Professor Mark Leake

Research

General themes of my Physics of Life research involve (i) developing new biophysical instrumentation for addressing open biological questions, and (ii) applying these coupled to molecular biology and biochemical approaches to investigating questions concerning single molecules under physiologically relevant environments. I have developed a valuable cluster of biophysical techniques enabling the imaging and manipulation of single molecules with extraordinary control. This scientific success founded on the single-molecule fluorescence microscopy (e.g. see Reyes-Lamothe et al, Science 2010; Badrinarayanan et al, Science 2012 to get a taster of what we can do!) with molecular and cellular manipulation and precision microfluidics technology.

My highly interdisciplinary single-molecule biophysics team are in an ideal position to take the leap from studying single molecules to investigating entire complex biological processes at much higher length scales of cells and tissues. My work has added insight into the behaviour of the flagellar motor of bacteria, DNA replication, repair and remodelling, protein transport, oxidative phosphorylation, and signal transduction and gene regulation. These advances have been underpinned by innovative tools and techniques enabling robust quantification of molecular and cellular properties: the spatiotemporal dynamics of functional molecular machines, their architecture and mechanical properties, the nature of their functional interactions, and their level of expression on a live cell-by-cell basis.

Key biological questions currently under study include:

DNA gyrase

Unpicking mechanisms of this crucial antibiotic target in bacteria which functions to resolve lethal supercoils ahead of translocating polymerases (Figure 1).

Figure 1. Discovery that Rep protein repairs DNA by two independent paths of replication restart and nucleoprotein barrier removal (Syeda et al, NAR 2019).

DNA replication/repair

Elucidating kinetics of turnover, recruitment and assembly of replication/repair machinery in bacteria models for those in higher organisms (Figure 2).

Figure 2. Discovery that the crucial bacterial enzyme DNA gyrase, a key antibiotic target, operates by processive catalysis in targeted hotspots ahead of the replication fork to relax otherwise fatal positive supercoiling of DNA (Stracy et al, NAR 2019).

Signal transduction/gene regulation

Using model yeast to study how chemical signals at cell membranes are converted to gene regulation in eukaryotic nuclei (Wollman et al, eLife 2017).

DNA topology

Investigating crucial effects of shape on roles of DNA in the cell, including its interactions with binding partners and the activity status of genes (Zhou et al, Photonics 2015).

Biomedical physics

Investigating a range of human diseases including cancer, and infection and antibiotic resistance using innovative biophysical technologies (Miller et al Front Immunol, 2018)

Teaching and scholarship

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My core teaching ethic is underpinned by a rich sense of collegiality, dedicated to the pursuit of the highest standards of scholarship, academic collaboration, and inspirational teaching, and I aim to invigorate all who study, research and work with me, in the broadest multidisciplinary way possible.

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My lecturing approach really sits on the line between biology and physics – I am not so much a “biophysicsist” but rather a “physics-of-life-ist”. As such I draw on physical questions which have biological implications and applications. I try to show that using physical science to understand biology really does enable substantive insights into the life sciences – these can be genuinely transformative, empowering, and, overall, fun! You will fell enrichened knowing you can not only converse with researchers from the physical sciences, but also that you have a basic depth of understanding to enable you to really understand biology in a far deeper way than you ever thought possible!