Our aim is to understand the dynamics of excitable cell networks found in the heart and brain. A big part of the research program is to develop imaging and computational methods - in particular new microscopy modalities, analysis and simulation programs, optogenetic techniques, and new ultra-fast sensors - and use these tools to study complex cardiac and neuronal excitable systems. Research themes goes into detail on new imaging techniques ( instrumentation), the data we collect in cardiac tissues ( excitable systems), and how we can control cells in real-time ( optogenetics).
Excitable cells in the heart and brain generate fast signals (action potentials) that have to be captured using specialized detectors at over a thousand frames per second. At the same time, the structure of these cells is complex, requiring high resolution detectors and advanced microscopy techniques. We're working on many technologies to help with these issues: two examples - temporal pixel multiplexing and remote focusing - are shown below.
Temporal pixel multiplexing (TPM) is an imaging method that embeds high speed information into still image frames. Camera chips have millions of pixels which integrate charge generated when light hits their surface over a set integration time. TPM controls the way individual pixels are exposed during a single frame to embed high speed information in static images. This allows a lower resolution high speed movie to be extracted, giving a high-res still and a high-speed movie in one shot.
The original TPM prototype was built using a micromirror array (similar to those used in many consumer overhead projectors) to control pixel exposure times in a off-the-shelf camera. We are now developing CMOS sensors that incorporate TPM technology at the pixel level. Unlike other imaging chips which store data every frame, TPM doesn't move data (or transfer charge) during acquisition allowing it to be extremely fast. Our new chips should be able to image activity at over a million frames/second.
Remote focusing is a microscopy technique, pioneered by Prof. Tony Wilson's Scanning Optical Microscopy group in Oxford, which allows tissue to be scanned in depth without moving the sample or the imaging objective. When combined with laser scanning two-photon microscopy, the technique allows capture of cell structure and function in living tissue.
One of the main limitations of scanning microscopes is that they're slow as the laser has to visit each point in an image. We're developing new remote focusing microscopes which split the laser into many beamlets, so we can increase acquisition speed. The aim of this project is to be able to measure cell-cell communication in intact heart and brain tissues.
more TPM: see the Nature Methods paper, the original TPM pages, and articles in New Scientist & IO9 magazines.
more remote focusing: see Tony Wilson's group original PNAS paper and our Circ Res paper.
collaborators: Roger Light, Ed Mann, Bei Li, Alex Corbett , Leonardo Sacconi , Martin Booth, Tony Wilson
industry & licencing: Cordin Scientific Imaging, STFC, Oxford University Innovation.
Excitable media are systems which have the ability to propagate signals spatially without damping. In the heart, waves of excitation synchronise cardiac muscle contraction with every heart beat, and changes in the spatial patterns of these waves cause potentially deadly arrhythmias. We study these waves using mathematical models, intact heart muscle and bioengineered sheets of tissue, using a variety of experimental techniques.
for more: the original excitable media pages, optical mapping database, the PNAS and PRL papers.
new software! Jakub Tomek's Ccoffinn Toolkit: paper and download:
collaborators: Leon Glass, Alvin Shrier , Emilia Entcheva , Kevin Webb, Rebecca Burton, Matt Daniels.
The term optogenetics refers to a set of methods for controlling and imaging genetically modified living tissue with light. Optogenetics has revolutionised the neurosciences and now is becoming increasingly popular in other tissues. In close collaboration with Emilia Entcheva's COOL lab , we've been sensitizing cardiac monolayers to light and seeing how we can control their behaviour.
One goal is to use optogenetics to control macroscopic wave dynamics. Macroscopic excitation waves are found in chemical reactions, slime mold colonies, as well as cardiac and neuronal tissues. In cardiac tissue, the patterns formed by these waves are different in healthy and diseased states. The ability to control wave shape, direction and velocity in cardiac tissue would expose new research targets: for example, since conduction velocity variability often causes re-entrant waves, control of wave velocity allows us to test hypotheses on spiral wave formation in a precise way.
The animated image (top right) shows an example of chirality control (chirality refers to the spirals rotation direction). A spiral wave in a cardiac monolayer (green) is coaxed into rotating in the opposite direction by a projected (red) spiral. Chirality control allows us to observe how spirals respond to stimuli: in this case the new spiral meanders to a prefered location, suggesting that the spiral probes its environment.
Future projects include controlling sympathetic neurons in intact heart and co-cultures, and revisiting the many classical experiments done on light sensitive chemical systems.
for more: the Nature Photonics paper and a review in the Journal of Physiology.
collaborators: Emilia Entcheva , Rebecca Burton, Elis Cooper, Leonardo Sacconi , and Alex Corbett .
Gil Bub (PI)
p: 514 398 8148
Sir Henry Dale Wellcome Trust Fellow
Department of Pharmacology
University of Oxford
DPhil student - graduated 2017
(supervised with Drs Rodriguez & Paterson)
University of Oxford