# Seminars (ICBW01)

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Event When Speaker Title
ICBW01 24th September 2001
13:30 to 13:40
Opening Remarks
ICBW01 24th September 2001
13:40 to 14:40
Modelling molecular events in a small volume of living cytoplasm
In a recent study, we proposed an atomic level structure for a lattice of chemotaxis receptors in coliform bacteria (Shimizu et al. Nature Cell Biol .2: 792-796, 2000). A unique feature of this model was that it created a small compartment between the plasma membrane and an extended hexagonal lattice of the signaling proteins CheA and CheW. The proposed compartment is 20-30 nm deep, perhaps 300-500 nm wide, and contains a thicket of extended coiled-coils forming the cytoplasmic domains of the chemotactic receptors. The compartment is not closed, and should be freely accessible to cytoplasmic proteins diffusing in from the lateral borders or through 10 nm diameter pores in the hexagonal lattice. Despite the absence of sealed boundaries, however, there is reason to think that this minute volume of bacterial cytoplasm will be highly enriched in two diffusible proteins, CheR and CheB, which are responsible for adaptation in the bacterial system. We are currently using computational methods to explore the possible movement of these enzymes through the "adaptation compartment". In particular we examined the possibility that these molecules might progress from receptor to receptor by swinging from one flexible region to another, like a monkey swinging through trees ("molecular brachiation"). We also attempted to predict temporal changes in protein conformation within such a molecular lattice. Could conformational changes in one receptor spread to neighboring receptors? If so, by what route and what will be the likely consequences for cellular behavior? Conclusions reached in this analysis are likely to lead to a clearer picture of the physiology of the chemotactic response in bacteria. They will also provide clues to the operation of other "privileged compartments" in both bacteria and eucaryotic cells.
ICBW01 24th September 2001
14:40 to 15:40
The role of the cytoskeleton in intracellular signalling
The cytoskeleton of eucaryotic cells represents an interconnected network of actin filaments, microtubulus and intemediate filaments, which extends over the entire cell. It has long been known that this network regulates cell motility, cell shape, gene expression and a number of other cell functions. Recently it has been recognized that mechanical forces may regulate intracellular signaling pathways and it has been suggested this may involve the cytoskeleton. On one hand the cytoskeleton provides docking sites for many signaling molecules, on the other hand, due to its interconnected character is capable to transmit mechanical signals between distinct parts of the cell. This dual role makes the cytoskeleton an ideal mechano-chemical conversion apparatus. The specific way, how the cytoskeleton may participate in intracellular signaling is not known. I will first show, using information from protein data basis and interaction networks that indeed there is a strong correlation between signaling molecules and cytoskeleton associated molecules. I will then present models for the specific mechanisms of the cytoskeleton's involvement in intracellular signal transduction.
ICBW01 24th September 2001
16:10 to 17:10
GATA-3 transcriptional memory in T helper lymphocytes a mathematical model of steady-state and temporal behaviour
T helper (Th) lymphocytes are central regulators of adaptive immune responses. Upon initial contact with antigen presenting cells, they differentiate into Th1 or Th2 cells. Th1 cells express activators of cellular immune responses such as IFN gamma, while Th2 cells stimulate humoral immune responses through the production of IL-4. The Th1/Th2 differentiation is determined by costimulatory cytokine signals acting on specific transcription factors. Recently, the transcription factor GATA-3 has been shown to induce the Th2 program of cytokine expression and to exhibit autoactivation of its expression. By means of a mathematical model of GATA-3 expression it is demonstrated how this autoregulatory loop can lead to an bistable switch between low and upregulated levels of GATA-3. On the basis of this mechanism, the establishment of a transcriptional memory for IL-4 expression through transient activation of the JAK/STAT6 pathway is analysed and compared with experimental results.
ICBW01 25th September 2001
09:20 to 09:30
Opening Remarks Meeting room 2 at Centre for Mathematical Sciences
ICBW01 25th September 2001
09:30 to 10:10
Reverse engineering of a developmental genetic regulatory network Meeting room 2 at the Centre for Mathematical Sciences
I will give an overview of a collaborative project with Prof. Eric Davidson (Caltech) in which we have been reverse engineering the genetic regulatory network underlying endoderm-mesoderm specification in sea urchin embryos.

To be able to carry out this work, we have developed - and are continuing to develop - a range of new software tools and an associated reverse engineering methodology which I will describe briefly.

ICBW01 25th September 2001
10:10 to 10:50
J Jäger Looking at the future of functional genomics from inside the Drosophila blastoderm -(Meeting Rm 2 at the Centre for Math. Sciences)
Functional genomics will ultimately involve the application of genomic methods to the full range of biological functions, including those that are properties of multicellular organisms. This includes areas such as neurobiology, development, macroevolution, and ecology. This talk will be concerned with the functional genomics of animal development. The central problem in animal development is the generation of body form. This problem was first considered by Aristotle, and in the nineteenth century is was shown that basic body form is determined by interactions among cells in a morphogenetic field. The determination of a morphogenetic field in development involves the expression of genes in spatial patterns. Spatially controlled gene expression cannot as yet be assayed in microarrays, but certain special properties of the fruit fly Drosophila which make it a premier system for developmental genetics also enable it to be used as a naturally grown differential display system for reverse engineering networks of genes. In this system we can approach fundamental scientific questions about development as well as certain computational questions that arise in the analysis of genomic level gene expression data.

Our approach is called the gene circuit method'', and it consists of 4 components: (1) The formulation of a theoretical model for gene regulation. (2) The acquisition of gene expression data using fluorescently tagged antibodies. (3) The determination of the values of parameters in the model or the demonstration that no such values exist by numerical fits to data. The results of (1), (2), and (3) are used (4) to validate the model by comparison to the existing experimental data and by making further predictions. Recent progress in all 4 of these areas will be discussed.

ICBW01 25th September 2001
11:10 to 11:50
G Von Dassow Models of modules: putting the molecular parts together into genetic devices (Meeting rm 2 at the Centre for Mathematical Sciences)
Our research into mathematical models of gene networks began with a curiosity about the genetic architecture of development: to what extent can we say that gene networks are modular building blocks of developmental mechanisms? By "module" we mean a small conspiracy of genes that together exhibit some functional behavior, intrinsic to the network itself and related to the functional role of that network in the organism. I emphasize that modularity is a working assumption, rather than something we are trying to prove rigorously. We've made an extended study of two such putative modules, the Drosophila segment polarity network, and the Drosophila neurogenic network. Our approach has been to do the computer-modeling equivalent of a biochemical reconstitution: add known facts to the model until it begins to exhibit life-like behaviors. The segment polarity module's job is to maintain boundaries; the neurogenic network's job is to mediate lateral inhibition; for both modules, minimal in silico reconstitutions exhibit those behaviors robustly with respect to the kinds of variation that we would expect genetic networks to experience in real life. I'll discuss a handful of results from these models that we find provocative: first, I'll discuss what we've learned about what makes these modules' functional behaviors robust to parameter variation and other insults, and how we think these models shed light on the phenomenon of canalization; next, I'll describe some instances in which the failure of the segment polarity models to account for certain details led us to mechanistic questions about the real network; and finally, I'll talk about some ideas, stimulated by the models, about how these two networks arose, highlighting the hierarchical, nested nature of gene networks.
ICBW01 25th September 2001
11:50 to 12:30
Microarrays and yeast: insights into gene regulation Meeting room 2 at the Centre for Mathematical Sciences
ICBW01 25th September 2001
13:50 to 14:00
K Vass Normalisation and local variation in microarrays Meeting room 2 at Centre for Mathematical Sciences
ICBW01 25th September 2001
14:00 to 14:40
A Brazma Reconstructing elements of gene networks from genome scale microarray data (Meeting rm 2 at the Centre for Mathematical Sciences)
ICBW01 25th September 2001
14:40 to 15:20
From gene expression to gene interaction Meeting room 2 at the Centre for Mathematical Sciences
ICBW01 25th September 2001
15:40 to 16:20
O Wolkenhauer System theoretic models of gene expression and gene interactions Meeting room 2 at the Centre for Mathematical Sciences
ICBW01 25th September 2001
16:20 to 16:45
Funding opportunities in bioinformatics and theoretical biology Meeting room 2 at the Centre for Mathematical Sciences
ICBW01 25th September 2001
16:45 to 17:20
Discussion Session Meeting room 2 at The Centre for Mathematical Sciences
ICBW01 26th September 2001
10:00 to 11:00
J Lewis Notch signalling in spatial and temporal patterning
ICBW01 26th September 2001
11:30 to 12:30
Extracellular matrix alignment by cells: discrete and continuous models compared
The basic event in the formation of scar tissue in a wound is the remodelling of extracellular matrix by fibroblasts cells. These cells enter the wound from surrounding tissue, break down the fibrin-based blood clot, and replace it with a collagen-based matrix. The orientation of the new collagen fibres involves a complex interplay between cells and matrix: cells tend to move along collagen fibres, and also reorient fibres towards their direction of movement. I will discuss and compare two different approaches to modelling this process of fibre reorientation by fibroblasts. I will describe a discrete formulation in which each cell is represented as a separate entity, within a continuum of collagen fibres. I will compare this with a continuous model with densities of cells and matrix that are functions of space and orientation. The two approaches offer different insights into the process of matrix alignment and I will discuss their implications for scar tissue formation.
ICBW01 26th September 2001
14:30 to 15:30
In vivo imaging as a bridge between molecular, cellular and tissue level data in embryonic vertebrate development
One of the beautiful aspects of embryonic developmental is the sculpting of cells and tissue into functioning structures. Although the recent explosion of molecular data has provided tremendous insight into the machinery underlying the sculpting processes, it is a major challenge to coordinate molecular and cellular data in dynamic systems. The next steps of determining the function of genes will rely on our ability to create a framework to visualize and analyze cell movements, cell signaling and gene expression in living systems in 2 and 3 dimensions. To approach this, we are using in vivo imaging as a bridge between the levels of the biology and between experiment and theoretical modeling. We have developed techniques to trace and analyze fluorescently labeled cell movements and study cell signaling dynamically in living chick and mouse embryos. To more accurately coordinate gene expression patterns with morphological changes, we use time-lapse imaging to pinpoint the location of cells at critical times during a process before fixing the embryo and comparing the pattern of gene expression to cell positions. An excellent model system to study the interaction of rapid changes in gene expression and morphology is the segmentation of tissue into somites and we will present data from our studies in chick. We will also present work from a new project investigating blood formation and cardiovascular development in mouse.
ICBW01 26th September 2001
16:00 to 17:00
Intracellular calicum cycling and control of action potential duration
Cardiac electrophysiology is a field with a rich history of integrative modeling. A particularly important milestone was the development of the first biophysically-based cell model describing interactions between voltage-gated membrane currents, pumps and exchangers, and intracellular calcium (Ca2+) cycling processes (DiFrancesco & Noble, Phil. Trans. Roy. Soc. Lond. B 307: 353), and the subsequent elaboration of this model to describe the cardiac ventricular myocyte action potential (Noble et al. Ann. N.Y. Acad. Sci. 639: 334; Luo, C-H and Rudy, Y. Circ. Res.74: 1071). These, and all other integrative models of the myocyte developed to date are of a type known as "common pool" models (Stern, Biophys. J. 63: 497). In such models, Ca2+ flux through L-type Ca2+ channels (LCCs) and ryanodine sensitive Ca2+ release channels (RyRs) in the junctional sarcoplasmic reticulum (JSR) membrane is directed into a common Ca2+ compartment. Ca2+ within this common pool also serves as activator Ca2+ triggering JSR Ca2+ release. In a modeling tour de force, Stern demonstrated that common pool models are structurally unstable, exhibiting all-or-none Ca2+ release except (possibly) over some narrow range of model parameters. Despite this inability to reproduce experimentally measured properties of graded JSR Ca2+ release, common pool models have been very successful in reproducing and predicting a range of myocyte behaviors. This includes properties of interval-force relationships that depend heavily on intracellular Ca2+ uptake and release mechanisms (Rice et al. Am. J. Physiol. 278: H913). Given these findings, one may wonder whether or not it is important to incorporate an accurate biophysical description of graded JSR Ca2+ release in computational models of the cardiac myocyte.

Stern went on to propose the "local-control" theory of Ca2+ release. In this theory, individual LCCs, the set of RyR with which they communicate, and the subspace within which they communicate, defines a functional release unit (FRU). Local control theory holds that while Ca2+ release within each FRU may be all or none, the averaged behavior of many independent FRUs reflects the probability of opening of LCCs. We have previously developed a model of the functional release unit (FRU) consisting of one LCC, eight RyR, and the volume in which they are enclosed (Biophys J 77:1871-84). To study the impact of local Ca2+ control in the context of the whole cell AP, we have developed a new class of ventricular cell model which combines the stochastic simulation of a large number of independent FRUs with the solution of a system of coupled ordinary differential equations describing the full complement of card

ICBW01 27th September 2001
10:00 to 11:00
Mechanisms, variation, conservation, and integration of early morphogenic machanies in vertebrates
Investigation of the mechanism and morphogenic function of convergence, extension, and ingression of cells in the early morphogenesis of several species of amphibians shows that similar morphogenic movements are driven by different cell behaviors and similar cell behaviors have different morphogenic consequences, depending on how the behaviors are integrated in the larger context. Convergence and extension of the axial mesoderm, the paraxial mesoderm and the neural plate play major roles in gastrulation, neurulation, and body axis formation in amphibians, and probably in other vertebrates as well. Convergent extension of both mesodermal and neural tissues in the anuran (tail-less amphibian), Xenopus laevis, share the feature of occurring by mediolateral intercalation of an initially short and wide array of cells to produce a longer, narrower array. These tissues differ in that intercalation of mesodermal cells is driven by a bipolar, mediolaterally oriented protrusive activity whereas intercalation of neural cells is driven by a medially directed, monopolar protrusive activity. They also differ in that the normal, monopolar mode of neural cell intercalation is dependent on the midline tissues of notoplate or notochord, whereas no midline is defined in the bipolar mode of mesodermal cell intercalation. Despite their differences, the biomechanical integration of these local cell intercalation behaviors is similar in the two tissues- a pushing force is exerted in the anterior-posterior axis and tension is exerted in the transverse, mediolateral axis. The result of the pushing forces result in extension of both the mesoderm and neural tissue in the anterior-posterior axis. The mesoderm stiffens in the anterior-posterior axis during extension, thus increasing its resistance to buckling. In contrast, the consequence of the transverse tension generated by convergence is context dependent and differs between neural and mesodermal tissues. The lateral edges of the neural plate are free to move to the midline as the attached, lateral epidermis spreads, allowing neural fold fusion and neural tube closure. In the mesodermal tissue, however, the lateral edges are attached to the contracting vegetal endoderm. As a result, convergence generates hoop stress across the dorsal lip, which pulls the dorsal midline ventrally, thus aiding and abetting involution and blastopore closure. Thus similar cell behaviors produce dramatically different morphogenic results, dependent on their context.
ICBW01 27th September 2001
11:30 to 12:30
Cell movements during early zebrafish morphogenesis
The development of the vertebrate embryo depends upon substantial cell rearrangement to shape an amorphous ball of cells into an animal. We know in general terms from fate mapping studies where cells will go during this process but in many cases we know little about the actual forces and movements involved. We are looking at these problems using the zebrafish as a model organism. The zebrafish has many advantageous qualities for these studies, notably it grows rapidly with a transparent embryo in which all cells can be visualised. There also exist many mutant lines deficient in aspects of morphogenesis. We have developed methods of following and analysing the movements of many hundreds of cells in the early zebrafish embryo. The philosophy of our approach is that if we can trace the movements all the cells within a significant volume of the embryo we can begin to ask questions about the cellular mechanisms that cause the tissue to change shape. Our analyses allow us to generate metrics that can be used to describe changes in behaviours in time and in space and to compare events inmutant embryos to those in the wild type. In this way we have begun to isolate the component mechanisms that are involved in the earliest stages of gastrulation. I will present two stages in this process, the organisation of the blastoderm into germ layers, and the subsequent convergence and extension of the axial mesoderm. In both cases, we compare the patterns of cell reorganisation in wild type and mutant animals and from this try to infer the underlying mechanisms.
ICBW01 27th September 2001
14:30 to 15:30
K Weijer The control of cell movement during Dictyostelium morphogenesis
Starvation results in the chemotactic aggregation of single cells of the social amoebae Dictyostelium discoideum to form a fruiting body. Morphogenesis results from the coordinated movement of differentiating cells. We study the dynamics and geometry signals controlling cell movement during all stages of development. Cell movement is controlled by propagating waves of the chemoattractant cAMP. During aggregation these waves have the form of target patterns or simple spirals. In the mound and slug stage of development the waves have more complex geometry's, such as multi-armed scroll waves. We can now visualise cAMP signal transduction at the single cell level in vivo and are analysing the dynamics of cAMP signalling in all celltypes during development in a series of signalling and movement mutants. We correlate the signalling and movement response of individual cells and begin to understand how the geometry of the waves in conjunction with a celltype specific differential chemotactic movement gives rise to the organism's characteristic morphogenesis. We have formalised these findings into both discrete and continuous mathematical models that can describe the aggregation, mound and slug stages of Dictyostelium development.
ICBW01 27th September 2001
16:00 to 17:00
P Hunter Physiome Projects: The heart, lungs and musculo-skeletal system
The IUPS Physiome Project uses anatomically and biophysically based computational modelling to analyse physiological function in terms of underlying structure, material properties and molecular mechanisms. Markup languages are being defined for describing cell, tissue and organ structure, material properties and physiological function. This talk will outline the development of these markup languages and their associated software tools and describe the development of Physiome models for the heart, lungs and musculo-skeletal system.
ICBW01 28th September 2001
09:00 to 10:00
ATP-sensitive K-channels and insulin secretion in health and disease
ATP sensitive K-channels (ATP channels) play important roles in a diverse range of tissues (including pancreatic beta-cells, neurones, and cardiac, skeletal and smooth muscles) by coupling the metabolic state of the cell to its electrical activity. In pancreatic beta-cells, for example, K ATP closure in response to glucose metabolism produces membrane depolarization, leading to Ca 2+ influx and insulin secretion. K ATP channels are also involved in glucose sensing in hypothalamic neurones, in ischemic preconditioning of cardiac muscle and, in vascular smooth muscle, in the regulation of vessel tone. Metabolic regulation is mediated by changes in intracellular ATP (which blocks the channel) and MgADP (which activates the channel). K ATP channels are inhibited by sulphonylurea drugs, which stimulate insulin secretion and are used to treat type 2 diabetes, and activated by K ATP-channel openers, a structurally diverse group of drugs with a wide range of potential therapeutic applications.

K ATP channels share a common pore-forming subunit, Kir6.2, which associates in a 4:4 heteromeric complex with different sulphonylurea receptor isoforms (SUR1 in beta-cells, SUR2A in heart, and SUR2B in smooth muscle). Kir6.2 serves as an ATP-sensitive pore while SUR acts as a regulatory subunit, endowing the channel with sensitivity to the stimulatory effects of MgADP and K ATP-channel openers and the inhibitory action of sulphonylureas. K ATP channels containing different types of SUR subunit show different sensitivities to sulphonylureas and K ATP-channel openers. Mutations in SUR1 or Kir6.2 that result in channel closure produce congenital hypoglycaemia of infancy in man, a disease of excessive insulin secretion. Conversely, impaired cell metabolism, or mutations in Kir6.2, which lead to enhanced channel activity, result in diabetes.

This talk will present an overview of our currents studies on the relationship between K ATP-channel structure and function, focusing on three main topics: inhibition by ATP; activation by Mg-nucleotides such as MgADP and MgATP; and the role of K ATP channels in disease.

ICBW01 28th September 2001
10:00 to 11:00
D Noble From genes to whole organs: vertical integration using mathematical simulation of the heart
Biological modelling of cells, organs and systems has reached a very significant stage of development. Particularly at the cellular level, there has been a long period of iteration between simulation and experiment (Noble & Rudy, 2001). We have therefore achieved the levels of detail and accuracy that are required for the effective use of models in drug development. To be useful in this way, biological models must reach down to the level of proteins (receptors, transporters, enzymes etc), yet they must also reconstruct functionality right up to the levels of organs and systems. This is now possible and three important developments have made it so:
• Relevant molecular and biophysical data on many proteins and the genes that code for them is now available. This is particularly true for ion transporters (Ashcroft, 2000) The complexity of the biological processes that can now be modelled is such that valuable counter-intuitive predictions are emerging (Noble & Colatsky, 2000). Multiple target identification is also possible.
• Computer power has increased to meet the demands. Even very complex cell models involving up to 50 different protein functions can be run on single processor machines, while parallel computers are now powerful enough to enable whole organ modelling to be achieved. (Kohl et al 2000)

I will illustrate these points with reference to models of the heart.

The criterion that models must reach down to the level of proteins automatically guarantees that they will also reach down to the level of gene mutations when these are reflected in identifiable changes in protein function (Noble 2001). Changes in expression levels characteristic of disease states can also be represented. These developments ensure that it will be possible to use simulation as an essential aid to patient stratification. I will illustrate these points with reference to sodium channel mutations.

• ICBW01 28th September 2001
11:30 to 12:30
Closing discussion and closing remarks