Research Summary

Life in single cells is dictated by chance: reactions that involve small numbers of molecules generate spontaneous fluctuations that then enslave all dependent processes. Such ‘noise’ can randomize developmental pathways, disrupt cell cycle control or force metabolites away from their optimal levels. It can also be exploited when heterogeneity is advantageous, or even to obtain more reliable and deterministic control. The goal of the laboratory is to identify and understand the guiding principles behind these different phenomena. To this end we derive mathematical methods to interpret fluctuations, develop experimental methods to count molecules in single cells, and combine the two to study the simplest natural and engineered networks. Different applications may use different organisms, but E. coli is the first choice.

The individual network analyses form three more comprehensive projects: 1) A study of basic dynamic differences between different motifs in replication, gene expression and metabolism. 2) A comparison of different evolutionary solutions to the same regulatory problem, exemplified by homeostatic noise suppression. 3) A thorough quantitative characterization of the perhaps most tractable life form on the planet, bacterial plasmid R1. This includes evaluating the molecular mechanisms behind replication control and DNA segregation in terms of precision, cost and selfishness/altruism.

The mathematical projects also aim to build a more systematic stochastic theory for biochemical systems, approximating structural classes of random processes collectively and concretizing the interpretations rather than the assumptions. For more information, see my homepages in Applied Mathematics at Harvard or Cambridge.

Opportunities are available for post-docs, graduate students and research assistant. The lab space is under construction and should be finished by January 2006. Temporary facilities are available in the meantime though, so any starting date is possible.

Selected References

Paulsson J. Prime movers of noisy gene expression. News and Views, Nature Genetics, 37 , 925-926 , 2005

Das N, Valjavec-Gratian M, Basuray AN, Fekete RA, Papp PP, Paulsson J & Chattoraj D. Multiple homeostatic mechanisms in the control of P1 plasmid replication. Proc. natl. Acad. Sci. USA, 102 , 2856-61, 2005

Paulsson J. Models of Stochastic Gene Expression. Phys. Life Rev. 2, 157-75, 2005

Paulsson J. Summing up the noise in gene networks. Nature427, 415-418, 2004

Paulsson J. Multileveled selection on plasmid replication. Genetics161, 1373-1384, 2002

Park K, Han E, Paulsson J & Chattoraj DK Origin pairing ('handcuffing') as a mode of negative control of P1 plasmid copy number. EMBO J.20, 7323-7332, 2002

Paulsson J & Ehrenberg M. Noise in a minimal regulatory network: plasmid copy number control. Quart. Rev. of Biophys. 34, 1-59 2001

Paulsson J, Berg OG & Ehrenberg M. Stochastic Focusing: Fluctuation enhanced sensitivity of intracellular regulation. Proc. natl. Acad. Sci. USA. 13 , 7148-7153, 2000

Paulsson, J & Ehrenberg M. Random signal fluctuations can reduce random fluctuations in regulated components of chemical regulatory networks. Phys. Rev. Lett. 23, 5447-5450, 2000