For the benefit of our readers who might not be familiar with the idea, could you briefly define the concept ofsystems biology?Systems biology is the ability to look at allof the elements in a biological system –by elements, I mean genes, messengerRNA, proteins, protein interactions and soforth – and to measure their relationshipsto one another as the system functions in response to biological or geneticperturbations. Then one can attempt tomodel the behaviour after integrating thedifferent levels of information, eithergraphically or mathematically, so that,ultimately, you will be able to describe the behaviour of the system given anykind of perturbation. In the future, we will be able to redesign systems bymodification or drugs to have completelynew systems properties. Whatdistinguishes systems biology from themore classical biology of the past 35 yearsor so, which looked at genes and proteinsone at a time, is the attempt to look at all,or at least most, of the elements and theirinterrelationships.

What, in your opinion, are the essentialelements that underpin and drive thedevelopment of a systems biologydepartment?The key elements are: first, to create across-disciplinary faculty environment whereone has physicists, computer scientists,engineers, chemists, biologists andmathematicians all working together. Thechallenge is to create a language that canbe commonly shared to allow them tocommunicate with one another with theaim of creating a focus on particular systemsproblems. The second challenge would beto create an environment that has all of thehigh-throughput platforms that one needsfor gathering biological information. Ingenomics, that would be large-scale DNAsequencing, DNA arrays and large-scalegenotyping. In proteomics, that would be

the ability to identify and quantify proteins,to look at their interactions and measuretheir compartmentalization and chemicalmodification, and so on. Metabolomics isthe ability to look at the small moleculesthat operate in the context of systems.A third requirement would be thedevelopment of new global technologiesand powerful new computational tools forgathering, classifying, analyzing, integratingand, ultimately, modeling biologicalinformation. That is one of the reasons youneed a cross-disciplinary environment. In allcases, the systems biology itself shoulddrive the nature and strategy of tooldevelopment, be it technical or be itcomputational.

Another element that is essential for doinggood systems biology is being able to partnereffectively with academia and, perhapsequally importantly, with industry. This isbecause one scientific entity is not going tobe able to invent all the technologies or allthe computational tools, nor will they haveaccess to all the biology that one can explore.So you need partnerships to be able tofacilitate the integration of technology,computation and biology. Another challengeis how you can then keep these new toolsthat have been developed and mature theminto high-throughput platforms that can beused to inexpensively generate enormousamounts of data. Finally, there are issues ofhow you can integrate what I call systemsbiology, which is hypothesis-driven, iterativeand integrative – a cyclical kind of process –with discovery science, which is identifyingall the elements in a transcriptome or theproteome of a particular cell type.Discovery information is useful for diseasestratification (classification) and providesthe elements for beginning systemsbiology. I would draw a sharp distinctionbetween performing array analyses anddoing systems biology; systems biologyhas to be necessarily integrative of manydifferent types of biological information.So, in the end, I think the challenge forsystems biology is how the academic orindustrial scientific entities can effectivelyintegrate technology with computation,biology and, ultimately, medicine.

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Leroy Hood expounds theprinciples, practice andfuture of systems biology

Interview by Stephen L. Carney

Leroy Hood, President, Institute for Systems Biology

Leroy Hood is recognized as one of the world’s leading scientists in molecularbiotechnology and genomics. In 2000, Hood co-founded, and is currently President of, theInstitute for Systems Biology in Seattle (http://www.systemsbiology.org), which pioneerssystems approaches to biology and medicine. He earned an MD from Johns HopkinsUniversity in 1964 and a PhD in Biochemistry from the California Institute of Technologyin 1968. His professional career began at Caltech where he and his colleagues pioneeredfour instruments, sequencers and synthesizers for DNA and protein. Hood was also oneof the first advocates of, and a key player in, the Human Genome Project. In 1992, hemoved to the University of Washington to create the cross-disciplinary Department ofMolecular Biotechnology as the William Gates III Professor of Biomedical Science. Hehas played a role in founding numerous biotechnology companies, including Amgen,Applied Biosystems, Systemix, Darwin, Rosetta and MacroGenics. In a distinguishedcareer, Hood has been honoured many times, most notably receiving the 1987 LaskerAward for his studies on the mechanism of immune diversity and the 2002 Kyoto Prizein Advanced Technology. He has a life-long commitment to making science accessibleand understandable to the general public, especially children. One of his foremostgoals is bringing hands-on, inquiry-based science to K-12 classrooms.

‘Systems biology is the ability to look at all of the elements in a biological system...’

‘You need partnerships to beable to facilitate the integrationof technology, computationand biology.’

If you were to highlight only one successthat has arisen from systems biology, what would it be and why?Together with Eric Davidson at Caltechand Hamid Bolouri here at the Institute forSystems Biology, we have used systemsapproaches to define the gene regulatorynetwork that controls the development ofthe endoderm of the sea urchin. This is a55 gene network. We know the linkagesand the interrelationships in some detail.From that network you can begin to makepredictions about how you could changedevelopment if you made modifications tothe network. To give you one example ofengineering the system, Eric and hiscolleagues perturbed the network in adefined manner and quite predictablygenerated an organism with not one gut,but two. This is a graphical illustration ofhow, if you rationally understand thegene regulatory networks that controldevelopment, you can redesign thosenetworks to get completely new systemsproperties. You can predict the behaviourof a network, given a particularperturbation in the system. This couldnever have been done in a million yearswith the classical, one-gene one-protein-at-a-time, approach to understandinggene regulatory networks.

What would you consider the role forsystems biology within the pharmaceuticalindustry? How would you envisage thisapproach driving the discovery of newpharmaceutical agents?Systems approaches to human systems(immune, cardiovascular, cancer, and soon) have the chance to enormouslyfacilitate the process of target selection andthe various aspects of pharmacogenomics;that is, the ability to identify adverse sideeffects or individuals that genetically donot react effectively to drugs. My feeling isthat systems biology is going to usher in anew kind of medicine, which I callpredictive, preventive and personalizedmedicine. The predictive will deal with,and be able to identify, hundreds if notthousands of variant genes that maypredispose, in particular combinations, to various late-onset diseases (e.g. heartdisease, cancer, autoimmune disease, andso on). It would therefore be possible toactually write out a probabilistic healthhistory for the individual. Diseaseprevention will use systems biology to place defective genes in the context of the networks in which they operate.

As I described with the sea urchin, it wouldthen be possible to circumvent the geneticlimitations with newly designed drugs, ormodified proteins or genes, and thus beable to say ‘a prediction for you is that youhave a 70% chance of getting breastcancer when you are 60 years of age, but ifat the age of 40, you start taking this drug,you need never get breast cancer, becausewe can circumvent whatever limitationsthe genes might create.’

I’ll say parenthetically that disease ariseseither as a consequence of gene defects ora combination of gene defects and/orpathologic, environmental cues, and wecan learn to deal with the circumvention of pathologic, environmental cues inexactly the same way using systemsbiology. My feeling is that systems biologywill be a central strategy for discovering,initially, therapeutic drugs and, eventually,preventive drugs.

In the future, the question is, how effectivebig pharma will be in utilizing systemsbiology? It requires a lot of integration thatthey are not very well set up to do. Onepossible alternative scenario is that a fewsuccessful systems biology companiescould emerge and focus on the early stageprocesses of drug target discovery anddrug identification, stratification of diseaseand pharmacogenetics.

The outcome for drug discovery is that youwill probably identify targets that aresignificantly more complex than have beenthe case in the past. How likely is it thatmedicinal chemistry will be able to deliverselective tools that can act upon multiple,possibly diverse, targets?I do not think that the targets will be morecomplex, rather they will be moreeffectively chosen. I think what thepharmaceutical industry has objected to is the concept that any given disease, suchas prostate cancer, is almost certainlystratified into a multiplicity of different

diseases caused by differing combinationsof genetic and environmental factors,even if their initial phenotypic outcome issimilar. For example, prostate cancer maybe considered as a disease that can bestratified on the basis of systemsapproaches into a number of disordersthat we will treat in different ways. Thetools of discovery and the tools of systemsbiology will be ideal for this process ofstratification. By stratifying disease entitiesand putting them individually throughclinical trials, you increase enormously theprobability that the drugs undergoing trialare actually going to work on a significantfraction of patients. Consider ahypothetical disease in which there are 10 different genetic predispositions givingsimilar phenotypes. Each of thesepredispositions accounts for 10% of thetotal, and you have one drug that worksperfectly in one of them. The resultantglobal efficacy of 10% would not appearto be a particularly effective clinical trial.With the systems approach, we can stratifydisease and look at the individual types ofdisease in the context of which drugswork. Then we can conduct clinical trialson the patient population predicted to beresponsive to the drug. In this case, thesuccess rate will be 100%. I think we canenormously increase the efficiency ofdefining drugs that are going to beeffective on a very high proportion ofselective stratified populations. Now theargument that has to be made is that foreach of these approaches, we’re going tocut down the total cost of creating thedrug because the markets will be smallerthan for the current blockbuster drugs, andbecause the disease is going to be highlystratified and the market fragmented.

I think that is consistent with what wecan expect from systems biology.Microfluidics and nanotechnology aregoing to enormously decrease the cost ofdoing the global and integrative studiesthat underlie both systems biology and themultiparameter analyses of predictivemedicine. For example, in the future wewill sequence an individual genome forunder US$1000, compared with today’scost of maybe US$50 million or more. This

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‘Systems approaches... have thechance to enormously facilitatethe process of target selection...’

‘In the future, the question is,how effective big pharma willbe in utilizing systems biology?’ ‘...we can enormously increase

the efficiency of defining drugsthat are going to be effective...’

will give you an idea of the scaling factorsthat we can think about as we move thesenew technologies first towards thediscovery and then towards targeted ways for designing drugs and ways tocircumvent gene defects andenvironmental cues.

With the exception of Eli Lilly’s US$140minvestment in a Centre for Systems Biologyin Singapore, there seems little big pharmainvolvement at present – do you think theyare waiting for the results of the Lilly forayor do you think the drug discovery industryis not receptive to the concept of systemsbiology at the moment?I think big pharma in general has a waitand see attitude about new approaches,as they should. The pharma business isnot to invent new approaches, but ratherto apply successful approaches. The keyissue for them is to determine when a newapproach should be applied. Systemsbiology is a nascent discipline and themost interesting systems in which wehave demonstrated its power are inmicrobes, yeast and sea urchins, and nothumans, to date. There is scepticismabout systems biology, possibly notwhether it’s going to be fruitful but howlong it will take to get to a point where itwill be useful to a drug company. Buthaving said that, many of the executivesin the drug industry don’t understandsystems biology. They have no idea aboutits potential but you’ve got to persuadethe executives that it deserves theinvestment. I am on Lilly’s Advisory Boardand their Centre for Systems Biology is amarvellously interesting experiment. I think the challenge for the pharmaceuticalindustry is going to be the challenge ofthe integrations necessary for systemsbiology; that is, the integration of newtechnologies with new computationaltools with hypothesis-driven systemsbiology all focused on medicine.

In the end, the important word in systemsbiology is biology. The biology has to drivethe development of the computationaltools. It also has to drive the developmentof the new technologies. It should also benoted that many academics are scepticalof systems biology. Some sceptics feelsystems biology really isn’t anything newbeyond the integrative physiology that hasbeen practiced for years. This was exactlythe same argument we heard in 1985 and1986 from the National Institutes of Healthwhen they said they didn’t need a Human

Genome Project; they were alreadyspending US$300,000,000 a year ongenetics and that was the same as theHuman Genome Project. At the time, they didn’t understand how profoundlydifferent those things really were.

In retrospect we can see that thearguments of doing things the same oldway have always been a barrier toadvancing new opportunities. Thepharmaceutical industry widely believesthat genomics really hasn’t advanced theircause very much. The reason for that istotally understandable. Genomics alone isa single dimension of information. Systemsbiology looks at many dimensions ofbiological information. Genomics alone isgood for classification; it isn’t necessarilygood for understanding biology andultimately providing powerful approachesto drug discovery. I think many in pharmaand academia do not understand thedifference between a one-dimensionalview of information that you see withDNA arrays and the global, integrative,iterative and hypothesis-driven approachof systems biology.

Freeman Dyson said that if you really wantto transform the field of science, invent anew technology. You clearly have a historyin this with DNA and protein sequencersand synthesizers – what would you see asbeing a key enabling technology in the next 10 years?I think without a doubt it’s the synthesis of microfluidics, microelectronics andnanotechnology for integrating,automating and creating high-throughputproduction of tools for data productionand analysis. It is nanotech we will use tosequence individual DNA molecules; it isnanotech we will use to measure RNAsand protein concentrations and proteininteractions. Microfluidics is the waynanotechnology communicates with theoutside world and, in the future, the twowill be beautifully integrated together. My very strong feeling, is that everyanalytic technique in biology and medicinewill be transformed by microfluidics andnanotechnology.

What would you see as being the nextmilestone achievement that might bedelivered by a systems biology approach?I think it’s going to be a series ofincremental steps, rather than one bigachievement. It will require thedevelopment of novel technologies,powerful new computational tools, as wellas their integrated application to theproblems of biology and medicine. Oneof the biggest challenges in systemsbiology is how to develop computationaltools for integrating the many differenttypes of biological information, DNA,RNA, protein, protein interactions and thephenotypes, that are required by systemsbiology approaches. The ultimate aim willbe to develop graphically integratedmodels that can be converted intomathematical descriptions of systems. I think that these computationalchallenges are some of the biggest weface at the Institute for Systems Biology.We are incrementally moving towardssuccess, but it isn’t going to be one bigdevelopment like the DNA sequencer; it’s going to be an incremental series ofintegrative plug-in algorithms to digitaland network platforms. I think developingthe computational tools to handle,analyze integrate and model informationis, however, one of the very biggestchallenges of the day.

Leroy HoodThe Institute for Systems Biology

1441 North 34th StreetSeattle, WA 98103-8904, USA

tel: +1 206 732 1200fax: +1 206 732 1299

e-mail: webmaster@systemsbiology.org

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‘...every analytic technique inbiology and medicine will betransformed by microfluidicsand nanotechnology.’

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