Past Mathematical Biology and Ecology Seminar

Natural killer (NK) cells are part of the innate immune system and are capable of killing diseased cells. As a result, NK cells are being used for adoptive cell therapies for cancer patients. The activation of NK cell stimulatory receptors leads to a cascade of intracellular phosphorylation reactions, which activates key signaling species that facilitate the secretion of cytolytic molecules required for cell killing. Strategies that maximize the activation of such intracellular species can increase the likelihood of NK cell killing upon contact with a cancer cell and thereby improve efficacy of NK cell-based therapies. However, NK cell exhaustion, a phenotype characterized by reduced effector functionality, can limit the NK cell’s capacity for cell lysis. Due to the complexity of intracellular signaling, it is difficult to deduce a priori which strategies can enhance species activation.  

To aid in the development of strategies to enhance NK cell activation and limit the NK cell exhaustion, we constructed a mechanistic model of the signaling pathways activated by stimulatory receptors in NK cells. We then extended the model to describe the dynamics of the cytolytic molecules granzyme B (GZMB) and perforin-1 (PRF1). We implemented an information-theoretic approach to perform a global sensitivity analysis and optimal control theory to investigate strategies to enhance intracellular signaling and maximize GZMB and PRF1 secretion. We recently expanded the modeling to investigate the role of NK cell heterogeneity on tumor cell killing. In total, we developed a theoretical framework that provides actionable insight into engineering robust NK cells for clinical applications.

The amazing results of DeepMind's AlphaFold2 in the last CASP experiment  caused a huge stir in both the AI and biology fields, and this was of 
course widely reported in the general media. The claim is that the  protein folding problem has finally been solved, but has it really? Not 
to spoil the ending, but of course not. In this talk I will not be  talking (much) about AlphaFold2 itself, but instead what inspiration we 
can take from it about future directions we might want to take in protein structure bioinformatics research using modern AI techniques. 
Along the way, I'll illustrate my thoughts with some recent and current  machine-learning-based projects from my own lab in the area of protein 
structure and folding.
 

The last years have seen an immense increase in high-throughput and high-resolution technologies for experimental observation as well as
high-performance techniques to simulate molecular systems at a microscopic level, resulting in vast and ever-increasing amounts of high-dimensional data.
However, experiments provide only a partial view of macromolecular processes and are limited in their temporal and spatial resolution. On the other hand,
atomistic simulations are still not able to sample the conformation space of large complexes, thus leaving significant gaps in our ability to study
molecular processes at a biologically relevant scale. We present our efforts to bridge these gaps, by exploiting the available data and using state-of-the-art
machine-learning methods to design optimal coarse models for complex macromolecular systems. We show that it is possible to define simplified
molecular models to reproduce the essential information contained both in microscopic simulation and experimental measurements.

Geometrical questions commonly arise in clinical practice: for example, what is the optimal shape for a particular medical device? or what shapes of anatomical structures are indicative of pathological events? In this talk we explore two disparate clinical applications of geometrical underpinning: (A) how to design the optimal device for kidney stone removal surgery? and (B) what blood vessel shapes are associated with biomechanical failure? (A) Flexible ureteroscopy is a minimally invasive treatment for the removal of kidney stones by irrigating dust-like stone fragments with a saline solution. Finding the optimal ureteroscope tip shape for efficient flushing of stone fragments is a pertinent but complex question. We represent the renal pelvis (the main hollow cavity within the kidney) as a 2D cavity and employ adjoint-based shape optimisation to identify tip geometries that shrink the size of recirculation zones thereby reducing stone washout times. (B) The aorta is the largest blood vessel in the body, with an archetypal arched “candy-cane” shape and is responsible for transporting blood from the heart to the rest of the body. Aortic dissection, in which the inner layer of the aorta tears, can lead to frank rupture and is often rapidly fatal. Accurate clinical assessment of dissection risk from a CT scan of a patient’s thorax is paramount to patient survival. We apply statistical shape analysis, coupled with hemodynamic simulations, to identify pathological shape features of the aortic arch and to elucidate mechanistic underpinnings of aortic dissection.

The circadian clock generates ~24h rhythms everyday via a transcriptional-translational negative feedback loop. Although this involves the daily entry of repressor molecules into the nucleus after random diffusion through a crowded cytoplasm, the period remains extremely consistent. In this talk, I will describe how we identified a key molecular mechanism for such robustness of the circadian clock against spatio-temporal noise by analyzing spatio-temporal timeseries data of clock molecules. Furthermore, I will illustrate a systemic modeling approach that can identify hidden molecular interactions from oscillatory timeseries with an example of a circadian clock and tumorigenesis system.  Finally, I will talk about a fundamental question underlying the model-based time-series analysis: “Can we always fit a model to given timeseries data as long as the number of parameters is large?”. That is, is Von Neumann's quote “With four parameters I can fit an elephant, and with five I can make him wiggle his trunk” true?

There has been a surge of interest in machine learning in the past few years, and deep learning techniques are more and more integrated into
the way we do quantitative science. A particularly exciting case for deep learning is molecular physics, where some of the "superpowers" of
machine learning can make a real difference in addressing hard and fundamental computational problems - on the other hand the rigorous
physical footing of these problems guides us in how to pose the learning problem and making the design decisions for the learning architecture.
In this lecture I will review some of our recent contributions in marrying deep learning with statistical mechanics, rare-event sampling
and quantum mechanics.

We propose a mathematical model that unifies the psychiatric concepts of drug-induced incentive salience (IST), reward prediction error

(RPE) and opponent process theory (OPT) to describe the emergence of addiction within substance abuse. The biphasic reward response (initially

positive, then negative) of the OPT is activated by a drug-induced dopamine release, and evolves according to neuro-adaptative brain

processes.  Successive drug intakes enhance the negative component of the reward response, which the user compensates for by increasing the

drug dose.  Further neuroadaptive processes ensue, creating a positive feedback between physiological changes and user-controlled drug

intake. Our drug response model can give rise to qualitatively different pathways for an initially naive user to become fully addicted.  The

path to addiction is represented by trajectories in parameter space that depend on the RPE, drug intake, and neuroadaptive changes.

We will discuss how our model can be used to guide detoxification protocols using auxiliary substances such as methadone, to mitigate withdrawal symptoms.

If this is useful here are my co-authors:
Davide Maestrini, Tom Chou, Maria R. D'Orsogna

The talk will discuss the use of mathematical models for understanding targeted cancer therapies. One area of focus is the treatment of chronic lymphocytic leukemia with tyrosine kinase inhibitors. I will explore how mathematical approaches have helped elucidate the mechanism of action of the targeted drug ibrutinib, and will discuss how evolutionary models, based on patient-specific parameters, can make individualized predictions about treatment outcomes. Another focus of the talk is the use of oncolytic viruses to kill cancer cells and drive cancers into remission. These are viruses that specifically infect cancer cells and spread throughout tumors. I will discuss mathematical models applied to experimental data that analyze virus spread in a spatially structured setting, concentrating on the interactions of the virus with innate immune mechanisms that determine the outcome of virus spread.  

Human life expectancy has been increasing steadily over the last century but this has resulted in an increasing incidence of age-related chronic diseases. Over 60% of people over the age of 65 will suffer from more than one disease at the same time (multimorbidity) and 25-50% of those over 80 years old develop frailty, defined as an accumulation of deficits and loss of reserve. Multimorbidity and frailty have complex medical needs and are strongly associated with disability and hospitalization. However, current treatments are suboptimal with problems of polypharmacy due to the fact that each disease is treated individually. Geroprotectors target fundamental mechanisms of ageing common to multiple age-related diseases and shows promise in delaying the onset of multimorbidity and frailty in animal models. However, their clinical testing in patients has been challenging due to the high level of complexity in the mode of action of geroprotectors and in the way multimorbidity and frailty develop.

 The talk will give an overview of these problems and make the case for the use of AI approaches to solve some of those complex issues with a view of designing appropriate clinical trials with geroprotectors to prevent age-related multimorbidity and frailty and extend healthspan.

Our current approach to cancer treatment has been largely driven by finding molecular targets, those patients fortunate enough to have a targetable mutation will receive a fixed treatment schedule designed to deliver the maximum tolerated dose (MTD). These therapies generally achieve impressive short-term responses, that unfortunately give way to treatment resistance and tumor relapse. The importance of evolution during both tumor progression, metastasis and treatment response is becoming more widely accepted. However, MTD treatment strategies continue to dominate the precision oncology landscape and ignore the fact that treatments drive the evolution of resistance. Here we present an integrated theoretical, experimental and clinical approach to develop treatment strategies that specifically embrace cancer evolution. We will consider the importance of using treatment response as a critical driver of subsequent treatment decisions, rather than fixed strategies that ignore it. Through the integrated application of drug treatments and drug holidays we will illustrate that, evolutionary therapy can drive either tumor control or extinction. Our results strongly indicate that the future of precision medicine shouldn’t be in the development of new drugs but rather in the smarter evolutionary application of preexisting ones.

Bacteria use intercellular signalling, or quorum sensing (QS), to share information and respond collectively to aspects of their surroundings. The autoinducers that carry this information are exposed to the external environment. Consequently, they are affected by factors such as removal through fluid flow, a ubiquitous feature of bacterial habitats ranging from the gut and lungs to lakes and oceans.

We develop and apply a general theory that identifies and quantifies the conditions required for QS activation in fluid flow by systematically linking cell- and population-level genetic and physical processes. We predict that cell-level positive feedback promotes a robust collective response, and can act as a low-pass filter at the population level in oscillatory flow, responding only to changes over slow enough timescales. Moreover, we use our model to hypothesize how bacterial populations can discern between increases in cell density and decreases in flow rate.

A major challenge in the study of biological systems is that of model discovery: turning data into reduced order models that are not just predictive, but provide insight into the nature of the underlying system that generated the data. We introduce a number of data-driven strategies for discovering nonlinear multiscale dynamical systems and their embeddings from data.  Such data-driven methods can be used in the biological sciences where rich data streams are affording new possibilities for the understanding and characterization of complex, networked systems.  In neuroscience, for instance, the integration of these various concepts (reduced-order modeling, equation-free, machine learning, sparsity, networks, multi-scale physics and adaptive control) are critical to formulating successful modeling strategies that perhaps can say something meaningful about experiments.   These methods will be demonstrated on a number of neural systems.  I will also highlight how such methods can be used to quantify cognitive and decision-making deficits arising from neurodegenerative diseases and/or traumatic brain injuries (concussions).

Genotype-phenotype associations can be results of direct effects, genetic nurturing effects and population stratification confounding (The nature of nurture: Effects of parental genotypes, Science, 2018, Deconstructing the sources of genotype-phenotype associations in humans, Science, 2019). Genotypes from parents and siblings of the proband can be used to statistically disentangle these effects. To maximize power, a comprehensive framework for utilizing various combinations of parents’ and siblings’ genotypes is introduced. Central to the approach is mendelian imputation, a method that utilizes identity by descent (IBD) information to non-linearly impute genotypes into untyped relatives using genotypes of typed individuals. Applying the method to UK Biobank probands with at least one parent or sibling genotyped, for an educational attainment (EA) polygenic score that has a R² of 5.7% with EA, its predictive power based on direct genetic effect alone is demonstrated to be only about 1.4%. For women, the EA polygenic score has a bigger estimated direct effect on age-at-first-birth than EA itself.

The puzzle-shaped cells that appear in the epidermis of many plants are a striking example of a complex cell shape. Since shape in an organism is often thought to be closely related to its function, it suggests that these unusual shapes must have some functional benefit to the plant. We 
propose that the creation of these complex shapes is an effective strategy to reduce mechanical stress in the cell wall. Although the 
formation of these shapes requires highly anisotropic and non-uniform growth at the sub-cellular level, it appears to be triggered by 
isotropic growth at the organ level. Analysis of cell shape over multiple species is consistent with the idea that the puzzle is in 
response to a developmental constraint, and that the mechanism is like to be conserved among higher plants.

 “In this talk, I shall present the past research track passing through quantum mechanical studies of small molecules to biomolecules, to proteome-wide big data analyses and computational genomics. Next, the ongoing research in our group will be presented that builds upon the expertise on different levels of information processing in life (genome, transcriptome, proteins, small molecules), to develop self-consistent “first principles” models in biology with a wide spectrum of usage. The immediate benefits and the targeted processes will be described covering different layers of the central dogma of biology, multigenic diseases and disease driver/passenger mutation predictions."

Signalling pathways can be modelled as a biochemical reaction network. When the kinetics are to follow mass-action kinetics, the resulting
mathematical model is a polynomial dynamical system. I will overview approaches to analyse these models with steady-state data using
computational algebraic geometry and statistics. Then I will present how to analyse such models with time-course data using differential
algebra and geometry for model identifiability. Finally, I will present how topological data analysis can be help distinguish models
and data.

While the pathological mechanisms in COVID-19 illness are still poorly understood, it is increasingly clear that high levels of pro-inflammatory mediators play a major role in clinical deterioration in patients with severe disease. Current evidence points to a hyperinflammatory state as the driver of respiratory compromise in severe COVID-19 disease, with a clinical trajectory resembling acute respiratory distress syndrome (ARDS) but how this “runaway train” inflammatory response emergences and is maintained is not known. In this talk, we present the first mathematical model of lung hyperinflammation due to SARS- CoV-2 infection. This model is based on a network of purported mechanistic and physiological pathways linking together five distinct biochemical species involved in the inflammatory response. Simulations of our model give rise to distinct qualitative classes of COVID-19 patients: (i) individuals who naturally clear the virus, (ii) asymptomatic carriers and (iii–v) individuals who develop a case of mild, moderate, or severe illness. These findings, supported by a comprehensive sensitivity analysis, points to potential therapeutic interventions to prevent the emergence of hyperinflammation. Specifically, we suggest that early intervention with a locally-acting anti-inflammatory agent (such as inhaled corticosteroids) may effectively blockade the pathological hyperinflammatory reaction as it emerges.

Influenza viruses infect millions of individuals each year and cause a significant amount of morbidity and mortality. Understanding how the virus spreads within the lung, how efficacious host immune control is, and how each influences acute lung injury and disease severity is critical to combat the infection. We used an integrative model-experiment exchange to establish the dynamical connections between viral loads, infected cells, CD8+ T cells, lung injury, and disease severity. Our model predicts that infection resolution is sensitive to CD8+ T cell expansion, that there is a critical T cell magnitude needed for efficient resolution, and that the rate of T cell-mediated clearance is dependent on infected cell density. 
We validated the model through a series of experiments, including CD8 depletion and whole lung histomorphometry. This showed that the infected area of the lung matches the model-predicted infected cell dynamics, and that the resolved area of the lung parallels the relative CD8 dynamics. Additional analysis revealed a nonlinear relation between disease severity, inflammation, and lung injury. These novel links between important host-pathogen kinetics and pathology enhance our ability to forecast disease progression.

Multi-modal data sets are growing rapidly in single cell genomics, as well as other fields in science and engineering. We introduce MultiMAP, an approach for dimensionality reduction and integration of multiple datasets. MultiMAP embeds multiple datasets into a shared space so as to preserve both the manifold structure of each dataset independently, in addition to the manifold structure in shared feature spaces. MultiMAP is based on the rich mathematical foundation of UMAP, generalizing it to the setting of more than one data manifold. MultiMAP can be used for visualization of multiple datasets as well as an integration approach that enables subsequent joint analyses. Compared to other integration for single cell data, MultiMAP is not restricted to a linear transformation, is extremely fast, and is able to leverage features that may not be present in all datasets. We apply MultiMAP to the integration of a variety of single-cell transcriptomics, chromatin accessibility, methylation, and spatial data, and show that it outperforms current approaches in run time, label transfer, and label consistency. On a newly generated single cell ATAC-seq and RNA-seq dataset of the human thymus, we use MultiMAP to integrate cells across pseudotime. This enables the study of chromatin accessibility and TF binding over the course of T cell differentiation.

 Inherent fluctuations may play an important role in biological and chemical systems when the copy number of some chemical species is small. This talk will present the recent work on the stochastic modeling of reaction-diffusion processes in biochemical systems. First, I will introduce several stochastic models, which describe system features at different scales of interest. Then, model reduction and coarse-graining methods will be discussed to reduce model complexity. Next, I will show multiscale algorithms for stochastic simulation of reaction-diffusion processes that couple different modeling schemes for better efficiency of the simulation. The algorithms apply to the systems whose domain is partitioned into two regions with a few molecules and a large number of molecules.

Femoral neck response to physiological loading during level walking can be better understood, if personalized muscle and bone anatomy is considered. Finite element (FE) models of in vivo cadaveric bones combined with gait data from body-matched volunteers were used in the earlier studies, which could introduce errors in the results. The aim of the current study is to report the first fully personalized multiscale model to investigate the strains predicted at the femoral neck during a full gait cycle. CT-based Finite element models (CT/FE) of the right femur were developed following a validated framework. Muscle forces estimated by the musculoskeletal model were applied to the CT/FE model. For most of the cases, two overall peaks were predicted around 15% and 50% of the gait. Maximum strains were predicted at the superior neck region in the model. Anatomical muscle variations seem to affect femur response leading to considerable variations among individuals, both in term of the strains level and the trend at the femoral neck.
 

Pattern formation emerges during development from the interplay between gene regulatory networks (GRNs) acting at the single cell level and cell movements driving tissue level morphogenetic changes. As a result, the timing of cell specification and the dynamics of morphogenesis must be tightly cross-regulated. In the developing zebrafish, mesoderm progenitors will spend varying amounts of time (from 5 to 10hrs) in the tailbud before entering the pre-somitic mesoderm (PSM) and initiating a stereotypical transcriptional trajectory towards a mesodermal fate. In contrast, when dissociated and placed in vitro, these progenitors differentiate synchronously in around 5 hours. We have used a data-driven mathematical modelling approach to reverse-engineer a GRN that is able to tune the timing of mesodermal differentiation as progenitors leave the tailbud’s signalling environment, which also explains our in vitro observations. This GRN recapitulates pattern formation at the tissue level when modelled on cell tracks obtained from live-imaging a developing PSM. Our “live-modelling” framework also allows us to simulate how perturbations to the GRN affect the emergence of pattern in zebrafish mutants. We are now extending this analysis to cichlid fishes in order to explore the regulation of developmental time in evolution.