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EPSRC Symposium Workshop - From molecules to bodies: spanning levels of biological organisation in medicine (M2B)

14-15 December 2009 - Organisers: Paul J Thornalley, Anatoly Shmygol, Hugo A van den Berg

The coming decades will see the advent of molecular medicine in the daily routine of clinical practice, with customized care based on patient genotyping and genetic recombination targeting the patient’s own cells and tissues. The success of such developments will depend critically on the ability to predict reliably how perturbations by either the disease or therapy at the molecular level will affect the behaviour at the level of the whole system. This calls for a renewed focus on the individual as an integrated dynamical system, in which links are forged between levels of biological organisation, from molecules, cells, and tissues up to organ systems.

Various deep mathematical problems are engendered by the need to establish inter-level connections that are, in some suitable sense, functionally meaningful. The typical problem is to characterize the functional consequences at the higher level of the structures modelled at the lower level, e.g. the translation of molecular heterogeneity of cell-cell contacts to the statistics of the fluctuations of a functional parameter at the systemic level. Such problems call for sophisticated statistical sampling techniques. Another example is the reduction of dynamic degrees of freedom as one passes to coarser spatiotemporal scales, for instance, from a network of endocrine interactions to the input-output behaviour at the whole-organism level.

We will discuss novel mathematical techniques which are being developed to address these problems, with an emphasis on a small number of selected model systems which can serve as case-studies for an in-depth discussion: (i) regulation of epitope recognition in the immune system, which could hold the key to a cure for auto-immune disease, aids and cancer; (ii) regulation activation patterns in smooth muscle cells and the myocardium, focussing on cell-to-tissue signalling; (iii) regulation of energy intake and expenditure, which we need to understand better in order to control diabetes and obesity, with a focus on lipoprotein metabolism, nutrigenomics linking diet and health, and trans-fatty acids impact on the risk of vascular disease.

Monday 14th December 2009

09.00 – 09.30

Registration /coffee B1.37 & Mathematics Institute Common Room

09.30 – 10.30

Michael Berridge (Brabham Inst)

Smooth muscle cell Ca2+ activation mechanisms

10.30 – 11.00

Coffee in Mathematics Institute Common Room

11.00 – 12.00

Barbara Sanborn (Colorado State)

Contractant and relaxant hormonal influences on calcium homeostasis in myometrium

12.00 – 13.00

Withrow Gil Wier (Maryland)

Genetically encoded biosensor molecules in transgenic animals enable observation of molecular function in vivo

13.00 – 14.00

Lunch Break in Mathematics Institute Common Room

14.00 – 15.00

Kenton Sanders (Nevada)

A new ionic conductance involved in the pacemaker activity of visceral smooth muscles

15.00 – 15.30

Tea in Mathematics Institute Common Room

15.30 – 16.30

Pierre De Meyts (Hagendorn)

Structure-based systems biology of insulin and IGF-I signal transduction

16.30 - 17.30

Leighton Izu (California)

How the spatial distribution of Ca2+ signalling molecules affects Ca2+ dynamics


Hot Buffet Dinner in Mathematics Institute Common Room

Tuesday 15th December 2009

09.00 – 10.00

Andrew Sewell (Cardiff)

Makeable T cell immunity: you can improve any antigen and you can improve any TCR

10.00 – 11.00

David Price (Cardiff)

Making sense of adaptive T cell immunity: repertoire selection and the antigenic universe

11.00 – 11.30

Coffee in Mathematics Institute Common Room

11.30 – 12.30

Ellen Baake (Bielefeld)

Statistical recognition by T cells: The importance of being rare

12.30 – 13.30

Jaap van den Born (Groningen)

Proteoglycans, role in renal diseases and glycosaminoglycans antibody mapping

13.30 – 14.30

Lunch Break in Mathematics Institute Common Room

14.30 - 15.30

Ben van Ommen (Zeist)

Challenging homeostasis to quantify health

15.30 – 16.30

Kevin Hall (National Inst of Health)

Mathematical models of whole-body metabolism and body weight change

16.30 – 17.30

Carla Ferreri (Bologna)

Membrane fatty acid transformations and radical stress in cardiovascular diseases


Drink and snacks in Mathematics Institute Common Room

Statistical recognition by T-cells: The importance of being rare

ELLEN BAAKE, Technische Fakultät, Universität Bielefeld (Deutschland - Germany)

We reconsider the problem of statistical recognition as it arises in the context of T-cell activation, namely, the discrimination of foreign antigens against a background of self molecules. We start from the stochastic model as introduced by Van den Berg, Rand, and Burroughs (2001). Here, the stimulation rate that results from an encounter of a randomly chosen T-cell with a randomly-chosen antigen-presenting cell (APC) is described as a sum of the individual stimulation rates that emerge from the binding of the T-cell's receptors to a mixture of self (and, possibly, one or a few foreign) antigens on the APC.

By means of large deviation theory and rare event simulations based on this, we investigate the details of the statistical recognition mechanism in this model. We then discuss various ways of how to include negative selection into the model. We formulate a new model that takes into account both the distribution of the stimulation rates of individual receptor-ligand pairs, and the stochastic mixture of self antigens presented by APCs in the thymus and the periphery. We investigate the efficiency of negative selection in this model, and, in particular, how this depends on the stimulation rate distribution.

This is joint work with Natali Zint and Florian Lipsmeier.

Smooth muscle cell Ca2+ activation mechanisms

MICHAEL J BERRIDGE, The Babraham Institute, Cambridge (United Kingdom)

Smooth muscle cells (SMCs) are characterized by their phenotypic plasticity and diversity. The activation mechanisms that control contraction display a similar diversity in that each SMC type has a Ca2+ signalling system that is uniquely adapted to control its particular function. Phasic SMCs (vas deferens, uterus and bladder) rely on membrane depolarization to drive Ca2+ influx across the plasma membrane. This depolarization can be induced by neurotransmitters or through the operation of a membrane oscillator. Many tonic SMCs (vascular, airway and corpus cavernosum) are driven by a cytosolic Ca2+ oscillator that generates periodic pulses of Ca2+. A similar oscillator is present in pacemaker cells such as the interstitial cells of Cajal (ICC) and atypical SMCs that control other tonic SMCs (gastrointestinal, urethra, ureter). The changes in membrane potential induced by these cytosolic oscillators does not drive contraction directly but it functions to couple together individual oscillators to provide the synchronization that is a characteristic feature of many tonic SMCs.

Proteoglycans, role in renal diseases and glycosaminoglycans antibody mapping

JAAP VAN DEN BORN, Nephrology, University Medical Centre Groningen (Nederland - The Netherlands)

Unlike proteins, glycan structures are not template-driven and consequently less well understood. A major class of glycoconjugates is formed by proteoglycans, which are protein-glycosaminoglycan (GAG) conjugates present in the extracellular matrix and on the cell surface of essentially all cells. Proteoglycans play important roles in development, cell-matrix interactions, proliferation and tissue stability. Best known is the heparan sulfate proteoglycan (HSPG) family, which bears heparan sulfates (HS) as the GAG polysaccharide side chains. The ability of HS to bind a myriad of different proteins depends on the chemical characteristics of the HS chain. A large number of Golgi enzymes orchestrate the relative abundance of certain domains in the HS chains. The activity of these enzymes is determined by cell type and external conditions, leading to large structural variability within the HS chain. We developed a number of monoclonal antibodies against various epitopes of HS. The precise epitope requirements were characterized in binding assays using fluid phase competition experiments with a library of modified heparin/HS-like polysaccharides. Basically the same technique has been applied to identify the basic characteristics of protein – HS interaction, exemplified by complement factor properdin. In order to visualize these functional domains in HS, we have set up in situ binding assays on tissue sections and/or cultured cells for adhesion molecules, growth factors, chemokines and complement factors. Major spatio-temporal differences in functional HS domain expression were observed between control and diseased kidneys. Using renal cell cultures, mouse proteoglycan KO models, and a biobank of human renal biopsies and urines we found evidence for essential roles of HSPGs in inflammatory cell recruitment, tissue remodeling (fibrosis and new vessel formation), and tubular epithelial regeneration. Mechanisms involved are guidance of leukocytes via L-selectin binding and chemokine gradients, and co-receptor functions for growth factors and complement factors. We speculate non-anticoagulant heparinoids to be a promising novel class of glycomimetica aiming at reduction of inflammation and amplification of tissue regeneration.

Membrane fatty acid transformations and radical stress in cardiovascular diseases

CARLA FERRERI, Consiglio Nazionale delle Ricerche, ISOF – BioFreeRadicals, Bologna (Italia - Italy)

The analysis of fatty acids that compose membrane lipids is an important tool for understanding cell status and metabolism, and for monitoring the homeostasis that produces the optimal membrane performance. The field of lipidomics deals with the dynamic changes occurring to the lipid pattern during cell life. In medicine, lipidomics can offer a valid tool for evaluating the metabolic scenario linked to a physiological or pathological condition, including the contribution of radical stress. In this context, cardiovascular diseases offer interesting cases for discussion, since they can be connected either to the fatty acid degradation by oxidative processes and to their transformation due to the conversion of the unsaturated fatty acid geometry from cis to trans. The seminar will give an overview of the main fatty acid changes observed in cardiovascular diseases and discuss some features from the lipidomic database gathered at the Lipinutragen srl, a spin-off company at the Consiglio Nazionale delle Ricerche in Bologna.

Mathematical models of whole-body metabolism and body weight change

KEVIN HALL, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda (United States)

Maintenance of a stable body weight requires that dietary carbohydrate, fat, and protein intake rates are balanced by their utilization rates. Any imbalance of these macronutrient fluxes will result in a change of body composition (i.e. body fat and fat-free masses) and body weight. But making quantitative predictions of body weight change resulting from various diets has proved difficult because of the complex nonlinear interactions between the metabolism of the macronutrients, as well as adaptations of energy expenditure, and nonlinear changes of body composition.

Several mathematical models have recently been developed by my group to integrate whole-body metabolism data with body composition data in an attempt to better understand these complex interactions. Our models make quantitative predictions about how diet perturbations result in adaptations of fuel selection and energy expenditure. I will describe a model of human metabolism that accurately predicts body weight and composition changes in both obese and non-obese men and women. Furthermore, I will show how this model might be used to estimate free-living energy intake during a long-term weight loss intervention – a variable that has never previously been accurately measured.

How the spatial distribution of Ca2+ signaling molecules affects Ca2+ dynamics

LEIGHTON T. IZU, University of California, Davis (United States)

Ca2+-dependent arrhythmias, a leading cause of sudden cardiac death, often arises unexpectedly in heart muscle. We examine the hypothesis that spatial remodeling of key intracellular Ca2+ signaling proteins may underlie this dysfunction. This hypothesis is based on our simulations showing that even a small (~10%) change in the spatial distribution of these proteins (ryanodine receptors) can dramatically alter the stability of the Ca2+ control system; as clusters of the proteins get closer together, dramatic instability arises and changes normal cellular stability into an arrhythmogenic substrate. I will discuss the mechanism underlying this sensitivity of the Ca2+ control system to even small changes in the spatial distribution of the ryanodine receptors. The variance in the spacing of the signaling proteins can have as profound effect on the stability of the Ca2+ control system as the mean spacing. We have tested these computational predictions in cardiomyocytes by pharmacologically manipulating the ryanodine receptor spacing. Altered ryanodine receptor spacing occurs in some forms of familial hypertrophic cardiomyopathy and the instabilities in the Ca2+ control system that may ensue might underlie the high rate of sudden cardiac deaths in people with this disease.

Structure-based systems biology of insulin and IGF-I signal transduction

PIERRE DE MEYTS, Hagedorn Research Institute, Gentofte (Danmark - Denmark)

Challenging homeostasis to quantify health

BEN VAN OMMEN, TNO Quality of Life (Nederland - The Netherlands)

The oral glucose tolerance test is used in clinical practice and research to assess the degree of insulin sensitivity by quantifying the plasma glucose clearance. Yet, the impact of this glucose challenge on human physiology goes way beyond this simple observation. Both the glucose metabolism and the effect of the triggered insulin response produce extensive reactions on the level of metabolism, oxidative stress and inflammation.

We have therefore quantified the impact of the OGTT on human physiology using a systems biology approach. In 19 study subjects with mild overweight, 340 metabolites were quantified in plasma during a 3-hour and 6-point time course. Also, 80 inflammation related plasma proteins and the complete PBMC transcriptome were quantified at fasting state. This resulted in a very comprehensive overview of metabolic, regulatory and physiological changes, comprising triglyceride, fatty acid and amino acid metabolism, ketone bodies, oxidative stress defense, inflammatory signaling, and many other processes. On the one hand, this resulted in extensive “textbook biochemistry”, but on the other hand revealed many subtleties in individual differences in response. These will be discussed during the lecture.

In a broader perspective, the concept of challenging homeostasis to quantify health is receiving increasing attention. With the growing need for preventive medicine and substantiated health claims for food products to maintain optimal health, a new generation of biomarkers is needed that does not describe a (pre)pathological state but indeed quantifies optimal health by quantifying the perturbation of homeostasis. The OGTT is a classical example of such a biomarker. These concepts and examples will also be discussed.

Making sense of adaptive T cell immunity: repertoire selection and the antigenic universe

DAVID A PRICE, Department of Medical Biochemistry and Immunology, Cardiff University School of Medicine, Cardiff (United Kingdom) & Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda (United States)

Adaptive T cell immunity requires that naïve T cells from a finite and numerically inadequate precursor pool respond effectively to a multitude of potential peptide-major histocompatibility complex (pMHC) antigens derived from dangerous entities. This discrepancy is resolved, at least in part, by the phenomenon of T cell cross-reactivity. Thus, a single T cell receptor (TCR) clonotype can recognize multiple pMHC antigens; similarly, a single pMHC antigen can be recognized by multiple TCR clonotypes. Furthermore, qualitative and quantitative disparities within the system can influence response patterns and biological outcome. In this workshop, emerging data will be presented that illustrate several relevant principles: (i) the naïve T cell landscape comprises an uneven distribution of clonotype frequencies due to a process termed "convergent recombination"; (ii) individual pMHC structures elicit architecturally distinct cognate TCR repertoires; and, (iii) individual clonotypes confer distinct properties on the antigen-specific T cell population. These features contribute to the apparent complexities of immune reactivity, but also provide a preliminary framework for the deconvolution of clonotypic signatures that can inform our basic understanding of adaptive immunity.

Funded by the Medical Research Council (UK) and the Intramural Research Program of the National Institutes of Health (USA).

A new ionic conductance involved in the pacemaker activity of visceral smooth muscles

KENTON SANDERS, University of Nevada School of Medicine, Reno (United States)

Pacemaker activity in gastrointestinal smooth muscles is generated by interstitial cells of Cajál (ICC). These cells form a dense network between the circular and longitudinal muscle layers. ICC have specialized clock mechanisms that periodically discharge inward currents and depolarize ICC, generating active events known as slow waves. These events propagate cell-to-cell via low resistance, gap junctions, and also spread to the surrounding muscle cells via gap junctions. Depolarization of smooth muscle cells activates voltage-dependent Ca2+ channels and Ca2+ entry via this pathway initiates contraction. Smooth muscle cells are not capable of active propagation of slow waves, thus, the continuity of the ICC network is necessary for long distance coordination of electrical excitation (and the normal physiological behavior of intact organs). Recently we have engineered mice that express a highly fluorescent green fluorescent protein, facilitating studies of ICC in mixed populations of cells. Our initial investigations have revealed a new Ca2+-activated Cl- conductance never measured previously in ICC. The characteristics of this conductance and its possible role in smooth muscle pacemaker activity will be discussed

Makeable T cell immunity: you can improve any antigen and you can improve any TCR

ANDREW SEWELL, Department of Medical Biochemistry and Immunology, Cardiff University School of Medicine, Cardiff (United Kingdom)

Contractant and relaxant hormonal influences on calcium homeostasis in myometrium

BARBARA M. SANBORN, Colorado State University, Colorado (United States)

Uterine smooth muscle (myometrium) is an interesting model in which to study regulation of calcium homeostasis, contraction and relaxation. Myometrium is intrinsically a phasic smooth muscle. The balance between contraction and relaxation is influenced by a number of factors (innervation, membrane potential, cell-cell communication, hormonal influences, physical forces) and changes markedly over pregnancy and at the time of parturition. The relative importance of signaling pathways that influence contractile pathways and calcium homeostasis at several levels, as well as crosstalk and negative feedback between these pathways, are influenced by contractile and relaxant hormones. Intracellular store dynamics are important regulators of sustained activity. The sum total of these influences is important in achieving the prolonged, coordinated uterine contractile activity required to achieve productive labour.

Genetically encoded biosensor molecules in transgenic animals enable observation of molecular function in vivo

W GIL WIER, University of Maryland School of Medicine, Maryland (United States)

Arteries in living animals (i.e. in vivo) are in a markedly different physiological state than arteries mounted on a wire myograph, a typical experimental situation. In vivo, arteries have myogenic tone (the response to intra-luminal pressure), undergo changes in diameter, and are influenced continuously by a very large number of humoral factors and neurotransmitters. For example, it is now known that molecular events as fundamental as Ca2+ signaling for contraction are profoundly influenced by the presence of myogenic tone. Thus, understanding the true physiological relevance of a particular molecular reaction would be aided greatly by the ability to observe molecular functions within the tissues of the living animal. Transgenic mice that express genetically encoded FRET (Forster Resonance Energy Transfer) based biosensors in their arterial smooth muscle cells have recently been developed. Most importantly, in vivo, or “Intra-vital” FRET imaging can be performed on arteries of the living animal. The ability to observe molecular function in vivo, through the use of transgenic animals opens a new path to spanning the gap between molecules and tissues or whole organisms. Here we report the use of a sensor based on myosin light chain kinase (MLCK); binding of Calcium/Calmodulin (Ca/CaM) causes a conformational change that changes FRET and activates the kinase. The sensor is therefore a quantitative (i.e. ratiometric) sensor of both Ca/CaM and of MLCK activation within smooth muscle cells of arteries in vivo. Intra-vital FRET imaging performed on arteries of the intact living animal reveals for the first time the physiological responses to vasoconstrictors. The technique presents an opportunity to observe dynamically specific molecular events, as indicated by FRET, within the context of the normal function of the tissue in the living animal.

Aerial photograph of Maths Houses

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