Improved Network Performance Via Antagonism: From Synthetic Rescues to Multi-drug Combinations

Overview

Journal Bioessays

Publisher Wiley

Specialties Biology
Cell Biology
Molecular Biology

Date 2010 Feb 4

PMID 20127700

Citations 17

Authors

Adilson E Motter

Affiliations

Soon will be listed here.

Abstract

Recent research shows that a faulty or sub-optimally operating metabolic network can often be rescued by the targeted removal of enzyme-coding genes - the exact opposite of what traditional gene therapy would suggest. Predictions go as far as to assert that certain gene knockouts can restore the growth of otherwise nonviable gene-deficient cells. Many questions follow from this discovery: What are the underlying mechanisms? How generalizable is this effect? What are the potential applications? Here, I approach these questions from the perspective of compensatory perturbations on networks. Relations are drawn between such synthetic rescues and naturally occurring cascades of reaction inactivation, as well as their analogs in physical and other biological networks. I specially discuss how rescue interactions can lead to the rational design of antagonistic drug combinations that select against resistance and how they can illuminate medical research on cancer, antibiotics, and metabolic diseases.

Citing Articles

Understanding Braess' Paradox in power grids.

Schafer B, Pesch T, Manik D, Gollenstede J, Lin G, Beck H Nat Commun. 2022; 13(1):5396.

PMID: 36104335 PMC: 9474455. DOI: 10.1038/s41467-022-32917-6.

Extreme Antagonism Arising from Gene-Environment Interactions.

Wytock T, Zhang M, Jinich A, Fiebig A, Crosson S, Motter A Biophys J. 2020; 119(10):2074-2086.

PMID: 33068537 PMC: 7732749. DOI: 10.1016/j.bpj.2020.09.038.

Network Pharmacology-Guided Development of a Novel Integrative Regimen to Prevent Acute Graft-vs.-Host Disease.

Lyu M, Zhou Z, Wang X, Lv H, Wang M, Pan G Front Pharmacol. 2019; 9:1440.

PMID: 30618740 PMC: 6300759. DOI: 10.3389/fphar.2018.01440.

Antagonistic Phenomena in Network Dynamics.

Motter A, Timme M Annu Rev Condens Matter Phys. 2018; 9:463-484.

PMID: 30116502 PMC: 6089548. DOI: 10.1146/annurev-conmatphys-033117-054054.

Experimental evolution of diverse Escherichia coli metabolic mutants identifies genetic loci for convergent adaptation of growth rate.

Wytock T, Fiebig A, Willett J, Herrou J, Fergin A, Motter A PLoS Genet. 2018; 14(3):e1007284.

PMID: 29584733 PMC: 5892946. DOI: 10.1371/journal.pgen.1007284.

References

Duarte N, Becker S, Jamshidi N, Thiele I, Mo M, Vo T . Global reconstruction of the human metabolic network based on genomic and bibliomic data. Proc Natl Acad Sci U S A. 2007; 104(6):1777-82. PMC: 1794290. DOI: 10.1073/pnas.0610772104. View

Feist A, Henry C, Reed J, Krummenacker M, Joyce A, Karp P . A genome-scale metabolic reconstruction for Escherichia coli K-12 MG1655 that accounts for 1260 ORFs and thermodynamic information. Mol Syst Biol. 2007; 3:121. PMC: 1911197. DOI: 10.1038/msb4100155. View

Hashimoto M, Ichimura T, Mizoguchi H, Tanaka K, Fujimitsu K, Keyamura K . Cell size and nucleoid organization of engineered Escherichia coli cells with a reduced genome. Mol Microbiol. 2004; 55(1):137-49. DOI: 10.1111/j.1365-2958.2004.04386.x. View

Dancey J, Chen H . Strategies for optimizing combinations of molecularly targeted anticancer agents. Nat Rev Drug Discov. 2006; 5(8):649-59. DOI: 10.1038/nrd2089. View

Isalan M, Lemerle C, Michalodimitrakis K, Horn C, Beltrao P, Raineri E . Evolvability and hierarchy in rewired bacterial gene networks. Nature. 2008; 452(7189):840-5. PMC: 2666274. DOI: 10.1038/nature06847. View

Reguly T, Breitkreutz A, Boucher L, Breitkreutz B, Hon G, Myers C . Comprehensive curation and analysis of global interaction networks in Saccharomyces cerevisiae. J Biol. 2006; 5(4):11. PMC: 1561585. DOI: 10.1186/jbiol36. View

Nishikawa T, Gulbahce N, Motter A . Spontaneous reaction silencing in metabolic optimization. PLoS Comput Biol. 2008; 4(12):e1000236. PMC: 2582435. DOI: 10.1371/journal.pcbi.1000236. View

Burgard A, Vaidyaraman S, Maranas C . Minimal reaction sets for Escherichia coli metabolism under different growth requirements and uptake environments. Biotechnol Prog. 2001; 17(5):791-7. DOI: 10.1021/bp0100880. View

Fischer E, Sauer U . Large-scale in vivo flux analysis shows rigidity and suboptimal performance of Bacillus subtilis metabolism. Nat Genet. 2005; 37(6):636-40. DOI: 10.1038/ng1555. View

10.

Keiser M, Setola V, Irwin J, Laggner C, Abbas A, Hufeisen S . Predicting new molecular targets for known drugs. Nature. 2009; 462(7270):175-81. PMC: 2784146. DOI: 10.1038/nature08506. View

11.

Kitano H . Systems biology: a brief overview. Science. 2002; 295(5560):1662-4. DOI: 10.1126/science.1069492. View

12.

HUTTENLOCHER P, Dabholkar A . Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol. 1997; 387(2):167-78. DOI: 10.1002/(sici)1096-9861(19971020)387:2<167::aid-cne1>3.0.co;2-z. View

13.

Chait R, Craney A, Kishony R . Antibiotic interactions that select against resistance. Nature. 2007; 446(7136):668-71. DOI: 10.1038/nature05685. View

14.

Hillenmeyer M, Fung E, Wildenhain J, Pierce S, Hoon S, Lee W . The chemical genomic portrait of yeast: uncovering a phenotype for all genes. Science. 2008; 320(5874):362-5. PMC: 2794835. DOI: 10.1126/science.1150021. View

15.

Motter A, Gulbahce N, Almaas E, Barabasi A . Predicting synthetic rescues in metabolic networks. Mol Syst Biol. 2008; 4:168. PMC: 2267730. DOI: 10.1038/msb.2008.1. View

16.

Hilgetag C, Theoret H, Pascual-Leone A . Enhanced visual spatial attention ipsilateral to rTMS-induced 'virtual lesions' of human parietal cortex. Nat Neurosci. 2001; 4(9):953-7. DOI: 10.1038/nn0901-953. View

17.

Herring C, Raghunathan A, Honisch C, Patel T, Applebee M, Joyce A . Comparative genome sequencing of Escherichia coli allows observation of bacterial evolution on a laboratory timescale. Nat Genet. 2006; 38(12):1406-12. DOI: 10.1038/ng1906. View

18.

Fong S, Palsson B . Metabolic gene-deletion strains of Escherichia coli evolve to computationally predicted growth phenotypes. Nat Genet. 2004; 36(10):1056-8. DOI: 10.1038/ng1432. View

19.

Hilgetag C, Kotter R, Young M . Inter-hemispheric competition of sub-cortical structures is a crucial mechanism in paradoxical lesion effects and spatial neglect. Prog Brain Res. 1999; 121:121-41. DOI: 10.1016/s0079-6123(08)63071-x. View

20.

Baba T, Ara T, Hasegawa M, Takai Y, Okumura Y, Baba M . Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol Syst Biol. 2006; 2:2006.0008. PMC: 1681482. DOI: 10.1038/msb4100050. View