Vol 438 | 24 November 2005 | doi : 10.1038 / nature04228 LETTERS Design principles of a bacterial signalling network Markus Kollmann1 , Linda L vdok2 , Kilian Bartholome1 , Jens Timmer1 ,3 & Victor Sourjik2 Cellular biochemical networks have to function in a noisy environment using imperfect components . In particular , networks involved in gene regulation or signal transduction allow only for small output tolerances , and the underlying network structures can be expected to have undergone evolution for inherent robustness against perturbations1 . Here we combine theoretical and experimental analyses to investigate an optimal design for the signalling network of bacterial chemotaxis , one of the most thoroughly studied signalling networks in biology . We experimentally determine the extent of intercellular variations in the expression levels of chemotaxis proteins and use computer simulations to quantify the robustness of several hypothetical chemotaxis pathway topologies to such gene expression noise . We demonstrate that among these topologies the experimentally established chemotaxis network of Escherichia coli has the smallest sufficiently robust network structure , allowing accurate chemotactic response for almost all individuals within a population . Our results suggest that this pathway has evolved to show an optimal chemotactic performance while minimizing the cost of resources associated with high levels of protein expression . Moreover , the underlying topological design principles compensating for intercellular variations seem to be highly conserved among bacterial chemosensory systems2 . Errors in signal transduction can lead to wrong development and behavioural decisions , and result in growth impairment or , in multicellular organisms , cancer1 . Therefore one expects a strong selective pressure towards networks showing intrinsic robustness against the various sources of inter - and intracellular perturbations , such as fluctuations in protein concentration . Owing to limitations in our quantitative understanding of most signalling networks , only few detailed studies of network robustness are currently available3 6 . In the simple signalling system of bacterial chemotaxis , activity of receptors on the cell surface is regulated by changes in ambient ligand concentration7 ,8 . Active receptors enhance autophosphorylation activity of the receptor-associated kinase CheA , which transmits the signal to the flagellar motors by phosphorylating a diffusible response regulator protein CheY . One of the key features of the chemotaxis pathway is precise adaptation -- its ability to return to the same level of pathway activity under conditions of continuous stimulation . Failure of this systems property can lead to permanent swimming or tumbling behaviour and thus would restrict chemotactic response to a narrow range of chemoeffector concentrations . The most simple topology of a chemotactic signalling network that allows for precise adaptation is a two-state model proposed in ref . 3 -LRB- BL model -RRB- . This model is schematically drawn in Fig. 1a . The core property of the model is that receptors can be reversibly methylated . A higher level of methylation increases the probability of a receptor to switch to an active state and thus balances the inhibiting effect of attractants . Almost perfect adaptation results from a constantly working methyltransferase -LRB- CheR -RRB- balanced by a methylesterase -LRB- CheB -RRB- , which works only on active receptors9 . The BL model can readily explain the robustness of precise adaptation against a wide range of variations in kinetic parameters and protein concentrations as a consequence of integral feedback control at the methylation level3 ,9 . However , precise adaptation would be only physiologically relevant when the adapted level of CheY-P falls within the working range of the flagellar motor10 . It is thus the stationary level of CheY-P rather than precise adaptation per se that should be under evolutionary selection , but in the BL model this quantity is not robust to large perturbations4 . By extending the BL model , it is possible to construct larger adaptive topologies having equal input output characteristics -LRB- Fig. 1b d -RRB- and analyse their robustness against intercellular variations in protein concentrations arising from protein synthesis . The latter represents the dominating source of variations in a bacterial cell population11 ,30 . Such intercellular variations can persist on the generation timescale because there is no evidence for an active degradation of chemotaxis proteins under standard growth and assay conditions , and the decrease in protein levels mainly results from dilution during cell division12 . Figure 1 | Four possible network topologies of bacterial chemotaxis showing precise adaptation . Links between proteins indicate activations -LRB- arrows -RRB- or repressions -LRB- bar ends -RRB- . The receptor can either be in an active state -LRB- red -RRB- or an inactive state -LRB- white -RRB- . The proteins involved are denoted , for example , by A CheA , and their phosphorylated forms by Ap CheA-P . a , Minimal model as proposed in ref . 3 . b , Same as model a but with a phosphatase CheZ substituting auto-dephosphorylation of CheY-P in topology a. c , Same as model b but only the phosphorylated form of CheB can form a complex with active receptors . This topology represents the experimentally established network of E. coli . d , Same as topology c but with an active form -LRB- Z * -RRB- of the CheY phosphatase27 ,28 . 1 Institut fur Physik , Universitat Freiburg , Hermann-Herder-Str . 3 , D-79104 Freiburg , Germany . 2ZMBH , University of Heidelberg , Im Neuenheimer Feld 282 , D-69120 Heidelberg , Germany . 3FDM , Universitat Freiburg , Eckerstr . 1 , D-79104 Freiburg , Germany . 504 2005 Nature Publishing Group NATURE | Vol 438 | 24 November 2005 LETTERS To measure experimentally the amplitude of such intercellular variations in the levels of chemotaxis proteins , we replaced a native cheY gene in E. coli with cheY fused to a yellow fluorescent protein -LRB- cheY eyfp -RRB- as a translational reporter . The reporter construct is thus expressed from the native promoter as part of polycistronic messenger RNA of the meche operon that also encodes Tar and Tap chemoreceptors , and most cytosolic chemotaxis proteins -LRB- Supplementary Fig . S1 -RRB- . CheA and CheW are expressed as part of another -LRB- mocha -RRB- operon . The protein levels in the population -LRB- Fig. 2a -RRB- show large intercellular variation with an apparently asymmetric distribution , consistent with previous observations12 . The gene expression noise h j/n , where j is the standard deviation and n is the mean expression , depends on the level of gene transcription , and decreases from 0.67 to 0.47 upon deletion of the upstream transcription inhibitor , the anti-sigma factor FlgM13 ,14 -LRB- Fig. 2a -RRB- . Recently , model-based analysis showed that transcription should dominate gene expression noise between proteins when expressed from the same mRNA transcript15 ,16 . We confirmed this conclusion by comparing the variation in the levels of CheY and CheZ expressed as fusions to yellow and cyan fluorescent proteins -LRB- YFP and CFP -RRB- from the same promoter in the same order as they are positioned on the chromosome and under their native ribosome-binding sequences -LRB- Fig. 2b -RRB- . There is a strong co-variation in the expression levels of both , which arises from fluctuations in transcriptional activity , and only a moderate independent variation as a consequence of stochastic effects in both transcription and translation11 ,17 . Proteins expressed from two different chemotaxis operons , mocha and meche , which belong to the same regulon , also show significant co-variation in gene expression noise -LRB- Fig. 2b inset -RRB- but with a 25 % increase of independent variations in comparison with proteins expressed from the same operon . We further experimentally determined the effect of co-variation in the levels of all signalling proteins on chemotactic behaviour -LRB- Fig. 3 -RRB- . Concerted overexpression of all proteins up to 6.6-fold above the native level had little effect on chemotaxis efficiency , as measured by a chemotaxis-driven spreading of bacteria in an attractant gradient created by nutrient depletion in soft agar -LRB- swarm assay -RRB- . Thus , the CheY-P concentration in the overexpressing cells must be in the working range of the flagellar motor . This conclusion was further confirmed by the observation that the average time the motor spends rotating clockwise -LRB- clockwise bias -RRB- was nearly unaffected by protein overexpression -LRB- Fig. 3b -RRB- . Notably , the corresponding standard deviation decreased with the level of expression , as expected from the decline in strength of gene expression noise -LRB- Fig. 2 and Supplementary Fig . S3 -RRB- . Relying on these experimental data , we analysed mathematically the robustness of the four network topologies drawn in Fig. 1 under conditions of physiological perturbations . Owing to a steep response of the flagellar motor10 , the level of CheY-P in adapted cells can vary only about one-third from its optimal value . Outside this concentration regime the cell mainly tumbles or swims continuously and can not properly respond to stimuli . For example , a fully tumbling cell can not respond to repellents and has a reduced sensitivity to attractants . The chemotatic efficiency of a population therefore depends on the fraction of bacteria for which the CheY-P levels are within these limits . We tested the different hypothetical network topologies , shown in Fig. 1 , for their ability to reproduce qualitatively the experimental data for concerted variations of mean expression levels -LRB- Fig. 3 -RRB- . In the computer simulations , we used the experimentally determined gene expression noise -LRB- Fig. 2 -RRB- as an estimate for the minimum intercellular variations . The established topology for E. coli -LRB- Fig. 1c -RRB- reproduces accurately the experimental data , whereas the simpler topology -LRB- Fig. 1a -RRB- fails to match the data . To quantify further the robustness of the different network topologies , we calculated the fraction of fully chemotactic bacteria for different strengths of gene expression noise -LRB- Fig. 4 -RRB- . The topologies in Fig. 1c , d allow for Figure 2 | Gene expression noise of the chemotaxis proteins . Intercellular variations in the level of CheY , expressed as a YFP fusion from the native chromosomal position . The distribution of wild-type -LRB- red line -RRB- and flgM -LRB- black line -RRB- cells is characterized by the means 1 and 6.6 and standard deviations 0.67 and 3.17 , respectively . Inset : same data normalized to the same maximum intensity and displayed on a logarithmic scale . b , Correlation of the expression of CheY YFP and CheZ CFP from a single pTrc promoter without induction . Values for uncorrelated and concerted variations of the gene expression noise are h in 0.20 and h ex 0.44 , respectively . Inset : correlation of the expression of CheY YFP and CheA CFP from the native chromosomal positions , with h in 0.26 and h ex 0.35 . AU , arbitrary units . Figure 3 | Effect of the total concentration of signalling proteins on chemotaxis . a , Chemotaxis efficiency of flgM -LRB- VS102 -RRB- cells , expressing varying levels of FlgM from a plasmid , determined in a swarm assay and normalized to the value of wild-type -LRB- RP437 -RRB- cells . The relative mean expression of chemotaxis proteins at each FlgM level was measured as in Fig. 2a , using the LL1 strain as a reporter . The solid line is a guide to the eye , and error bars indicate standard errors . Inset : simulated fraction of fully chemotactic cells for topologies in Fig. 1a -LRB- red line -RRB- , b -LRB- blue line -RRB- , c -LRB- black line -RRB- and d -LRB- green line -RRB- . b , Clockwise motor bias as a function of expression of chemotaxis proteins . Each point represents a mean of 20 30 cells . Error bars indicate standard deviations and illustrate intercellular variation . The solid line shows the clockwise bias calculated from the mathematical model of Fig. 1c under gene expression noise estimated from Fig. 2 . The calculated standard deviation is depicted for the topology in Fig. 1c , assuming a steepness of the motor response curve with a Hill coefficient of five29 -LRB- thick dashed lines -RRB- or ten10 -LRB- thin dashed lines -RRB- . 505 2005 Nature Publishing Group LETTERS NATURE | Vol 438 | 24 November 2005 Figure 4 | Simulated fraction of chemotactic cells as a function of gene expression noise . Topologies are marked as in Fig. 3 . The native level of gene expression noise is indicated by dotted lines . a , Concerted variations ranging up to twofold of the wild-type strength with uncorrelated variations kept at the wild-type value , h in 0.2 . b , Same as a but with varying strength of uncorrelated variations and with concerted variations fixed to the wildtype value , h ex 0.44 . Supplementary Fig . S3 -RRB- . The location of the wild-type concentration as shown in Fig. 3a seems to reflect a selective pressure towards overall low protein concentrations18 . The second topological feature leading to higher swarming efficiency is CheB phosphorylation resulting in an additional negative feedback loop -LRB- Fig. 1c , d -RRB- . As shown in Box 2 , this second feedback loop compensates partially for deviations from the optimal CheY-P level without changing the input output characteristics . CheB phosphorylation has been previously shown to be non-essential for adaptation3 ,4 , and our analysis suggests that its main function might be in noise reduction . The essential features for the two design principles described above seem to be present among most established pathway topologies of bacterial chemotaxis2 . In particular , the CheB phosphorylation feedback is almost universal , and although many bacteria lack CheZ , the function of CheY phosphatase is taken over by another protein or by the kinase itself . The even higher robustness of the topology in Fig. 1d arises from the activation of CheZ by CheY-P that follows the same noise compensatory mechanism as the CheB phosphorylation feedback . the highest fraction of cells in the population to respond accurately to changes in ligand concentration . Furthermore , the topologies in Fig. 1b d are sufficiently robust to compensate for co-variations in expression levels -LRB- Fig. 4a -RRB- but tolerate only a moderate increase in independent fluctuations in protein concentrations -LRB- Fig. 4b -RRB- . There are two key features accounting for the higher robustness of the topologies shown in Fig. 1c , d. First , robustness against concerted variations requires a balance of phosphatase and kinase reactions and similar requirements for the methylation process , as shown by mathematical analysis in Box 1 . The condition for a robust adaptive chemotaxis pathway is that CheY-P demands a phosphatase -LRB- CheZ -RRB- whereas CheB-P must not have one . But this kind of robustness is only valid for concentrations larger than the wild-type level -LRB- Fig. 3a -RRB- . The strong decrease in the number of chemotactic bacteria at lower expression levels -LRB- Fig. 3a inset -RRB- arises because the total CheY concentration drops below the working range of the flagellar motor . The increase in chemotatic performance of the topologies in Fig. 1b d with the mean expression level can be explained by an accompanying decline of the gene expression noise11 -LRB- Fig. 2a and Box 2 | Error reduction mechanisms Errors in the output signal arising from uncorrelated variations of protein levels and deviations from the optimal rate constants can be partially compensated by additional negative feedback loops22 -LRB- Fig. 1 -RRB- . Here , we focus on the gain in robustness due to activation of the methylesterase -LRB- CheB -RRB- by phosphotransfer from CheA . We simplify the E. coli chemotaxis topology -LRB- Fig. 1c -RRB- such that any receptor has only one methylation site and the average activity of methylated receptors depends on the ambient chemoeffector concentration . Non-methylated receptors remain inactive . Using Michaelis Menten kinetics , the steady-state equation for the methylation process reads TA > t T M kR R 2 kB Bp 0 3 KB T A with k R and k B the associated rate constants and K B the Michaelis Menten constant for binding of CheB-P to active receptor complexes3 . The concentrations of methylated and active receptors are denoted by T M and T A , and the concentrations of the methyltransferase and active methylesterase by R and Bp , respectively . For the topologies in Fig. 1c , d the methylesterase , CheB , is active only in the phosphorylated form and thus depends on the concentration of the phosphodonor , Ap -LSB- CheA-P -RSB- . We have also assumed that the methyltransferase , CheR , works at saturation . The steady-state equation for Ap is given by kA T A AT 2 Ap 2 kY Ap Y T 2 Yp 0 4 T with Yp k Y Ap Y / -LRB- k Y Ap k Z Z -RRB- and where k Z Z is the dephosphorylation rate of CheY-P . The superscript T indicates total protein concentrations . In the above equation we neglected the small contribution of the phosphoacceptor CheB as -LRB- ref . 23 -RRB- 0 kY Y T . kB BT , with k Y and kB the rates of phosphate transfer from . 0 CheA-P to CheY and CheB , respectively . As Ap and R are linked through equations -LRB- 3 -RRB- and -LRB- 4 -RRB- , a small increase in the amount of methyltransferase , R DR , results in a change of phosphorylated receptors given by ! > Bp 21 DAp a b gDR 5 > Ap To arrive at equation -LRB- 5 -RRB- we have performed a linear expansion around fixed values for the remaining protein concentrations . The linear expansion coefficients a and b can be shown to have equal sign -LRB- see Supplementary Information -RRB- . The derivative > Bp / > Ap . 0 manifests the higher robustness against perturbations of the network topologies in Fig. 1c , d . This contribution increases the amount of active methylesterase -LRB- CheB-P -RRB- whenever the average activity of the receptors is rising , and thus partially compensates for an increased amount of methyltransferase . This term is absent in the topologies of Fig. 1a , b , as here the methylesterase is not phosphorylated and thus > Bp / > Ap 0 . Fluctuations in other protein levels are compensated for in an equivalent way . Box 1 | Robustness against variations in transcriptional activity A general deterministic description for the concentrations of the N different phosphorylation and methylation states y t -LCB- y1 t ; ... ; yN t -RCB- of a signalling pathway are given by the equations > t yi t F i y t jx T 1 -LRB- see Supplementary Information for details and definitions -RRB- . The sum over different states , -LRB- y i -RRB- k , of the protein with index k is P connected to its total concentration by -LCB- yi -RCB- k yi t xT . For the k stationary solution , F i y t jx T 0 , to be invariant against covarying total protein concentrations , for example due to a l-fold change in transcriptional activity x T xT ; ... ; xT ! lxT ; ... ; lxT of 1 M 1 M the M chemotaxis proteins , we have to demand homogeneity of F T with respect to x , F i y t jlx T lmi F i y t jx T 2 with m i . 0 . For the equations corresponding to the topology in Fig. 1a the homogeneity condition can not be satisfied . For the topologies in Fig. 1b d we have the case F i y t jlx T < T lF i y t jx for l . 1 and therefore these topologies are invariant against changes in transcriptional activity of signalling proteins at expression levels higher than the wild type . For example , to keep the level of CheY-P invariant under a l-fold overexpression , the resulting increase of phosphotransfer to CheY has to be balanced by an increase in dephosphorylation rate . This is achieved by a simultaneous upregulation of the phosphatase CheZ . The conditions of invariance and the consequences of their violation are discussed in the Supplementary Information . 506 2005 Nature Publishing Group NATURE | Vol 438 | 24 November 2005 LETTERS Reflecting strong selection , the chemotaxis pathway in E. coli seems to be optimized for high sensitivity , fast response and perfect adaptation7 ,8,19,20 . As shown in this work , the experimentally established design of the chemotaxis network in E. coli represents a minimal topology providing high robustness to physiological perturbations . This network design can compensate for the observed strong co-variations in gene expression but the negative effect of uncorrelated variations on the efficiency of chemotaxis can only be attenuated . Similar correlations in expression have been found recently in eukaryotes for genes under identical control21 . We can therefore expect that analogous design principles , compensating for intercellular variations , will apply to all signalling networks and gene regulation systems whenever precise regulation of an output signal is demanded . METHODS Bacterial strains and plasmids . All strains used in this study were derived from a wild-type chemotaxis strain RP437 using a pAMPts homologous recombination system of allele exchange , described before24 . Strain VS162 carries a cheY eyfp fusion construct in place of a cheY gene on the chromosome , and strain LL6 carries cheY eyfp and cheA ecfp fusion constructs in place of cheYand cheA genes on the chromosome . Strains VS102 -LRB- flgM -RRB- and LLI -LRB- cheY eyfp flgM -RRB- carry inframe deletions of an anti-sigma factor -LRB- FlgM -RRB- that negatively controls the expression of all chemotaxis and flagellar -LRB- class III -RRB- genes . Plasmid pLLl6 Ampr encodes FlgM expressed under control of an isopropyl b-D - thiogalactoside -LRB- IPTG -RRB- - inducible promoter pTrc . Plasmid pVS88 encodes CheY YFP and CheZ CFP fusion proteins transcribed as one polycistronic mRNA from the pTrc promoter25 . The level of CheY YFP expression in the absence of IPTG closely matched the expression from a native promoter -LRB- VS162 -RRB- . Growth conditions . All strains were grown under standard chemotaxis conditions at 34 8C in tryptone broth -LRB- TB -RRB- as described before24 ,25 in the presence of varying amounts of IPTG . Swarm assays were performed at 34 8C on TB plates supplemented with 0.3 % agar -LRB- Applichem -RRB- and indicated concentrations of IPTG . Quantification of gene expression . Expression of fluorescent reporter proteins in individual cells was quantified using flow cytometry on a FACScan -LRB- BD Biosciences -RRB- equipped with a 488-nm argon laser , or fluorescence imaging on an Axiovert 200 fluorescence microscope equipped with an ORCA AG CCD camera -LRB- Hamamatsu -RRB- . FACScan data were analysed using CellQuest Pro 4.0.1 software . Imaging data were analysed using ImageJ software -LRB- W. Rasband -RRB- to quantify fluorescence of the entire cell . When tested on the same population , both methods gave essentially identical results . Tethering . Cells were tethered to a glass coverslip as described earlier26 . The rotation of tethered cells was recorded for 3 min at 25 8C with a microscope -LRB- Zeiss Axiostar plus -RRB- equipped with a CCD camera -LRB- Panasonic WV-BP330 -RRB- and a DV Recorder -LRB- Panasonic AG-DV1DC -RRB- . The analysis was performed using IPS image recognition software from the Visometrics Group . Description of the mathematical model . The dynamical behaviour of the networks was described on the level of ordinary differential equations assuming Michaelis Menten kinetics . The kinetic constants were taken from in vivo and in vitro measurements , except for the methylation process and the CheY CheZ feedback loop shown in Fig. 1d , where constants were determined from optimization of a population of 70 cells with respect to their least deviation from the midpoint of the motor response curve10 -LRB- 3.2 mM -RRB- under the experimentally determined gene expression noise . Fully chemotactic cells were defined as cells for which the level of CheY-P was within the interval 2.2 4.3 mM and for determination of their proportion in Figs 3 and 4 a population size of 104 cells was assumed . A detailed description of the mathematical model is given in the Supplementary Information . Received 25 May ; accepted 12 September 2005 . 1 . 2 . 3 . Kitano , H. Biological robustness . Nature Rev. 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This work was supported by ZMBH funding , DFG grants to V.S. and K.B. , and the BMBF project ` Systems of Life Systems Biology ' . Author Contributions V.S. designed the experiments and L.L. carried them out . M.K. performed the mathematical modelling together with K.B. . The paper was written by M.K. and V.S. with comments from J.T. L.L. and K.B. contributed equally to this work . Author Information Reprints and permissions information is available at npg.nature.com/reprintsandpermissions . The authors declare no competing financial interests . Correspondence and requests for materials should be addressed to M.K. -LRB- markus.kollmann@fdm.uni-freiburg.de -RRB- or V.S. -LRB- v.sourjik@zmbh.uni-heidelberg.de -RRB- . 2005 Nature Publishing Group 507

O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O B O O O O O O O O O O O O O O O O O B B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

network signalling evolution robustness noise


Service-Oriented

Science

Ian

Foster

et

al.

Science

-LRB-

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NN

G

I

I

TRI

I

UTED

OMPUTI

I

G

S

PECIAL

S

ECTION

VIEWPOINT

Service-Oriented

Science

Ian

Foster

New

information

architectures

enable

new

approaches

to

publishing

and

accessing

valuable

data

and

programs

So-called

service-oriented

architectures

define

standard

interfaces

and

protocols

that

allow

developers

to

encapsulate

information

tools

as

services

that

clients

can

access

without

knowledge

of

or

control

over

their

internal

workings

Thus

tools

formerly

accessible

only

to

the

specialist

can

be

made

available

to

all

previously

manual

data-processing

and

analysis

tasks

can

be

automated

by

having

services

access

services

Such

service-oriented

approaches

to

science

are

already

being

applied

successfully

in

some

cases

at

substantial

scales

but

much

more

effort

is

required

before

these

approaches

are

applied

routinely

across

many

disciplines

Grid

technologies

can

accelerate

the

development

and

adoption

of

service-oriented

science

by

enabling

a

separation

of

concerns

between

disciplinespecific

content

and

domain-independent

software

and

hardware

infrastructure

Paul

ErdPs

claimed

that

a

mathematician

is

a

machine

for

turning

coffee

into

theorems

The

scientist

is

arguably

a

machine

for

turning

data

into

insight

However

advances

in

information

technology

are

changing

the

way

in

which

this

role

is

fulfilled

by

automating

time-consuming

activities

and

thus

freeing

the

scientist

to

perform

other

tasks

In

this

Viewpoint

I

discuss

how

service-oriented

computing

technology

that

allows

powerful

information

tools

to

be

made

available

over

the

network

always

on

tap

and

easy

for

scientists

to

use

may

contribute

to

that

evolution

The

practice

of

science

has

of

course

already

been

affected

dramatically

by

information

technology

and

in

particular

by

the

Internet

For

example

the

hundreds

of

gigabytes

of

genome

sequence

available

online

means

that

for

a

growing

number

of

biologists

Bdata

-LSB-

is

something

that

they

find

on

the

Web

not

in

the

lab

Similarly

emerging

Bdigital

observatories

-LSB-

Ealready

several

hundred

terabytes

in

dozens

of

archives

-LRB-

-RRB-

allow

astronomers

to

pose

and

answer

in

seconds

questions

that

might

previously

have

required

years

of

observation

In

fields

such

as

cosmology

and

climate

supercomputer

simulations

have

emerged

as

essential

tools

themselves

producing

large

data

sets

that

when

published

online

are

of

interest

to

many

-LRB-

-RRB-

An

exploding

number

of

sensors

-LRB-

-RRB-

the

rapidly

expanding

computing

and

storage

capabilities

of

federated

Grids

-LRB-

-RRB-

and

advances

in

optical

networks

-LRB-

-RRB-

are

accelerating

these

trends

by

making

increasingly

powerful

capabilities

available

online

Sometimes

however

the

thrill

of

the

Web

seems

to

blind

us

to

the

true

implications

of

these

developments

Human

access

to

online

resources

is

certainly

highly

useful

putting

a

global

library

at

our

fingertips

But

ultimately

it

Mathematics

and

Computer

Science

Division

Argonne

National

Laboratory

Argonne

IL

USA

and

Department

of

Computer

Science

University

of

Chicago

Chicago

IL

USA

E-mail

foster@mcs.anl.gov

is

automated

access

by

software

programs

that

will

be

truly

revolutionary

simply

because

of

the

higher

speeds

at

which

programs

can

operate

In

the

time

that

a

human

user

takes

to

locate

one

useful

piece

of

information

within

a

Web

site

a

program

may

access

and

integrate

data

from

many

sources

and

identify

relationships

that

a

human

might

never

discover

unaided

Two

dramatic

examples

are

systems

that

automatically

integrate

information

from

genome

and

protein

sequence

databases

to

infer

metabolic

pathways

-LRB-

-RRB-

and

systems

that

search

digital

sky

surveys

to

locate

brown

dwarfs

-LRB-

-RRB-

The

key

to

such

success

is

uniformity

of

interface

so

that

programs

can

discover

and

access

services

without

the

need

to

write

custom

code

for

each

specific

data

source

program

or

sensor

Electric

power

transmission

standards

and

infrastructure

enabled

development

of

the

electric

power

grid

and

spurred

the

development

of

a

plethora

of

electric

tools

In

a

similar

manner

service

technologies

enable

the

development

of

a

wide

range

of

programs

that

integrate

across

multiple

existing

services

for

purposes

such

as

metabolic

pathway

reconstruction

categorization

of

astronomical

objects

and

analysis

of

environmental

data

If

such

programs

are

themselves

made

accessible

as

services

the

result

can

be

the

creation

of

distributed

networks

of

services

each

constructed

by

a

different

individual

or

group

and

each

providing

some

original

content

and/or

value-added

product

-LRB-

-RRB-

We

see

this

evolution

occurring

in

the

commercial

Internet

As

the

Web

has

expanded

in

scale

so

the

preferred

means

of

finding

things

has

evolved

from

manually

assembled

lists

to

automatically

computed

indices

Now

Google

is

making

its

indices

accessible

spurring

development

of

yet

other

services

What

makes

indices

feasible

is

the

existence

of

large

quantities

of

data

in

a

uniform

format

-LRB-

HTML

HyperText

Markup

Language

-RRB-

and

two

important

factors

that

must

be

considered

when

we

turn

to

science

smart

VOL

SCIENCE

Creating

and

Sharing

Services

Creating

a

service

involves

describing

in

some

conventional

manner

the

operations

that

the

service

supports

defining

the

protocol

used

to

invoke

those

operations

over

the

Internet

and

operating

a

server

to

process

incoming

requests

A

set

of

technologies

called

Web

services

-LRB-

-RRB-

are

gaining

wide

acceptance

for

these

purposes

A

variety

of

commercial

and

open-source

Web

services

tools

exist

for

developing

services

deploying

and

operating

services

and

developing

client

applications

A

fair

amount

of

experience

has

been

gained

with

the

creation

of

services

and

applications

in

different

science

domains

Although

problems

remain

-LRB-

e.g.

efficiency

interoperability

of

different

vendor

offerings

-RRB-

the

technology

is

well

beyond

the

experimental

stage

Nevertheless

it

can

still

be

a

big

step

to

realize

the

full

potential

of

serviceoriented

science

for

reasons

that

I

now

discuss

Interoperability

Services

have

little

value

if

others

can

not

discover

access

and

make

sense

of

them

Yet

as

Stein

has

observed

-LRB-

-RRB-

today

's

scientific

communities

too

often

resemble

medieval

Italy

's

collection

of

warring

city

states

each

with

its

own

legal

system

and

dialect

Web

services

mechanisms

for

describing

discovering

accessing

and

securing

services

provide

a

common

alphabet

but

a

true

lingua

franca

requires

agreement

on

protocols

data

formats

and

ultimately

semantics

-LRB-

-RRB-

For

example

the

definition

of

VOTable

a

standard

XML

-LRB-

eXtensible

Markup

Language

-RRB-

based

representation

for

tabular

data

-LRB-

-RRB-

has

been

a

powerful

force

for

progress

in

astronomy

Scale

Services

must

often

deal

with

data

volumes

computational

demands

and

numbers

of

users

beyond

the

capacity

of

a

typical

PC

Responding

to

a

user

request

or

to

the

arrival

of

new

data

can

involve

large

amounts

of

computation

For

example

the

Argonne

GNARE

system

searches

periodically

through

DNA

and

protein

databases

for

new

and

updated

genomes

and

then

computes

and

pub

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computer

scientists

to

develop

the

algorithms

and

software

required

to

manage

the

computers

used

-LRB-

at

last

count

-RRB-

to

analyze

Web

link

structure

and

smart

businesspeople

to

raise

the

money

that

pays

for

those

computers

The

term

Bservice-oriented

architecture

-LSB-

refers

to

systems

structured

as

networks

of

loosely

coupled

communicating

services

-LRB-

-RRB-

Thus

Bservice-oriented

science

-LSB-

refers

to

scientific

research

enabled

by

distributed

networks

of

interoperating

services

EThe

term

Be-Science

-LSB-

coined

by

John

Taylor

has

a

similar

but

broader

connotation

-LRB-

-RRB-

DISTRIBUTED

COMPUTING

S

PECIAL

S

ECTION

Downloaded

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cialization

so

that

being

a

service

developer

is

oriented

science

realizes

its

promise

of

being

a

lishes

derived

values

-LRB-

-RRB-

-LRB-

Fig.

-RRB-

Analysis

as

honorable

as

being

an

experimentalist

or

democratizing

force

rather

than

increasing

the

of

a

single

bacterial

genome

of

sequences

theorist

Intellectual

property

issues

must

also

gap

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the

haves

and

have-nots

by

three

bioinformatics

tools

-LRB-

BLAST

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be

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so

that

people

feel

comfortable

Part

of

the

solution

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a

familiar

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in

and

BLOCKS

-RRB-

requires

steps

each

making

data

available

freely

It

is

perhaps

not

commercial

information

technology

namely

taking

on

the

order

of

s

of

run

time

GNARE

surprising

that

astronomy

has

led

the

way

in

outsourcing

Building

and

deploying

a

service

is

able

to

perform

these

tasks

in

a

timely

fashion

putting

data

online

given

that

its

data

have

no

require

expertise

and

resources

in

three

distinct

only

because

it

has

access

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distributed

known

commercial

value

areas

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i

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the

domain-specific

content

data

resources

provided

by

two

U.S.

national-scale

Scientists

are

certainly

not

alone

in

grapsoftware

and

processes

that

is

to

be

shared

infrastructures

TeraGrid

and

Open

Science

pling

with

these

challenges

However

science

-LRB-

ii

-RRB-

the

domain-independent

software

functions

Grid

-LRB-

see

below

-RRB-

needed

to

operate

and

manThe

impact

of

autoage

the

service

and

to

mation

on

service

load

enable

community

access

must

also

be

considered

such

as

membership

serIt

is

improbable

that

even

vices

registries

metadata

a

tiny

fraction

of

the

percatalogs

and

workflow

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biologists

chestration

services

and

-LRB-

iii

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worldwide

will

decide

to

the

physical

resources

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GenBank

GNARE

networks

storage

and

or

any

other

service

at

the

computers

needed

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host

same

time

However

it

is

content

and

functions

quite

conceivable

that

The

last

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capabilities

agents

operating

functions

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behalf

would

do

in

principle

be

handed

off

so

and

that

each

such

to

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providers

If

agent

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want

to

gensuch

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can

deliver

erate

thousands

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a

quired

functions

for

many

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usecommunities

then

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again

ful

service

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become

in

principle

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economies

of

overloaded

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we

scale

can

be

achieved

need

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control

who

uses

while

scientists

can

focus

services

and

for

what

puron

what

they

are

good

at

poses

Particularly

valuproviding

content

and

adable

services

may

become

vancing

science

In

adcommunity

resources

redition

individual

services

quiring

coordinated

mancan

scale

more

easily

and

agement

Grid

architectures

efficiently

when

needed

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software

a

set

of

To

see

how

this

strategy

Web

services

technologies

can

work

consider

the

focused

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distributed

sysSourceForge

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tem

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can

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an

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developing

open-source

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control

As

software

A

new

openthe

number

and

variety

of

services

grow

and

inter

Fig.

What

it

can

take

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build

a

service

A

powerful

approach

to

the

interpretation

of

newly

source

project

is

provided

dependencies

among

ser

sequenced

genomes

is

comparative

analysis

against

all

annotated

sequences

in

publicly

with

access

to

code

archivvices

increase

it

becomes

available

resources

Currently

the

largest

sequence

database

at

the

National

Center

for

ing

mailing

lists

and

other

important

to

automate

pre

Biotechnology

Information

contains

million

protein

sequences

The

precision

of

genetic

related

functions

as

well

as

viously

manual

quality

sequence

analysis

and

assignment

of

function

to

genes

can

be

increased

markedly

by

the

use

the

hardware

required

to

control

processes

so

that

of

multiple

bioinformatics

algorithms

for

data

analysis

The

GNARE

system

discussed

in

the

host

those

functions

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text

precomputes

analysis

results

for

every

sequence

finding

protein

similarities

-LRB-

BLAST

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for

example

users

can

de

protein

family

domains

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BLOCKS

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and

structural

characteristics

Grid

resources

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used

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of

function

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the

provenance

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abil

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National

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with

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ity

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users

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metadata

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accessing

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services

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services

workWe

need

to

change

incentives

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spelenging

How

do

we

ensure

that

servicewww.sciencemag.org

SCIENCE

VOL

MAY

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S

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Fig.

The

Open

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Grid

links

storage

and

computing

resources

at

more

than

sites

across

the

United

States

to

support

a

variety

of

services

and

applications

many

concerned

with

largescale

data

analysis

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show

a

subset

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Open

Science

Grid

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lines

indicate

communications

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international

partners

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Image

credit

I.

Legrand

Caltech

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flow

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hardware

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operate

both

those

functions

and

the

application-specific

services

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constitute

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communities

content

In

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the

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much

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control

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provisioning

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issues

As

noted

above

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architectures

and

software

-LRB-

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address

many

of

these

concerns

allowing

users

to

focus

on

providing

content

which

in

this

case

comprises

not

just

Web

pages

but

also

services

data

and

programs

SourceForge

's

hardware

requirements

are

not

substantial

and

thus

can

easily

be

provided

by

a

centralized

system

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cyberinfrastructure

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to

support

scientific

communities

need

not

be

centralized

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example

the

Open

Science

Grid

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OSG

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collaboration

has

constructed

a

distributed

Grid

linking

clusters

at

sites

across

the

United

States

that

total

thousands

of

computers

and

tens

of

terabytes

of

storage

-LRB-

-RRB-

-LRB-

Fig.

-RRB-

The

Enabling

Grids

for

eScience

in

Europe

project

EGEE

has

a

similar

structure

Major

research

universities

and

national

laboratories

participate

in

OSG

and

EGEE

but

so

do

smaller

institutions

which

can

thus

enhance

educational

and

research

opportunities

For

example

Florida

International

University

is

an

important

OSG

resource

provider

thanks

to

its

Linux

cluster

All

participants

can

obtain

access

to

large

quantities

of

distributed

storage

and

computational

power

when

they

need

it

These

systems

are

being

used

by

researchers

in

high-energy

physics

biology

chemistry

radiology

and

computer

science

This

separation

of

concerns

also

suggests

new

roles

for

campus

information

technology

organizations

In

addition

to

operating

commodity

services

such

as

Internet

and

e-mail

these

organizations

can

host

functions

and

provide

resources

Approaches

to

Scaling

The

many

groups

working

to

apply

serviceoriented

techniques

to

science

are

each

exploring

one

or

more

of

three

different

approaches

to

the

problem

of

scaling

In

the

first

cookiecutter

approach

researchers

create

dedicated

domain-specific

infrastructures

in

which

uniformity

is

enforced

across

the

board

at

the

content

function

and

resource

level

Here

the

community

standardizes

the

domain-specific

software

and

often

also

the

hardware

that

participants

must

deploy

in

order

to

provide

required

functions

and

resources

I

give

three

examples

of

such

systems

The

Biomedical

Informatics

Research

Network

BIRN

-LRB-

-RRB-

is

a

National

Institutes

of

Health

initiative

to

facilitate

collaboration

in

the

biomedical

sciences

BIRN

has

deployed

standard

compute

and

storage

clusters

at

sites

across

the

United

States

These

systems

plus

various

functions

such

as

catalogs

and

ontologies

support

a

variety

of

collaborative

research

programs

in

areas

such

as

mouse

brain

morphology

-LRB-

-RRB-

The

National

Science

Foundation

's

Network

for

Earthquake

Engineering

Simulation

NEES

is

a

national

collaboratory

enabling

commuVOL

SCIENCE

nity

access

to

specialized

instrument

data

and

simulation

resources

for

earthquake

engineering

Each

of

its

instrument

sites

runs

a

NEES

Point

of

Presence

-LRB-

a

modest

PC

with

a

standard

hardware

configuration

-RRB-

with

standard

software

enabling

teleobservation

teleoperation

data

collection

and

related

functions

Central

services

include

catalogs

and

data

archives

NEES

has

already

enabled

unique

distributed

experiments

involving

facilities

at

multiple

sites

-LRB-

-RRB-

The

PlanetLab

computer

science

testbed

is

a

collection

of

several

hundred

PCs

at

universities

and

research

laboratories

worldwide

each

with

a

standard

configuration

and

each

running

standard

software

-LRB-

-RRB-

Computer

scientists

can

obtain

access

to

slices

on

distributed

collections

of

these

PCs

on

which

they

can

deploy

and

evaluate

experimental

distributed

services

Pushing

the

electric

power

grid

analogy

perhaps

farther

than

we

should

cookie-cutter

approaches

give

each

participant

their

own

electricity

generator

This

strategy

has

the

advantage

of

achieving

a

high

degree

of

central

control

and

thus

uniformity

On

the

other

hand

the

cost

of

expanding

capability

is

high

requiring

the

acquisition

and

deployment

of

new

hardware

In

the

second

more

bottom-up

approach

researchers

develop

service

ecologies

in

which

agreements

on

interfaces

allow

participants

to

provide

content

and

function

in

any

way

they

see

fit

I

referred

above

to

the

international

virtual

observatory

community

's

VOTable

format

and

to

work

in

bioinformatics

The

Department

of

Energy

's

Earth

System

Grid

ESG

-LRB-

-RRB-

is

another

example

of

a

discipline-specific

service

that

emphasizes

the

definition

and

implementation

of

standard

interfaces

Building

on

the

widely

used

OPeNDAP

protocol

for

publishing

and

accessing

environmental

data

ESG

has

deployed

services

that

provide

access

to

over

TB

of

climate

simulation

data

from

the

National

Center

for

Atmospheric

Research

's

Community

Climate

Simulation

Model

and

other

models

involved

in

the

International

Panel

on

Climate

Change

assessment

Many

terabytes

of

data

are

downloaded

from

these

services

each

month

As

a

second

example

the

UK

myGrid

project

-LRB-

-RRB-

has

developed

tools

that

allow

biologists

to

define

workflows

that

integrate

information

from

multiple

sources

including

both

biological

databases

and

bioinformatics

applications

These

workflows

can

be

archived

and

then

run

periodically

to

identify

new

phenomena

of

interest

as

for

example

in

a

recent

study

of

Williams-Beuren

syndrome

-LRB-

-RRB-

For

a

third

example

the

Department

of

Energy

's

Fusion

Collaboratory

-LRB-

-RRB-

operates

services

that

enable

online

access

to

simulation

codes

By

reducing

barriers

to

use

these

services

are

increasing

use

of

advanced

computational

techniques

Project

members

have

also

demonstrated

on-demand

coupling

of

simulation

capabilities

with

physical

experiments

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May

DISTRIBUTED

COMPUTING

S

PECIAL

S

ECTION

Continuing

the

electric

power

grid

analogy

such

service

ecologies

define

relevant

standards

but

leave

each

site

to

acquire

and

configure

its

own

equipment

This

approach

has

the

advantage

that

the

cost

of

entry

can

be

low

particularly

if

appropriate

software

is

available

On

the

other

hand

individual

service

providers

have

no

immediate

means

of

scaling

capability

beyond

acquiring

more

hardware

The

third

approach

involves

the

definition

and

deployment

of

general-purpose

infrastructures

that

deliver

discipline-independent

resources

or

functions

I

have

already

mentioned

OSG

and

EGEE

As

a

third

example

the

National

Science

Foundation

's

TeraGrid

links

resources

at

nine

sites

across

the

United

States

with

each

site

deploying

a

common

software

distribution

that

permits

secure

remote

access

to

computers

and

storage

systems

monitoring

of

system

components

accounting

for

usage

and

so

on

TeraGrid

targets

not

only

high-end

power

users

but

also

the

larger

community

through

the

deployment

of

science

gateways

discipline-specific

services

hosted

on

TeraGrid

in

support

of

specific

communities

General-purpose

infrastructures

can

be

compared

with

power

plants

which

operate

to

provide

electricity

to

any

consumer

connected

to

the

electric

power

grid

Like

power

plants

they

have

the

potential

to

achieve

economies

of

scale

but

also

must

grapple

with

the

challenges

of

supporting

many

users

with

diverse

requirements

In

addition

to

these

national

or

transnational

efforts

many

university

campuses

are

deploying

campus

Grids

to

support

faculty

and

students

For

example

Purdue

University

's

NanoHub

provides

students

and

faculty

with

access

to

various

applications

while

the

UCLA

Grid

federates

multiple

clusters

across

campus

and

provides

online

access

to

popular

simulation

codes

These

projects

and

many

others

like

them

are

important

experiments

in

the

policies

organizational

structures

and

mechanisms

required

to

realize

service-oriented

science

Elements

of

all

three

approaches

will

be

required

if

we

are

to

achieve

broad

adoption

In

particular

it

can

not

be

efficient

for

every

scientist

and

community

to

become

a

service

provider

Instead

individual

communities

especially

smaller

communities

should

be

able

to

outsource

selected

functions

and

physical

resources

thus

allowing

them

to

focus

on

developing

their

domain-specific

content

The

successful

creation

and

operation

of

the

service

providers

that

support

this

outsourcing

require

both

Grid

infrastructure

software

and

organizational

and

funding

structures

that

expose

real

costs

so

that

build

versus

buy

decisions

can

be

made

in

an

informed

manner

Summary

Service-oriented

science

has

the

potential

to

increase

individual

and

collective

scientific

productivity

by

making

powerful

information

tools

available

to

all

and

thus

enabling

the

widespread

automation

of

data

analysis

and

computation

Ultimately

we

can

imagine

a

future

in

which

a

community

's

shared

understanding

is

no

longer

documented

exclusively

in

the

scientific

literature

but

is

documented

also

in

the

various

databases

and

programs

that

represent

and

automatically

maintain

and

evolve

a

collective

knowledge

base

Service-oriented

science

is

also

a

new

way

of

doing

business

with

implications

for

all

aspects

of

the

scientific

enterprise

Students

and

researchers

must

acquire

new

skills

to

build

and

use

services

New

cyberinfrastructure

is

required

to

host

services

especially

as

demand

increases

Policies

governing

access

to

services

must

evolve

Above

all

much

hard

work

must

be

done

in

both

disciplinary

science

and

information

technology

in

order

to

develop

the

understanding

needed

for

this

potential

to

be

fully

exploited

References

and

Notes

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Szalay

J.

Gray

Science

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D.

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science

VIEWPOINT

Cyberinfrastructure

for

e-Science

Tony

Hey

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Anne

E.

Trefethen

Here

we

describe

the

requirements

of

an

e-Infrastructure

to

enable

faster

better

and

different

scientific

research

capabilities

We

use

two

application

exemplars

taken

from

the

United

Kingdom

's

e-Science

Programme

to

illustrate

these

requirements

and

make

the

case

for

a

service-oriented

infrastructure

We

provide

a

brief

overview

of

the

UK

plug-andplay

composable

services

vision

and

the

role

of

semantics

in

such

an

e-Infrastructure

It

is

no

coincidence

that

it

was

at

CERN

the

particle

physics

accelerator

laboratory

in

Engineering

and

Physical

Sciences

Research

Council

Polaris

House

North

Star

Avenue

Swindon

UK

Geneva

that

Tim

Berners-Lee

invented

the

World

Wide

Web

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distributed

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of

the

multi-institute

collaborations

required

for

modern

particle

physics

experiments

researchers

desperately

needed

a

tool

for

exchanging

information

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a

slow

start

SCIENCE

VOL

the

community

enthusiastically

adopted

the

Web

for

information

exchange

within

their

global

experimental

collaborations

Since

its

beginnings

in

the

early

the

Web

has

become

an

indispensable

tool

not

just

for

the

scientific

world

but

for

the

humanities

business

and

recreation

Now

just

a

decade

later

scientists

are

attempting

to

develop

capabilities

for

collaboration

that

go

far

beyond

those

of

the

Web

Besides

being

able

to

access

information

from

different

sites

they

want

to

be

able

to

integrate

federate

and

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et

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Science

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Engineering

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Cyberinfrastructure

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National

Science

Foundation

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Science

Foundation

Washington

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et

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et

al.

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I

gratefully

acknowledge

helpful

discussions

with

C.

Catlett

C.

Kesselman

M.

Livny

A.

Szalay

and

R.

Stevens

This

work

was

supported

in

part

by

the

Mathematical

Information

and

Computational

Sciences

Division

subprogram

of

the

Office

of

Advanced

Scientific

Computing

Research

Office

of

Science

U.S.

Department

of

Energy

under

Contract

and

by

the

NSF

The

author

is

Founder

of

and

Chief

Open

Source

Strategist

at

Univa

Corporation

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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