss and Dongre saythey’ve kept in touch with Yates, whohas been very supportive of his post-docs as their careers unfold. MacCosssays, “I remember the first couplegrants I was writing, and I was get-ting bad reviews.” He would send theproposals to Yates for feedback, and“he was always very positive with hiscomments,” MacCoss says.

That candor (along with a drysense of humor) is something Yates’students know well, says Dongre.“The thing I liked about him wasthat I always knew where I stoodwith him,” he says. “If he doesn’tlike something, he’ll tell you so.”

Evolving? Don’t change jobs without us.

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JOHN YATES


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