Project

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Multispecies interacting stochastic systems in biology

Applicant Böttcher Lucas
Number 191888
Funding scheme Early Postdoc.Mobility
Research institution Department of Mathematics University of California (UCLA) University Park
Institution of higher education Institution abroad - IACH
Main discipline Mathematics
Start/End 01.02.2020 - 31.07.2021
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All Disciplines (3)

Discipline
Mathematics
Other disciplines of Physics
Biophysics

Keywords (6)

Computational Biology; Mathematical Biology; Stochastic Processes; Statistical Physics; Cell Biology; Computational Physics

Lay Summary (German)

Lead
Zellpopulationen im menschlichen Körper weisen eine sehr hohe Diversität auf. Dies ist zum Beispiel wichtig für ein gut funktionierendes Immunsystem, welches uns vor einer Vielzahl von Krankheiten bewaren soll. Empirische Resultate zeigen, dass von bestimmten Immunzellen mehr als eine Milliarde verschiedene Typen existieren. Um die Prozesse der Entstehung von Blut- und Immunzellen besser zu verstehen, ist das Ziel dieses Projektes mathematische Modelle zu entwickeln und Modellvorhersagen mit klinischen Daten zur Dynamik von Stammzellen und Entstehung von akuter lymphatischer Leukämie zu vergleichen.
Lay summary

Inhalt und Ziele des Forschungsprojekts
Fortschritte in der empirischen Zellbiologie machen es möglich die Diversität gewisser Zellpopulationen zu bestimmen. Zum Beispiel gibt es von einigen Immunzellen (Leukozyten oder weisse Blutzellen) mehr als eine Milliarde Verschiedene. Diese hohe Diversität von Immunzellen ist wichtig um ein funktionierendes Immunsystem zu gewährleisten. Verschiedene Blutzellen entstehen aus sogennanten hämatopoetischen Stammzellen während der Hämatopoese (Blutbildung). An der University of California, Los Angeles werden empirische Studien durchgeführt bei denen die Aktivität von Stammzellen gemessen werden kann. Um die gewonnen empirischen Einblicke besser interpretieren und verstehen zu können, ist das Ziel dieses Projektes mathematische Modelle zu entwickeln und diese mit den dazugehörigen Messdaten zu vergleichen. Eine Herausforderung bei der Entwicklung dieser Modelle ist die hohe Diversität mathematisch zu beschreiben. Zudem ist es wichtig zu beachten, dass die Messergebnisse oft aus nur sehr kleinen Blutproben gewonnen werden. Daher müssen geeignete statistische Methoden entwickelt werden, um mit diesen Messunsicherheiten umzugehen. Ein weiteres Ziel dieses Projektes ist mit den gewonnen Einblicken zu einem besseren Verständnis zur Entstehung von akuter lymphatischer Leukämie beizutragen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts
Das Projekt befasst sich mit Grundlagenforschung. Das Ziel dieses Projektes ist ein besseres Verständnis zur Dynamik von Stammzellen und Entstehung von akuter lymphatischer Leukämie zu gewinnen.


Direct link to Lay Summary Last update: 15.12.2019

Responsible applicant and co-applicants

Name Institute

Publications

Publication
From classical to quantum walks with stochastic resetting on networks
Wald Sascha, Böttcher Lucas (2021), From classical to quantum walks with stochastic resetting on networks, in Physical Review E, 103(1), 012122-012122.
Using excess deaths and testing statistics to determine estimates of COVID-19 mortalities
BöttcherLucas, D'OrsognaMaria, ChouTom (2021), Using excess deaths and testing statistics to determine estimates of COVID-19 mortalities, in Eur. J. Epidemiol., 545.
The great divide: drivers of polarization in the US public
Böttcher Lucas, Gersbach Hans (2020), The great divide: drivers of polarization in the US public, in EPJ Data Science, 9(1), 32-32.
Why case fatality ratios can be misleading: individual- and population-based mortality estimates and factors influencing them
Böttcher Lucas, Xia Mingtao, Chou Tom (2020), Why case fatality ratios can be misleading: individual- and population-based mortality estimates and factors influencing them, in Physical Biology, 17(6), 065003-065003.
Aging and equilibration in bistable contagion dynamics
Richter Paul, Henkel Malte, Böttcher Lucas (2020), Aging and equilibration in bistable contagion dynamics, in Physical Review E, 102(4), 042308-042308.
A Random-Line-Graph Approach to Overlapping Line Segments
Böttcher Lucas (2020), A Random-Line-Graph Approach to Overlapping Line Segments, in Journal of Complex Networks, 8(4), cnaa029.
Unifying continuous, discrete, and hybrid susceptible-infected-recovered processes on networks
Böttcher Lucas, Antulov-Fantulin Nino (2020), Unifying continuous, discrete, and hybrid susceptible-infected-recovered processes on networks, in Physical Review Research, 2(3), 033121-033121.
Learning the Ising model with generative neural networks
D'Angelo Francesco, Böttcher Lucas (2020), Learning the Ising model with generative neural networks, in Physical Review Research, 2(2), 023266-023266.
A statistical model of COVID-19 testing in populations: effects of sampling bias and testing errors
Böttcher Lucas, D'Orsogna Maria, Chou Tom, A statistical model of COVID-19 testing in populations: effects of sampling bias and testing errors, in Philos. Trans. Royal Soc. A, -.
Classical and quantum random-walk centrality measures in multilayer networks
BöttcherLucas, PorterMason, Classical and quantum random-walk centrality measures in multilayer networks, in SIAM J. Appl. Math., -.

Collaboration

Group / person Country
Types of collaboration
Caltech United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
ESPCI Paris France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Macroeconomics, Innovation, and Policy/ ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Max Planck Institute for the Physics of Complex Systems Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Université de Lorraine France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Computational Social Science/ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Royal Society Workshop on Data Science Approach to Infectious Disease Surveillance Talk given at a conference A statistical model of COVID-19 testing in populations: effects of sampling bias and testing errors 11.07.2021 Zoom, United States of America Böttcher Lucas;
Networks '21 Talk given at a conference Classical and quantum random-walk centrality in multilayer networks 09.07.2021 Zoom, United States of America Böttcher Lucas;
MIDAS Seminar Series Talk given at a conference Using excess deaths and testing statistics to determine COVID-19 mortalities 28.05.2021 Zoom, United States of America Böttcher Lucas;
NIH Viral Pandemics Working Group Meeting Talk given at a conference Using excess deaths and testing statistics to improve estimates of COVID-19 mortalities 11.02.2021 Zoom, United States of America Böttcher Lucas;
Research Frontiers in Biomathematics seminar series Individual talk A Refunding Scheme to Incentivize Narrow-Spectrum Antibiotic Development 01.10.2020 Los Angeles, United States of America Böttcher Lucas;
Network seminar series Individual talk Unifying continuous, discrete, and susceptible-infected-recovered processes on networks 24.09.2020 Los Angeles, United States of America Böttcher Lucas;
SNSF conference Individual talk Why case fatality ratios can be misleading: individual- and population-based mortality estimates and factors influencing them 01.07.2020 Online, United States of America Böttcher Lucas;
QCBio research seminar Individual talk Unifying continuous, discrete, and susceptible-infected-recovered processes on networks 03.02.2020 Los Angeles, United States of America Böttcher Lucas;


Self-organised

Title Date Place
Epidemic Datathon 30.03.2020 Zurich, Switzerland

Communication with the public

Communication Title Media Place Year
Media relations: radio, television Are COVID-19 Mortality Rates Really What They Seem? AirTalk 89.3 KPCC International 2020
Media relations: print media, online media Italy's Coronavirus Death Toll Is Far Higher Than Reported Wall Street Journal International 2020
Media relations: print media, online media Understanding the dynamics of the epidemic ETH News International 2020

Abstract

This research project seeks to formulate the fundamental high-dimensional mathematical structure shared by a number of related problems in cellular and developmental systems biology. Although the overall goal is to develop and analyze new mathematical and statistical approaches, we will focus on two specific biological systems studied at UCLA, for which significant data will be available:(i) Clonal tracking and stem cell dynamics: The overall process of hematopoiesis, the generation of blood and the adaptive immune system, involves a relatively small number of hematopoietic stem cells (HSCs) in the bone marrow, each occasionally differentiating to produce “transit-amplifying” or progenitor cells which expand in number while further differentiating into a diverse set of cell types (lineages). Recent experiments have used barcoded hematopoietic stem cells transplanted into rhesus macaques. Blood samples are then sequenced to determine the abundances of barcodes in samples of mature differentiated cells across different lineages. These data will, with appropriate theory and analysis, provide insight into the mechanisms of HSC differentiation, blood tissue aging, and clonal response to perturbations.(ii) Clonal distributions in Acute Myeloid Leukemia (AML): Another related system for which longitudinal clonal data will be available is the evolution of AML. Recent high-throughput sequencing studies have identified somatic mutations in individuals across a wide range of ages, including those who display significant mutational burden but who are completely asymptomatic to those with severe leukemia. Aging results in a gradual overall decline in hematopoiesis, a decrease in immunity, an accumulation in age-related mutations in most somatic cells. The clonal abundances of mutations in the hematopoietic system will also evolve, sharing processes that are expected in the HSC barcoding experiments. We will explore the hypothesis that aging of the immune system interacts with the mutational load to tip such stochastic differences in outcomes. We will model the above problems using a stochastic, heterogeneous, multispecies interacting birth-deathimmigration-mutation process. The different species or clones represent the different barcodes and cell lineages or mutational states. Immigration is mediated by differentiation of a relatively fixed pool of barcoded stem cells, while proliferation and mutation mediate differentiation and cancer progression. Interactions arise from global population regulation of myeloblast maintenance, HSC activation, or progenitor proliferation. Finally, in all of the above problems, clone abundances are determined through small (blood) samples randomly drawn from the organism. Thus, a statistical estimation framework (probably Bayesian) also needs to be developed in order to quantitatively incorporate the data being collected at UCLA.The expected results of this proposed project will include new data-motivated high-dimensional models of evolution of cell populations, providing mechanistic insight and parameter inference into hematopoiesis and leukemia progression. These new mathematical frameworks and statistical analyses will allow future testing and calibrating of models and inference of interaction terms amongst subpopulations. In particular, we expect the models and theoretical methods we develop will help guide experimentalists and clinicans in developing new experiments and measurements in the context of hematopoiesis and cancer progression.
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