In this talk, I will describe a smoothed particle hydrodynamics method for simulating the motion and deformation of red blood cells. After validating the model and numerical method using the dynamics of healthy red cells in shear and channel flows, we focus on the loss of red cell deformability as a result of malaria infection. The current understanding ascribes the loss of RBC deformability to a 10-fold increase in membrane stiffness caused by extra cross-linking in the spectrin network. Local measurements by micropipette aspiration, however, have reported only an increase of about 3-fold in the shear modulus. We believe the discrepancy stems from the rigid parasite particles inside infected cells, and have carried out 3D numerical simulations of RBC stretching tests by optical tweezers to demonstrate this mechanism. Our results show that the presence of a sizeable parasite greatly reduces the ability of RBCs to deform under stretching. Thus, the previous interpretation of RBC-deformation data in terms of membrane stiffness alone is flawed. With the solid inclusion, the apparently contradictory data can be reconciled, and the observed loss of deformability can be predicted quantitatively using the local membrane elasticity measured by micropipettes.
By incorporating positive and negative feedback into phosphorylation cycles of proteins such as GTPases (described in Lecture 2), one arrives at a biochemical mini-circuits with properties of a switch or an oscillator. I provide examples from papers by Boris Kholodenko. I also show the connection between bistability and hysteresis and relaxation oscillations (e.g. in the Fitzhugh-Nagumo model). I briefly
discuss applications of such ideas to models of the cell cycle proposed over the years by John Tyson.
This triplet of introductory lectures summarizes a few of the most basic biochemical models with the simple rate equations that they satisfy. I describe production-decay, with Michaelis-Menten and sigmoidal terms, showing how the latter can lead to bistable behaviour and hysteresis. I describe two bistable genetic circuits: the toggle switch by Gardner et al (2000) Nature 403, and the phage-lambda gene by Hasty et al (2000) PNAs 97. The idea of bifurcations is discussed. Finally, I introduce
phosphorylation cycles, and show that sharp responses can arise when the enzymes responsible (kinase and phosphatase) operate near saturation. (This is the so called Goldbeter-Koshland ultrasensitivity).
The mathematical context of the third story, Small Number and the Basketball Tournament, contains some basic principles of combinatorics. The plot of the story and the closing question are structured in a manner that allows the moderator to introduce the notion of permutations and combinations. Since the numbers used in the story are relatively small, this can be used to encourage the young audience to explore on their own. Mathematics is also present in the background. Small Number and his friends do mathematics after school in the Aboriginal Friendship Centre. He loves playing the game of Set and when he comes home his sister is just finishing her math homework. Small Number and his friend would like to participate in a big half-court tournament, and so on.
This opening lecture lists some of the questions and issues propelling current research in Cell Biology and modelling in this field. I introduce basic features of eukaryotic cells that can crawl, and explain briefly the role of the actin cytoskeleton in cell motility. I also introduce the biochemical signalling that regulates the cytoskeleton and the concept of cell polarization. By simplifying the
enormously complex signalling networks, and applying tools of mathematics (nonlinear dynamics, scaling, bifurcations), we can hope to get some understanding of a few of the basic mechanisms that areresponsible for symmetry breaking, robustness, pattern formation, self-assembly, and other cell-level phenomena.
Central to Alan Turing's posthumous reputation is his work with British codebreaking during the Second World War. This relationship is not well understood, largely because it stands on the intersection of two technical fields, mathematics and cryptology, the second of which also has been shrouded by secrecy. This lecture will assess this relationship from an historical cryptological perspective. It treats the mathematization and mechanization of cryptology between 1920-50 as international phenomena. It assesses Turing's role in one important phase of this process, British work at Bletchley Park in developing cryptanalytical machines for use against Enigma in 1940-41. It focuses on also his interest in and work with cryptographic machines between 1942-46, and concludes that work with them served as a seed bed for the development of his thinking about computers.