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THE ROLE OF ENERGY EXPENDITURE IN MOLECULAR INFORMATION PROCESSING

Postdoctoral Research Fellowship at Harvard Medical School
Application deadline: this position will remain open until it is filled.

Applications are invited to work with Professor Jeremy Gunawardena on the above project, funded by the Giovanni Armenise Foundation. The Gunawardena laboratory studies cellular information processing using a combination of experimental, mathematical and computational methods and offers an intellectual space between the mathematical and the biological sciences.

In recent work (PMID 27368104), we put forward the concept of "Hopfield barriers". John Hopfield's classic work on kinetic proofreading (PMID 4530290) can be interpreted as follows: to undertake any information processing task, if the molecular mechanism implementing this task operates at thermodynamic equilibrium, then there is a barrier, which is set by detailed balance, to how well the task can be performed. The only way to exceed this "Hopfield barrier" is to expend energy and maintain the system away from thermodynamic equilibrium. Hopfield exhibited, for the task of fidelity in copying nucleic acids (replication, transcription, translation), a particular mechanism – kinetic proofreading – which he showed was able to improve copying fideilty beyond any bound, provided only that sufficient energy was expended. Subsequent work has shown that kinetic proofreading plays a key role in many aspects of cellular information processing.

An important biological context for these ideas is gene regulation in eukaryotes. One of the most striking differences between eukaryotes and eubacteria is the presence in the former of several energy expending mechanisms for regulating genes: chromatin reorganisation; nuclesome remodelling; post-translational modification of histones, co-regulators and the transcriptional machinery; and DNA methylation. What does this energy buy for the organism that could not have been achieved by bacterial gene regulation? We have found a partial answer to this question for the task of sharp activation of a gene (27368104), using the linear framework for timescale separation that we introduced in previous work (22606254, 24018536, 24103070, 25475875). One of the advantages of the linear framework is that it reduces to equilibrium statistical mechanics for systems at thermodynamic equilibrium but also provides an analytical solution for non-equilibrium steady states.

This project will use the linear framework to explore biological information processing from the perspective of Hopfield barriers and non-equilibrium physics. What are the Hopfield barriers for different tasks? How can energy be expended to break these barriers and how much is gained by doing so? How can departure from thermodynamic equilibrium be detected experimentally? What are the trade-offs in expending energy, for instance, for achieving not just fidelity but also speed and minimum energy dissipation (q-bio.MN:1710.06038)? Following the energy may be a way to rise above the overwhelming molecular complexity and disentangle the evolutionary logic of processes like eukaryotic gene regulation. The development of single-molecule methods and super-resolution microscopy are providing the right kinds of experimental tools for doing this but they need an appropriate theoretical foundation from which to interpret data and design experiments. That is what we hope to provide.

The position is available for two years; an extension beyond that will depend on additional grant funding. Applicants should have a PhD in one of the mathematical and physical sciences, a good track record of creative work, a strong interest in modern biology and an enthusiasm for working at the interface between disciplines. Applications should be sent to jeremy(AT)hms(DOT)harvard(DOT)edu and should include a CV, a cover letter describing suitability for this specific project and contact details for up to three referees. We are an equal opportunity employer and all qualified candidates will receive consideration for the position.

Copies of the papers mentioned above can be found on our website.

Internships and rotations

The lab has a tradition of recruiting undergraduate students in the mathematical sciences for summer internships and rotations. Please contact us if you are interested.

 

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