Professor Mark Leake
Anniversary Chair of Biological Physics

Profile

Career

2013-

Anniversary Chair of Biological Physics

 

Depts of Physics and Biology, University of York

2007-2012 

Royal Society University Research Fellow (URF)

Dept of Physics, University of Oxford

2007-2012 

Senior Research Fellow and PI in Systems Biology

Dept of Biochemistry, University of Oxford

2008-2011

Hertford College Science Fellowship

Hertford College, University of Oxford

2008

M.A. (Oxon)

University of Oxford

2007-2009

PI, Interdisciplinary Research Collaboration in Bionanotechnology

University of Oxford

2006-2007

Leverhulme Trust Early Career Fellow

University of Oxford

2003-2006

Fellow, Interdisciplinary Research Collaboration in Bionanotechnology

University of Oxford

2002-2003

DFG Postdoctoral Research Fellow

Ruprect-Karls-Universität Heidelberg, Germany

2001-2002

Postdoctoral Research Fellow in Biological Physics

University of Oxford

1997

M.A. (Cantab)

University of Cambridge

1996-2001

Ph.D Biophysics

University of London

1994-1995

M.Sc Medical Physics

University of Surrey

1990-1993

B.A. Natural Sciences (Cantab)

University of Cambridge

Research

Overview

Research groupBiological Physics Group

I am the Anniversary Professorial Chair of Biological Physics, heading an interdisciplinary science team across the Depts of Physics and Biology. The group specializes in developing and applying novel forms of optical microscopy to investigate complex biological processes at the level of single molecules.

Our research specializes on the theme of 'Single-molecule cellular biophysics'. This is becoming a highly topical area of life sciences research which strives to move towards a greater physiological relevance to single molecule biophysics experimentation, either by combining in vivo cellular biology techniques with those of cutting-edge single molecule biophysics or by creating a  greater level of molecular complexity to single biomolecule experiments in vitro, and is in effect emerging as a novel disciple in its own right which is likely to increase in application significantly over the next few years as these techniques become more widely used. We use a range of cutting-edge biophotonics and photophysical methods in combination with state-of-the-art genetics. Our group has a depth of expertise in physics applied to biology at the single molecule level, and has  worked on bio-molecule mechanical manipulation and force spectroscopy using both AFM and laser-tweezers, low-light fluorescence imaging in vivo and customized advanced microscope design involving development of nanometre length scale imaging with millisecond time resolution. We have a reputation in single molecule investigations on living cells involving several multi-institutional collaborations.

General biological questions of interest to us involve addressing the molecular basis of the cell, seeing how single molecule properties in a living organism scale up to bring about whole-organism functionality, striving to bridge our gap in understanding between molecular biology and cell science in a rational, predictive context. These  pose some of the hardest and most fundamental challenges to the future of biophysics research. Full understanding of processes in living organisms is only achievable if all molecular interactions are considered. Cell biology strives to cultivate a full insight into the mechanisms of living cells by investigating interactions that elicit and direct cellular events, though to date the shear complexity of biological systems has caused precise single-molecule experimentation to be far too demanding, instead focusing on studies of single systems using relatively crude bulk ensemble-average measurements. One way forward which we're currently pushing is to monitor several biological systems simultaneously in living, functioning cells using more powerful and precise single molecule techniques, in effect investigating systems level biology from a bottom-up molecular level, eradicating noise rife in systems biology data associated with cell population stochasticity.

Using novel microscopy techniques and state-of-the-art genetics (Nature 2006, 443, 355; PNAS 2008, 105, 15376; Science 2010, 328, 498, Science 2012, 338, 528), we have developed means to monitor single proteins within a living, functioning cell and to observe exchange with other molecules in a complex, functioning biological system. Our objectives are  to drive these optical techniques to a much higher level to permit fast, real-time, molecular in vivo imaging of several different proteins in multiple, complex biological systems, to establish and validate mathematical models of complex systems down to the molecular level, and to push forward the genetic development of cell strains for use in these 'optical proteomics' studies. Currently we are targeting several biological systems including motility, protein transport, cell signalling and bioenergetics, but over half of our work is devoted to studies of  and the 'lifecycle' of the DNA molecule through from replication to segregation. 

Our primary experimental technique utilizes advanced approaches of  fluorescence microscopy such as total-internal-reflection fluorescence (TIRF) and Slimfield imaging, generally necessitating customized construction, combined with cutting-edge Fluorescent protein  fusion molecular genetics technology.

Projects

  • Development of millisecond 3D superresolution imaging with photoblinking
  • Designing and applying bio-molecular force transduction tools of laser/magnetic tweezers combined with nanoscale fluorescence imaging
  • Probing cellular DNA replication/segregation using single-molecule biophysics
  • Investigating molecular-level signal transduction in living cells
  • Studying cell membrane biophysics at the nanoscale
  • Investigating live-cell molecular bio-energetics

Contact Professor Leake for available vacancies in the group

Available PhD research projects

Single-molecule biophysics (2015-16)

A variety of PhD projects are available to enthusiastic, competitive self-funded graduate students in a world-class lab in the general area of single-molecule biophysics, involving utilizing either in vivo single-molecule fluorescence imaging techniques, or in vitro single-molecule manipulation and superresolution imaging using magneto-optical tweezers combined with superresolution microscopy, or a combination of both. Biological systems under study currently include DNA topology control, bacterial DNA replication, bacterial DNA repair, bacterial cell division, and yeast signal transduction. Projects could include elements of practical molecular biology, DNA construct design and protein purification, chemical conjugation technologies, application of single-molecule biophysics technologies and, if appropriate to the student, design and construction of new single-molecule biophysics technologies

  

Developing a single-molecule ‘Enviroscope’ to probe molecular processes in living cells in real-time. 

Biological processes in living cells possess enormous complexity involving highly cooperative and coordinated effects between remarkable, nanoscopic molecular machines composed of individual protein molecule components. The PhD student will work with Prof. Leake in the Depts of Physics and Biology at York. Prof Leake is the Chair of Biological Physics and the Director of the Biological Physical Sciences Institute (BPSI) at York encompassing multiple exceptional research teams across several different departments of the University, including Physics, Biology, Chemistry, Electronics, Mathematics, Psychology and Computer Science, which serves to nurture collaborative research at the cutting-edge interface between the physical and life sciences (http://york.ac.uk/physics/bpsi ). Prof. Leake’s team has an international reputation in the fields of single-molecule biophysics. The University of York is an exciting, young institution with a strong focus on cutting-edge interdisciplinary research.

The project will apply new bespoke/home-built super-resolution optical microscopy methodologies to image multiple protein components simultaneously in single, living cells down to a precision of single molecules with a spatial precision of a few tens of nanometre and a millisecond temporal resolution, permitting the real-time observation of functional molecular machines across all spatial regions of single live cells [1, 2].  The project will involve the design and construction of a new single-molecule ‘Enviroscope’ light microscope  – a device which can tracking single fluorescently tagged molecules in addition to quantifying  their spectral emission profile as a function of emission wavelength. This spectral emission property is a signature for the local physical and chemical environment, and so can be used to probe local pH, ion concentrations, hydrophobicity, viscosity and many more important physical parameters in the living cell. The student will work with an expert team to learn aspects of optical design, in addition to cellular growth and preparation and several invaluable cell biology and biochemistry skills. The new device will be applied to a range of biology questions in live cell studies through several current collaborations in the Leake lab, including DNA replication, gene regulation and signal transduction.

It is a unique interdisciplinary opportunity for a highly motivated student to engage at the exciting interface between the life and physical sciences and gain an exceptional PhD education in cutting-edge science.

For more information please contact mark.leake@york.ac.uk

  

Combining magnetic and optical tweezers with super-resolution imaging of DNA to probe new candidate antibiotics. 

We are seeking a talented and ambitious PhD student who can push forward developments of the core technologies of a prototype diagnostic system for bacterial resistance to antibiotics which utilizes molecular biosensing of the key antibiotic target enzyme DNA gyrase. The device uses a novel combination of mechanical/optical detection from single-molecule pull-down binding to synthetic DNA target constructs.  The PhD student will work with Prof. Leake in the Depts of Physics and Biology at York. Prof Leake is the Chair of Biological Physics and the Director of the Biological Physical Sciences Institute (BPSI) at York encompassing multiple exceptional research teams across several different departments of the University, including Physics, Biology, Chemistry, Electronics, Mathematics, Psychology and Computer Science, which serves to nurture collaborative research at the cutting-edge interface between the physical and life sciences (http://york.ac.uk/physics/bpsi ). Prof. Leake’s team has an international reputation in the fields of single-molecule biophysics. The University of York is an exciting, young institution with a strong focus on cutting-edge interdisciplinary research.

The project will use and further adapt a powerful new technology developed in the Leake lab which combines magnetic and optical tweezers to tether, extended and twist single molecules and DNA [1] whilst simultaneously imaging them using super-resolution fluorescence microscopy [2].  The objective of the project is to develop a prototype diagnostic device which uses the mechanical responses of specifically designed linear DNA probes to the binding of DNA gyrase from lysed E. coli cells and the gyrase-targeting antibiotic ciprofloxacin. This will be used to to determine if gyrase is resistant to the action of ciprofloxacin in addition to probing novel variants of ciprofloxacin developed by Prof. Leake’s collaborators in the Chemistry Dept. The student will work with an expert team to learn aspects of experimental single-molecule biophysics, in addition to computational and mathematical analysis tools, biochemical preparation procedures and chemical synthesis  techniques. The ultimate aim is to miniaturize this new device to generate a handheld machine which can be used in clinics.

It is a unique interdisciplinary opportunity for a highly motivated student to engage at the exciting interface between the life and physical sciences and gain an exceptional PhD education in cutting-edge science.

For more information please contact mark.leake@york.ac.uk

 

Mark, Professor Leake

Contact details

Prof. Mark Leake
Anniversary Chair of Biological Physics
Department of Biology
University of York
Heslington
York
YO10 5DD

Tel: Biology (01904) 328566; Physics (01904) 322697

http://single-molecule-biophysics.org/