bisi5603 192-1962006... · and fungi. the biogeography of the se-quences is likely to have...

Metagenomics Reveals Microbial Diversity

Author: BEARDSLEY, TIMOTHY M.

Source: BioScience, 56(3) : 192-196

Published By: American Institute of Biological Sciences

URL: https://doi.org/10.1641/0006-3568(2006)056[0192:MRMD]2.0.CO;2

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192 BioScience • March 2006 / Vol. 56 No. 3 www.biosciencemag.org

Aglorious Indian summer was hav-ing its last hurrah this past Octo-

ber as 400 research leaders gathered at abeachside resort in Hilton Head Island,South Carolina, for the annual conferenceorganized by genomics innovator J. CraigVenter.Venter has directed the heady mixof frolic and big-budget biology for the

past 17 years, but last fall’s meeting wasto have a somewhat different emphasis.It had a new name—“Genomes, Medi-cine,and the Environment Conference”—that signaled Venter’s developing interestin metagenomics: large-scale sequenc-ing of genes sampled directly from the environment.

Venter is best known as the brash sci-entific rebel who, as head of Celera Ge-nomics, had seemed poised to beat thegovernment to a draft sequence of the hu-man genome. He successfully adaptedthe technique of whole-genome shotgunsequencing for the task, a computation-ally demanding approach previously usedonly for much smaller genomes. But Ven-ter has moved on since the politically en-gineered announcement at the WhiteHouse in 2000 that the race had ended ina tie. Since his ouster as head of Celeratwo years later, he has increasingly turnedhis attention to applications of genomicsthat might yield solutions to global cli-mate change and other such dauntingchallenges. To pursue that agenda, Ven-ter established several institutes that havenow merged into one, the J. Craig VenterInstitute in Rockville, Maryland.

Kicking off the proceedings at HiltonHead was an overview of institute pro-jects to shotgun sequence DNA from environmental microbes. Shotgun se-quencing breaks up an organism’s DNAinto myriad short fragments that caneach be quickly analyzed, then virtuallyreassembles the whole genome in a com-puter. The Venter Institute’s effort in-cludes a high-profile, round-the-worldocean sampling expedition in the 95-foot sloop Sorcerer II. Workers on thevessel have spent much of the past 18months sampling and filtering seawaterfrom a few feet down near coastlines and

Metagenomics RevealsMicrobial Diversity

T I M O T H Y M . B E A R D S L E Y

J. Craig Venter’s 95-foot sloop Sorcerer II recently completed a globalcircumnavigation sampling microorganisms in surface seawater. Shotgun

sequencing of the DNA in the samples has revealed unprecedented levels ofgenomic diversity. Expedition leader Venter (left) and Anthony Knap, director

of the Bermuda Biological Station for Research, are pictured on board.Photograph courtesy of J. Craig Venter Institute.

Faster sequencing machines and computers are opening up new vistas for

genomics. Better understanding of environmental processes could be one result.


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www.biosciencemag.org March 2006 / Vol. 56 No. 3 • BioScience 193

at sites in the open ocean spaced 200miles apart. The filters are frozen andsent to Rockville, where the DNA is shot-gun sequenced by scores of automatedanalyzers and a nest of computers.

Because fewer than 1 percent of themicrobes in sea water can now be cul-tured, DNA sequences are assembled andclassified without, for the most part, theintrusion of traditional notions of species.Researchers group the sequences by theirsimilarity to previously known genes, anexercise that yields pointers to new, pos-sibly metabolically related, gene familiesand, not infrequently, apparent newspecies. A pilot project conducted in theSargasso Sea, which had been thoughtrelatively nondiverse because of its lownutrient levels, yielded 150 new species ofbacteria and over 1.2 million new genes,including 782 new rhodopsin-like pho-toreceptors, according to a paper pub-lished in Science (2 April 2004).

Genomics goes globalThe Sorcerer II survey has now found as-tonishing levels of genetic diversity world-wide. Karin Remington recounted howthe Venter Institute team was unable toput an upper limit on the species richnessof all but the most extreme environmentssampled, because even with the millionsof sequences logged so far, additionalsample sequences still increase the esti-mated number of species proportion-ately. Nevertheless, the clustering patternof the sequence data is likely to yield con-tinuing evolutionary insights, Remingtonsaid. One of her group’s objectives is touse the DNA data to discern the shape ofglobal “protein space”: the full variety ofproteins encoded in living organisms.

Another surprise relates to bacterio-phages, the viruses that infect bacteria.Genomic data indicate that these preda-tors on the lowliest life-forms (at least bysize) play a far more important role in dis-tributing genetic information amongtheir prey than has been thought. Rem-ington’s group found 20-fold variationsin the level of incorporation of a specificphage between closely related samplesof the marine cyanobacterium Prochloro-coccus, the most numerous photosyn-thesizing microorganism of tropical and

subtropical oceans. That points to a dy-namic predator–prey relationship.

The torrent of data from the projecthas stymied even the computers of Ven-ter’s institute, which perform at the levelof trillions of floating point operationsper second (known as “teraFLOPS”).That is one reason the Gordon and BettyMoore Foundation in California recentlyawarded the institute, along with the University of California–San Diego, a$24.5 million grant to develop a cyber-infrastructure for analyzing marine microbes. The Moore Foundation hasalso bankrolled a project to sequence thecomplete genomes of over 150 of the organisms.

Not content with charting global ma-rine biodiversity, Venter’s institute haslaunched what it calls the air genomeproject. Researchers are shotgun se-quencing DNA from pollen and mi-crobes of different size classes trapped byair filters, including viruses, bacteria,and fungi. The biogeography of the se-quences is likely to have important im-plications for health, because thesemotes of biological information mayhave profound effects on immune sys-

tems. As with the marine work, the dis-tribution of phage genes is of specialinterest and may reveal much abouthitherto uncharted natural processes.A pilot project is under way in New YorkCity.

Sallie W. Chisholm of the Massachu-setts Institute of Technology, a Prochloro-coccus guru, took the conference podiumto expand on that bacterium as theemerging “E. coli ” of microbial ecologyin the ocean. The estimated global totalof 1025 Prochlorococcus cells, which havea very high level of diversity at the ge-nomic level, may account for over half thechlorophyll in some ocean regions,Chisholm declared. Closely related co-existing lineages of Prochlorococcus differin their degree of light-adaptedness, theirability to utilize phosphorus and nitrogen,their tolerance for trace metals, and, no-tably, their temperature sensitivity, shereported. Most surprising, however, hasbeen the discovery that some phagegenomes commonly found in Prochloro-coccus encode photosynthetic pigments.Because photosynthesis is essential forthe bacterium to generate maximal num-bers of phages, it appears that, by infect-

The marine cyanobacterium Prochlorococcus (typically 0.5 to 0.7 micrometers in diameter), the most numerous photosynthesizing microorganism oftropical and subtropical oceans, has been found to show high levels of

diversity at the genomic level. Electron micrograph: Claire Ting.


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ing Prochlorococcus, these phages are aug-menting photosynthesis for the phages’own benefit.

E. Virginia Armbrust also noted theimportance of captured genes in her talkon the whole-genome analysis of ma-rine diatoms, unicellular algae with elab-orate shells of silica. Armbrust estimatesthat diatoms are responsible for up to40 percent of global marine photosyn-thesis, an amount comparable to all ter-restrial rainforests. Moreover, diatomsplay a particularly vital role in the globalcarbon cycle, because, on sinking, their re-mains take carbon out of circulation forcenturies. Yet the genome sequence ofthe marine diatom Thalassiosira pseudo-nana reveals that its photosynthetic plas-tid was acquired from another eukaryoticcell through the process known as sec-ondary endosymbiosis. (The sequencealso reveals the unexpected presence of aurea cycle in the diatom, again suggestiveof hijacked genes.) Armbrust is analyzingthe activities of diatoms by using a flowcytometer at sea so that she can selectspecific diatom populations “right outof the water.” She hopes to learn enoughto use the organisms to monitor oceanhealth in real time with sensors con-nected by undersea cables.

Forest Rohwer, a researcher at SanDiego State University who sequencesviruses from extreme environments andfrom human blood and stool, reportedthat marine sediments have much thelargest number of viral genotypes in hissamples. Rohwer, too, stressed the criti-cal role of genes that wander between mi-crobial hosts. Some 54 percent of theenvironmental sequences he detects areunknown, Rohwer said, and it seemsthat mobile DNA elements composemost of the uncharacterized diversity.To the totemic question, “Is everythingeverywhere?”—meaning, is there a richstable of sequences in all environments?—Rohwer answered with an emphatic yes. The environment then selects thosesequences that become numericallydominant. The population dynamics ofphages and their microbial prey proba-bly maintain the high diversity in themobile gene pool, Rohwer suggested,and thus account for most of the differ-ences between microbial species.

A similar notion was discussed by Jil-lian Banfield, a professor in the Depart-ment of Earth and Planetary Science atthe University of California–Berkeley,who studies genomes of bacteria thatproduce biofilms in acid mine drainage.She has concluded that viruses are animportant source of the novel genes thebacteria use to make a living in unwel-coming situations.

Metagenomics does not begin and endwith DNA sequences. Jo Handelsman ofthe University of Wisconsin–Madisonhas taken the concept to the next level bycloning DNA from environmental sam-ples into bacteria and testing the func-tional capabilities of the resultingtransformants. Clones that share a bio-chemical activity are then analyzed bysequence. Handelsman maintains thather functional approach can flag activi-ties of interest that would not be foundby sequence analysis alone. She has usedthe technique to discover antibiotic re-sistance genes, for example, and novelquorum-sensing systems, which are com-munications protocols employed by bac-teria to assess their population density.

Building up biologyThe South Carolina event was not onlyabout analysis. Several sessions focusedon “synthetic biology”—attempts to buildorganisms with new capabilities throughsophisticated genetic engineering in-formed by genomics. Environmentalgoals drive some of this. Venter himself,along with longtime colleague and Nobellaureate Hamilton O. Smith and others,is working on creating a stripped-downversion of the already small genome ofMycoplasma genitalium G37 that wouldinclude only the components essentialfor life. The team is systematically delet-ing subsets of individually dispensablegenes from a synthetic M. genitalium G37chromosome to learn which groupingsthe organism can manage without. Smithsaid he expects there to be several an-swers that depend on conditions. Theexercise should expose how the truly es-sential components of cells work,Ventermaintained (see the interview on page197).

Andrew D. Endy of the MassachusettsInstitute of Technology described a dif-

Nobel prize winner Hamilton O.Smith, vice president for synthetic

biology and biological energy at the J.Craig Venter Institute, told the

conference how his research group isdesigning and constructing a synthetic

chromosome for the bacterial humanpathogen Mycoplasma genitalium.

Photograph courtesy ofJ. Craig Venter Institute.

Marvin E. Frazier, vice president forresearch at the J. Craig Venter Institute,

spoke movingly of how the anticancerdrug imatinib mesylate (Gleevec)

shrank his gastrointestinal stromaltumors when he had been thought to

be only weeks from death. Researchersat the conference described ways in

which genomic research couldcontribute to the design of other

anticancer drugs. Photograph courtesyof J. Craig Venter Institute.


ferent approach to creating novel life-forms. Endy is creating “biobricks,”minigenomes for functional chemicalpathways that can be added to host or-ganisms. The bricks are available to re-searchers by mail order, and the schemeis now being promoted by a nonprofit organization.

The ability to manipulate biology withthat degree of sophistication may makeplausible an idea Venter has entertainedin recent years to engineer microorgan-isms to produce hydrogen, the cleanestpossible fuel, from water and sunlight.The needed enzymes, or something likethem, exist separately in nature, but to beuseful they would need to be combinedin a new type of microbe. Genomics maysuggest other strategies for the great prob-lems as well. Venter and some of his col-leagues have published the genomesequences of methanotrophic bacteria,which metabolize the potent greenhousegas methane to yield hydrogen. Ventersaid he has no breakthroughs to report,but allowed that he is driven by a desireto find new options to combat globalwarming and threats to the energy supply.

High-speed chemistryCompanies touting new, faster DNA sequencing technologies were much inevidence at Venter’s beachside jamboree.Almost all large-scale genomic sequenc-ing to date has been done with machinesmade by Applied Biosystems, now part ofApplera Corporation. The company’stechnology employs what is known asSanger chemistry (named for its inven-tor, double Nobelist Frederick Sanger)and fine capillaries to separate taggedDNA fragments. But several upstart en-trants to the field employ quite differentschemes that, although not yet as reli-able as Applied Biosystems’ workhorsemachines, promise quantum jumps insequencing speed. These could make fea-sible medical applications that requireanswers to specific questions about a pa-tient’s genome in hours or days. Notableamong the new players, to judge by gos-sip in the exhibition hall, were machinesintroduced by 454 Life Sciences and bySolexa, which promises its machine cansequence a billion bases of DNA in two

days. Both sequence DNA by synthesisrather than by separation, the principleunderlying traditional approaches.

Medical applications of new genomicstechnologies were not ignored. Severalsessions focused on innovative ways in

which genomic data are being employedto gain insights into the complex processof tumor formation—and ideas for possible therapies. Imatinib mesylate(Gleevec), a powerful drug approved forthe treatment of chronic myelogenousleukemia, is one product of rational drugdesign whose effectiveness may be ex-tended as a result of genomic studies.Mutations in tumor cells that affect thecellular sites where the drug binds canmake a tumor resistant to the drug. Theability to quickly detect such mutationswould allow physicians to select imatinibvariants that would still be effective.

Officialdom observesThe emerging themes were witnessed byofficials with some clout, who seemedenthusiastic about the gains reported.Maryanna Henkart of the National Sci-ence Foundation said her agency soughtto develop tools that would make it pos-sible to simulate changes in microbialpopulations and the resulting impactson other organisms and the environ-ment. Aristides Patrinos, at the time as-sociate director of the office of biologicaland environmental research at the USDepartment of Energy (and broker ofthe tie agreement on the human genomethat took Venter to the White House),

David T. Kingsbury, deputy chiefprogram officer of the Gordon and

Betty Moore Foundation, chaired asession on environmental

metagenomics at the conference.Kingsbury’s foundation has supportedseveral of the Venter Institute’s majorprograms, including one that aims tosequence over 150 genomes of marine

microbes. Photograph courtesy ofJ. Craig Venter Institute.

Aristides Patrinos (left), now president of Synthetic Genomics, Inc., confers at theHilton Head conference with Andrew D. Endy, of the Massachusetts Institute of

Technology. Endy, a pioneer in the field of synthetic genomics, makes segments ofDNA encoding chemical functions available to researchers as “biobricks.”

Photograph courtesy of J. Craig Venter Institute.

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www.biosciencemag.org March 2006 / Vol. 56 No. 3 • BioScience 195Downloaded From: https://bioone.org/journals/BioScience on 28 Feb 2020Terms of Use: https://bioone.org/terms-of-use

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observed that metagenomic data are arriving so rapidly that “our ignorance isgrowing as fast as our knowledge.”Patri-nos said he thought that biology hadhitherto been unjustly neglected in the USClimate Change Science Program andannounced that he was now “in the re-pentance stage.”But he told the assembledmetagenomicists they were “sloppy”and“fall very short” in organizing to developthe needed teraFLOPS of scientific com-puting resources. Even so, he was con-vinced that “we will be able to use thisnew science to get a better understandingof Earth systems.”

With concerns about climate changegrowing, some participants were in-

evitably drawn to speculate about howmetagenomics may help in the searchfor practical solutions to environmentalproblems. One researcher asked, for ex-ample, about the availability of grants tostudy how oceanic diatoms might be en-gineered to synthesize long carbon poly-mers and thus sequester more carbonfrom the global cycle (he was encour-aged to enquire at the National ScienceFoundation). But Patrinos was cautiousabout large-scale biological engineering.There is, he pointed out, a widespread re-luctance to sanction such research, and,especially,“we probably shouldn’t diddlewith the oceans.”

Patrinos was backed up by David T.Kingsbury of the Gordon and BettyMoore Foundation, who declared thatdespite the plethora of new studies, thereis still much scope for learning frommetagenomic surveys of specific eco-systems. There are, Kingsbury said,“manyenvironments we haven’t really touchedyet.” By the time metagenomicists meetthis fall at the 2006 Venter Institute con-ference in Hilton Head, it’s a fair bet thatthere will be fewer.

Timothy M. Beardsley (e-mail:

[email protected]) is editor in chief

of BioScience.


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