Key information
Research topics
Cell Biology Computational & Systems Biology Developmental Biology Imaging
A 2023 Crick PhD project with Katie Bentley.
Project background and description
Our lab primarily aims to understand how individual endothelial cells (that comprise blood vessel walls) collectively coordinate (move, communicate and compete) during “angiogenesis” (the extension of new blood vessels from pre-existing ones), generating emergent tissue patterning dynamics that lead to the diversity of vascular branching structures throughout our bodies. We aim to understand how changes to tissue conditions or cell properties in different diseases drive the cells to collective construct maladapted and dysfunctional vessels with a focus on blindness causing retinopathies, where abnormal vessels greatly exacerbate patient prognosis.
To untangle this dynamic, collective cell construction process we integrate predictive, computational agent-based model (ABM) simulations following an “adaptive systems” approach [1], with closely tied in vitro/in vivo experiments (performed either within our lab or by our close network of leading UK and International vascular biology/bioengineer collaborators).
Our predictive models, validated in vivo, have already uncovered several key angiogenesis mechanisms and most recently pointed to an unappreciated role for cell shape-signalling feedback or “active perception” in enhancing cells collective patterning “decisions”, which determine where new vessels will sprout from [2]. The cells appear to utilise their flexible body shape (their “embodiment”) to rapidly relocalise sensors (e.g. growth factor receptors) by extending long motor-driven finger-like protrusions moving them further into the environment, e.g. to more quickly detect tissue regions needing oxygen, speeding up their collective patterning and vessel building response. In related work we found that slower patterning decisions among cells lead directly to sparser branched networks, as less new branches are able to grow in time [3, 4]. And in pathological conditions such as cancer and retinopathy we identified a phase shift where cells abnormally oscillate, unable to stick to a collective branching decision driving enlarged and poorly branched vessels [5].
This project can explore and extend from these studies in a number of potential directions, allowing the project to be influenced by the candidates own interests while helping us to uncover deeper understanding of how cells exploit their shape changing ability to make timely decisions and understand how this goes awry during aberrant angiogenesis in retinopathy, e.g. by interacting with our clinical ophthalmologists collaborators.
Sitting at this exciting interface of disciplines gives a rare opportunity to learn and develop as an interdisciplinary scientist training in both state of the art dry lab approaches (performing careful development and analysis of emergent cell behaviour in multiscale ABM simulations) and wet lab techniques (in cell culture experiments/imaging using in vitro bioengineered devices, closely coupled to the simulations). Full support and training on wet or dry lab methods that may be less familiar will be given from our small friendly and supportive cross disciplinary lab. By integrating both computational and experimental work in the first stages of the project you can gain a deeper appreciation for the nuances of the system while later choosing to either continue integrating both sides or focus fully on either modelling or experiments, as you take more informed ownership of the key questions you want to investigate and lead the project forward yourself.
Candidate background
This project will suit a candidate keen to develop as an interdisciplinary scientist tackling complex systems problems, with either 1) some experience/fascination already developed in simulation/programming, theoretical biology/pattern formation and wetlab cell-based experiments or 2) more likely, is much stronger in experience in one side of this, e.g. computational modelling/programming or in vitro cell culture/microscopy imaging experiments, but can demonstrate a clear enthusiasm and commitment to try out learning the other skillsets required to understand collective self-organising behaviour/pattern formation processes.
For example the ideal candidate would have a proportion of the skills/experiences listed below, with a willingness to learn those others not yet encountered:
Computational: Our core simulation codebases in the lab are written in C++ to maintain useability, efficiency and allow new projects to leverage and benefit from existing code and peer support so either prior experience or a willingness to learn C++ is required. Full C++ training and support from the lab will be given if needed and non-core code, e.g. analysis scripts or prototyping new simulations can be written in any language, e.g. python. Experience with simulation methods that capture 1) biomechanics (e.g. node-spring or particle force modelling) 2) signalling dynamics, e.g. differential equations; 3) cell behaviours using discrete, rule-based ABM methods or 4) information theory methods to understand decision-making and communication would be a definite plus.
Wetlab: experience of cell culture, antibody staining, western blots, qPCR, microscopy imaging and/or image analysis or would be a plus and an interest to learn state of the art microcontact printing/microfabrication methods to design tailor made devices to test cell behaviour theories a plus, but full training will be provided.
References
1. Bentley, K., Philippides, A. and Ravasz Regan, E. (2014)
Do endothelial cells dream of eclectic shape?
Developmental Cell 29: 146-158. PubMed abstract
2. Zakirov, B., Charalambous, G., Thuret, R., Aspalter, I.M., Van-Vuuren, K., Mead, T., . . . Bentley, K. (2021)
Active perception during angiogenesis: filopodia speed up Notch selection of tip cells in silico and in vivo.
Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 376: 20190753. PubMed abstract
3. Kur, E., Kim, J., Tata, A., Comin, C.H., Harrington, K.I., Costa, L.D.F., . . . Gu, C. (2016)
Temporal modulation of collective cell behavior controls vascular network topology.
eLife 5: e13212. PubMed abstract
4. Bentley, K. and Chakravartula, S. (2017)
The temporal basis of angiogenesis.
Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 372: 20150522. PubMed abstract
5. Ubezio, B., Blanco, R.A., Geudens, I., Stanchi, F., Mathivet, T., Jones, M.L., . . . Gerhardt, H. (2016)
Synchronization of endothelial Dll4-Notch dynamics switches blood vessels from branching to expansion.
eLife 5: e12167. PubMed abstract
