Past Mathematical Biology and Ecology Seminar

This will be a whistle-stop tour of a few topics on infectious disease modelling, mainly influenza. Topics to include:

• challenges in capturing dynamics of pathogens with multiple co-circulating strains
• untangling the 2009 influenza pandemic from medical insurance claims data from the US
• bioinformatic methods to detect viral packaging signals
• and a big science project (top secret until the talk!)

Julia will be visiting the Mathematical Institute on sabbatical this term, and hopes this talk will help us find areas of overlapping interests.

Image use continues to increase in both biomedical sciences and clinical practice. State of the art acquisition techniques allow characterisation from subcellular to whole organ scale, providing quantitative information of structure and function. In the heart, for example, images acquired from a single modality (cardiac MRI) can characterise micro- and macrostructure, describe mechanical function and measure blood flow. In the lungs, new contrast agents can be used to visualise the flow of gas in free breathing subjects. This provides rich new sources of information as well as new challenges to extract data in a way that is useful to clinicians as well as computer modellers.
I will describe efforts in my group to use the latest advances in machine learning to analyse images, and explain how we are applying these to the development of accurate computer models of the heart.
 

Hypoxia, i.e. a reduction in dissolved oxygen concentration below physiologically normal levels, has been identified as playing a critical role
in the progression of many types of disease and as a key determinant of the success of cancer treatment. It poses a particular challenge for treatments
such as radiotherapy, photodynamic and sonodynamic therapy which rely on the production of reactive oxygen species. Strategies for treating hypoxia have
included the development of hypoxia-selective drugs as well as methods for directly increasing blood oxygenation, e.g. hyperbaric oxygen therapy, pure
oxygen or carbogen breathing, ozone therapy, hydrogen peroxide injections and administration of suspensions of oxygen carrier liquids. To date, however,
these approaches have delivered limited success either due to lack of proven efficacy and/or unwanted side effects. Gas microbubbles, stabilised by a
biocompatible shell have been used as ultrasound contrast agents for several decades and have also been widely investigated as a means of promoting drug
delivery. This talk will present our recent research on the use of micro and nanobubbles to deliver both drug molecules and oxygen simultaneously to a
tumour to facilitate treatment.

We adopt the paradigm of understanding how the heart develops during pregnancy as a first principal to inform on adult heart repair and regeneration. Our target for cell-based repair is the epicardium and epicardium-derived cells (EPDCs) which line the outside of the forming heart and contribute vascular endothelial and smooth muscle cells to the coronary vasculature, interstitial fibroblasts and cardiomyocytes. The epicardium can also act as a source of signals to condition the growth of the underlying embryonic heart muscle. In the adult heart, whilst the epicardium is retained, it is effectively quiescent. We have sought to extrapolate the developmental potential of the epicardium to the adult heart following injury by stimulating dormant epicardial cells to give rise to new muscle and vasculature. In parallel, we seek to modulate the local environment into which the new cells emerge: a cytotoxic mixture of inflammation and fibrosis which prevents cell engraftment and integration with survived heart tissue. To this end we manipulate the lymphatic vessels in the heart given that, elsewhere in the body, the lymphatics survey the immune system and modulate inflammation at peripheral injury sites. We recently described the development of the cardiac lymphatic vasculature and revealed in the adult heart that they undergo increased vessel sprouting (lymphangiogenesis) in response to injury, to improve function, remodelling and fibrosis. We are currently investigating whether increased lymphangiogenesis functions to clear immune cells and constrain the reparative response for optimal healing.

Feedback control is found extensively in many natural and technological systems. Indeed, many biological processes use feedback
to regulate key processes – examples include bacterial chemotaxis and negative autoregulation in genetic circuits. Despite the prevalence of
feedback in natural systems, its design and implementation in a Synthetic Biological context is much harder.  In this talk I will give
examples of how we implemented feedback systems in three different biological systems. The first one concerns the design of a synthetic
recombinase-based feedback loop, which results into robust expression. The second describes the use of small RNAs to post-transcriptionally
regulate gene expression through interaction with messenger RNA (mRNA). The third involves the introduction of negative feedback in a
two-component signalling system through a controllable phosphatase.  Closing, I will outline the challenges posed by the design of such
systems, both theoretical and on their implementation.

Current medical practice is driven by the experience of clinicians, by the difficulties of integrating enormous amounts of complex and heterogeneous static and dynamic data and by clinical guidelines designed for the “average” patient. In this talk, I will describe some of my research on developing novel, specially-crafted machine learning theories, methods and systems aimed at extracting actionable intelligence from the wide variety of information that is becoming available (in electronic health records and elsewhere) and enabling every aspect of medical care to be personalized to the patient at hand. Because of the unique and complex characteristics of medical data and medical questions, many familiar machine-learning methods are inadequate.  My work therefore develops and applies novel machine learning theory and methods to construct risk scores, early warning systems and clinical decision support systems for screening and diagnosis and for prognosis and treatment.  This work achieves enormous improvements over current clinical practice and over existing state-of-the-art machine learning methods.  By design, these systems are easily interpretable and so allow clinicians to extract from data the necessary knowledge and representations to derive data-driven medical epistemology and to permit easy adoption in hospitals and clinical practice. My team has collaborated with researchers and clinicians in oncology, emergency care, cardiology, transplantation, internal medicine, etc. You can find more information about our past research in this area at: http://medianetlab.ee.ucla.edu/MedAdvance.

Building on advancements in computer vision we now have an array of visual tracking methods that allow the reliable estimation of cellular motion in high-throughput settings as well as more complex biological specimens. In many cases the underlying assumptions of these methods are still not well defined and result in failures when analysing large scale experiments.

Using organotypic co-culture systems we can now mimic more physiologically relevant microenvironments in vitro.  The robust analysis of cellular dynamics in such complex biological systems remains an open challenge. I will attempt to outline some of these challenges and provide some very preliminary results on analysing more complex cellular behaviours.

In the first part of my presentation, I will briefly summarize a dynamic view of the cell cycle created in collaboration with Prof John Tyson over the past 25 years. 
In our view, the decisions a cell must make during DNA synthesis and mitosis are controlled by bistable switches, which provide abrupt and irreversible transition 
between successive cell cycle phases. In addition, bistability provides the foundation for 'checkpoints' that can stop cell proliferation if problems arise 
(e.g., DNA damage by UV irradiation). In the second part of my talk, I will highlight a few representative examples from our ongoing BBSRC Strategic LoLa grant 
(http://cellcycle.org.uk/) in which we are testing the predictions of our theoretical ideas in human cells in collaboration with four experimental groups.

Proteomics is seen as the next logical step after genomics to understand life processes at the molecular level. With increasing capabilities of modern mass spectrometers the deep proteome (>8000 proteins detected) has become widely accessible, only to be replaced recently by the "Ultra-deep proteome" with ~14000 proteins detected in a single cell line. Furthermore, new data search algorithms and sample preparation methods allow not only to achieve comprehensive sequence coverage for the majority of proteins, but also to detect protein variations and single amino acid polymorphisms in proteins, further linking genomic variation to protein phenotypes. The combination of genomic and proteomic information on individual (patient) level could mark the beginning of the "Post-Proteomic Era".

Please register via https://www.eventbrite.co.uk/e/qbiox-colloquium-trinity-term-2017-ticke…

The ability to study the transcriptome, proteome – and other aspects – of many individual cells represents one of the most important technical breakthroughs and tools in biology and medical science of the past few years. They are revolutionising study of biological systems and human disease, enabling for example: hypothesis-free identification of rare pathogenic (or protective) cell subsets in chronic diseases, routine monitoring of patient immune phenotypes and direct discovery of mole cular targets in rare cell populations. In parallel, new computational and analytical approaches are being intensively developed to analyse the vast data sets generated by these technologies. However, there is still a huge gap between our ability to generate the data, analyse their technical soundness and actually interpret them. The QBIOX network may provide for a unique opportunity to complement recent investments in Oxford technical capabilities in single-cell technologies with the development of revolutionary, visionary ways of interpreting the data that would help Oxford researchers to compete as leaders in this field.

Please register via https://www.eventbrite.co.uk/e/qbiox-colloquium-trinity-term-2017-ticke…

Biomedical research and clinical practice rely on complex and multimodality

datasets for the characterisation of human organs in health and disease. In

computational biomedicine, we often argue that multiscale computational

models are and will be increasingly required as tools for data integration,

for probing the established knowledge of physiological systems, and for

predictions of the effects of therapies and disease. But what has

computational biomedicine delivered so far? This presentation will describe

successes, failures and future directions of computational models in

cardiac research from basic to translational science.

All data intelligence processes are designed for processing a finite amount of data within a time period. In practice, they all encounter
some difficulties, such as the lack of adequate techniques for extracting meaningful information from raw data; incomplete, incorrect 
or noisy data; biases encoded in computer algorithms or biases of human analysts; lack of computational resources or human resources; urgency in 
making a decision; and so on. While there is a great enthusiasm to develop automated data intelligence processes, it is also known that
many of such processes may suffer from the phenomenon of data processing inequality, which places a fundamental doubt on the credibility of these 
processes. In this talk, the speaker will discuss the recent development of an information-theoretic measure (by Chen and Golan) for optimizing 
the cost-benefit ratio of a data intelligence process, and will illustrate its applicability using examples of data analysis and 
visualization processes including some in bioinformatics.

The management of natural resources, from fisheries and climate change to gut bacteria colonies, all require the development of ecological models that represent the full spectrum of population interactions, from competition, through mixotrophy and mutualism, to predation.

Mixotrophic plankton, that both photosynthesise and eat other plankton, underpin all marine food webs and help regulate climate by facilitating gas exchange between the ocean and atmosphere. We show the recent discovery that their feeding preferences change with increasing temperature implies climate change could dramatically alter the structure of marine food webs.

We describe a theoretical framework that reveals the key role of mixotrophy in facilitating transitions between trophic interactions. Mixotrophy smoothly and stably links competition to predation, and extends this linkage to include mutualism in both facultative and obligate forms. Such smooth stable transitions further allow the development of eco-evolutionary theory at the population level through quantitative trait modelling.

Regenerative medicine offers great hope in curing many currently untreatable diseases. Tissue engineering and stem cell therapy are the two main components of regenerative medicine. In this talk, I will discuss how engineering can make contributions to this highly interdisciplinary field, including biomaterials as 3D scaffolds, bioreactor design, and stem cell bioprocessing.

We adopt the paradigm of understanding how the heart develops during pregnancy as a first principal to inform on adult heart repair and regeneration. Our target for cell-based repair is the epicardium and epicardium-derived cells (EPDCs) which line the outside of the forming heart and contribute vascular endothelial and smooth muscle cells to the coronary vasculature, interstitial fibroblasts and cardiomyocytes. The epicardium can also act as a source of signals to condition the growth of the underlying embryonic heart muscle. In the adult heart, whilst the epicardium is retained, it is effectively quiescent. We have sought to extrapolate the developmental potential of the epicardium to the adult heart following injury by stimulating dormant epicardial cells to give rise to new muscle and vasculature. In parallel, we seek to modulate the local environment into which the new cells emerge: a cytotoxic mixture of inflammation and fibrosis which prevents cell engraftment and integration with survived heart tissue. To this end we manipulate the lymphatic vessels in the heart given that, elsewhere in the body, the lymphatics survey the immune system and modulate inflammation at peripheral injury sites. We recently described the development of the cardiac lymphatic vasculature and revealed in the adult heart that they undergo increased vessel sprouting (lymphangiogenesis) in response to injury, to improve function, remodelling and fibrosis. We are currently investigating whether increased lymphangiogenesis functions to clear immune cells and constrain the reparative response for optimal healing.

Oxford Nanopore Technologies aim to enable the analysis of any living thing, by any person, in any environment. The world's first and only nanopore DNA
sequencer, the MinION is a portable, real time, long-read, low cost device that has been designed to bring easy biological analyses to anyone, whether in
scientific research, education or a range of real world applications such as disease/pathogen surveillance, environmental monitoring, food chain
surveillance, self-quantification or even microgravity biology. Gordon will talk the about the technology, applications and future direction.
Stuart will talk about the nanopore signal, computational methods and informatics challenges associated with reading DNA directly.

Atomistic Molecular Dynamics is a well established biomolecular modelling tool that uses the wealth of information available in the Protein Data Bank (PDB). However, biophysical techniques that provide structural information at the mesoscale, such as cryo-electron microscopy and 3D tomography, are now sufficiently mature that they merit their own online repository called the EMDataBank (EMDB). We have developed a continuum mechanics description of proteins which uses this new experimental data as input to the simulations, and which we are developing into a software tool for use by the biomolecular science community. The model is a Finite Element algorithm which we have generalised to include the thermal fluctuations that drive protein conformational changes, and which is therefore known as Fluctuating Finite Element Analysis (FFEA) [1].

We will explain the physical principles underlying FFEA and provide a practical overview of how a typical FFEA simulation is set up and executed. We will then demonstrate how FFEA can be used to model flexible biomolecular complexes from EM and other structural data using our simulations of the molecular motors and protein self-assembly as illustrative examples. We then speculate how FFEA might be integrated with atomistic models to provide a multi-scale description of biomolecular structure and dynamics.

1. Oliver R., Read D. J., Harlen O. G. & Harris S. A. “A Stochastic finite element model for the dynamics of globular macromolecules”, (2013) J. Comp. Phys. 239, 147-165.

A holy grail of nano-technology is to create truly complex, multi-component structures by self assembly.
 

Most self-assembly has focused on the creation of `structural complexity'. In my talk, I will discuss `Addressable Complexity': the creation of structures that contain hundreds or thousands of
distinct building blocks that all have to find their place in a 3D structure.

If the abundances of the constituent molecules of a biochemical reaction system  are sufficiently high then their concentrations are typically modelled by a coupled set of ordinary differential equations (ODEs).  If, however, the abundances are low then the standard deterministic models do not provide a good representation of the behaviour of the system and stochastic models are used.  In this talk, I will first introduce both the stochastic and deterministic models.  I will then provide theorems that allow us to determine the qualitative behaviour of the underlying mathematical models from easily checked properties of the associated reaction network.  I will present results pertaining to so-called ``complex-balanced'' models and those satisfying ``absolute concentration robustness'' (ACR).  In particular, I will show how  ACR models, which are stable when modelled deterministically, necessarily undergo an extinction event in the stochastic setting.  I will then characterise the behaviour of these models prior to extinction.