Synthetically engineered microbes reveal interesting principles of cooperation
Michael D. Dressler, Corey J. Clark, Chelsea A. Thachettu, Yasmine Zakaria, Omar Tonsi Eldakar, Robert P. Smith
Synthetically engineered microbes reveal interesting principles of cooperation
Cooperation is ubiquitous in biological systems. However, if natural selection favors traits that confer an advantage to one individual over another, then helping others would be paradoxical. Nevertheless, cooperation persists and is critical in maintaining homeostasis in systems ranging from populations of bacteria to groupings of mammals. Developing an understanding of the dynamics and mechanisms by which cooperation operates is critical in understanding ecological and evolutionary relationships. Over the past decade, synthetic biology has emerged as a powerful tool to study social dynamics. By engineering rationally controlled and modulatable behavior into microbes, we have increased our overall understanding of how cooperation enhances, or conversely constrains, populations. Furthermore, it has increased our understanding of how cooperation is maintained within populations, which may provide a useful framework to influence populations by altering cooperation. As many bacterial pathogens require cooperation to infect the host and survive, the principles developed using synthetic biology offer promise of developing novel tools and strategies to treat infections, which may reduce the use of antimicrobial agents. Overall, the use of engineered cooperative microbes has allowed the field to verify existing, and develop novel, theories that may govern cooperative behaviors at all levels of biology.
synthetic biology / engineered bacteria / cooperation / cheater / quorum sensing
[1] |
Nowak M A. Five rules for the evolution of cooperation. Science, 2006, 314(5805): 1560–1563
CrossRef
Google scholar
|
[2] |
Axelrod R, Hamilton W D. The evolution of cooperation. Science, 1981, 211(4489): 1390–1396
CrossRef
Google scholar
|
[3] |
Fehr E, Fischbacher U. Social norms and human cooperation. Trends in Cognitive Sciences, 2004, 8(4): 185–190
CrossRef
Google scholar
|
[4] |
Shan W, Hamilton W. Country—specific advantage and international cooperation. Strategic Management Journal, 1991, 12(6): 419–432
CrossRef
Google scholar
|
[5] |
Hardin G. The tragedy of the commons. Science, 1968, 162(3859): 1243–1248
CrossRef
Google scholar
|
[6] |
Feeny D, Berkes F, McCay B J, Acheson J M. The tragedy of the commons: twenty-two years later. Human Ecology, 1990, 18(1): 1–19
CrossRef
Google scholar
|
[7] |
Hamilton W. The evolution of altruistic behavior. American Naturalist, 1963, 97(896): 354–356
CrossRef
Google scholar
|
[8] |
Eldakar O T, Wilson D S. Eight criticisms not to make about group selection. Evolution, 2011, 65(6): 1523–1526
CrossRef
Google scholar
|
[9] |
Wilson D S, Wilson E O. Rethinking the theoretical foundation of sociobiology. Quarterly Review of Biology, 2007, 82(4): 327–348
CrossRef
Google scholar
|
[10] |
Rapoport A, Chammah A M. Prisoner’s dilemma: A study in conflict and cooperation. Michigan: University of Michigan press, 1965: 31–44
|
[11] |
Doebeli M, Hauert C. Models of cooperation based on the Prisoner’s Dilemma and the Snowdrift game. Ecology Letters, 2005, 8(7): 748–766
CrossRef
Google scholar
|
[12] |
Allee W C. Cooperation among animals. American Journal of Sociology, 1951, 1: 93–95
|
[13] |
Seger J. Cooperation and conflict in social insects. Behavioural Ecology: An Evolutionary Approach, 1991, 338–373
|
[14] |
West S A, El Mouden C, Gardner A. Sixteen common misconceptions about the evolution of cooperation in humans. Evolution and Human Behavior, 2011, 32(4): 231–262
CrossRef
Google scholar
|
[15] |
Gintis H, Bowles S, Boyd R, Fehr E. Explaining altruistic behavior in humans. Evolution and Human Behavior, 2003, 24(3): 153–172
CrossRef
Google scholar
|
[16] |
Sober E, Wilson D S. Unto others: The evolution and psychology of unselfish behavior. Massachusetts: Harvard University Press, 1999, 6–14
|
[17] |
Tanouchi Y, Smith R, You L. Engineering microbial systems to explore ecological and evolutionary dynamics. Current Opinion in Biotechnology, 2012, 23(5): 791–797
CrossRef
Google scholar
|
[18] |
Benner S A, Sismour A M. Synthetic biology. Nature Reviews. Genetics, 2005, 6(7): 533–543
CrossRef
Google scholar
|
[19] |
Jusiak B, Daniel R, Farzadfard F, Nissim L, Purcell O, Rubens J, Lu T K. Synthetic gene circuits. Reviews in Cell Biology and Molecular Medicine, 2014, 1‒56
|
[20] |
Khalil A S, Collins J J. Synthetic biology: Applications come of age. Nature Reviews. Genetics, 2010, 11(5): 367–379
CrossRef
Google scholar
|
[21] |
Bracho O R, Manchery C, Haskell E C, Blanar C A, Smith R P. Circumvention of learning increases intoxication efficacy of nematicidal engineered bacteria. ACS Synthetic Biology, 2016, 5(3): 241–249
CrossRef
Google scholar
|
[22] |
Escalante A E, Rebolleda-Gómez M, Benítez M, Travisano M. Ecological perspectives on synthetic biology: Insights from microbial population biology. Frontiers in Microbiology, 2015, 6: 1–10
CrossRef
Google scholar
|
[23] |
Pianka E R. On r- and K-selection. American Naturalist, 1970, 104(940): 592–597
CrossRef
Google scholar
|
[24] |
Miller M B, Bassler B L. Quorum sensing in bacteria. Annual Review of Microbiology, 2001, 55(1): 165–199
CrossRef
Google scholar
|
[25] |
Berendsen R L, Pieterse C M, Bakker P A. The rhizosphere microbiome and plant health. Trends in Plant Science, 2012, 17(8): 478–486
CrossRef
Google scholar
|
[26] |
Antunes L C M, Ferreira R B R, Buckner M M C, Finlay B B. Quorum sensing in bacterial virulence. Microbiology, 2010, 156(8): 2271–2282
CrossRef
Google scholar
|
[27] |
De Kievit T R, Gillis R, Marx S, Brown C, Iglewski B H. Quorum-sensing genes in Pseudomonas aeruginosa biofilms: Their role and expression patterns. Applied and Environmental Microbiology, 2001, 67(4): 1865–1873
CrossRef
Google scholar
|
[28] |
De Kievit T R, Iglewski B H. Bacterial quorum sensing in pathogenic relationships. Infection and Immunity, 2000, 68(9): 4839–4849
CrossRef
Google scholar
|
[29] |
Stewart P S, Costerton J W. Antibiotic resistance of bacteria in biofilms. Lancet, 2001, 358(9276): 135–138
CrossRef
Google scholar
|
[30] |
Darch S E, West S A, Winzer K, Diggle S P. Density-dependent fitness benefits in quorum-sensing bacterial populations. Proceedings of the National Academy of Sciences, 2012: 8259–8263
|
[31] |
Pai A, Tanouchi Y, You L. Optimality and robustness in quorum sensing (QS)-mediated regulation of a costly public good enzyme. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109(48): 19810–19815
CrossRef
Google scholar
|
[32] |
An J H, Goo E, Kim H, Seo Y S, Hwang I. An J H, Goo E, Kim H, Seo Y-S, Hwang I. Bacterial quorum sensing and metabolic slowing in a cooperative population. Proceedings of the National Academy of Sciences of the United States of America, 2014, 111(41): 14912–14917
CrossRef
Google scholar
|
[33] |
Allee W, Emerson A, Park O, Park T, Schmidt K. Principles of Animal Ecology. Philadelphia, Pennsylvania, USA, 1949, 416–425
|
[34] |
Driscoll W W, Espinosa N J, Eldakar O T, Hackett J D. Allelopathy as an emergent, exploitable public good in the bloom-forming microalga Prymnesium parvum. Evolution, 2013, 67(6): 1582–1590
CrossRef
Google scholar
|
[35] |
Liebhold A M, Tobin P C. Exploiting the Achilles heels of pest invasions: Allee effects, stratified dispersal and management of forest insect establishment and spread. New Zealand Journal of Forestry Science, 2010, 40: S25–S33
|
[36] |
Robinet C, Lance D R, Thorpe K W, Onufrieva K S, Tobin P C, Liebhold A M. Dispersion in time and space affect mating success and Allee effects in invading gypsy moth populations. Journal of Animal Ecology, 2008, 77(5): 966–973
CrossRef
Google scholar
|
[37] |
Tobin P C, Berec L, Liebhold A M. Exploiting Allee effects for managing biological invasions. Ecology Letters, 2011, 14(6): 615–624
CrossRef
Google scholar
|
[38] |
Hackney E E, McGraw J B. Experimental demonstration of an Allee effect in American ginseng. Conservation Biology, 2001, 15(1): 129–136
CrossRef
Google scholar
|
[39] |
Smith R, Tan C, Srimani J, Pai A, Riccione K, Song H, You L. Programmed Allee effect results in a tradeoff between population spread and survival. Proceedings of the National Academy of Sciences of the United States of America, 2014, 111(5): 1969–1974
CrossRef
Google scholar
|
[40] |
Myers R A, Hutchings J A, Barrowman N J. Why do fish stocks collapse? The example of cod in Atlantic Canada. Ecological Applications, 1997, 7(1): 91–106
CrossRef
Google scholar
|
[41] |
Myers R, Barrowman N, Hutchings J, Rosenberg A. Population dynamics of exploited fish stocks at low population levels. Science, 1995, 269(5227): 1106–1108
CrossRef
Google scholar
|
[42] |
Dai L, Vorselen D, Korolev K S, Gore J. Generic indicators for loss of resilience before a tipping point leading to population collapse. Science, 2012, 336(6085): 1175–1177
CrossRef
Google scholar
|
[43] |
Dai L, Korolev K S, Gore J. Relation between stability and resilience determines the performance of early warning signals under different environmental drivers. Proceedings of the National Academy of Sciences of the United States of America, 2015, 112(32): 10056–10061
CrossRef
Google scholar
|
[44] |
Liebhold A M, Tobin P C. Population ecology of insect invasions and their management. Annual Review of Entomology, 2008, 53(1): 387–408
CrossRef
Google scholar
|
[45] |
Visick K L, Foster J, Doino J, McFall-Ngai M, Ruby E G. Vibrio fischeri lux genes play an important role in colonization and development of the host light organ. Journal of Bacteriology, 2000, 182(16): 4578–4586
CrossRef
Google scholar
|
[46] |
Bahassi E M, O’Dea M H, Allali N, Messens J, Gellert M, Couturier M. Interactions of CcdB with DNA gyrase. Journal of Biological Chemistry, 1999, 274(16): 10936–10944
CrossRef
Google scholar
|
[47] |
Dai L, Korolev K S, Gore J. Slower recovery in space before collapse of connected populations. Nature, 2013, 496(7445): 355–358
CrossRef
Google scholar
|
[48] |
Ratzke C, Gore J. Self-organized patchiness facilitates survival in a cooperatively growing Bacillus subtilis population. Nature Microbiology, 2016: 16022
|
[49] |
Wong C M, Zhou Y, Ng R W, Kung H F, Jin D Y. Cooperation of yeast peroxiredoxins Tsa1p and Tsa2p in the cellular defense against oxidative and nitrosative stress. Journal of Biological Chemistry, 2002, 277(7): 5385–5394
CrossRef
Google scholar
|
[50] |
Boulant J A. Hypothalamic mechanisms in thermoregulation. Federation Proceedings, 1981, 40(14): 2843-50
|
[51] |
Stephens P A, Frey-Roos F, Arnold W, Sutherland W J. Model complexity and population predictions. The alpine marmot as a case study. Journal of Animal Ecology, 2002, 71(2): 343–361
CrossRef
Google scholar
|
[52] |
Liermann H, Hilborn. Depensation: Evidence, models and implications. Fish and Fisheries, 2001, 2(1): 33–58
CrossRef
Google scholar
|
[53] |
Aizenman E, Engelberg-Kulka H, Glaser G. An Escherichia coli chromosomal “addiction module” regulated by guanosine 3',5'-bispyrophosphate: A model for programmed bacterial cell death. Proceedings of the National Academy of Sciences of the United States of America, 1996, 93(12): 6059–6063
CrossRef
Google scholar
|
[54] |
Misselwitz B, Barrett N, Kreibich S, Vonaesch P, Andritschke D, Rout S, Weidner K, Sormaz M, Songhet P, Horvath P, Chabria M, Vogel V, Spori D M, Jenny P, Hardt W D. Near surface swimming of Salmonella typhimurium explains target-site selection and cooperative invasion. PLoS Pathogens, 2012, 8(7): e1002810
CrossRef
Google scholar
|
[55] |
Tan C, Smith R P, Srimani J, Riccione K, Prasada S, Kuehn M, You L. The inoculum effect and band-pass bacterial response to periodic antibiotic treatment. Molecular Systems Biology, 2012, 8(1): 679–688
|
[56] |
Lee H H, Molla M N, Cantor C R, Collins J J. Bacterial charity work leads to population-wide resistance. Nature, 2010, 467(7311): 82–85
CrossRef
Google scholar
|
[57] |
Vega N M, Allison K R, Samuels A N, Klempner M S, Collins J J. Salmonella typhimurium intercepts Escherichia coli signaling to enhance antibiotic tolerance. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(35): 14420–14425
CrossRef
Google scholar
|
[58] |
Meredith H R, Srimani J K, Lee A J, Lopatkin A J, You L. Collective antibiotic tolerance: Mechanisms, dynamics and intervention. Nature Chemical Biology, 2015, 11(3): 182–188
CrossRef
Google scholar
|
[59] |
Nedelcu A M, Driscoll W W, Durand P M, Herron M D, Rashidi A. On the paradigm of altruistic suicide in the unicellular world. Evolution, 2011, 65(1): 3–20
CrossRef
Google scholar
|
[60] |
Ackermann M, Stecher B, Freed N E, Songhet P, Hardt W D, Doebeli M. Self-destructive cooperation mediated by phenotypic noise. Nature, 2008, 454(7207): 987–990
CrossRef
Google scholar
|
[61] |
Rice K C, Bayles K W. Death’s toolbox: Examining the molecular components of bacterial programmed cell death. Molecular Microbiology, 2003, 50(3): 729–738
CrossRef
Google scholar
|
[62] |
Ameisen J C. The origin of programmed cell death. Science, 1996, 272(5266): 1278–1279
CrossRef
Google scholar
|
[63] |
Brown S P, West S A, Diggle S P, Griffin A S. Social evolution in micro-organisms and a Trojan horse approach to medical intervention strategies. Philosophical Transactions of the Royal Society of London B: Biological Sciences, 2009, 364(1533): 3157–3168
|
[64] |
Moran N A, Degnan P H, Santos S R, Dunbar H E, Ochman H. The players in a mutualistic symbiosis: Insects, bacteria, viruses, and virulence genes. Proceedings of the National Academy of Sciences of the United States of America, 2005, 102(47): 16919–16926
CrossRef
Google scholar
|
[65] |
Breznak J A. Symbiotic relationships between termites and their intestinal microbiota. Symposia of the Society for Experimental Biology, 1975, 29: 559–580
|
[66] |
Glaser R. The intracellular bacteria of the cockroach in relation to symbiosis. Journal of Parasitology, 1946, 32(5): 483–489
CrossRef
Google scholar
|
[67] |
Uhlig H H, Powrie F. Dendritic cells and the intestinal bacterial flora: a role for localized mucosal immune responses. Journal of Clinical Investigation, 2003, 112(5): 648–651
CrossRef
Google scholar
|
[68] |
Wintermute E H, Silver P A. Dynamics in the mixed microbial concourse. Genes & Development, 2010, 24(23): 2603–2614
CrossRef
Google scholar
|
[69] |
Wintermute E H, Silver P A. Emergent cooperation in microbial metabolism. Molecular Systems Biology, 2010, 6(1): 820–833
|
[70] |
Shou W, Ram S, Vilar J M G. Synthetic cooperation in engineered yeast populations. Proceedings of the National Academy of Sciences of the United States of America, 2007, 104(6): 1877–1882
CrossRef
Google scholar
|
[71] |
Brenner K, Karig D K, Weiss R, Arnold F H. Engineered bidirectional communication mediates a consensus in a microbial biofilm consortium. Proceedings of the National Academy of Sciences of the United States of America, 2007, 104(44): 17300–17304
CrossRef
Google scholar
|
[72] |
Brenner K, You L, Arnold F H. Engineering microbial consortia: A new frontier in synthetic biology. Trends in Biotechnology, 2008, 26(9): 483–489
CrossRef
Google scholar
|
[73] |
Hu B, Du J, Zou R Y, Yuan Y J. An environment-sensitive synthetic microbial ecosystem. PLoS One, 2010, 5(5): e10619
CrossRef
Google scholar
|
[74] |
Kerner A, Park J, Williams A, Lin X N. A programmable Escherichia coli consortium via tunable symbiosis. PLoS One, 2012, 7(3): e34032
CrossRef
Google scholar
|
[75] |
Mee M T, Collins J J, Church G M, Wang H H. Syntrophic exchange in synthetic microbial communities. Proceedings of the National Academy of Sciences of the United States of America, 2014, 111(20): 2149–2156
CrossRef
Google scholar
|
[76] |
Berryman A A. The orgins and evolution of predator-prey theory. Ecology, 1992, 73(5): 1530–1535
CrossRef
Google scholar
|
[77] |
Balagadde F K, Song H, Ozaki J, Collins C H, Barnet M, Arnold F H, Quake S R, You L. A synthetic Escherichia coli predator-prey ecosystem. Molecular Systems Biology, 2008, 4: 187
CrossRef
Google scholar
|
[78] |
Wangersky P J. Lotka-Volterra population models. Annual Review of Ecology and Systematics, 1978, 9(1): 189–218
CrossRef
Google scholar
|
[79] |
Sun G Q, Jin Z, Liu Q X, Li L. Dynamical complexity of a spatial predator-prey model with migration. Ecological Modelling, 2008, 219(1-2): 248–255
CrossRef
Google scholar
|
[80] |
Yuan S, Xu C, Zhang T. Spatial dynamics in a predator-prey model with herd behavior. Chaos (Woodbury, N.Y.), 2013, 23(3): 033102
CrossRef
Google scholar
|
[81] |
Song H, Payne S, Gray M, You L. Spatiotemporal modulation of biodiversity in a synthetic chemical-mediated ecosystem. Nature Chemical Biology, 2009, 5(12): 929–935
CrossRef
Google scholar
|
[82] |
Yamamura N, Higashi M, Behera N, Yuichiro Wakano J. Evolution of mutualism through spatial effects. Journal of Theoretical Biology, 2004, 226(4): 421–428
CrossRef
Google scholar
|
[83] |
Poisot T, Bever J D, Thrall P H, Hochberg M E. Dispersal and spatial heterogeneity allow coexistence between enemies and protective mutualists. Ecology and Evolution, 2014, 4(19): 3841–3850
CrossRef
Google scholar
|
[84] |
Park J, Kerner A, Burns M A, Lin X N. Microdroplet-enabled highly parallel co-cultivation of microbial communities. PLoS One, 2011, 6(2): e17019
CrossRef
Google scholar
|
[85] |
Wilson W, Morris W, Bronstein J. Coexistence of mutualists and exploiters on spatial landscapes. Ecological Monographs, 2003, 73(3): 397–413
CrossRef
Google scholar
|
[86] |
Brenner K, Arnold F H. Self-organization, layered structure, and aggregation enhance persistence of a synthetic biofilm consortium. PLoS One, 2011, 6(2): e16791
CrossRef
Google scholar
|
[87] |
Chuang J S, Rivoire O, Leibler S. Cooperation and Hamilton’s rule in a simple synthetic microbial system. Molecular Systems Biology, 2010, 6: 398
CrossRef
Google scholar
|
[88] |
Chuang J S, Rivoire O, Leibler S. Simpson’s paradox in a synthetic microbial system. Science, 2009, 323(5911): 272–275
CrossRef
Google scholar
|
[89] |
Gore J, Youk H, van Oudenaarden A. Snowdrift game dynamics and facultative cheating in yeast. Nature, 2009, 459(7244): 253–256
CrossRef
Google scholar
|
[90] |
Griffin A S, West S A, Buckling A. Cooperation and competition in pathogenic bacteria. Nature, 2004, 430(7003): 1024–1027
CrossRef
Google scholar
|
[91] |
West S A, Pen I, Griffin A S. Cooperation and competition between relatives. Science, 2002, 296(5565): 72–75
CrossRef
Google scholar
|
[92] |
Celiker H, Gore J. Competition between species can stabilize public—goods cooperation within a species. Molecular Systems Biology, 2012, 8(1): 621
|
[93] |
Bergstrom T, Blume L, Varian H. On the private provision of public goods. Journal of Public Economics, 1986, 29(1): 25–49
CrossRef
Google scholar
|
[94] |
Driscoll W W, Pepper J W. Theory for the evolution of diffusible external goods. Evolution, 2010, 64(9): 2682–2687
CrossRef
Google scholar
|
[95] |
Zhang F, Kwan A, Xu A, Süel G M. A synthetic quorum sensing system reveals a potential private benefit for public good production in a biofilm. PLoS One, 2015, 10(7): e0132948
CrossRef
Google scholar
|
[96] |
Waite A J, Shou W. Adaptation to a new environment allows cooperators to purge cheaters stochastically. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109(47): 19079–19086
CrossRef
Google scholar
|
[97] |
Chen A, Sanchez A, Dai L, Gore J. Dynamics of a producer-freeloader ecosystem on the brink of collapse. Nature Communications, 2014, 5: 3713
|
[98] |
Venturi V, Bertani I, Kerényi Á, Netotea S, Pongor S. Co-swarming and local collapse: Quorum sensing conveys resilience to bacterial communities by localizing cheater mutants in Pseudomonas aeruginosa. PLoS One, 2010, 5(4): e9998
CrossRef
Google scholar
|
[99] |
Bihary D, Tóth M, Kerényi Á, Venturi V, Pongor S. Modeling bacterial quorum sensing in open and closed environments: potential discrepancies between agar plate and culture flask experiments. Journal of Molecular Modeling, 2014, 20(7): 1–6
CrossRef
Google scholar
|
[100] |
Pepper J W. The evolution of bacterial social life: From the ivory tower to the front lines of public health. Evolution, Medicine, and Public Health, 2014, 2014(1): 65–68
CrossRef
Google scholar
|
[101] |
Ross-Gillespie A, Weigert M, Brown S P, Kümmerli R. Gallium-mediated siderophore quenching as an evolutionarily robust antibacterial treatment. Evolution, Medicine, and Public Health, 2014, 2014(1): 18–29
CrossRef
Google scholar
|
[102] |
Hood M I, Skaar E P. Nutritional immunity: Transition metals at the pathogen-host interface. Nature Reviews. Microbiology, 2012, 10(8): 525–537
CrossRef
Google scholar
|
[103] |
Skaar E P. The battle for iron between bacterial pathogens and their vertebrate hosts. PLoS Pathogens, 2010, 6(8): e1000949
CrossRef
Google scholar
|
[104] |
Köhler T, Buckling A, van Delden C. Cooperation and virulence of clinical Pseudomonas aeruginosa populations. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(15): 6339–6344
CrossRef
Google scholar
|
[105] |
Merlo L M F, Pepper J W, Reid B J, Maley C C. Cancer as an evolutionary and ecological process. Nature Reviews. Cancer, 2006, 6(12): 924–935
CrossRef
Google scholar
|
[106] |
Pepper J W. Defeating pathogen drug resistance: Guidance from evolutionary theory. Evolution, 2008, 62(12): 3185–3191
CrossRef
Google scholar
|
[107] |
Boehm T, Folkman J, Browder T, O’Reilly M S. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature, 1997, 390(6658): 404–407
CrossRef
Google scholar
|
[108] |
Folkman J. Angiogenesis. Annual Review of Medicine, 2006, 57: 1–18
CrossRef
Google scholar
|
[109] |
Duan F, March J C. Engineered bacterial communication prevents Vibrio cholerae virulence in an infant mouse model. Proceedings of the National Academy of Sciences of the United States of America, 2010, 107(25): 11260–11264
CrossRef
Google scholar
|
[110] |
Saeidi N, Wong C K, Lo T M, Nguyen H X, Ling H, Leong S S J, Poh C L, Chang M W. Engineering microbes to sense and eradicate Pseudomonas aeruginosa, a human pathogen. Molecular Systems Biology, 2011, 7(1): 521
CrossRef
Google scholar
|
/
〈 | 〉 |