application of computer algorithms to someof the thorniest problems in astrophysics.Their goal is to give molecular biology a freshoutlook. “The approach to biology for thepast 30 years has been to study individualproteins and genes in isolation,” says Hood.“The future will be the study of the genes andproteins of organisms in the context of theirinformational pathways or networks.”

A model approachHood is not alone in embracing this sys-tems approach. For example, a consortiumcalled the Alliance for Cellular Signalling,which is based at the University of TexasSouthwestern Medical Center at Dallas andheaded by Nobel laureate Al Gilman, aimsto compile a map of the interactionsbetween 1,000 proteins in two types ofmouse cell. But Hood’s vision is moreexpansive. In addition to studying simplesystems in model cells, the ISB plans tostudy the immune system and complexconditions such as cancer and heart disease.

To finance these projects, Hood wants tosupplement grant funding by seeking endow-ments for the ISB worth some US$200 mil-lion. He aims to swell the institute from itscurrent roster of some 80 staff to around 400.An initial US$5 million came from an anony-mous donor, and in July the drugs giantMerck & Co. provided a matching sum.Negotiations are underway with further cor-porate donors, and other companies are pro-viding contributions in kind. The agribiotechfirm Monsanto, for instance, has let Hoodkeep the 30 automated DNA sequencers heused when leading the team that in Aprilcompleted a draft of the rice genome.

But even with the finance in place, theroad ahead will be difficult. Hood likens thedata gathered by the Human Genome Projectand other genomics efforts to an incompleteparts list for a car, in which some entries aremissing and others are illegible. Althoughsome parts have been grouped with othersand seem to fit together, others remainunidentified and isolated. The ISB aims tobuild from this information and produce thebiological equivalent of a virtual automobile.

Car troubleDeveloping the mathematical models onwhich this effort will depend is much morecomplicated than assembling a car’s enginefrom a pile of incompletely labelled parts.For a start, biological systems encompassseveral different levels of information. Onone level, a cell can be characterized byrecording the genes that are expressed at anyone time. But to understand the cell as anintegrated biological system, you also need tostudy the structures of the proteins the genesencode, and the interactions of these pro-teins with each other as well as with othergenes. “At the higher levels, things happenthat you can’t predict at the lower levels,” saysHood. Consider also that each gene can codefor more than one protein and that severalgenes can work together to produce individ-ual proteins, and the enormity of the taskfacing the ISB becomes clear.

Trying to render each element’s role in aprocess mathematically is also extremely

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Many people in Leroy Hood’s positionwould be resting on their laurels. Inthe 1980s, while at the California

Institute of Technology in Pasadena, he led ateam that invented the automated genesequencer — spawning a multimillion dollarbusiness and helping to lay the foundationsfor the Human Genome Project. In 1992,believing interdisciplinarity to be the key toprogress in biology, Hood convincedMicrosoft founder Bill Gates to establish theDepartment of Molecular Biotechnology atthe University of Washington in Seattle. Thedepartment united biologists with mathe-maticians, chemists, engineers, appliedphysicists and computer scientists, and wentfrom strength to strength — boasting anannual budget of US$35 million by 1998.

But in December last year, Hood resignedfrom his academic post to take on his biggestchallenge yet. The university, facing a longlist of requests for building projects, haddeclined to back Hood’s plan to create aninstitute for the emerging discipline of sys-tems biology — so Hood decided to strikeout on his own. He founded the independentInstitute for Systems Biology (ISB), a non-profit research corporation housed in some3,000 square metres of office space near theuniversity campus. Here Hood is nowassembling a multidisciplinary team to meldbiology with the tools of mathematics to pro-vide a complete description of biologicalprocesses and systems. “Biology is an infor-mation science” is his mantra.

Hood has already been joined by four ofhis former university’s brightest stars — sci-entists whose expertise spans proteomics,immunology and cell biology, as well as the

For my nexttrick…Is it possible toproduce a completemathematicaldescription of complexbiological systems?Leroy Hood thinks so,as Paul Smaglikdiscovers.

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Under the hood: astrophysicist George Lake(right) will help Leroy Hood assemble thebiological equivalent of a virtual car.

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hard. Some systems biologists aim to charac-terize every aspect in a system as fully as pos-sible, then construct the cellular equivalentof a wiring diagram — using differentialequations to describe the interactionsbetween each node. Gilman’s consortium,for example, appears to be heading initiallyin this direction. Others believe that, becausecellular systems are constantly changing,such a linear approach will fall short of pro-viding a full description of a biological sys-tem. Instead, they are putting their faith inanalysing how different components, such asmessenger RNA (mRNA) levels and proteinexpression, relate to each other under vari-ous conditions, and then using probabilitiesto recreate these relationships. The idea isthat this better captures the dynamic, non-linear workings of a biological system.

Both approaches may find their niche.But either way, Lee Hartwell, president anddirector of the Fred Hutchinson CancerResearch Center in Seattle, and a member ofthe ISB’s scientific advisory board, believesthat the key is to keep things simple, at least tostart with. If scientists at the institute want tocharacterize every aspect of every systemthey are interested in, “then they’re way tooearly”, he says. Instead, Hartwell recom-mends a modular approach, concentratingon understanding each component of a sys-tem, then integrating them later.

Sweet success?Hood seems to be heeding that advice.Returning to his automotive analogy, theinstitute will first produce schematics show-ing how parts fit together into discrete sys-tems — the transmission, for example —and will then build mathematical modelsthat predict what these component systemsdo when they work in concert. For now, theISB is working with relatively well-under-stood and simple systems in model organ-isms — akin to understanding how thebrakes work in a vintage car.

Initial studies, so far unpublished, havebeen on sugar metabolism in yeast. As theyeast genome has been sequenced and sugarmetabolism in the organism is fairly wellcharacterized, Hood decided to use it as abenchmark to see if systems biology couldpoint towards the same conclusions. ISB sci-entists, including postdoc Vesteinn Thors-son and graduate student Trey Ideker, per-formed experiments on yeast fed a steadydiet of either the sugar raffinose or galactose.They focused on a handful of genes known tohelp yeast process galactose rather than raffi-nose, knocking them out one at a time. Aftereach knockout, the researchers usedmicroarrays to measure which other geneswere expressed, and used a novel mass spec-trometry technique to measure the abun-dance of individual proteins.

Measuring both gene expression and pro-tein production paints a clearer picture, says

Ruedi Aebersold, the ISB’s proteomicsexpert, and one of its high-profile recruitsfrom the University of Washington. Justmeasuring levels of mRNA, as is typical ingene-expression studies, tells scientists that agene has been activated, but does not detailthe amount of protein it encodes, or whetherthat protein is functional. The automotiveequivalent, explains Aebersold, is knowingthat an engine contains a spark plug. Theprotein analysis, he says, allows you to ask:“Is this spark plug actually firing or is it justsitting in the engine doing nothing?”

The scientists detected around 1,000genes involved with the switch to galactosemetabolism. They then used a series of algo-rithms to group the mRNAs produced bythese genes into families, based on commonpatterns of changes in the knockout experi-ments. Finally, they integrated the mRNAand protein data into a simple mathematicalmodel that illustrates how yeast adapts to usegalactose rather than other sugars.

Comparing the results with what is actu-ally known about yeast sugar metabolismrevealed that the model still needs work. “Itactually does a reasonable job of predicting alot of things, but it’s way, way too simple,” saysHood. The ISB’s scientists will now tweaktheir algorithms, do more experiments, thenadjust the model some more. “The wholeprocess is incredibly iterative,” says Hood.

Developing better computer algorithmswill help. And the ISB has just gained avaluable asset in the form of another recruit

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from the University of Washington: GeorgeLake, an astrophysicist who is projectscientist for the Earth and Space Sciencespart of NASA’s High Performance Comput-ing and Communications initiative. Lake’sforte is developing algorithms that, untilnow, have mostly been applied to problemsof cosmology, astrophysics and planetaryscience. His algorithms, for instance, havemade simulations of planetary formationrun a million times faster.

Lake believes that building the modelsHood needs will be tricky, but not impossi-ble. He likens the challenge to modellingglobal climate, another field to which he hasapplied his skills. Climate models haveimproved through constant mathematicaltinkering and by incorporating new kinds ofdata, says Lake, and the same will be true forsimulations of biological systems. He isenthused by his crash course in biology. “It’sscary and daunting,” he says. “Quite frankly,it just wasn’t scary and daunting to go to theoffice as an astrophysicist anymore.”

Hood’s expertise in technology develop-ment might also prove to be important whenit comes to gathering the new kinds of cellu-lar data that Lake predicts will be needed.It is still too early to tell whether systems biol-ogy’s virtual automobile will ever move withthe speed and grace of a sports car. But givenHood’s track record, if it does, it is a fair betthat the ISB will help lead the way. ■

Paul Smaglik is Nature’s Washington DC correspondent.

➧ www.systemsbiology.org

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The future will be the study ofthe genes and proteins of

organisms in the context of theirinformational pathways or networks.Leroy Hood

Systems analysts: in addition to Hood and Lake, the Institute for Systems Biology’s staff includes(from left) proteomics expert Ruedi Aebersold, immunologist and cell biologist Alan Aderem, andGer van den Engh, who works on high-speed cell sorting.

© 2000 Macmillan Magazines Ltd