Systems and synthetic biology approaches in understanding biological oscillators

Abstract

Background: Self-sustained oscillations are a ubiquitous and vital phenomenon in living systems. From primitive single-cellular bacteria to the most sophisticated organisms, periodicities have been observed in a broad spectrum of biological processes such as neuron firing, heart beats, cell cycles, circadian rhythms, etc. Defects in these oscillators can cause diseases from insomnia to cancer. Elucidating their fundamental mechanisms is of great significance to diseases, and yet challenging, due to the complexity and diversity of these oscillators.

Results: Approaches in quantitative systems biology and synthetic biology have been most effective by simplifying the systems to contain only the most essential regulators. Here, we will review major progress that has been made in understanding biological oscillators using these approaches. The quantitative systems biology approach allows for identification of the essential components of an oscillator in an endogenous system. The synthetic biology approach makes use of the knowledge to design the simplest, de novo oscillators in both live cells and cell-free systems. These synthetic oscillators are tractable to further detailed analysis and manipulations.

Conclusion: With the recent development of biological and computational tools, both approaches have made significant achievements.

Graphical abstract

Keywords

biological oscillators / synthetic oscillators / circuit design principles

References

[1] Yang, Q. and Ferrell, J. E. Jr. (2013) The Cdk1-APC/C cell cycle oscillator circuit functions as a time-delayed, ultrasensitive switch. Nat. Cell Biol., 15, 519–525

[2] Ferrell, J. E. Jr, Tsai, T. Y. and Yang, Q. (2011) Modeling the cell cycle: why do certain circuits oscillate? Cell, 144, 874–885

[3] Periasamy, M., Bhupathy, P. and Babu, G. J. (2008) Regulation of sarcoplasmic reticulum Ca²⁺ ATPase pump expression and its relevance to cardiac muscle physiology and pathology. Cardiovasc. Res., 77, 265–273

[4] Liu, N. and Priori, S. G. (2008) Disruption of calcium homeostasis and arrhythmogenesis induced by mutations in the cardiac ryanodine receptor and calsequestrin. Cardiovasc. Res., 77, 293–301

[5] Bénazéraf, B. and Pourquié, O. (2013) Formation and segmentation of the vertebrate body axis. Annu. Rev. Cell Dev. Biol., 29, 1–26

[6] Mara, A. and Holley, S. A. (2007) Oscillators and the emergence of tissue organization during zebrafish somitogenesis. Trends Cell Biol., 17, 593–599

[7] Bell-Pedersen, D., Cassone, V. M., Earnest, D. J., Golden, S. S., Hardin, P. E., Thomas, T. L. and Zoran, M. J. (2005) Circadian rhythms from multiple oscillators: lessons from diverse organisms. Nat. Rev. Genet., 6, 544–556

[8] Hodgkin, A. L. and Huxley, A. F. (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol., 117, 500–544

[9] Tomida, T., Takekawa, M. and Saito, H. (2015) Oscillation of p38 activity controls efficient pro-inflammatory gene expression. Nat. Commun., 6, 8350

[10] Zambrano, S., De Toma, I., Piffer, A., Bianchi, M. E. and Agresti, A. (2016) NF-κB oscillations translate into functionally related patterns of gene expression. eLife, 5, e09100

[11] Batchelor, E., Loewer, A., Mock, C. and Lahav, G. (2011) Stimulus-dependent dynamics of p53 in single cells. Mol. Syst. Biol., 7, 488

[12] Dunlap, J. C. (1999) Molecular bases for circadian clocks. Cell, 96, 271–290

[13] Gallego, M. and Virshup, D. M. (2007) Post-translational modifications regulate the ticking of the circadian clock. Nat. Rev. Mol. Cell Biol., 8, 139–148

[14] Brown, H., Difrancesco, D. and Noble, S. (1979) Cardiac pacemaker oscillation and its modulation by autonomic transmitters. J. Exp. Biol., 81, 175–204

[15] Paydarfar, D. and Eldridge, F. L. (1987) Phase resetting and dysrhythmic responses of the respiratory oscillator. Am. J. Physiol., 252, R55–R62

[16] Hartwell, L. H. and Kastan, M. B. (1994) Cell cycle control and cancer. Science, 266, 1821–1828

[17] McDonald, E. R. 3rd and El-Deiry, W. S. (2000) Cell cycle control as a basis for cancer drug development (Review). Int. J. Oncol., 16, 871–957

[18] Kastan, M. B. and Bartek, J. (2004) Cell-cycle checkpoints and cancer. Nature, 432, 316–323

[19] Gelens, L., Anderson, G. A. and Ferrell, J. E. Jr. (2014) Spatial trigger waves: positive feedback gets you a long way. Mol. Biol. Cell, 25, 3486–3493

[20] Novák, B. and Bentrup, F. W. (1972) An electrophysiological study of regeneration in Acetabularia mediterranea. Planta, 108, 227–244

[21] Gerisch, G. (1968) Cell aggregation and differentiation in Dictyostelium. Curr. Top. Dev. Biol., 3, 157–197

[22] Chang, J. B. and Ferrell, J. E. Jr. (2013) Mitotic trigger waves and the spatial coordination of the Xenopus cell cycle. Nature, 500, 603–607

[23] Goodwin, B. C. and Cohen, M. H. (1969) A phase-shift model for the spatial and temporal organization of developing systems. J. Theor. Biol., 25, 49–107

[24] Oates, A. C., Morelli, L. G. and Ares, S. (2012) Patterning embryos with oscillations: structure, function and dynamics of the vertebrate segmentation clock. Development, 139, 625–639

[25] Purvis, J. E., Karhohs, K. W., Mock, C., Batchelor, E., Loewer, A. and Lahav, G. (2012) p53 dynamics control cell fate. Science, 336, 1440–1444

[26] Isomura, A. and Kageyama, R. (2014) Ultradian oscillations and pulses: coordinating cellular responses and cell fate decisions. Development, 141, 3627–3636

[27] Ainsworth, M., Lee, S., Cunningham, M. O., Traub, R. D., Kopell, N. J. and Whittington, M. A. (2012) Rates and rhythms: a synergistic view of frequency and temporal coding in neuronal networks. Neuron, 75, 572–583

[28] Nelson, D. E., Ihekwaba, A. E., Elliott, M., Johnson, J. R., Gibney, C. A., Foreman, B. E., Nelson, G., See, V., Horton, C. A., Spiller, D. G., (2004) Oscillations in NF-κB signaling control the dynamics of gene expression. Science, 306, 704–708

[29] Proctor, C. J. and Gray, D. A. (2008) Explaining oscillations and variability in the p53-Mdm2 system. BMC Syst. Biol., 2, 75

[30] Salazar, C., Politi, A. Z. and Höfer, T. (2008) Decoding of calcium oscillations by phosphorylation cycles: analytic results. Biophys. J., 94, 1203–1215

[31] Cai, L., Dalal, C. K. and Elowitz, M. B. (2008) Frequency-modulated nuclear localization bursts coordinate gene regulation. Nature, 455, 485–490

[32] Hodgkin, A. L., Huxley, A. F. and Katz, B. (1952) Measurement of current-voltage relations in the membrane of the giant axon of Loligo. J. Physiol., 116, 424–448

[33] Hodgkin, A. L. and Katz, B. (1949) The effect of temperature on the electrical activity of the giant axon of the squid. J. Physiol., 109, 240–249

[34] Hodgkin, A. L. and Huxley, A. F. (1952) The dual effect of membrane potential on sodium conductance in the giant axon of Loligo. J. Physiol., 116, 497–506

[35] Hodgkin, A. L. and Huxley, A. F. (1952) The components of membrane conductance in the giant axon of Loligo. J. Physiol., 116, 473–496

[36] Hodgkin, A. L. and Huxley, A. F. (1952) Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J. Physiol., 116, 449–472

[37] Ghosh, A. and Chance, B. (1964) Oscillations of glycolytic intermediates in yeast cells. Biochem. Biophys. Res. Commun., 16, 174–181

[38] Chance, B., Hess, B. and Betz, A. (1964) DPNH oscillations in a cell-free extract of S. carlsbergensis. Biochem. Biophys. Res. Commun., 16, 182–187

[39] Chance, B., Schoener, B. and Elsaesser, S. (1965) Metabolic control phenomena involved in damped sinusoidal oscillations of reduced diphosphopyridine nucleotide in a cell-free extract of Saccharomyces carlsbergensis. J. Biol. Chem., 240, 3170–3181

[40] Higgins, J. (1964) A chemical mechanism for oscillation of glycolytic intermediates in yeast cells. Proc. Natl. Acad. Sci. USA, 51, 989–994

[41] Pye, K. and Chance, B. (1966) Sustained sinusoidal oscillations of reduced pyridine nucleotide in a cell-free extract of Saccharomyces carlsbergensis. Proc. Natl. Acad. Sci. USA, 55, 888–894

[42] Gerisch, G., Fromm, H., Huesgen, A. and Wick, U. (1975) Control of cell-contact sites by cyclic AMP pulses in differentiating Dictyostelium cells. Nature, 255, 547–549

[43] Olsen, L. F. and Degn, H. (1978) Oscillatory kinetics of the peroxidase-oxidase reaction in an open system. Experimental and theoretical studies. Biochim. Biophys. Acta, 523, 321–334

[44] Goodwin, B. C. (1963) Temporal Organization in Cells. In A Dynamic Theory of Cellular Control Processes. New York: Academic Press

[45] Liu, Y., Tsinoremas, N. F., Johnson, C. H., Lebedeva, N. V., Golden, S. S., Ishiura, M. and Kondo, T. (1995) Circadian orchestration of gene expression in cyanobacteria. Genes Dev., 9, 1469–1478

[46] Crosthwaite, S. K., Dunlap, J. C. and Loros, J. J. (1997) Neurospora wc-1 and wc-2: transcription, photoresponses, and the origins of circadian rhythmicity. Science, 276, 763–769

[47] Hamblen, M. J., White, N. E., Emery, P. T. J., Kaiser, K. and Hall, J. C. (1998) Molecular and behavioral analysis of four period mutants in Drosophila melanogaster encompassing extreme short, novel long, and unorthodox arrhythmic types. Genetics, 149, 165–178

[48] Antoch, M. P., Song, E. J., Chang, A. M., Vitaterna, M. H., Zhao, Y., Wilsbacher, L. D., Sangoram, A. M., King, D. P., Pinto, L. H. and Takahashi, J. S. (1997) Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell, 89, 655–667

[49] Millar, A.J. and Kay, S. A. (1997) The genetics of phototransduction and circadian rhythms in Arabidopsis. BioEssays, 19, 209–214

[50] Goldbeter, A. (1996) Biochemical Oscillations and Cellular Rhythms: The Molecular Bases of Periodic and Chaotic Behaviour. In Physics Today. New York: Cambridge University Press

[51] Goldbeter, A. (2007) Biological Rhythms as Temporal Dissipative Structures. Special Volume in Memory of Ilya Prigogine: Advances in Chemical Physics. pp. 253–295. New York: John Wiley & Sons, Inc.

[52] Yang, Q., Pando, B. F., Dong, G., Golden, S. S. and van Oudenaarden, A. (2010) Circadian gating of the cell cycle revealed in single cyanobacterial cells. Science, 327, 1522–1526

[53] Bieler, J., Cannavo, R., Gustafson, K., Gobet, C., Gatfield, D. and Naef, F. (2014) Robust synchronization of coupled circadian and cell cycle oscillators in single mammalian cells. Mol. Syst. Biol., 10, 739

[54] Feillet, C., van der Horst, G. T., Levi, F., Rand, D. A. and Delaunay, F. (2015) Coupling between the circadian clock and cell cycle oscillators: implication for healthy cells and malignant growth. Front. Neurol., 6, 96

[55] Sevim, V., Gong, X. and Socolar, J. E. S. (2010) Reliability of transcriptional cycles and the yeast cell-cycle oscillator. PLoS Comput. Biol., 6, e1000842

[56] Longtin, A. (1993) Stochastic resonance in neuron models. J. Stat. Phys., 70, 309–327

[57] Glass, L. (2001) Synchronization and rhythmic processes in physiology. Nature, 410, 277–284

[58] Prigogine, I., Lefever, R., Goldbeter, A. and Herschkowitz-Kaufman, M. (1969) Symmetry breaking instabilities in biological systems. Nature, 223, 913–916

[59] FitzHugh, R. (1961) Impulses and physiological states in theoretical models of nerve membrane. Biophys. J., 1, 445–466

[60] Morris, C. and Lecar, H. (1981) Voltage oscillations in the barnacle giant muscle fiber. Biophys. J., 35, 193–213

[61] Goodwin, B. C. (1965) Oscillatory behavior in enzymatic control processes. Adv. Enzyme Regul., 3, 425–428

[62] Friesen, W. O. and Block, G. D. (1984) What is a biological oscillator? Am. J. Physiol., 246, R847–R853

[63] Barkai, N. and Leibler, S. (2000) Circadian clocks limited by noise. Nature, 403, 267–268

[64] Novák, B. and Tyson, J. J. (2008) Design principles of biochemical oscillators. Nat. Rev. Mol. Cell Biol., 9, 981–991

[65] Tsai, T. Y., Choi, Y. S., Ma, W., Pomerening, J. R., Tang, C. and Ferrell, J. E. Jr. (2008) Robust, tunable biological oscillations from interlinked positive and negative feedback loops. Science, 321, 126–129

[66] Elowitz, M. B. and Leibler, S. (2000) A synthetic oscillatory network of transcriptional regulators. Nature, 403, 335–338

[67] Atkinson, M. R., Savageau, M. A., Myers, J. T. and Ninfa, A. J. (2003) Development of genetic circuitry exhibiting toggle switch or oscillatory behavior in Escherichia coli. Cell, 113, 597–607

[68] Stricker, J., Cookson, S., Bennett, M. R., Mather, W. H., Tsimring, L. S. and Hasty, J. (2008) A fast, robust and tunable synthetic gene oscillator. Nature, 456, 516–519

[69] Fung, E., Wong, W. W., Suen, J. K., Bulter, T. , Lee, S. G. and Liao, J. C. (2005) A synthetic gene-metabolic oscillator. Nature, 435, 118–122

[70] Tigges, M., Marquez-Lago, T. T., Stelling, J. and Fussenegger, M. (2009) A tunable synthetic mammalian oscillator. Nature, 457, 309–312

[71] Tigges, M., Dénervaud, N., Greber, D., Stelling, J. and Fussenegger, M. (2010) A synthetic low-frequency mammalian oscillator. Nucleic Acids Res., 38, 2702–2711

[72] Mondragón-Palomino, O., Danino, T., Selimkhanov, J., Tsimring, L. and Hasty, J. (2011) Entrainment of a population of synthetic genetic oscillators. Science, 333, 1315–1319

[73] Butzin, N. C., Hochendoner, P., Ogle, C. T., Hill, P. and Mather, W. H. (2016) Marching along to an offbeat drum: entrainment of synthetic gene oscillators by a noisy stimulus. ACS Synth. Biol., 5, 146–153

[74] Hussain, F., Gupta, C., Hirning, A. J., Ott, W., Matthews, K. S., Josic, K. and Bennett, M. R. (2014) Engineered temperature compensation in a synthetic genetic clock. Proc. Natl. Acad. Sci. USA, 111, 972–977

[75] Potvin-Trottier, L., Lord, N. D., Vinnicombe, G. and Paulsson, J. (2016) Synchronous long-term oscillations in a synthetic gene circuit. Nature, 538, 514–517

[76] Danino, T., Mondragón-Palomino, O., Tsimring, L. and Hasty, J. (2010) A synchronized quorum of genetic clocks. Nature, 463, 326–330

[77] Chen, Y., Kim, J. K., Hirning, A. J., Josić, K. and Bennett, M. R. (2015) Emergent genetic oscillations in a synthetic microbial consortium. Science, 349, 986–989

[78] Toettcher, J. E., Mock, C., Batchelor, E., Loewer, A. and Lahav, G. (2010) A synthetic-natural hybrid oscillator in human cells. Proc. Natl. Acad. Sci. USA, 107, 17047–17052

[79] Niederholtmeyer, H., Sun, Z. Z., Hori, Y., Yeung, E., Verpoorte, A., Murray, R. M. and Maerkl, S. J. (2015) Rapid cell-free forward engineering of novel genetic ring oscillators. eLife, 4, e09771

[80] Purcell, O., Savery, N. J., Grierson, C. S. and di Bernardo, M. (2010) A comparative analysis of synthetic genetic oscillators. J. R. Soc. Interface, 7, 1503–1524

[81] Prindle, A., Samayoa, P., Razinkov, I., Danino, T., Tsimring, L. S. and Hasty, J. (2011) A sensing array of radically coupled genetic “biopixels”. Nature, 481, 39–44

[82] Scott, S. R. and Hasty, J. (2016) Quorum sensing communication modules for microbial consortia. ACS Synth. Biol., 5, 969–977

[83] Marguet, P., Tanouchi, Y., Spitz, E., Smith, C. and You, L. (2010) Oscillations by minimal bacterial suicide circuits reveal hidden facets of host-circuit physiology. PLoS One, 5, e11909

[84] Dies, M., Galera-Laporta, L. and Garcia-Ojalvo, J. (2016) Mutual regulation causes co-entrainment between a synthetic oscillator and the bacterial cell cycle. Integr. Biol., 8, 533–541

[85] Chen, A. H., Lubkowicz, D., Yeong, V., Chang, R. L. and Silver, P. A. (2015) Transplantability of a circadian clock to a noncircadian organism. Sci. Adv., 1, e1500358

[86] Din, M. O., Danino, T., Prindle, A., Skalak, M., Selimkhanov, J., Allen, K., Julio, E., Atolia, E., Tsimring, L. S., Bhatia, S. N., (2016) Synchronized cycles of bacterial lysis for in vivo delivery. Nature, 536, 81–85

[87] Murray, A. W., Solomon, M. J. and Kirschner, M. W. (1989) The role of cyclin synthesis and degradation in the control of maturation promoting factor activity. Nature, 339, 280–286

[88] Murray, A. W. (1991) Cell cycle extracts. Methods Cell Biol., 36, 581–605

[89] Heald, R., Tournebize, R., Habermann, A., Karsenti, E. and Hyman, A. (1997) Spindle assembly in Xenopus egg extracts: respective roles of centrosomes and microtubule self-organization. J. Cell Biol., 138, 615–628

[90] Kim, S. Y. and Ferrell, J. E. Jr. (2007) Substrate competition as a source of ultrasensitivity in the inactivation of Wee1. Cell, 128, 1133–1145

[91] Pomerening, J. R., Kim, S. Y. and Ferrell, J. E. Jr. (2005) Systems-level dissection of the cell-cycle oscillator: bypassing positive feedback produces damped oscillations. Cell, 122, 565–578

[92] Trunnell, N. B., Poon, A. C., Kim, S. Y. and Ferrell, J. E. Jr. (2011) Ultrasensitivity in the regulation of Cdc25C by Cdk1. Mol. Cell, 41, 263–274

[93] Lohka, M. J. and Maller, J. L. (1985) Induction of nuclear envelope breakdown, chromosome condensation, and spindle formation in cell-free extracts. J. Cell Biol., 101, 518–523

[94] Lohka, M. J., Hayes, M. K. and Maller, J. L. (1988) Purification of maturation-promoting factor, an intracellular regulator of early mitotic events. Proc. Natl. Acad. Sci. USA, 85, 3009–3013

[95] Sudakin, V., Ganoth, D., Dahan, A., Heller, H., Hershko, J., Luca, F. C., Ruderman, J. V. and Hershko, A. (1995) The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis. Mol. Biol. Cell, 6, 185–197

[96] Kumagai, A. and Dunphy, W. G. (1992) Regulation of the cdc25 protein during the cell cycle in Xenopus extracts. Cell, 70, 139–151

[97] Mueller, P. R., Coleman, T. R. and Dunphy, W. G. (1995) Cell cycle regulation of a Xenopus Wee1-like kinase. Mol. Biol. Cell, 6, 119–134

[98] Novak, B. and Tyson, J. J. (1993) Numerical analysis of a comprehensive model of M-phase control in Xenopus oocyte extracts and intact embryos. J. Cell. Sci., 106, 1153–1168

[99] Thron, C. D. (1996) A model for a bistable biochemical trigger of mitosis. Biophys. Chem., 57, 239–251

[100] Pomerening, J. R., Sontag, E. D. and Ferrell, J. E. Jr. (2003) Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2. Nat. Cell Biol., 5, 346–351

[101] Ferrell, J. E. Jr. (2008) Feedback regulation of opposing enzymes generates robust, all-or-none bistable responses. Curr. Biol., 18, R244–R245

[102] Nakajima, M., Imai, K., Ito, H., Nishiwaki, T., Murayama, Y., Iwasaki, H., Oyama, T. and Kondo, T. (2005) Reconstitution of circadian oscillation of cyanobacterial KaiC phosphorylation in vitro. Science, 308, 414–415

[103] Rust, M. J., Markson, J. S., Lane, W. S., Fisher, D. S. and O’Shea, E. K. (2007) Ordered phosphorylation governs oscillation of a three-protein circadian clock. Science, 318, 809–812

[104] Forster, A. C. and Church, G. M. (2007) Synthetic biology projects in vitro. Genome Res., 17, 1–6

[105] Nakano, M., Komatsu, J., Matsuura, S., Takashima, K., Katsura, S. and Mizuno, A. (2003) Single-molecule PCR using water-in-oil emulsion. J. Biotechnol., 102, 117–124

[106] Tan, C., Saurabh, S., Bruchez, M. P., Schwartz, R. and Leduc, P. (2013) Molecular crowding shapes gene expression in synthetic cellular nanosystems. Nat. Nanotechnol., 8, 602–608

[107] Shin, J. and Noireaux, V. (2012) An E. coli cell-free expression toolbox: application to synthetic gene circuits and artificial cells. ACS Synth. Biol., 1, 29–41

[108] Noireaux, V. and Libchaber, A. (2004) A vesicle bioreactor as a step toward an artificial cell assembly. Proc. Natl. Acad. Sci. USA, 101, 17669–17674

[109] Kim, J., White, K. S. and Winfree, E. (2006) Construction of an in vitro bistable circuit from synthetic transcriptional switches. Mol. Syst. Biol., 2, 68

[110] Ackermann, J., Wlotzka, B. and McCaskill, J. S. (1998) In vitro DNA-based predator-prey system with oscillatory kinetics. Bull. Math. Biol., 60, 329–354

[111] Fujii, T. and Rondelez, Y. (2013) Predator-prey molecular ecosystems. ACS Nano, 7, 27–34

[112] Kim, J. and Winfree, E. (2011) Synthetic in vitro transcriptional oscillators. Mol. Syst. Biol., 7, 465

[113] Montagne, K., Plasson, R., Sakai, Y., Fujii, T. and Rondelez, Y. (2011) Programming an in vitro DNA oscillator using a molecular networking strategy. Mol. Syst. Biol., 7, 466

[114] Franco, E., Friedrichs, E., Kim, J., Jungmann, R., Murray, R., Winfree, E. and Simmel, F. C. (2011) Timing molecular motion and production with a synthetic transcriptional clock. Proc. Natl. Acad. Sci. USA, 108, E784–E793

[115] Weitz, M., Kim, J., Kapsner, K., Winfree, E., Franco, E. and Simmel, F. C. (2014) Diversity in the dynamical behaviour of a compartmentalized programmable biochemical oscillator. Nat. Chem., 6, 295–302

[116] Hasatani, K., Leocmach, M., Genot, A. J., Estévez-Torres, A., Fujii, T. and Rondelez, Y. (2013) High-throughput and long-term observation of compartmentalized biochemical oscillators. Chem. Commun. (Camb.), 49, 8090–8092

[117] Epstein, I. R., Vanag, V. K., Balazs, A. C., Kuksenok, O., Dayal, P. and Bhattacharya, A. (2012) Chemical oscillators in structured media. Acc. Chem. Res., 45, 2160–2168

[118] Vanag, V. K. and Epstein, I. R. (2001) Pattern formation in a tunable medium: the Belousov-Zhabotinsky reaction in an aerosol OT microemulsion. Phys. Rev. Lett., 87, 228301

[119] Good, M. C., Vahey, M. D., Skandarajah, A., Fletcher, D. A. and Heald, R. (2013) Cytoplasmic volume modulates spindle size during embryogenesis. Science, 342, 856–860

[120] Telley, I. A., Gáspár,I., Ephrussi, A. and Surrey, T. (2013) A single Drosophila embryo extract for the study of mitosis ex vitro. Nat. Protoc., 8, 310–324

[121] Telley, I. A., Gáspár, I., Ephrussi, A. and Surrey, T. (2012) Aster migration determines the length scale of nuclear separation in the Drosophila syncytial embryo. J. Cell Biol., 197, 887–895

[122] Ho, K. K., Lee, J. W., Durand, G., Majumder, S. and Liu, A. P. (2017) Protein aggregation with poly(vinyl) alcohol surfactant reduces double emulsion-encapsulated mammalian cell-free expression. PLoS One, 12, e0174689

[123] Zemella, A., Thoring, L., Hoffmeister, C. and Kubick, S. (2015) Cell-free protein synthesis: pros and cons of prokaryotic and eukaryotic systems. ChemBioChem, 16, 2420–2431

[124] Richard, P. (2003) The rhythm of yeast. FEMS Microbiol. Rev., 27, 547–557

[125] Lu, Y., Lee, B. H., King, R. W., Finley, D. and Kirschner, M. W. (2015) Substrate degradation by the proteasome: a single-molecule kinetic analysis. Science, 348, 1250834

[126] Lu, Y., Wang, W. and Kirschner, M. W. (2015) Specificity of the anaphase-promoting complex: a single-molecule study. Science, 348, 1248737

[127] Shimizu, Y., Kanamori, T. and Ueda, T. (2005) Protein synthesis by pure translation systems. Methods, 36, 299–304

[128] Nevin, D. E. and Pratt, J. M. (1991) A coupled in vitro transcription-translation system for the exclusive synthesis of polypeptides expressed from the T7 promoter. FEBS Lett., 291, 259–263

[129] Garamella, J., Marshall, R., Rustad, M. and Noireaux, V. (2016) The all E. coli TX-TL Toolbox 2.0: a platform for cell-free synthetic biology. ACS Synth. Biol., 5, 344–355

[130] Genot, A. J., Baccouche, A., Sieskind, R., Aubert-Kato, N., Bredeche, N., Bartolo, J. F., Taly, V., Fujii, T. and Rondelez, Y. (2016) High-resolution mapping of bifurcations in nonlinear biochemical circuits. Nat. Chem., 8, 760–767

[131] Wang, F. and Fan, C. (2016) DNA reaction networks: providing a panoramic view. Nat. Chem., 8, 738–740

[132] Semenov, S. N., Kraft, L. J., Ainla, A., Zhao, M., Baghbanzadeh, M., Campbell, V. E., Kang, K., Fox, J. M. and Whitesides, G. M. (2016) Autocatalytic, bistable, oscillatory networks of biologically relevant organic reactions. Nature, 537, 656–660

[133] Tyson, J. J. and Novák, B. (2010) Functional motifs in biochemical reaction networks. Annu. Rev. Phys. Chem., 61, 219–240

[134] Nguyen, L. K. (2012) Regulation of oscillation dynamics in biochemical systems with dual negative feedback loops. J. R. Soc. Interface, 9, 1998–2010

[135] Lomnitz, J. G. and Savageau, M. A. (2014) Strategy revealing phenotypic differences among synthetic oscillator designs. ACS Synth. Biol., 3, 686–701

[136] Guantes, R. and Poyatos, J. F. (2006) Dynamical principles of two-component genetic oscillators. PLoS Comput. Biol., 2, e30

[137] Wagner, A. (2005) Circuit topology and the evolution of robustness in two-gene circadian oscillators. Proc. Natl. Acad. Sci. USA, 102, 11775–11780

[138] Noman, N., Monjo, T., Moscato, P. and Iba, H. (2015) Evolving robust gene regulatory networks. PLoS One, 10, e0116258

[139] Castillo-Hair, S. M., Villota, E. R. and Coronado, A. M. (2015) Design principles for robust oscillatory behavior. Syst. Synth. Biol., 9, 125–133

[140] Woods, M. L., Leon, M., Perez-Carrasco, R. and Barnes, C. P. (2016) A statistical approach reveals designs for the most robust stochastic gene oscillators. ACS Synth. Biol., 5, 459–470

[141] Mukherji, S. and van Oudenaarden, A. (2009) Synthetic biology: understanding biological design from synthetic circuits. Nat. Rev. Genet., 10, 859–871

[142] Anafi, R. C., Lee, Y., Sato, T. K., Venkataraman, A., Ramanathan, C., Kavakli, I. H., Hughes, M. E., Baggs, J. E., Growe, J., Liu, A. C., (2014) Machine learning helps identify CHRONO as a circadian clock component. PLoS Biol., 12, e1001840

[143] Caschera, F., Bedau, M. A., Buchanan, A., Cawse, J., de Lucrezia, D., Gazzola, G., Hanczyc, M. M. and Packard, N. H. (2011) Coping with complexity: machine learning optimization of cell-free protein synthesis. Biotechnol. Bioeng., 108, 2218–2228

[144] Trejo Banos, D., Millar, A. J. and Sanguinetti, G. (2015) A Bayesian approach for structure learning in oscillating regulatory networks. Bioinformatics, 31, 3617–3624

[145] Malumbres, M. and Barbacid, M. (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer, 9, 153–166

[146] Dart, A. (2016) Tumorigenesis: cancer goes tick tock. Nat. Rev. Cancer, 16, 409

ACKNOWLEDGEMENTS

This work was supported by the National Science Foundation (Early CAREER Grant #1553031) and the National Institutes of Health (MIRA #GM119688).

COMPLIANCE WITH ETHICAL GUIDELINES

The authors Zhengda Li and Qiong Yang declare that they have no conflict of interests.

This article is a review article and does not contain any studies with human or animal subjects performed by any of the authors.

RIGHTS & PERMISSIONS

2018 Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature