Supervisors: Prof Tomo Tanaka and Dr David McGloin
Living matter must continuously make yes or no decisions based on judgements of a noisy environment. The consequences of failure to make a correct decision can lead to decreased fitness, up to and including a state change from living to non-living matter. These types of decisions occur throughout the range of scales and strategies for survival occupied by living things: a pluripotent cell committing to a differentiated fate, the apoptotic decision made by a sick cell, and the boundaries of a beetle’s segmented body plan are all meaningful, intuitive examples of living processes making discrete decisions based on noisy environmental inputs. A fundamental example of biological decision-making is eukaryotic cell division. Each daughter cell requires a complete set of instructions to carry out the activities of life effectively. If a dividing cell makes the wrong decision in allocating chromosomes, the next generation will have too many or too few copies (aneuploidy), potentially resulting in illness or death of the organism.
This project investigates the interactions carried out by the biomolecular machinery of cell division. We are making use of optical tweezers to interrogate the mechanical nature of isolated compone involved in harnessing the force of cellular division to segregate chromosomes. In particular, we are studying the interface of microtubules and components of the outer kinetochore, a protein complex operating as a nanometre scale computational and force coupling machine. The study builds upon a background of genetics and molecular biology experiments used to identify the necessary actors in the machinery of cell-division as well as previous biophysical studies.
To investigate questions of biomolecular decision-making during cell division, we are developing an optical tweezers and computational optics microscope. The system has to be able to visualise transparent microtubules at just 25 nanometres wide, resolve forces on the order of picoNewtons, and operate in a way that can consistently measure the forces acting on small cohorts and single biomolecules. The capabilities incorporated to date include quantitative polarisation microscopy, intensity transport quantitative phase imaging, video-enhanced contrast for visualisation of microtubules, and optical trapping with position sensing on a quad-photodiode. These capabilities bring us closer to investigating current ideas about decisions made during cell division decisions from a mechanical, biophysical perspective.
In winter 2015/2016, Tyrell went on research placement at Tübingen Universität. While there he contributed to the design and initial build-up of a single-molecule fluorescence microscope, as well as investigating single-molecule Kip3 kinesin motility on microtubules. Tyrell’s work broadly encompasses label-free computational optics (in polarisation and phase) and optical trapping.
Journal and Conference Papers and Posters
[November 2017] Transport of intensity equation microscopy for dynamic microtubules, arXiv preprint arXiv:1707.04139,
[August 2016] Catching the perfect wavelet: multi-resolution signal analysis for biophysics. Oral presentation at the Biophotonic approaches: From molecules to living systems conference, Dundee, Scotland, 23rd August 2016.