ISSN: 1050–6101, Issue number 46 Vol. 11, Nos. 1–2 ...

ISSN: 1050–6101, Issue number 46 Vol. 11, Nos. 1–2, November 2000

HGP and the Private SectorOn the Shoulders of Giants .......1

Congressional Hearing ..............3

HGP MilestonesMilestone Celebration................4

Human Genome Project FAQs..4

Sequencing at JGI ....................6

Chromosomes 21, 22 ................7

Post-Sequencing Challenges ....7

In the NewsPower of Proteins ......................8

Images of Protein Machine........8

Gene Patenting Update .............9

House Hearing on Patenting .....9

SNP Consortium......................10

SNP Meetings..........................10

Mouse Consortium ..................12

BERAC Report ........................12

ELSIFast Forward to 2020 ..............13

Judging Molecular Biology.......14

DOE Grantee Award................15

DOE ELSI Grants ....................16

For Your InformationHGMIS Resources...................17

Resources .........7, 12, 14, 17, 19

Event, Training Calendars ...... 18

Funding Information.................19

Subscription, Requests............20

Acronyms.................................20

The deluge of data and related technologies generated by the HumanGenome Project (HGP) and other genomic research presents a broad array

of commercial opportunities. Seemingly limitless applications cross boundariesfrom medicine and food to energy and environmental resources, and predictionsare that life sciences may become the largest sector in the U.S. economy.

On the Shoulders of Giants: PrivateSector Leverages HGP SuccessesData, Technologies Catalyze a New, High-ProfileLife Sciences Industry

Human Genome News issues are placed on the Web soon after going to press. Archived issues are also online.

In This Issue

Established companies are scramblingto retool, and many new ventures areseeking a role in the information revo-lution with DNA at its core. IBM,Compaq, DuPont, and major pharma-ceutical companies are among thoseinterested in the potential for target-ing and applying genome data.

In the genomics corner alone, dozensof small companies have sprung up tosell information, technologies, andservices to facilitate basic research intogenes and their functions. These newentrepreneurs also offer an abundanceof genomic services and applications,including additional databases withDNA sequences from humans, animals,plants, and microbes.

Other applications include gene frag-ments to use for drug developmentand target identification and evalua-tion, identification of candidate genes,and RNA expression informationrevealing gene activity. Productsinclude protein profiles; particulargenotypes associated with such spe-cific medically important phenotypesas disease susceptibility and drugresponsiveness; hardware, software,and reagents for DNA sequencing andother DNA-based tests; microarrays(DNA chips) containing tens of thou-sands of known DNA and RNA frag-ments for research or clinical use; andDNA analysis software.

Broader applications reaching intomany areas of the economy includethe following:

Clinical medicine. Many moreindividualized diagnostics andprognostics, drugs, and othertherapies.

Agriculture and livestock.Hardier, more nutritious, andhealthier crops and animals.

Industrial processes. Cleanerand more efficient manufacturingin such sectors as chemicals, pulpand paper, textiles, food, fuels,metals, and minerals.

Environmental biotechnology.Biodegradable products, newenergy resources, environmentaldiagnostics, and less hazardouscleanup of mixed toxic-waste sites.

DNA fingerprinting. Identifica-tion of humans and other animals,plants, and microbes; evolutionaryand human anthropological studies;and detection of and resistance toharmful agents that might be usedin biological warfare.

From the start, HGP planners antici-pated and promoted the private sec-tor’s participation in developing andcommercializing genomic resourcesand applications. The HGP’s successes

p. 2ß

2 Human Genome News 11(1–2) November 2000

(from p. 1)

in establishing an infrastructure andfunding high-throughput technologydevelopment are giving rise to com-mercially viable products and services,with the private sector now taking onmore of the risk.

A Public LegacySubstantial public-sector R&D invest-ment often is needed in feasibilitydemonstrations before such start-upventures as those by Celera Genomics,Incyte, and Human Genome Sciencescan begin. In turn, these companiesfurnish valuable commercial servicesthat the government cannot provide,and the taxes returned by their suc-cesses easily repay fundamental

public investments. Following are afew key public R&D contributionsthat made some current genomicsventures commercially feasible. Theseexamples describe DOE investments,but substantial commitments by NIHand the Wellcome Trust in the UnitedKingdom were equally important.

Scientific Infrastructure. The sci-entific foundation for a human genomeinitiative existed at the national labo-ratories before DOE established thefirst genome project in 1986. Besidesexpertise in a number of areas criticalto genomic research, the laboratorieshad a long history of conducting largemultidisciplinary projects.

Genomic Science and PioneeringTechnology. GenBank, the world’s

DNA sequence repository, was devel-oped at Los Alamos National Labora-tory (LANL) and later transferred tothe National Library of Medicine.Chromosome-sorting capabilitiesdeveloped at LANL and LawrenceLivermore National Laboratoryenabled the development of DNAclone libraries representing the indi-vidual chromosomes. These librarieswere a crucial resource in genomesequencing.

Sequencing Strategies. When theHGP was initiated, vital automationtools and high-throughput sequencingtechnologies had to be developed orimproved. The cost of sequencing asingle DNA base was about $10 then;today, sequencing costs have fallen

HGP and the Private Sector: Rivals or Partners?

With the June 26 announcement bythe publicly funded Human

Genome Project (HGP) and CeleraGenomics that the draft sequence ofthe human genome was essentiallycomplete, the complementary aspectsof the public and private sectors’sequencing projects were realized.

Since spring 1998, when CeleraGenomics announced its sequencinggoal, other private companies also havedeclared their intention to sequence ormap genomic regions to varyingdegrees. Some people questionedwhether the HGP and the private sec-tor were duplicating work, and theywondered who would “win” the race tosequence the human genome. Althoughthe HGP and private companies dohave overlapping sequencing goals,their “finish lines” are different becausetheir ultimate goals are not the same.

In a sense, through its policy of opendata release, the HGP has all alongfacilitated the research of others.Additionally, the HGP funds projectsat small companies to devise neededtechnologies. DOE, NIH, the NationalInstitute for Standards and Technol-ogy, and other governmental fundingsources also are supporting furtherapplication and commercialization ofHGP-generated resources.

HGP products have spurred a boom insuch spin-off programs as the NIH

Cancer Genome Anatomy Project andthe DOE Microbial Genome Program.Genomes of numerous animals, plants,and microbes are being sequenced,and the number of private endeavorsis increasing. Technology transferfrom developers to users and participa-tion in collaborative, multidisciplinaryprojects closely unite researchers atacademic, industrial, and governmen-tal laboratories.

Scientific vs Commercial GoalsThe HGP’s commitment from the out-set has been to create a scientific stan-dard (an entire reference genome).Most private-sector human genomesequencing projects, however, focus ongathering just enough DNA to meettheir customers’ needs—probably inthe 95% to 99% range for gene-rich,potentially lucrative regions. Suchprivate data continue to be enrichedgreatly by accurate free public mapping(location) and sequence information.

Celera’s shotgun sequencing strategy,for example, creates millions of tinyfragments that must be ordered andoriented computationally using HGPresearch results. Most data atCelera, Incyte, and other genomicsinformation–based companies areproprietary or available only for afee. In addition, companies are filingnumerous patent applications tostake early claims to genes andother potentially important DNAfragments (see p. 9).

More than the Reference SequenceDNA sequencing will continue to bea major emphasis for the foreseeablefuture as gene sequences are surveyedacross various populations. Both theDOE and NIH genome programs arecontinuing to support the develop-ment of fully integrated and innova-tive approaches to rapid, low-costsequencing.

Other near-term HGP goals from thelatest 5-year plan are to enhancebioinformatics (computational)resources to support future researchand commercial applications. TheHGP also aims to explore gene func-tion through comparative mouse-human studies, train future scientists,study human variation, and addresscritical societal issues arising fromthe increased availability of humangenome data and related analyticaltechnologies.¨

Shoulders of Giants

Continued Support for LifeSciences IndustryA congressional hearing in April of thisyear presented testimony on the impor-tance of both public and private sectorsto future discoveries and the need forcontinued federal support of the bur-geoning life sciences industry (see box,p. 3).

à

November 2000 Human Genome News 11 (1–2) 3

about 100-fold to $.10 to $.20 a baseand still are dropping rapidly.

DOE-funded enhancements to sequenc-ing protocols, chemical reagents, andenzymes contributed substantially toincreasing efficiencies. The commer-cial marketing of these reagents hasgreatly benefitted basic R&D, genome-scale sequencing, and lower-cost com-mercial diagnostic services.

Sequencing Technologies andBiological Resources. Other majorfactors in cost and time reduction aregreatly improved sequencing instru-ments and efficient biologicalresources such as the following:

DOE-funded research on capillary-based DNA sequencing contributedto the development of the two majorsequencing machines now in use.The core optical system concept ofthe Perkin-Elmer 3700 sequencingmachine (used by Celera and others)was pioneered with DOE support.The instrumentation concepts thatmatured as the MegaBACEsequencer were pioneered by Rich-ard Mathies (University of Califor-nia, Berkeley). The DOE JGI chosethis sequencing hardware platformafter competitive trials.

DNA sequencing originally was donewith radiolabeled DNA fragments.Today, DOE improvements to fluo-rescent dyes decrease the amountof DNA needed and increase theaccuracy of sequencing data.

Bacterial artificial chromosome(BAC) clones, developed in the DOEprogram, became the preferredstarting resource in sequencingprocedures because of their superiorstability and large size. A criticalcomponent of public- and private-sector sequencing, BACs were used

to assemble both the draft and finalhuman DNA reference sequences.

Further extending the usefulnessof BACs, the DOE HGP fundedthe production of sequence tagconnectors (STCs) from BAC ends.This early information enabled theselection of optimal BACs for com-plete sequencing, thus savingtime and money. STC use for theHGP was advocated by CraigVenter and Nobelist HamiltonSmith (both at Celera), and LeroyHood (now at the Institute for Sys-tems Biology).

A Successful TransformationThese successes transferred much ofthe repetitive labor from humans toautomated machines. In addition,new software for data processing bothalleviated and sped human decisionmaking. Over the last decade, advancesin instrumentation, automation, andcomputation have transformed theentire process. Further innovations,however, still are needed for completingmany large sequences and increasingthe effectiveness of sequencing.[Denise Casey (HGMIS) and MarvinStodolsky (DOE)]¨

Shoulders of Giants

Congressional Hearing ExploresControversies, Benefits of Genomics

In April the Subcommittee on Energy and Environment of the Commit-tee on Science of the U.S. House of Representatives conducted hearings

on the status and benefits of genome sequencing in the public and privatesectors (www.house.gov/science/106_hearing.htm#Energy_and_Environment).Speakers included representatives of the U.S. HGP and Celera Genomics,members of Congress, and the director of the Office of Science and Tech-nology Policy.

Robert Waterston, director of the HGP sequencing center at WashingtonUniversity, St. Louis, pointed to fruitful data sharing by the HGP and theprivate sector. Examples include (1) collaborations led by the pharmaceu-tical company Merck to develop partial sequences identifying genes and(2) the fruit fly sequencing project by Celera and the HGP.

Examples of private-sector enrichment of public data include the SNPconsortium, which is generating a publicly available map containinghuman DNA variations (see SNP articles, p. 10). In September, CeleraGenomics announced a reference database with more than 2.8 millionunique SNPs, including those screened from public-sector databases. InOctober a public-private consortium announced the joint sequencing ofthe laboratory mouse (see article, p. 12). Also, a Monsanto–University ofWashington project recently generated a draft sequence of the rice plantgenome to be released to the public. These efforts show the value of sharingdata to increase knowledge and ensure future discoveries for mutual benefit.

Neal Lane (Assistant to the President for Science and Technology andDirector of the Office of Science and Technology Policy) echoed the impor-tance of partnerships between public and private sectors in his testimonyto the House committee. His observations follow.

“Sequencing the genome. . . is only the beginning of genomics,” he said.“It is the first step into a future of discoveries and innovations thatgenomics will enable, that the public and private sectors must pursuetogether. . . . An expanding, evolving partnership has made humangenomic discoveries possible and is now poised to make those discoveriesbeneficial for everyone. . . . I believe that the policies we have pursuedwill help to strengthen this partnership, allowing genomic discoveries andinnovations to move steadily forward for the benefit of our nation and forall humankind.”¨

G. Christian Overton,Founding Director, Center forBioinformatics, University ofPennsylvania, Philadelphia, wasa pioneer in genomic research.His family, friends, and colleagueswill miss his charm, wit, goodnature, and academic brilliance.


HGP Milestones

When is a GenomeCompletely Sequenced?In December 1999, the 56-Mb sequenceof human chromosome 22 was declaredessentially complete, yet only 33.5 Mbwere sequenced. In early spring of thisyear, the fruit fly Drosophila’s 180-Mbgenome also was announced as

Working Draft vs FinishedSequence: What’s theDifference?In generating the draft sequence, scien-tists determined the order of base pairsin each chromosomal area at least 4 to 5times (4× to 5×) to ensure data accuracyand to help with reassembling DNA frag-ments in their original order. Thisrepeated sequencing is known as genome“depth of coverage.” Draft sequence dataare mostly in the form of 10,000 bp–sizedfragments whose approximate chromo-somal locations are known.

To generate finished high-qualitysequence, additional sequencing isneeded to close gaps, reduce ambiguities,and allow for only a single error every10,000 bases, the agreed-upon standard

for HGP finished sequence. Investigatorsbelieve that a high-quality sequence iscritical for recognizing regulatory compo-nents of genes that are very important inunderstanding human biology and suchdisorders as heart disease, cancer, anddiabetes. The finished version will providean estimated 8× to 9× coverage of eachchromosome. Thus far, finished sequenceshave been generated for only two humanchromosomes–21 and 22 (see article, p. 7).

completed, although just 120 Mb werecharacterized. What’s the deal?

Animal genomes have large DNAregions that currently cannot be clonedor assembled. In the human genomesequence, these regions include telo-meres and centromeres (chromosometips and centers), as well as many chro-mosomal areas packed with other typesof sequence repeats.

Most unsequenceable areas containheterochromatic DNA, which has fewgenes and many repeated regions thatare difficult to maintain as clones forDNA sequencing. HGP scientists striveto sequence the entire euchromatic DNA,which generally is defined as gene-richareas (including both exons and introns)that are translated into RNA duringgene expression. In the case of human

On June 26, Human GenomeProject (HGP) leaders and repre-

sentatives from the private companyCelera Genomics joined President BillClinton at the White House to announcethe completion of a working draft ref-erence DNA sequence of the humangenome. Clinton observed that theworking draft is a “starting point foreven greater discoveries.”

This achievement provides scientistsworldwide with a virtual road map toan estimated 95% of all genes. All HGPdata are available on the Internet, andpublication in Science and Nature isexpected early in 2001.

Human Genome Project FAQs

Human Genome Project Milestones Celebrated at White HouseClinton Calls Working Draft “Starting Point for Even Greater Discoveries”

Craig Venter (head of CeleraGenomics), Ari Patrinos (director,DOE Human Genome Program andBiological and EnvironmentalResearch Program), and FrancisCollins (director, NIH NationalHuman Genome Research Institute).

The draft contains gaps and errors, butit provides a valuable scaffold for gener-ating the high-quality reference genomesequence—the ultimate HGP goalexpected to be achieved by 2003 orsooner. This knowledge will speed theunderstanding of how genetics influ-ences disease development, aid scientistslooking for genes associated with par-ticular diseases, and contribute to thediscovery of new treatments.

Ari Patrinos, head of the DOE HumanGenome Program, led a series of meet-ings this year at his home that resultedin the joint announcement and agree-ment by the public- and private-sectorprojects to publish at the same time.

Speaking of the value of genome dataand technologies, Patrinos said, “Weare eager to offer a future to our childrenand grandchildren in which ‘cancer’ willbe only a constellation in the sky.”

“Researchers in a few years will havetrouble imagining how we studiedhuman biology without genomesequence in front of us,” said FrancisCollins, head of the NIH genomeprogram.

More than $3 billion has been spentworldwide on the Human GenomeProject since its formal inception in1990 (see box, p. 5, for U.S. costssince 1987).

Although 16 institutions participatein the HGP, most sequencing takesplace at 5 locations. These are theDOE Joint Genome Institute, Wash-ington University (St. Louis), SangerCentre (U.K.), Baylor College ofMedicine, and Whitehead Institute.

Bioinformatics teams at the Ensembldatabase project and the Universityof California, Santa Cruz, generatedan ordered view of the 400,000sequenced DNA fragments in theworking draft.

In July, the Wellcome Trust (U.K.)announced a 5-year investment inEnsembl of more than $14 million(£8.8 million) for automatic annotationof human genome data, includingidentification of genes and other bio-logically important sequence features.

CD-ROM, VideoA CD-ROM and educational videoon the HGP, sponsored by DOEand NIH and a number of otherorganizations, will be released in2001. Contact: HGMIS, p. 16, toorder.


HGP Milestones

Whose Genomes Are BeingSequenced?Diversity RepresentedAll humans share the same basic set ofgenes and genomic regulatory regions thatcontrol the development and maintenanceof biological structures and processes.Therefore, the human reference sequencewill not, and does not need to, represent anexact match for any one person’s genome.

Why DOE?DOE’s role in the HGP arose from thehistoric congressional mandate of itspredecessor agencies (the AtomicEnergy Commission and the EnergyResearch and Development Administra-tion) to study the genetic and healtheffects of radiation and chemicalby-products of energy production. Fromthis work the recognition grew that thebest way to learn about these effectswas to study DNA directly.¨

chromosome 22, the sequenced 60% repre-sents 97% of euchromatic DNA. Similarly,nearly all the euchromatic regions weresequenced for Drosophila.

Although the HGP goal is to have completestrings of sequence for each chromosomefrom tip to tip, obtaining this high level ofresolution presents a great challenge.

used for these studies came from 24anonymous donors of European, Afri-can, American (north, central, south),and Asian ancestry.

Although the sequence information willcome from the DNA of many persons, itwill be applicable to everyone.

Investigators are using DNA from donorsrepresenting widely diverse populations.For example, HGP researchers collectedsamples of blood (female) or sperm(male) from a large number of people;only a few samples were processed, withsource names protected so neither donorsnor scientists know whose genomes arebeing sequenced. The private companyCelera Genomics collected samples fromfive individuals who identified them-selves as Hispanic, Asian, Caucasian, orAfrican-American.

In addition to generating the referencesequence, another important HGP goal isto identify many of the small DNA regionsthat vary among individuals and couldunderlie disease susceptibility and drugresponsiveness. The most common varia-tions are called SNPs (single nucleotidepolymorphisms). The DNA resources

See Web site for answers to many more “Frequently Asked Questions”: www.ornl.gov/hgmis/faq/faqs1.html

Lowering Public, Private Costs

The project’s early phase was charac-terized by efforts to generate the bio-logical, instrumentational, andcomputational resources necessaryfor efficient production-scale DNAsequencing. Pilot studies on large-scale sequencing began in 1996, andsuccesses led to a ramp up in 1998.

In 1999, international HGP leaders setthe accelerated goal of completing arough draft of all 24 human chromo-somes a year ahead of schedule. Thisever-increasing pace was facilitated bythe commercialization of a new gener-ation of automated capillary DNAsequencing machines and by BACs(DNA fragments) pioneered inDOE-sponsored projects. Researchersin both the public and private sectorsuse BACs to speed their sequencingprocedures (see articles, pp. 1–3).

The extraordinary achievements ofthe HGP stand as a testimony to thesuccessful collaborations among sci-entists intent on overcoming massivetechnological challenges to movetoward the common goal of under-standing life at its most basic level.

The situation today is well captured bythe words of Winston Churchill, whosaid in November 1942, after 3 yearsof war, “Now this is not the end. It isnot even the beginning of the end. Butit is, perhaps, the end of the beginning.”

And so it is for the new biology.[See “Post-Sequencing ResearchChallenges,” p. 7.]¨

U.S. Human Genome ProjectFunding ($ Millions)

FY DOE* NIH U.S. Total

1987 5.5 0 5.5

1988 10.7 17.2 27.9

1989 18.5 28.2 46.7

1990 27.2 59.5 86.7

1991 47.4 87.4 134.8

1992 59.4 104.8 164.2

1993 63.0 106.1 169.1

1994 63.3 127.0 190.3

1995 68.7 153.8 222.5

1996 73.9 169.3 243.2

1997 77.9 188.9 266.8

1998 85.5 218.3 303.8

1999 89.9 225.7 315.6

2000 88.9 271.7 360.6

*Note: These numbers do not includeconstruction funds, which are a verysmall part of the budget.

HGP Data SitesSites with Assembled HumanGenome (including Browsing Tools)European Bioinformatics Institutewww.ensembl.orgNational Center for BiotechnologyInformationwww.ncbi.nlm.nih.gov/genome/guide(click on “Map Viewer”)

University of California,Santa Cruzhttp://genome.ucsc.edu

Other SitesBaylor College of Medicinewww.hgsc.bcm.tmc.eduComputational Biosciences, ORNLhttp://compbio.ornl.gov/toolshttp://genome.ornl.gov/jgiDNA Data Bank of Japanwww.ddbj.nig.ac.jpDOE Joint Genome Institutewww.jgi.doe.govEuropean Bioinformatics Institutewww.ebi.ac.ukGenome Databasehttp://gdbwww.gdb.orgGenBankhttp://www.ncbi.nlm.nih.gov/genbankSanger Centrewww.sanger.ac.ukStanford Human Genome Centerwww-shgc.stanford.eduWashington University, St. Louishttp://genome.wustl.edu/gscWhitehead Institutewww-genome.wi.mit.edu


HGP Milestones

DOE Hits Sequencing GoalJGI Strategies Pay Off for Chromosomes 5, 16, 19

On April 13, the U.S. Secretary ofEnergy announced that research-

ers at the DOE Joint Genome Institute(JGI) had determined the draftsequence for human chromosomes 5,16, and 19. The three contain morethan 300 million bases or about 10% ofthe total human genome, with an esti-mated 10,000 to 15,000 genes (see boxfor associated disorders).

“These three chapters in the referencebook of human life are nearly com-plete,” said Energy Secretary Richard-son. “Scientists already can mine thistreasure trove of information for theadvances it may bring in our basicunderstanding of life and in suchapplications as diagnosing, treating,and eventually preventing disease.”

JGI, now headed by Trevor Hawkins,*was established by DOE at WalnutCreek, California, in 1997. It is one ofthe largest publicly funded humangenome sequencing centers in the world.

JGI Sequencing StrategiesA critical part of JGI’s strategy was tosequence paired-end plasmids insteadof M13 subclones used in most otherHGP sequencing facilities. Because ofthe forward and reverse links betweenthem, however, plasmids providedexcellent order and orientation valuewhen the fragments were assembledinto large contiguous stretches (contigs).The result was “virtual” megabase-sizedcontigs whose lengths facilitate genediscovery. This is immensely helpful togene hunters, who are finding thatdata on order and orientation are notavailable for many contigs in the cur-rent human genome maps.

Computational Analysis of Draft DataThe Oak Ridge National Laboratory’s(ORNL) Computational Biology Sec-tion enriched the draft sequence bymaximizing fragment order and orien-tation, assembling contiguous sequencestretches, and finding genes. An IBMSP3 supercomputer, one of the world’smost powerful, provided the massive

computing capability foranalyzing millions of DNAbase pairs. Standarddata-analysis methods firstidentified such genomic fea-tures as sequence taggedsites (STSs), BAC endsequence tag connectors(STCs), and expressedsequence tags (ESTs). Datawere refined further by programs forgene identification such as GRAIL-Expthat use both EST and complete cDNAdata to add greater confidence in geneprediction. These analyses not onlyallowed for gene identification but alsoprovided some fragment- or clone-ordering information.

The Java-based Genome Channelbrowser developed at ORNL provides aview of genomic sequences, computa-tional and experimental annotation,and related links. The HTML-basedGenome Catalog includes genomic sum-mary reports, gene and protein lists,homologies, and other Internet capabil-ities (http://genome.ornl.gov).

Finishing the Draft to High QualitySome limitations of rough draft datainclude project-to-project contamina-tion, floating contigs (sequence readsthat don’t seem to belong anywhere),and false joins and other assemblyerrors. Finding useful biological infor-mation, even with accompanying cDNAsequences, is extremely difficult withgaps, incomplete order and orientation,incorrect assemblies, and base-pairerrors. Prefinishing steps at StanfordHuman Genome Center involve reas-sembling and analyzing the sequence,with the goal of fixing low-qualityregions and filling in gaps. Finishingincludes performing computationalanalysis of the assembly and resolvingdiscrepancies. Final finished data aresubmitted to GenBank when clonesare completely contiguous (see p. 5 fordata Web sites).

Bug MonthDuring October, JGI launched its first“Microbial Month,” turning out high-quality draft sequences at a rate ofmore than one every 1.5 working days.JGI sequence data is sent to ORNL’s“annotation pipeline,” where it is

Some Disorders Linked to Geneson Chromosomes 5, 16, and 19Chromosome 5 (est. 194 Mb, ~6% of humangenome): Colorectal cancer, basal cell carcinoma,acute myelogenous leukemia, salt-resistanthypertension, and a type of dwarfism

Chromosome 16 (est. 98 Mb, ~3% of humangenome): Breast and prostate cancers, Crohn’sdisease, and adult polycystic kidney disease

Chromosome 19 (60 Mb, ~2% of humangenome): DNA damage repair, atherosclerosis,diabetes mellitus, and myotonic dystrophy

analyzed rapidly for genes and otherimportant biological features. In addi-tion to the basic research value of the15 selected bacterial genomes, manyhave immediate implications for theeconomy and the environment (dataat www.jgi.doe.gov/tempweb/JGI_microbial/html). The next two bugmonths are scheduled for March andAugust 2001.

Future DirectionsSequencing has begun on mousegenomic regions that are similar togene-containing regions in humanchromosomes 5, 16, and 19. Theextensive 9× coverage of chromosome19 has enabled the rapid generationof sequence-ready mouse maps thatare providing clones for the sequenc-ing pipeline. These maps also furnishreagents for basic studies of genomeevolution and analysis of mouse muta-tions. Furthermore, a collaborativeproject is in the works to sequence 30to 50 Mb of mouse genomic clones gen-erated by ORNL-developed knockoutmice (those with deleted or inactivatedgenomic regions).

In October, JGI announced a collabo-ration to sequence the genome ofFugu rubripes (pufferfish). JoiningJGI are the Institute for Molecularand Cell Biology (Chris Tan), U.K.HGMP Resource Centre (Greg Elgar),Molecular Sciences Institute (SydneyBrenner), and Institute for SystemsBiology (Leroy Hood). Because of itsstrong similarity to the humangenome in number of genes and con-trol sequences, the Fugu genome isconsidered a powerful, compact toolfor identifying these regions in themuch larger human genome. Scien-tists expect to sequence more than95% of Fugu by March 2001(www.jgi.doe.gov).¨

*On November 3, DOE announced TrevorHawkins’ appointment as JGI director. JGI’sfirst director Elbert Branscomb will assumeleadership in developing the new OBERprogram, Bringing the Genome to Life.


HGP Milestones

High-Quality Sequence of HumanChromosomes 21, 22 Achieved

Two international research consortiamarked major milestones in the

Human Genome Project (HGP) withthe completion of the first high-qualityDNA sequences for two human chro-mosomes. Chromosomes 22 and 21sequences, respectively, were reportedin the December 2, 1999, and May 18,2000, issues of Nature. These two chro-mosomes, smallest in the humangenome, account for 2% to 3% of thetotal 3 billion DNA bases. [For anexplanation of when a chromosome isconsidered “finished,” see sidebar, p. 4.]

Chromosome 22Chromosome 22’s euchromatic(gene-containing) portion is estimatedto be a 33.5-Mb structure comprisingat least 545 and possibly up to 1000genes ranging in size from 1000 to583,000 bases. Genes are pinpointedby their sequence similarities to thosealready identified in other organismsand by complex computer modeling ofpotential (“putative”) genes that maybe only partially accurate. Chromo-some 22’s sequenced DNA is ofextremely high quality with an errorrate of less than 1 in 50,000 bases.

Gene variants on chromosome 22 havebeen implicated in immune systemfunction and in at least 27 disorders,including congenital heart disease,schizophrenia, mental retardation,birth defects, and leukemia and othercancers. Scientists reported that atleast eight regions are present induplicate, leading to speculation aboutthis phenomenon’s evolutionary impor-tance. Duplication can be studiedclosely when comparable animalgenome sequences become available.

Chromosome 21Chromosome 21 revealed a relativelylow gene density, estimated at about225 active genes in the 33.8 Mb ofDNA covering 99.7% of the chromo-some’s long arm. Scientists speculatethat this gene scarcity could contrib-ute to the viability of individualspossessing a third copy of the chromo-some, resulting in trisomy 21 (Downsyndrome). The sequence also includesa contig of 28.5 Mb, the longest con-tinuous DNA sequence reported thus

far. The entire sequence has only3 gaps totaling about 100,000 bases,compared with 10 gaps (totalingabout 1 Mb) for chromosome 22’slong arm.

Analysis of chromosome 21 genes maypermit a deeper understanding of

The working draft DNA sequenceand the more polished version

planned for 2003 or sooner representan enormous achievement, akin in sci-entific importance, some say, to devel-oping the periodic table of elements.And, as in most major scientificadvances, much work remains torealize the full potential of theaccomplishment.

Early explorations into the humangenome, now joined by projects on thegenomes of dozens of other organisms,are generating data whose volumeand complex analyses are unprece-dented in biology. Genomic-scale tech-nologies will be needed to study andcompare entire genomes, sets ofexpressed RNAs or proteins, genefamilies from a large number of spe-cies, variation among individuals,and the classes of gene regulatoryelements.

Deriving meaningful knowledge fromDNA sequence will define biologicalresearch through the coming decadesand require the expertise and creativityof teams of biologists, chemists, engi-neers, and computational scientists,among others. A sampling follows ofsome research challenges in genetics—

what we still won’t know, even withthe full human sequence in hand.

Gene number, exact locations, andfunctions

Gene regulation

DNA sequence organization

Chromosomal structure and organi-zation

Noncoding DNA types, amount, dis-tribution, information content, andfunctions

Coordination of gene expression, pro-tein synthesis, and post-translationalevents

Interaction of proteins in complexmolecular machines

Predicted vs experimentally deter-mined gene function

Evolutionary conservation amongorganisms

Protein conservation (structure andfunction)

Proteomes (total protein content andfunction) in organisms

Correlation of SNPs (single-baseDNA variations among individuals)with health and disease

Disease-susceptibility predictionbased on gene sequence variation

Genes involvedin complex traitsand multigenediseases

Complex systemsbiology includingmicrobial consor-tia useful forenvironmentalrestoration

Developmentalgenetics,genomics¨

Post-Sequencing Research Challenges

Online Bioinformatics NewslettersBioInformer (EMBL European Bioinformatics Institute):Quarterly. Bioinformatics research, developments, andservices (http://bioinformer.ebi.ac.uk)

NCBI News (National Center for Biotechnology Informa-tion): Quarterly. Research activities, new databases, andsoftware services (www.ncbi.nlm.nih.gov/About/newsletter.html)

What’s New (DNA Data Bank of Japan): Updated asneeded. News, upgrades, and release information(www.ddbj.nig.ac.jp/whatsnew-e.html)¨

Down syndrome and its complications,as well as a range of such other linkedgenetic disorders as Alzheimer’s dis-ease and some forms of cancer.¨

Chromosomes 21 and 22 Papersin Nature OnlineSee “Library of Original ResearchPapers” at

www.nature.com/genomics


In the News

Seven new grants, four of themawarded to scientists at DOE sites,

are key components in the StructuralGenome Initiative started by the NIHNational Institute of General MedicalSciences (NIGMS). Over the next decade,the new study will determine the formand function of thousands of proteins.

“These awards demonstrate the contin-ued importance of the physical sciencesto life-science research and the strongrole the national laboratories play inproviding expertise and world-classfacilities in our quest to understandthe structure and function of genes,”noted Dr. Mildred Dresselhaus, Direc-tor of the DOE Office of Science.

Proteins come in many sizes and shapes,and their functions often depend on tinystructural details. Obtaining the 3-Dstructure may help scientists understandhow each protein functions normally andhow faulty structures can cause or con-tribute to disease. “We expect thiseffort to yield major biological findingsthat will improve our understanding ofhealth and disease,” said NIGMSDirector Marvin Cassman in announc-ing the grants. These data also canhelp in designing drugs that bind tothe proteins and affect their activity.

The grants total around $4 millioneach for the first year. NIGMS plans tospend about $150 million on the sevengrants over the next 5 years. The fourDOE-involved projects are listed firstbelow. Investigators at DOE nationallaboratories also are involved in someof the other projects.

Grant Recipients, Team Leaders,Specific Goals

Structural Genomic Center (Sung-Hou Kim, Lawrence BerkeleyNational Laboratory): Speed upstructure determination by X-raycrystallography; study proteinsessential for independent life byfocusing on two extremely small,closely related bacteria (Mycoplasmagenitalium and M. pneumoniae)[www.lbl.gov/Science-Articles/Archive/nigms-grant.html].

Tuberculosis Structural GenomicsConsortium of 13 institutions in6 countries (Tom Terwilliger, LosAlamos National Laboratory):

Determine and analyze structuresof about 400 proteins from Myco-bacterium tuberculosis to facilitatenew and improved drugs and vac-cines for tuberculosis [www.lanl.gov/worldview/news/releases/archive/00-127.html].

Midwest Center for StructuralGenomics consortium of seven insti-tutions (Andrzej Joachimiak, ArgonneNational Laboratory): Reduce theaverage cost of determining a proteinstructure from $100,000 to $20,000;select protein targets from all threekingdoms of life, with emphasis onpreviously unknown folds and on pro-teins from disease-causing organisms.

New York Structural GenomicsResearch Consortium of five institu-tions (Stephen K. Burley, RockefellerUniversity): Develop techniques tostreamline structural genomics andsolve several hundred human andmodel-organism protein structures.

Joint Center for Structural Genomics(Ian Wilson, Scripps Research Insti-tute): Develop high-throughputmethods for protein production,crystallization, and structure deter-mination by initially focusing onnovel structures from Caenorhab-ditis elegans and human proteinsthought to be involved in cell

DOE and NIH Teams to Unlock Power of Proteins

signaling; determine structures ofsimilar proteins from other organ-isms to include the greatest num-ber of different protein folds[www.stanford.edu/dept/news/report/news/september27/ssrl-927.html].

Northeast Structural GenomicsConsortium (Gaetano Montelione,Rutgers University): Target pro-teins from various model organ-isms including the fruit fly, yeast,and roundworm and relatedhuman proteins; use both X-raycrystallography and nuclear mag-netic resonance spectroscopy todetermine protein structures.

Southeast Collaboratory for Struc-tural Genomics (Bi-Cheng Wang,University of Georgia): Analyzepart of human genome and all oftwo representative organisms,C. elegans and Pyrococcus furiosus;emphasize technology development,especially for automated crystal-lography and nuclear magneticresonance imaging techniques.¨

Using a high-energy X-ray beamfrom the National Synchrotron

Light Source (NSLS) at BrookhavenNational Laboratory, researchers atYale University and the HowardHughes Medical Institute obtained themost detailed images ever seen of theribosome (the protein-making struc-ture inside all living cells). NSLS is aDOE Office of Biological and Environ-mental Research structural biologyuser facility.

In prokaryotes (bacteria and other sim-ple organisms) as well as the morecomplex eukaryotes, ribosomes helptranslate gene-encoded informationinto a specific protein. Ribosomes con-sist of two unequally sized subunits

Award informationwww.nigms.nih.gov/news/releases/sgpilots.html

High-Resolution Image RevealsStructure of Protein Machine

containing RNA and proteins. Thesmaller component binds the mes-senger RNA (mRNA), which containsgenetic instructions that specify theamino acids required to build a par-ticular protein. The larger ribosomalsubunit attaches one amino acid tothe next in the growing proteinchain.

In the August 11 issue of Science,investigators reported visualizingthe atomic structure of the bacteriumHaloarcula marismortui’s largerribosomal subunit at an unprece-dented resolution of 2.4 Å. Until thisreport was published, researchersdid not know whether ribosomal

Proteins, p. 19à


In the News

Massive amounts of data flowingfrom the Human Genome Project

and other genomics projects havestimulated an avalanche of applica-tions to the U.S. Patent and Trade-mark Office (PTO) for patents ongenes and gene fragments. Some3 million ESTs (fragments that identifypieces of genes) and thousands of otherpartial and whole genes are includedwithin pending patents. This situationhas sparked controversy among scien-tists, many of whom have urged thePTO not to grant broad patents at thisearly stage to applicants who have nei-ther characterized the genes nor deter-mined their functions and specific uses.

Genes and other biological resourceshave been patentable since the land-mark 1980 U.S. Supreme Court deci-sion in Diamond v Chakrabarty thatgranted a patent for an oil-dissolvingmicrobe. Patents give owners exclusiverights to their inventions or ideas for20 years from the filing date. Therationale is to allow inventors time torecoup their investment costs inexchange for a public description of theirknowledge, thereby revealing technicaladvances to competitors and the generalpublic and avoiding duplicated efforts.Biological inventions are patentable ifthey meet the standard requirementsfor all patents: they must be novel,useful, not obvious, and described suf-ficiently for others to reproduce.

A single gene may be patented, in prin-ciple, by different scientists or compa-nies. One concern is that such “patentstacking” may discourage productdevelopment because royalties areowed to all patent owners. Additionally,because applications remain secret,companies may work on developing aproduct, only to find that “submarinepatents” already have been granted,leading to unexpected licensing costsand possible infringement penalties.

Some past controversies have centeredaround the “utility” requirement. Somefear the large-scale patenting of genefragments by biotechnology companieswho are unaware of their functionsbut would stake a claim to all futurediscoveries on those genes (sometimescalled “reach-through patents”).

In December 1999, the PTOpublished revised interimguidelines clarifying the utilityrequirement for patent claimson genomic and other biotech-nological inventions. The new rulescall for “specific and substantial utilitythat is credible,” but some still feel therules are not stringent enough. Publiccomments have been posted to thePTO Web site (www.uspto.gov; scrollto “Notices of Public Comments”).

In the comments, the National AdvisoryCouncil for Human Genome Researchobserves that “a broad allowance ofclaims is unjustified and will stronglydiscourage the further research effortsnecessary to translate gene discoveryinto medically important therapies.”

Instead of patent protection for spe-cific gene sequences, Bruce Alberts,President of the National Academy ofSciences, advocates patents for “thenew treatments and drugs that willresult from the research and develop-ment efforts of many different individ-uals and companies working from thebasic information in the humangenome sequence.”

Final revised guidelines are expectedfrom the PTO (see also box below).[Denise Casey, HGMIS]¨

Witnesses Testify About Patenting Genes

On July 13, witnesses presented testimony during a House of Representa-tives hearing on “Gene Patents and Other Genomic Inventions” held by

the Committee on the Judiciary, Subcommittee on Courts and IntellectualProperty. A complete transcript is on the Web (www.house.gov/judiciary/4.htm).

At the hearing, Harold Varmus (Memorial Sloan-Kettering Cancer Center)stated that some of the issued patents appear to reward the obvious in DNAsequencing and diminish the innovative work required to determine genefunction and utility. This new environment, he said, has led many academicinstitutions to establish expensive offices to protect intellectual property andregulate the exchange of biological materials that once would have beenshared freely. The use of new scientific findings has been hampered, and theopen exchange of ideas and materials has been inhibited, he continued.

Dennis Hopper (Genentech, Inc.) testified that his company invests about$400 million a year in the research and development of therapeutic products,focusing on identifying human proteins. He said patent protection and marketexclusivity are very important considerations in making such investments.

Jon Merz (University of Pennsylvania, Philadelphia) expressed concern aboutexclusive licensing of disease-gene patents that claim a gene sequence and oneor more mutations leading to disease. In addition to covering all uses of thechemical sequences, patents claim all methods of diagnosing disease in a specificpatient through the identification of the disclosed genetic alleles, mutations,or polymorphisms. Merz stated that some licensees thus are exercising theirpatent rights to prevent physicians—in particular, molecular pathologists—from performing genetic testing on their patients.

Merz pointed out that most disease genes are found, at least in part, throughfederally funded research. Exclusive licensing is contrary to the longstandingpolicy that the public should not have to pay twice. Merz recommends reserv-ing exclusive licensing for inventions that require substantial downstreaminvestment. Other witnesses said that patents should be even more availableto encourage the development of critically needed medical advances.

PTO Director Q. Todd Dickenson stated that both points of view are relevantand that his office is responsible for balancing them. To that end, he said, thePTO is finalizing guidelines to require the demonstration of “real-world” utilityfor gene-related patents, rather than just theoretical uses.¨

More patenting information:www.ornl.gov/hgmis/elsi/patents.html

Gene Patenting Update: U.S. PTO Tightens RequirementsWorries Continue over “Patent Stacking” and Early, Broad Patents


In the News

The Human Genome Project (HGP)and The SNP Consortium (TSC,

http://snp.cshl.org) announced plans togenerate a new set of human DNAsequence data that will contribute125,000 to 250,000 validated and usefulDNA markers known as SNPs. The DNAto be sequenced will come from 24 anony-mous, unrelated donors with diverse geo-graphic origins, and all data will be madepublicly available. Researchers expectto complete the project by December.

A high-density map of SNPs (singlebase-pair variations that occur aboutonce every 100 to 300 bp throughouthuman DNA) is expected to be a valu-able research tool. It will help scien-tists pinpoint genetic differences thatpredispose some people to disease andunderlie variable individual responsesto treatment.

Three genome research centers areparticipating in the HGP-TSC collabora-tion: Whitehead Institute, WashingtonUniversity School of Medicine (St. Louis),and the Sanger Centre (United King-dom). These centers will isolate at least2.5 million DNA fragments (each about6000 bp long) from the human genomeand determine the sequence of about500 bp at both ends of the fragments,resulting in paired-end sequences aknown distance from each other. Thesequences then will be compared to thosealready in GenBank. The paired-enddata will help span some gaps in thehuman genome working draft, thusmaking the draft more accurate.

“The collaboration between the HGPand TSC demonstrates that public-private cooperation can be an efficientmeans for developing basic research

tools essential for the application ofgenetic information to the under-standing and treatment of diseases,”noted Arthur Holden, chairman andchief executive officer of TSC.

The nonprofit TSC foundation wasestablished by the Wellcome Trustand a group of pharmaceutical andtechnological companies with the ini-tial goal of identifying and locatingup to 300,000 SNPs by the end of2001. An exponential increase in theamount of HGP data, however, hassince enabled TSC to proceed at amuch faster pace. By September, ithad identifed more than 350,000SNPs and mapped almost 250,000 tothe working draft sequence. With theHGP collaboration, the total numberof useful SNPs mapped may exceed750,000 by December.

First TSC DNA Variation MapThe first publications on the method-ology and progress of TSC appeared

SNP Consortium Collaborates with HGP,Publishes First Progress Reports

International SNP Meetings

Some 100 invited internationalresearchers from industry and aca-

demia attended the Second Interna-tional Meeting on Single NucleotidePolymorphism (SNP) and ComplexGenome Analysis held in Munich,Germany, in September 1999. Below isa summary of meeting highlights withupdates from the September 2000meeting in Taos, New Mexico.

The overall tone of the 1999 meetingshowed that SNP research still lacks asolid consensus about how best toproceed—and this is at a time whenvast sums of money are being spenton public and private SNP programs.This state of affairs is only partiallyimproved today. SNP discovery alonewill not determine how and whetherSNPs should be used. Instead, thisknowledge has to come from empiri-cally determined guidelines and stud-ies based upon best guesses and theoryusing the latest technologies.

SNP DiscoveryThe SNP Consortium (TSC) has estab-lished a well-structured programtoward discovery and public catalogingof many hundreds of thousands of ran-dom genomic SNPs (at a 95% accuracytarget) in 2 years, plus detailed

mapping of over 170,000 of these. Orig-inal goals are being greatly surpassed.Other projects involve automatedalignment and comparison of expressedsequence tag (EST) sequences for SNPdiscovery. Although limited by thedepth and number of distinct ESTcontigs to perhaps a few tens of thou-sands of SNPs, the exercise is highlycost-effective. Furthermore, theintragenic location of these variantscould make them individually moreuseful than TSC-discovered markers.

SNP Scoring and DetectionA plethora of competing SNP genotyp-ing methods is being developed, butuseful approaches must meet stringentrequirements of both high throughputand accuracy. A fully ideal method stilldoes not exist today. Extremely largesample materials may be required toachieve sufficient statistical power inassociation studies, and a genotypingerror rate of as little as 1% could havea disastrous effect on statistical power.Claimed genotyping costs still rangefrom a fraction of one dollar to manydollars per sample.

Two principal approaches to SNP scor-ing are in individual reactions and in amultiplexed fashion, usually achieved

by using immobilized oligonucleotideson microarrays. The requirement forPCR before the detection reactionremains a major bottleneck. Simulta-neous analysis of pooled DNA sam-ples may be useful for increasingthroughput and decreasing the costof SNP scoring in association studies.

Diseases and PhenotypesSNPs and association analysis arebeing used to (1) home in on disease-related mutations within large regionspreviously identified by linkage scans,(2) screen several variations surround-ing a few or many prechosen candi-date genes, or (3) follow extensivesequence studies of single candidategenes to determine associationsbetween specific haplotypes and dis-ease. These strategies can sometimeswork—although how best to maximizethe rate of success is not known.

If there is no initial linkage to guidethe search, however, the currentanswer seems to be to make educatedguesses about which genes are likelyto be important. Presenters summa-rized attempts to do this for Alzhei-mer’s disease, schizophrenia, dyslexia,and substance dependence. Thesestudies began with a strong priorbelief in the relevance of the testedcandidate gene. Other presented

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In the News

in the September 28 issue of Nature.Eric Lander and his team at the White-head Institute Center for GenomeResearch reported on a new methodcalled reduced representation shot-gun sequence (RSS) that increasesthe accuracy of SNP mapping. RSSscans subsets of markers from severalpeople and compares the resultingsequences to identify DNA variations.

In a second Nature paper, a team ofTSC researchers from the SangerCentre presented a human chromo-some 22 map featuring 2730 SNPsidentifed by RSS and aligned to thehuman genomic sequence. Most of theSNPs are within 25 kb of a transcribedexon (protein-coding region), makingthem useful for association studies.Chromosome 22, the second smallest ofthe chromosomes, is linked to morethan 35 diseases and syndromes includ-ing some cancers, schizophrenia, andheart disease.

The goal of TSC is to build a map con-taining one SNP every 5 kb that isintegrated with the human genomesequence and freely available to allresearchers (600,000 SNPs evenlyspaced throughout the human genome’s3 billion bases). In September, scientistsreported the total number of SNPs nowin the public domain to be more than1.2 million, scattered across the genome.

The ultimate aim of SNP studies is todevelop customized therapies to treator prevent disease. In the September13 issue of Proceedings of the NationalAcademy of Sciences, researchersmoved a step closer to that goal asthey reported for the first time theability to predict an individual’sresponse to a drug based on that per-son’s particular group of SNP

markers. The study involved asth-matic volunteers and responses toalbuterol, a drug commonly used to

achieve rapid improvement in lungfunction.

As more clinical studies get underway and advances eventually becomeestablished in clinical practice, theurgency increases to find effectiveways to protect the genetic privacy ofindividuals. In response to these pro-jected needs, several members of TSCformed a new company, First GeneticTrust, Inc., to act as an independentintermediary between genetic infor-mation providers (individuals) andusers (researchers and healthcareproviders). The company aims to pro-tect the rights of individuals in regardto the confidentiality and access oftheir genetic data. The first priority ofthe company will be to address theneeds of the pharmaceutical industryas it conducts clinical trials.¨

More information on SNPs:www.ornl.gov/hgmis/faq/snps.html

Detailed 1999 Meeting Reportwww.ornl.gov/meetings/brookes.html;Eur. J. Hum. Genet. 8(2), 154–56 (2000)

September 2000 Meetingwww.cgr.ki.se/cgr/groups/brookes/snp2000/abstracts.htm

data showed how intricate estimationsof haplotype configurations, regression,and cladistic analyses can lead towardthe precise intragenic location of thepathogenic allele and genotype combi-nations. This evolutionary perspectivewas a key take-home message.

The emphasis of most SNP researchon tools and genotyping (finding thelink between marker and pathogenicallele) was contrasted with the rela-tive lack of attention to careful studydesign and sample ascertainment(finding the link between pathogenicallele and disease). Many case-controlassociation studies may be futilebecause the lack of even rare familiessegregating the disease could indicatetoo-high genetic complexity.

Population GeneticsSpeakers presented work on character-izing extant haplotypes and developingmaps describing typical distances upto which allelic variants can be expectedto be in linkage disequilibrium. These

efforts can benefit disease-gene andpopulation-genetics studies. Identifyingpotential targets of selective fixationvia SNP analyses may be useful inrevealing footprints of adaptive evolu-tion. Revealing such dominant benefi-cial alleles could provide importanttargets for study.

Databases and BioinformaticsFuture high-throughput detection willrequire efficient systems for collectingand integrating voluminous amountsof data in high-quality databases.Representatives from the EuropeanMolecular Biology Laboratory–EuropeanBiotechnology Institute presentedsoftware and database solutions tolinking various locus-specific mutationdatabases with SNP databases allow-ing complex queries.

Many groups endeavor to mine SNPsfrom EST data, but measuring allelefrequencies in silico is difficult, andmany rare alleles might be amongthem. Prediction accuracy is estimatedat only 60% to 80% in most cases,although this identifies gene candidatesfor further investigation. Others areattempting to map large numbers ofSNPs onto human chromosomes andthree-dimensional protein structuresto understand phenotypic differencesand human evolution using SNP data.

Intellectual Property, CommerceA clear trend is toward granting pat-ents on partial nucleic acid sequencesor SNPs only when functions and com-mercial applications can be defined.Commercially, profits are expected tobe generated in three areas: applyingSNPs to pharmacogenomics by discov-ering functional implications, genotyp-ing individuals for particular SNPs,and creating technology platforms forSNP discovery and use.

In the first situation, proprietaryrights to the “important” SNPs areexpected to generate profits via licens-ing. In the third instance, profits canbe generated over shorter times bysales and licensing of patented tech-nologies. But the greatest businesssuccess from SNP knowledge may berealized only if and when solid correla-tions between SNPs and gene functionare determined.

A key question is whether the mostobvious and rewarding SNPs (from acost-benefit standpoint) already havebeen discovered and patented or iflatecomers still have a good chance offinding valuable SNPs. [Reported byAnthony Brookes; Center for GenomicsResearch; Karolinska Institute; Stock-holm, Sweden ([email protected])]¨


In the News

¶ Microbial Genome Program ReportA color booklet on the DOE Microbial Genome Program (MGP), published inFebruary 2000, is available in print and electronic formats. It includes programorigins, targeted microbes and their potential uses, graphics, and abstracts ofMGP research. The MGP, which DOE initiated in 1994 as a spinoff of its HumanGenome Program, has been extremely successful. As of November, MGPresearchers had completed the sequencing of 14 microbes, with around 35 morein progress. Future plans call for more detailed microbial analysis. At least5 other governmental agencies have begun their own microbial programs, andabout 170 microbial genomes are being sequenced and studied at present.

• Print copies: 865/574-7582,Fax: /574-9888, [email protected]• Web: www.ornl.gov/hgmis/publicat/microbial• PDF (printer-friendly) file: www.ornl.gov/hgmis/publicat/microbial/mgp.pdf¨

¶ Microbial GenomicsInteragency Report on the Federal Investment in Microbial Genomics discusseseach relevant federal agency’s activities, plans, and areas of interest in microbialgenomics and summarizes opportunities for and limitations to microbial research.Prepared for the Executive Office of the President of the United States in 2000.[Print copies: HGMIS, 865/574-7582, [email protected], http://whitehouse.gov/WH/EOP/OSTP/html/microbial/nsf00203_1.html] ¨

Public, Private Sectors Join in Mouse ConsortiumSequencing Results will Spur Discovery of Human Genes and Their Functions

BERAC Report Endorses New Program

three private companies. It providesanother example of public and privatesectors joining forces to supportlarge-scale genomics research andgenerate freely available data crucialfor basic biomedical research (seerelated articles, pp. 1–3).

Bringing the Genome to Life: Energy-Related Biology in the Post-Genomic

World, issued in June, recommends anew research program for the DOEOffice of Biological and EnvironmentalResearch (BER), headed by AriPatrinos. At the request of the DOEOffice of Science, the report was pro-duced by the BER Advisory Com-mission’s (BERAC) GenomeSubcommittee, chaired by RaymondGesteland (University of Utah). Itsuggests that the new program’s

¶ Intimate Strangers: Unseen Life on EarthThe four-part documentary series Intimate Strangers: Unseen Life on Earth,which was broadcast on public television last November with partial supportfrom DOE, is available on videotapes (800/532-7637 or 800/423-1212).A 225-page companion book of the same name can be purchased at 800/546-2416.The MicrobeWorld Web site, tailored to middle and high school students as wellas professional and lay audiences, includes downloadable hands-on educationalactivities correlated with the television series, information and stories aboutmicrobes, and teacher resources (www.microbeworld.org).¨

In October, a collaboration wasannounced to speed up sequencing of

the mouse genome and produce a draftmap by spring 2001. The MouseSequencing Consortium (MSC) con-sists of six NIH institutes, theWellcome Trust philanthropy, and

MSC members and their contribu-tions are SmithKline Beecham($6.5 million), the Merck GenomeResearch Institute ($6.5 million),Affymetrix, Inc. ($3.5 million),Wellcome Trust ($7.75 million), andNIH ($34 million). Total funding of$58 million will support sequencingfor 6 months at three centers:Whitehead Institute (Cambridge),Washington University (St. Louis),and the Sanger Centre in theUnited Kingdom. àmajor challenge is to understand and

predict the responses of single- andmulticellular organisms to biologicaland environmental cues. ElbertBranscomb, first director of DOE’sJoint Genome Institute, is in chargeof developing the program.¨

BERAC Report:www.er.doe.gov/production/ober/berac/genome-to-life-rpt.html

¶ Federal TechnologyFunding GuideThe fifth edition of the 2001 FederalTechnology Funding Guide may bedownloaded free in PDF (printer-friendly) format from www.larta.org/ecommerce/FTFG2001.htm. Createdby the Los Angeles Regional Technol-ogy Alliance (larta), the 152-page guideprofiles nearly 100 regularly scheduledfederal programs that support technol-ogy development and deployment. Morethan half of all U.S. research anddevelopment (over $77 billion) is fundedby the federal government. [Larta con-tact: 213/743-4150, www.larta.org] ¨

¶ Genetics, Public HealthGenetics and Public Health in the 21stCentury: Using Genetic Information toImprove Health and Prevent Diseaseexplores the genetic revolution’s impacton public health practices and delin-eates a framework for the integrationof related advances and technologies.Editors are Muin Khoury (Centers forDisease Control and Prevention), WylieBurke (University of Washington, Seat-tle), and Elizabeth Thomson (NIHNational Human Genome ResearchInstitute). Some 75 contributors repre-sent a wide range of disciplines. Por-tions of the book are online at www.cdc.gov/genetics/publications/21stcentury.htm [639 pp., Oxford University Press,2000].¨

¶ Genetic TestingEnhancing the Oversight of GeneticTests, by the Secretary’s Advisory Com-mittee on Genetic Testing, assessescurrent oversight and offers recom-mendations on ensuring public accessto quality genetic tests (http://www4.od.nih.gov/oba/sacgtfinal.pdf).¨

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In the News / ELSI

The first phase of the ambitiousinternational effort to determine

the entire sequence of the humanchromosome set is virtually complete.Human Genome Project scientistsplan to finish the human sequence by2003, along with a database of themost common sequence variations thatdistinguish one person from another.This knowledge base, freely availableto any interested person over theInternet, will revolutionize biologyand medicine. But how? What will bedifferent 20 years from now becausethe human genome was sequenced?

Only time will prove the accuracy of thefollowing predictions, but here is a listof some effects we might expect in 2020.

More Effective Pharmaceuticals

A virtually complete list of humangene products will give us a vast rep-ertoire of potential new drugs. From500 or so drugs in 2000, at least six

times this number will have beenidentified, tested, and commercializedin 2020. Most will be manufacturedby recombinant DNA technology sothey will be “reagent-grade pure,” justas human insulin and growth hor-mone are today.

Your medical record will include yourcomplete genome as well as a cata-logue of single base-pair variationsthat can be used to accurately predictyour responses to certain drugs andenvironmental substances. This willpermit you to be treated as a bio-chemical and genetic individual, thusmaking medical interventions morespecific, precise, and successful. Inaddition, the increased power of medi-cine to predict susceptibility to spe-cific diseases will allow you to alteryour lifestyle to reduce the likelihoodof developing such diseases or to betreated with preventive or disease-delaying medicine.

Why the Mouse?With the working draft sequence ofthe human genome in hand, scientistsin industry and academia now seek tointerpret its meaning. The mousegenomic sequence is a powerful compar-ative tool because genes in the twoorganisms are very similar. Under-standing gene function in the mousewill accelerate knowledge about compa-rable human genes and will aid inunderstanding human disease and indeveloping new treatments.

On average, protein-coding regions inthe mouse and human genomes are85% identical. These regions areevolutionarily conserved because theyare required for biological functionsshared by both organisms. In contrast,noncoding genomic regions are lessthan 50% identical. When comparingthe same DNA regions from humanand mouse, therefore, functional ele-ments stand out clearly because ofgreater similarity.

“Data from this project will beinvaluable to us in annotating thefinal draft of the human genome,”observed researcher John McPherson(Washington University). “It isexciting that we are moving rapidlytoward completion of both projects,”he said.

Rapid Data ReleaseThe consortium project focuses on the“black six” (C57Black/6) mouse strain,which is different from the threestrains being sequenced by CeleraGenomics. Celera’s data are availableby paid subscription.

The MSC data-release policy calls forraw data (individual DNA sequencetraces, about 500 bases long) takendirectly from automated instrumentsto be deposited in two public databases.These are operated by the NationalCenter for Biotechnology Information(www.ncbi.nlm.nih.gov) and theEuropean Bioinformatics Institute(www.ebi.ac.uk). Individual sequences

Fast Forward to 2020: What to Expect in Molecular MedicineThis article was originally written for and will appear in the online magazine TNTY Futures(www.tnty.com/newsletter). Free subscriptions are available through the Web site. In the article, the authorsspeculate about possible future changes in medical practice resulting from genome research.

will be assembled into larger units assoon as a working draft is obtained.

Sequencing StrategyMSC sequencing melds the best fea-tures of two strategies used to producea working draft of the human genome:the map-based shotgun method usedby the public Human Genome Projectconsortium and the whole-genomeshotgun system used by Celera. Theoverall depth of coverage for themouse genome will be 2.5× to 3×, alevel of detail useful to researchers; afinished, highly accurate sequence isexpected at a later date.¨

Treatment failures occasionally hap-pen today with drugs for hepatitis Cinfections, antihypertensives, andcertain antidepressants (selectiveserotonin reuptake inhibitors likeProzac). In the next 15 to 20 years,more effective drugs will be devel-oped, and doctors will test individualgenetic profiles against panels ofdrugs available for a specific condi-tion and choose the treatment withthe greatest potential benefit foreach patient.

Today, some 100,000 people die eachyear from adverse reactions to drugs,and millions of others must bearuncomfortable or even dangerousside effects. We see such currentexamples as heart-valve abnormali-ties from diet drugs, muscle damagefrom some hormone-regulatingdrugs, and nervous system effectswith certain types of antidepressant

More information on the MSCwww.nhgri.nih.gov/news/mousegenes/mouse_release.html

Trans-NIH Mouse Initiativewww.nih.gov/science/models/mouse/index.html


ELSI

medications. As genes and other DNAsequences that influence drug responseare identified, we can expect the num-ber of toxic responses to drop dramati-cally and most side effects to beeliminated.

Societal ImplicationsAnother consequence of greater knowl-edge about individual variation ismore disturbing, and we may facesome unpleasant consequences unlesssociety makes some hard choices.These considerations include the like-lihood that your medical informationwill be available to others not in themedical profession—your insurer oremployer, perhaps. Employers mayhave a strong motive to learn aboutyour risks of developing certain condi-tions so they can avoid hiring you orrestrict the kinds of work you may do.

Genetic Testing, TherapyAlthough now plagued by technicaldifficulties, gene therapy for single-gene diseases will be routine and suc-cessful in 20 years. Certain aberrantdisease-associated genes will bereplaced with normally functioningversions, and several hundred dis-eases will be curable. Neonatal genetictesting for these treatable conditionswill be routine.

Some of the mysteries of early embry-onic development will be solved. Weshould know the timing of expressionof most, perhaps all, of the humangene set. We may have learned how todirect differentiation so that a desiredcell type or even relatively “simple”organs and parts of more complexorgans can be grown for transplanta-tion. In 2020, we will have made sub-stantial progress towards true “cloning”of certain organs, but many difficulttechnical steps will remain before suc-cessful cloning of a heart or liver.

As genetic testing using DNAsequence becomes less expensive andmore accurate, it will be used com-monly and reliably in cases of mis-taken identity, false or misattributedpaternity, and the identification ofmissing persons. Misguided attemptsto ascribe behavioral tendencies to aperson’s genes will cause many

problems, especially for the courts thatmust resolve disputes when an indi-vidual’s behavior and actions conflictwith laws. Should society (via thecourts) interpret behavior as a conse-quence of free will or as influenced bygenetic constitution? At what pointdoes society mitigate responsibility orpunishment?

Understanding LifeOn the brighter side, an inevitableconsequence of the genome project willbe a much greater understanding offundamental biology. Already, morethan three dozen organisms (mostlyone-celled microbes) have been com-pletely sequenced. The fruit fly, thelatest organism to be sequenced, isbeing used to model the essential fea-tures of human disorders such as Par-kinson’s, making possible a powerfulgenetic approach to garnering knowl-edge about diseases as well as todeveloping more effective treatments.In 2020, perhaps 1000 completegenomes will be in hand. Besides fur-nishing insights into evolution, thisvast repertoire of new genes and theirproducts can be explored for theirpotential in solving challenging prob-lems such as environmental cleanup.

We will fitfully and slowly gain someinsights into biological complexity. In2020, we will know how to build a

functioning cell capable of free-livingexistence. We will understand cer-tain pathways used by this simplestcell, but there still will be unan-swered questions about it. We will bevirtually no closer than we are todayto the mysteries of such true “emer-gent” properties as intelligence incomplex multicellular organisms.

ChallengesWe speculate that the HumanGenome Project will have vast andlargely positive impacts on peopleliving in 2020. Of the various predic-tions noted above, the last two arethe most profound because the mostpowerful and momentous impactscome from fundamental knowledge,usually in unforeseen ways. As thisastonishing treasure trove is intro-duced into society, we need to bealert to challenges and misuses ofthe knowledge about ourselves.Society as a whole, not just genomescientists, must address these con-siderations. It has to be all of us.[Daniel Drell (DOE) and AnneAdamson (HGMIS)]¨

Forward to 2020 (from p. 13)

More information on Medicineand the New Genetics

www.ornl.gov/hgmis/medicine/medicine.html

Judging Molecular Biology of Murder,Addictive Disorders, and Dementia

Sixty learners stare at cross-sectionimages of living brains projected on

the screen at Airlie Conference Center,an hour out of Washington in NorthernVirginia’s rolling horse country. Drawnto a specialized 3-day training

program on neurobehavioral genet-ics, they strain to find red and whitespots indicating mental activity. Asthey search intently for dark stretchesof turned-off brain segments, theymight be mistaken for participantsin a medical school’s clinical semi-nar. But these are judges absorbedin the speaker’s rapid, precise lan-guage as she points out image slicesof brains from murderers, cocaineaddicts, demented elderly persons,and gunshot victims.

Today’s judges are beginning to viewdefendants and plaintiffs in a newlight while presiding over some15 million cases a year in the nation’sstate and federal courts, where they

p. 15à

¶ Judges’ GuidebookThe Biology of Conduct: Judges’Guidebook to Neuro- and Behav-ioral Genetics serves as anup-to-date archive, a case-relatedteaching tool for the next advancedconference, and a means for forginga community of discourse amongthe nation’s adjudicators(www.einshac.org).¨


ELSI

are accustomed to observing behaviorand its results. At the conference,they peer into genotypes and pheno-types linked to behavior they will findon their dockets upon their returnhome. For most, it is an opportunityto assess scientific progress in discov-ering causes of violence, addictions,and dementia. They are able to com-pare clues from neuroscience withthose from genetic and behavioraldevelopment.

Among 22 science advisors at Airlie,the judges’ guide is Nora Volkow,Brookhaven National Laboratory’sbrain-mapping expert. Sacrificing aholiday weekend in aid of the courts,she has joined her colleagues—basicand clinical scientists, psychiatrists,and psychologists—to paint a land-scape of molecular and organic knowl-edge. In the past 3 years, more than250 neutral and independent scientistshave served as advisors for Geneticsin the Courtroom conferences spon-sored nationwide by the Ethical,Legal, and Social Implications compo-nent of DOE’s Human Genome Pro-gram. These courses were conceived

and are carried out byFranklin Zweig and his col-leagues at the EinsteinInstitute for Science, Health,and the Courts (EINSHAC).

Each scientific expert has partici-pated in one or more workshops toprepare judges for the testimony ofnonneutral experts in cases involvinggenetics. To date, 1900 jurists haveparticipated, and another thousandare expected next year. Subject mat-ter ranges from basic molecular biol-ogy to advanced biotechnology tobriefings about policy.

At this meeting on behavioral genet-ics, an advanced offering, the jurists’attention ratchets up as Volkow andothers project photos of brainsplagued by chronic alcoholism. All thejustices have attended the basiccourse, so they have a grasp of DNAstructure and function, the nature ofgenes, and the fundamental dynamicsof protein production. They strive forsomething more—the link betweengenetic predisposition or susceptibil-ity and the trouble-causing conduct

they see every day. They monitor cur-rent scientific developments, hopingfor the day when alcoholism’s rootcauses are known and judges candirect defendants to effective treat-ments. At Airlie, the judges areexposed to the connections (and thedisconnects) between underlying cau-sation and behavior. The disconnectsdominate in alcoholism’s case, butjurists agree that breakthroughs areso rapid that the next one might bevalid and could be introduced in oneof their cases.

The judiciary appears to share a gen-eral belief that biological inheritancefuels generations of cases involvingviolence, alcohol, drugs, and familybreakdown. They are urged by law-yers to use their authority to protectthe mentally ill, and they intuit thatthe schizophrenia and bipolar ill-nesses frequently appearing in theircourtrooms are, at least in part,forged by genetics gone wrong.

On the conference’s final day, the dis-cussion turns from science to itsimplications for judicial management.The judges are looking to the timewhen molecular medicine will makepossible the substitution of effectivetreatment for long jail sentences. Onespeaker warns against blaming biol-ogy for behavior, but the judges aremore concerned about having insuffi-cient tools against a tidal wave ofchallenges. They also worry that their

Genetics in the Courtroomhttp://www.ornl.gov/hgmis/courts.html

p. 16à

¶ Genes and JusticeThe Genes and Justice symposiumissue of Judicature 83(3), the journalof the American Judicature Society,focuses on the growing societalimpact of DNA technology andrelated issues that courts will con-front in the near future (www.ornl.gov/hgmis/publicat/judicature). TheDOE Human Genome Program’sEthical, Legal, and Social Issuescomponent contributed to the publi-cation of this issue and its distribu-tion to judges nationwide. DeniseCasey (HGMIS) served as editor.¨

Bari ScottSoundVisions Productions

SoundVisions Productions, foundedand directed by Barinetta Scott

and Jude Thilman, won a SilverBaton award for The DNA Files inthe 2000 Alfred I. Du Pont–ColumbiaUniversity television and radio compe-tition. Hosted by John Hockenberry,the series consisted of nine 1-hourprograms broadcast on National Pub-lic Radio. It was funded in part bythe Ethical, Legal, and Social Impli-cations component of DOE’s HumanGenome Program.

Twelve winners were selected from650 submissions aired betweenJuly 1, 1998, and June 30, 1999. BillMoyers won a Gold Baton for Facingthe Truth, a 2-hour documentaryabout the aftermath of apartheid inSouth Africa. Other Silver Batonwinners included Diane Sawyer(20/20: The Unwanted Children ofRussia); Youth Radio, Berkeley(E-Mails from Kosovo); and CBSNews and Bob Simon (60 Minutes II:The Shame of Srebrenica). The

Du Pont–Columbia awards, amongthe most prestigious in broadcastjournalism, began in 1943.

For this school year, Scott is a KnightScience Journalism fellow at theMassachusetts Institute ofTechnology.

[Orders for The DNA Files tapes andtranscripts: www.dnafiles.org/about/tapes.html or 510/486-1185.]¨

DOE Grantee Scott Wins Award


ELSI

This newsletter is intended to facilitate communi-cation and collaboration, help prevent duplica-tion of research effort, and inform personsinterested in genome research. Views ex-pressed are not necessarily those of the Depart-ment of Energy Office of Biological andEnvironmental Research. Suggestions are in-vited.Human Genome ManagementInformation System (HGMIS)Oak Ridge National Laboratory1060 Commerce Park, MS 6480Oak Ridge,TN 37830865/576-6669, Fax: /574-9888www.ornl.gov/hgmisManaging EditorBetty K. [email protected]

Production AssistantsMarissa D. MillsSheryl A. MartinLaura N. YustU.S. Department of EnergyOffice of Biological andEnvironmental ResearchAri Patrinos, Associate Directorwww.er.doe.gov/production/ober/ober_top.htmlLife Sciences Division, OBERMarvin E. Frazier, Directorwww.er.doe.gov/production/ober/lsd_top.htmlContact: Daniel W. Drell, 301/903-6488,Fax: [email protected] [email protected]

This newsletter is prepared at the requestof the DOE Office of Biological and Envi-ronmental Research by the Life SciencesDivision at Oak Ridge National Labora-tory, which is managed by UT-Battelle,LLC, under contract AC05-00OR22725.

Editors/Writers/DesignersAnne E. AdamsonDenise K. CaseyJudy M. Wyrick

DOE ELSI Grants, FY 2001

FY 2001 sees the tenth cycle of appli-cations, merit reviews, and awards

in the Ethical, Legal, and Social Impli-cations (ELSI) component of the DOEHuman Genome Program (HGP). Of 26applications received and reviewed bya peer panel, the DOE HGP funded6 new, 2 renewed, and 3 small explor-atory projects for FY 2001. These aresummarized below. A more completeversion and abstracts of previousDOE ELSI projects are on the Web(www.ornl.gov/hgmis/research/elsi.html).

DOE ELSI goals encompass researchon the uses, impacts, implications,privacy, and protection of genetic infor-mation in the workplace and in data-bases; ELSI implications of complex ormultigenic characteristics and condi-tions; gene-environment interactionsthat result in diseases or disease suscep-tibilities; and human polymorphisms.DOE also produces and distributes rel-evant ELSI educational materials forthe public or specified groups, espe-cially Institutional Review Boards andEthics Boards.

NEW PROJECTS

Model Program for Public LibrariesMiriam Pollack, North SuburbanLibrary System, Chicago

Focus: Use libraries for educationproject to encourage public “genetic liter-acy.” Activities include organizingexperts, gathering resources, and estab-lishing programs about genetic scienceand ELSI issues.

Ethical Concepts in Laws LimitingGenetic ScreeningLynn Pasquerella and LawrenceRothstein, University of Rhode Island,Kingston

Focus: Collect documents concerninglaws and legislative proposals of teneastern states and the federal govern-ment to determine how ethical conceptshave influenced legislation on the use ofgenetic information in the workplace.

Genetics, Mental Illness, and Com-plex DiseaseJoe McInerney, National Coalition forHealth Professional Education in Genetics,Baltimore

Focus: Produce an interactive CD-ROMfor instructing genetic counselors aboutmental disorders believed to have agenetic basis.

Economic Analysis of HGP Intel-lectual Property RightsDavid Bjornstad, Oak Ridge NationalLaboratory, Oak Ridge, Tennessee

Focus: Explore the economic implica-tions of different intellectual-propertystrategies for commercializinggenomic information and products.The work is based in part on theresearch of Rebecca Eisenberg (Uni-versity of Michigan Law School).

Tribal Ethical, Moral, Cultural, andLegal Issues Related to the HGPMervyn Tano, Institute for IndigenousResource Management, Denver

Focus: Introduce Native Americantribes to the HGP by identifying spe-cific factors that influence perceptionsof genetic research. Educate membersin the basics of genetics and relatedresearch and inform DOE HGPmanagers about Native Americanperspectives.

Bioinformatics and the HGPMark Bloom, Biological SciencesCurriculum Study, Colorado Springs,Colorado

Focus: Produce and distribute educa-tional module, Bioinformatics and theHuman Genome Project, for high schoolaudiences. The module will addressELSI issues surrounding genetic data-bases and will introduce teachers andstudents to bioinformatics.

Judicial Conference for Maine,New Hampshire, and VermontElizabeth Hodges, AdministrativeOffice of the Courts, Concord, NewHampshire

Focus: Plan and conduct a conferenceto introduce judges of three states tothe basics of genomics and genetics.The approach is modeled on theEINSHAC conferences that have trainedsome 1900 judges (see article, p. 14).

RENEWAL PROJECTS

Science Literacy Workshops forPublic RadioBarinetta Scott, SoundVisionsProductions, Berkeley, California

Focus: Enlarge the pool of skilledpublic-radio science reporters and pro-ducers and increase the number andaccuracy of science reports. Four-dayworkshops will teach basic science,journalistic skills, and methods forcrafting complex science stories.

Airlie advisors are not typical of anexpert-witness industry bent onmade-for-litigation research, expertswho have a biased stake in caseoutcomes.

Conference cochairmen summarizesentiments near the meeting’s close.“We need at least a coherent state ofthe science merged with new develop-ments in the law,” Chief Judge EugeneN. Hamilton declares. Judge JohnGarrett Penn rejoins, “We need a legalguide to the scientific landscape facingfederal judges.” The meeting ends, butits work continues. [Franklin M. Zweig,Einstein Institute for Science, Health,and the Courts, www.einshac.org]¨

ELSI Grants, p. 17à


For Your Information

Science Education on the InternetConferenceRay Gesteland, University of Utah, SaltLake City

Focus: Plan and organize the secondconference for developers and Webmastersof science and biological science sites.Maximize these resources by makingthe sites more effective and increasingtheir educational value.

SMALL EXPLORATORY PROJECTS“All Not Fit to Breed”: Survivors ofAmerica’s First Eugenics MovementMary Bishop, Virginia Polytechnic Insti-tute and State University, Blacksburg

Focus: Collect and preserve the experi-ences of some ten people forcibly steril-ized under Virginia’s eugenics policies ofthe 1920s and conduct interviews withpeople in authority then.

Worker Perspectives on ComplexDiseasesLaura Roberts, University of New Mexico,Albuquerque

Focus: Explore a possible connectionbetween workplace exposures and com-plex genetic disorders by studying peoplewith many different illnesses and exam-ining occupational healthcare issues.

Genetics Conference for ClergyPaul Sullins, Catholic University,Washington, D.C.

Focus: Hold a conference for the clergy,modeled on the EINSHAC series forjudges (see article, p. 14). The clergyoften are counsels in cases involvingmoral and ethical issues, such as genetictest results and reproductive choices.¨

HGMIS Resources AvailableNew Version of Web Site

To address the evolving needs of a pub-lic facing unfamiliar genomic issues

and challenges, HGMIS has redesignedthe Human Genome Project InformationWeb site (www.ornl.gov/hgmis). Nearlya dozen pages have been added, and thesite has been rearranged into suites.

Pharmacogenomics, Gene Therapy, andGenetic Counseling pages are new in theMedicine and the New Genetics suite,and the Gene Testing and Home pageshave been revised.

The Ethical, Legal, and Social Issuessuite now incorporates pages on Privacyand Legislation, Patenting, Forensics,Behavioral Genetics, and Genetics in theCourtroom, along with updated Homeand ELSI Research Information pages. Anonline edition of the DOE ELSI Bibliogra-phy (1995) has been added to the site.The Audio/Video Online Webcasts pagehas been revamped as part of the Educa-tional Resources suite.

The News Sources suite combines thetraditional What’s New with a weeklyresearch digest and the new Genome

Calling All Teachers!HGMIS would like to know how ourHuman Genome Project InformationWeb site is being used in teaching biol-ogy, genetics, and other subjects at alllevels (www.ornl.gov/hgmis). Responsesincluding lesson plans may be postedwith the author’s permission on theEducation page (www.ornl.gov/hgmis/education/education.html). [Contact:Anne Adamson, 865/574-9851,[email protected]]

HGP HandoutsHGMIS will send multiple copies of HGNand other genomics-related materials torelevant meetings on request and with-out charge (contact: see above).¨

European Commission’s socioeco-nomic research in the life sciences(www.biosociety.dms.it)Nature’s Genome Gateway: Researchpapers and news service from Natureand Nature Genetics, postgenomicssection, and links; free access(www.nature.com/genomics)

Report on DOE’s Microbial CellProject (http://microbialcellproject.org)

International database on legal,social, and ethical aspects of humangenetics (www.humgen.umontreal.ca)GeneLetter: Originally funded by DOE,now published online monthly byGeneSage; issues since July 1996 alsoaccessible (www.genesage.com)Genetics & Your Practice: Set ofprofessional education services forphysicians and other health and socialworkers, sponsored by the March ofDimes (www.modimes.org/programs2/profed/gyp.htm)

HGBASE (Human Genic Bi-AllelicSequences): Summaries of all knownhuman genome sequence variations(http://hgbase.cgr.ki.se)International Journal for Parasi-tology: Genome issue 30(4), April 2000(www.elsevier.com)

Resources

ELSI Grants (from p. 16)

Poster Shows Disorders,Traits Mapped toChromosomesThe revised and updated “HumanGenome Landmarks: Selected Traitsand Disorders Mapped to Chromo-somes” is a colorful wall poster pre-pared by HGMIS, with printing andmailing costs supported by QIAGEN.Informative sidebars explain geneticterms and provide URLs for findingmore detailed information on the Web.Expanded version: www.ornl.gov/hgmis/posters. A copy will be mailed toall HGN print subscribers. Others mayrequest a copy from HGMIS (see p. 16)or visit the Web site.¨

Headlines and Genetics News Sources.In addition to up-to-date backgroundtext on HGP history and science, theMedia Guide includes graphics thatwould be valuable to any interested per-sons as well as to those preparing newsarticles and presentations. An alphabeti-cal index complements the site’s existingsubject-style index and search engine.

Genetic Secrets: Protecting Privacyand Confidentiality in the GeneticEra: Now in paperback, Yale UniversityPress (203/432-0960 or www.yale.edu/yup)Biotechnology: Law, Business, andRegulation: Aspen Law & Business;1100 pp., one volume (800/638-8437,www.aspenpublishers.com)

Joint degree: University of Minne-sota, combines law with graduatedegree in health or life sciences(612/625-0055, [email protected],www.jointdegree.org)Mapping Public Policy for GeneticTechnologies: A Legislator’s ResourceGuide: Legislators and staff, free;(National Conference of State Legisla-tures; 303/830-2200, ext. 157;[email protected]; www.ncsl.org/programs/employ/Genetics/BOOK)Genes and Society: Impact of NewTechnologies on Law, Medicine, andPolicy: Audios of speakers at the Maymeeting (www.aslme.org/news/index.html); Free CD-ROM ([email protected])

“The Human Genome Project: Whata Legal Assistant Needs to Know”:Article by Dan Drell (DOE) in Facts andFindings, Aug. 2000 (www.ornl.gov/hgmis/publicat/miscpubs/legalasst.html)¨


Calendar of Genome and Biotechnology Meetings*

January 2001 ...................................3–7. Pacific Symp. on Biocomputing; Honolulu[K. Lauderdale, 650/725-0659, Fax: -7944;http://psb.stanford.edu]6–11. Gene Therapy 2001: Gene Odyssey;Snowbird, UT [Keystone, 970/262-1230,Fax: -1525; [email protected];www.symposia.com]9–14. Cell Cycle 2001; Taos, NM [see contact:Jan. 6–11]13–17. Plant and Animal Genome IX;San Diego [D. Scherago, 212/643-1750,ext. 20, Fax: -1758; [email protected];www.ag-microbial.org]17–19. Agricultural Microbes Genome II;San Diego [see contact: Jan. 13–17]22–24. Lab on a Chip and Microarrays forBiomedical and Biotechnical Applications;Zurich, Switzerland [CHI, 617/630-1300,Fax: -1325; [email protected];www.healthtech.com]24–26. 3rd Annu. Integrated Bioinformatics:High-Throughput Interpretation of Pathwaysand Biol.; Zurich, Switzerland [see contact:Jan. 22–24]25–27. Oncogenomics: Dissecting Cancerthrough Genomics Research; Tucson, AZ[AACR, 215/440-9300, Fax: -9313; [email protected]; www.aacr.org]28–31. TIGR/ASM Microbial Genomes;Monterey, CA [TIGR, 301/610-5959,Fax: /838-0229; [email protected]; www.tigr.org/cet]

February 2001 .................................1–2. NCHPEG 2001 Annu. Meeting;Bethesda, MD [NCHPEG, 410/337-6728;www.nchpeg.org]2–7. Impact of Genomics on Drug Discoveryand Development; Santa Fe, NM [see contact:Jan. 6–11]3–6. Advances in Genome Biol. and Technol.in conj. with Automation in DNA Mappingand Sequencing; Marco Island, FL [G. Corp.,877/343-8895, Fax: 781/466-9988; [email protected]; www.gcorp.org]4–8. 26th Annu. Lorne Conf. on ProteinStructure and Function; Lorne, Australia[Secretariat, +613/9662-7284, Fax: -7101;[email protected]; http://grimwade.biochem.unimelb.edu.au/lorne.htm]7–13. Bacterial Chromosomes; Santa Fe, NM[see contact: Jan. 6–11]8–11. 13th Annu. Lorne Conf. on Cancer;Lorne, Australia [J. Laird, +603/9496-3548;Fax: -3577; [email protected];www.ludwig.edu.au/lorne]12–13. NIH NHGRI Advisory Council;Bethesda, MD [K. Malone, 301/402-2205,Fax: -0837; [email protected]]11–15. 22nd Lorne Genome Conf; Lorne,Australia [Secretariat; +612/9351-2233;Fax: -4726; [email protected]; http://lorne-genome.angis.org.au]15–20. AAAS Annu. Meeting; San Francisco[AAAS, 202/326-6450, Fax: /289-4021;[email protected]; www.aaas.org]

March 2001 ......................................3–4. 4th Annu. Genomic Partnering:Emerging and Early Stage Companies; SanFrancisco [see contact: Jan. 22–24]5–7. 8th Annu. Human Genome Discovery:Commercial Implications; San Francisco[see contact: Jan. 22–24]5–11. Membrane Protein Structure/FunctionRelationships; Tahoe City, CA [see contact:Jan. 6–11]6–11. Microbe Interactions with Their Envi-ronments: Genome Perspectives; Taos, NM[see contact: Jan. 6–11]8–9. 5th Annu. Gene Functional Analysis;San Francisco [see contact: Jan. 22–24]13–18. 21st Fungal Genetics Conf.; PacificGrove, CA [K. McCluskey, 913/588-7044,Fax: -7295; [email protected];www.fgsc.net/fungalgenetics2001]21–25. 42nd Annu. Drosophila Conf.; Wash-ington, DC [M. Ryan, 301/571-1825; [email protected]; http://flybase.bio.indiana.edu:82/docs/news/announcements/meetings/42_Dros_Conf.html]31–April 4. ASBMB in conj. with Experi-mental Biol.; Orlando, FL [Secretariat,301/530-7010 Fax: -7014; [email protected];www.faseb.org/meetings/eb2001]31–April 6. Human Genetics andGenomics; Breckenridge, CO [see contact:Jan. 6–11]

April 2001.........................................2–4. Proteome Project; Washington, DC[see contact: Jan. 22–24]5–6. Protein Expression; Washington, DC[see contact: Jan. 22–24]18–22. 4th European Symp. Protein Society;Paris [Secretariat, 301/530-7010, Fax: -7014;[email protected]; www.faseb.org/meetings/ep01]19–22. HGM 2001; Edinburgh [HUGO,+44-20/7935-8085, Fax: -8341; [email protected]; www.gene.ucl.ac.uk/hugo]21–24. RECOMB 01: Fifth Annu. Intl. Conf.on Computational Molecular Biol.; Montreal[T. Langauer, +49-2241/142-777, Fax: -656;[email protected]; http://recomb2001.gmd.de]

May 2001..........................................15–19. 10th Intl. Congress of HumanGenetics 2001; Vienna [Secretariat,+431-405/138322; [email protected];www.ichg2001.org]20–24. Toxicology: Environment MeetsGenetics in the Genomics Era; Victoria, BC,Canada [G. Heaton, +44-1865/373-625,Fax: /375-855; [email protected]]20–24. ASM 101st General Meeting;Orlando, FL [ASM, 202/942-9356, Fax: -9340;[email protected]; www.asmusa.org/mtgsrc/mtgs.htm]30–June 3. ASGT 4th Annu. Meeting;Seattle [J. Geiger, 414/278-1341, Fax: /276-3349;[email protected]; www.asgt.org]

June 2001 ........................................1–2. 22nd Annu. Health Law Teachers Conf.;Boston [S. Black, 617/262-4990, Fax: /437-7596;[email protected]; www.aslme.org/conferences]24–27. BIO 2001; San Diego [BIO, 202/857-0244, Fax: -0357; www.bio.org/events/2001/2001main.html]30–July 5. 11th Intl. Congress on Genes,Gene Families, and Isozymes; Stockholm[Secretariat, +46-8/459-6600, Fax: /661-9125;[email protected]; www.gene2001.org]

July 2001..........................................8–11. Behavior Genetics Assoc. 2001 Meeting;Cambridge, UK [T. Eley, +44-20/7848-0863,Fax: -0866; [email protected]; www.bga.org/meetings]30–Aug. 3. 4th Intl. Conf. on BiologicalPhysics; Kyoto, Japan [Secretariat, [email protected]; http://kokusai.phys.nagoya-u.ac.jp]¨

More comprehensive lists of genome-related meetings and organizations offering training are available on the Web(www.ornl.gov/hgmis) from HGMIS (see p. 16 for contact information).

*Dates and meeting status may change; courses may also be offered at other timesand places; check with contact person. Attendance may be either limited or restricted.

Training Calendar

January 2001 ...................................8–12. Advanced Linkage Course; New York[K. Montague, 212/327-7979, Fax: -7996;[email protected]; http://linkage.rockefeller.edu]

February 2001 .................................19–20. System-Based Modeling in Bioinfor-matics; Piscataway, NJ [M. Liebman, [email protected]; http://dimacs.rutgers.edu/Workshops/index-compmolecbiol.html]

March 2001 ......................................8–9. Protein Structure and Structural Genomics:Prediction, Determination, Technol., and Algo-rithms; Piscataway, NJ [S. Istrail, [email protected]; http://dimacs.rutgers.edu/Workshops/index-compmolecbiol.html]

April 2001.........................................19–20. DNA Sequence and Topology; Piscataway,NJ [W. Olson, [email protected];http://dimacs.rutgers.edu/Workshops/index-compmolecbiol.html]

May 2001..........................................6–9. Genetic Analysis of Complex Human Dis-eases; Durham, NC [V. Scales, 919/684-2458,Fax: -2275; [email protected];http://phg.mc.vanderbilt.edu/gachd.htm]14–26. Bioinformatics; Ottawa [F. Ouellette,[email protected]; www.bioinformatics.ca]

June 2001 ........................................11–16. Proteomics; Edmonton, AB, Canada[see contact: May 14–26]21–22. Integration of Diverse Biological Data;Piscataway, NJ [A. Califano, [email protected][see Web site: Apr. 19–20]

July 2001..........................................16–21. Genomics; Fredericton, NB, Canada[see contact: May 14–26]

August 2001 ....................................7–Sept. 1. Developing Tools; Ottawa[see contact: May 14–26]¨


For Your Information

NIH Centers of Excellencesin Genomic Science (CEGS)PAR-00-101http://grants.nih.gov/grants/guide/pa-files/PAR-00-101.htmlTopic: NHGRI will establish academiccenters (P50 grants) for advanced genomeresearch and support multi-investigatorinterdisciplinary teams to develop innova-tive approaches. CEGS grant (P20) offeredto facilitate planning. Inquiries stronglyencouraged (301/496-7531, [email protected]). [Check Web site for due dates.]¨

¶ Imaging Workshop ReportImaging Gene Expression In Vivo:Extending Nuclear Medicine for theNext Millennium is the final reportof a June 1999 workshop on imaginggene expression and the technicaland scientific obstacles to this meth-odology. With this workshop, theDOE Office of Biological and Environ-mental Research took the first steptoward applying fruits of the HumanGenome Project to nuclear medicine.[Print copy: Sharon Betson (see Medi-cal Sciences contact at right); PDF(printer-friendly) file: www.er.doe.gov/production/ober/73_reports/lajolla_report.pdf ] ¨

Computational MolecularBiologyThe Center for Discrete Mathematicsand Theoretical Computer Science(DIMACS) at Rutgers University issponsoring the 2000–2003 SpecialFocus on Computational MolecularBiology (http://dimacs.rutgers.edu/SpecialYears/2000_2003).¨

U.S. Genome-RelatedResearch FundingInvestigators wishing to apply for funding areurged to discuss projects with agency staffbefore submitting proposals.

DOE Office of Biological andEnvironmental ResearchHuman and Microbial GenomePrograms• Funding opportunities: www.sc.doe.gov/

production/grants/grants.html• Life Sciences Division:

[email protected] or 301/903-6488• Medical Sciences Division:

301/903-3213, [email protected] Hollaender DistinguishedPostdoctoral FellowshipsResearch opportunities in energy-related life,biomedical, and environmental sciences,including human and microbial genomes,global change, and supporting disciplines.• Note: No awards will be made in 2001

(www.orau.gov/ober/hollaend.htm)Computational Molecular BiologyPostdoctoral FellowshipsSupport career transitions into computationalmolecular biology from other scientific fields.Funded by DOE and the Alfred P. SloanFoundation.• Next deadline: February 1, 2001• Contact: Pat Stanley, Sloan Foundation;

212/649-1628, [email protected],www.sloan.org/main.htm

NIH National Human GenomeResearch Institute• NHGRI program: 301/496-7531,

www.nhgri.nih.gov/About_NHGRI

• Funding opportunities:www.nhgri.nih.gov/Grant_info

• ELSI: 301/402-4997

Small Business InnovationResearch GrantsDOE and NIH invite small business firms(under 500 employees) to submit grantapplications addressing the human genometopic. The two agencies also support the SmallBusiness Technology Transfer (STTR) programto foster transfers between research institu-tions and small businesses.Contacts:• DOE SBIR/STTR Office: 301/903-1414 or

-0569, Fax: -5488, [email protected],http://sbir.er.doe.gov/sbir; DOE SBIR andSTRR due February 20, 2001.

• Bettie Graham (see ELSI contact, NHGRI).NIH SBIR and STTR due April 1, August 1,and December 1.

• National resources, calendar:www.zyn.com/sbir

• National SBIR/STTR conferences:360/683-5742, Fax: -5391, [email protected].

• Alerting service: http://lyris.pnl.gov/cgi-bin/?enter=sbir-alert¨

¶ Workers as Human SubjectsCreating an Ethical Framework forStudies that Involve the Worker Commu-nity was produced by the Human Sub-jects Research Program of the DOEOffice of Biological and EnvironmentalResearch. The book contains chapterson the need for worker protection, foun-dations of an ethical framework, chal-lenges in using genetic data, protectionof privacy, stakeholder concerns andresponsibilities, and planning andimplementing worker studies. [Printcopies: 301/903-4731, www.science.doe.gov/ober/humsubj/wsguidebk.html]¨

¶ Computers and BiotechnologyThe Computers and Biotechnology issueof Your World: Biotechnology and You[9(1), Fall 1999] includes molecular puz-zles and stories on gene hunting, SNPsand chips, viewing molecules and pro-teins, and searching for drugs. In simplelanguage for all ages, Your World is pub-lished by the Biotechnology Institute,which is supported by ten leading bio-technology and pharmaceutical compa-nies. Price, subscription, orderinginformation, and a sample teacher’sguide in PDF and HTML formats are onthe Web, as are back issues and Biotech-nology and AIDS, published this year(800/796-5806 or 814/238-4083, Fax: 814/238-4081, www.biotechinstitute.org).¨

¶ Bridging the Gap Between LifeInsurer and Consumer“Bridging the Gap Between Life Insurerand Consumer in the Genetic TestingEra: The RF Proposal,” by ChristopherKeefer (Barrett Law), is on the Web(www.ornl.gov/hgmis/resource/keefer.html). Published in the Indiana LawJournal in 1999, the article deals withstresses between life insurers and con-sumers in light of newly available geneticinformation that can reveal predispositionsand presymptomatic conditions. Con-sumers fear unfair discrimination basedon their genetic profiles, and insurersthink applicants may conceal such datato attain higher coverage or a more favor-able premium rate. Keefer discusses gov-ernment response to this dilemma andproposes a solution based on risk factors.¨ RNA or protein was responsible for

catalyzing link formation. The newimages revealed the proteins deeplyembedded in the RNA and theiressential role in its folding. Theimages also showed where bindingtakes place, proving RNA’s ability tobreak or form bonds. Further studiesshould show the orientation of mRNAand the growing protein’s compo-nents in the ribosome’s active cata-lytic site.

In this study, researchers used the2.5-billion–electron volt beam to per-form crystallography on painstak-ingly grown crystals of the 50Ssubunits. Additional data were gath-ered using the Advanced PhotonSource at Argonne NationalLaboratory.

During X-ray crystallography, intensebeams pass through and bounce offatoms in the crystal, where theyleave a diffraction pattern that canbe analyzed to determine the protein’s3-D shape. Researchers resolved theatomic structures of all 100,000 or socrystal atoms in the RNA 50S subunit.This involved carefully growing larger,more complete ribosome crystals andsolving their structures at progres-sively higher resolutions. Each levelprovided information that helped sci-entists understand the final high-resolution map.¨

Proteins (from p. 8)

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