CellBranch : a toolset for exploring Stem Cell Differentiation and Pluripotency with Branching Process Theory
Lead Research Organisation:
University of York
Department Name: Computer Science
Abstract
One important biological application area is stem cell differentiation. Embryonic stem (ES) cells have the potential to produce all an animal's cell types: this is called pluripotency. In theory, stem cells could be directed to differentiate into any cell type, for therapeutic purposes. However, we cannot yet reliably direct their behaviour, and so cannot yet fully exploit this potential.
To further our understanding of such biological systems, we need sophisticated tools to analyse the system's complexity and the vast amounts of data available. Computational tools provide an important route to gaining such understanding.
Here we will build computational models and simulation tools based on Branching Process Theory, targeted to research questions in the domain of embryonic stem cell differentiation, as informed by high volumes of data.
We will validate the tool, to ensure that it is working as desired, by application to specific existing biological datasets.
Tools need to be usable and accessible to benefit the wider community. We will make the fully documented tools available to the wider research community through York's HEFCE-funded YouShare "Software as a Service" portal.
To further our understanding of such biological systems, we need sophisticated tools to analyse the system's complexity and the vast amounts of data available. Computational tools provide an important route to gaining such understanding.
Here we will build computational models and simulation tools based on Branching Process Theory, targeted to research questions in the domain of embryonic stem cell differentiation, as informed by high volumes of data.
We will validate the tool, to ensure that it is working as desired, by application to specific existing biological datasets.
Tools need to be usable and accessible to benefit the wider community. We will make the fully documented tools available to the wider research community through York's HEFCE-funded YouShare "Software as a Service" portal.
Technical Summary
One important biological application area is stem cell differentiation. Embryonic stem (ES) cells have the potential to produce all an animal's cell types: this is called pluripotency. In theory, stem cells could be directed to differentiate into any cell type, for therapeutic purposes. However, we cannot yet reliably direct their behaviour, and so cannot yet fully exploit this potential.
To further our understanding of such biological systems, we need sophisticated tools to analyse the system's complexity and the vast amounts of data available. Computational tools provide an important route to gaining such understanding.
We will exploit the established CoSMoS simulation approach, applied to an important theoretical framework, branching process theory (BPT). We will use BPT to model information flow based on genome-wide patterns of binding of key pluripotency transcription factors (TFs), capturing the expression of these TFs in terms of branching processes that propagate through time. Genome location data, which describe interactions between TFs and other genes at genome-wide scales, can be used to simulate these branching processes and estimate patterns of interference that give rise to individual cell trajectories.
Here we will build computational models and simulation tools based on BPT, targeted to research questions in the domain of embryonic stem cell differentiation regulation, and epigenetic control, as informed by high throughput data sources.
We will validate the tool by application to specific existing datasets.
Tools need to be usable and accessible to benefit the wider community. We will make the fully documented tools available to the wider research community through York's HEFCE-funded YouShare "Software as a Service" portal.
To further our understanding of such biological systems, we need sophisticated tools to analyse the system's complexity and the vast amounts of data available. Computational tools provide an important route to gaining such understanding.
We will exploit the established CoSMoS simulation approach, applied to an important theoretical framework, branching process theory (BPT). We will use BPT to model information flow based on genome-wide patterns of binding of key pluripotency transcription factors (TFs), capturing the expression of these TFs in terms of branching processes that propagate through time. Genome location data, which describe interactions between TFs and other genes at genome-wide scales, can be used to simulate these branching processes and estimate patterns of interference that give rise to individual cell trajectories.
Here we will build computational models and simulation tools based on BPT, targeted to research questions in the domain of embryonic stem cell differentiation regulation, and epigenetic control, as informed by high throughput data sources.
We will validate the tool by application to specific existing datasets.
Tools need to be usable and accessible to benefit the wider community. We will make the fully documented tools available to the wider research community through York's HEFCE-funded YouShare "Software as a Service" portal.
Planned Impact
1. Branching Process Theory applied to Stem Cell Differentiation provides a novel theoretical framework for analysing an essential aspect of stem cell biology: how to understand complex multilayered high throughput data, and ultimately how better to control the development of stem cells into differentiated tissue.
2. CellBranch takes the impact of BPT from the theoretical to the practical domain. By providing an executable computational tool, BPT can be used to explore and analyse high volume data sets for greater biological understanding.
3. Deploying CellBranch through YouShare takes the impact from the individual laboratory to the entire community, by providing open access to the toolset, and compute resource to run the analyses.
4. By allowing the entire community access to the toolset and theory, we hasten the day that stem cell science is advanced enough to provide the promised therapeutic benefits to the world at large.
2. CellBranch takes the impact of BPT from the theoretical to the practical domain. By providing an executable computational tool, BPT can be used to explore and analyse high volume data sets for greater biological understanding.
3. Deploying CellBranch through YouShare takes the impact from the individual laboratory to the entire community, by providing open access to the toolset, and compute resource to run the analyses.
4. By allowing the entire community access to the toolset and theory, we hasten the day that stem cell science is advanced enough to provide the promised therapeutic benefits to the world at large.
Organisations
Publications
Greaves RB
(2017)
A conceptual and computational framework for modelling and understanding the non-equilibrium gene regulatory networks of mouse embryonic stem cells.
in PLoS computational biology
Richard B. Greaves
(2016)
CellBranch CoSMoS model : increments 1, 2 and 3
| Description | Pluripotent stem cells possess the capacity both to renew themselves indefinitely and to differentiate to any cell type in the body. Thus the ability to direct stem cell differentiation would have immense potential in regenerative medicine. There is a massive amount of biological data relevant to stem cells, and we need to use this to understand cell behaviour and complexity, not merely to describe it. These cells contain a dynamic, non-equilibrium network of genes regulated by transcription factors expressed by the network itself. We have taken an existing theoretical framework, Transcription Factor Branching Processes, which explains how these genetic networks can have critical behaviour, and can tip between quiescence and full expression. We have used this theory as the basis for the design and implementation of a computational simulation platform, which we have used to run a variety of simulation experiments, to gain a better understanding how these various transcription factors can combine, interact, and influence each other. The simulation parameters are derived from experimental data relating to the core factors in stem cell differentiation. The simulation results determine the critical values of branching process parameters, and how these are modulated by the various interacting transcription factors. |
| Exploitation Route | The software tools and documentation we have developed are publically available at github.com/CellBranch/CellBranch |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Title | CellBranch simulation software |
| Description | Comprises the code for the CellBranch simulation, batch scripts for running the simulation on an SGE enabled compute cluster, Python scripts for generating real or synthetic cistromes, and example R scripts for processing simulation results into graphical form. |
| Type Of Technology | Software |
| Year Produced | 2016 |
| Open Source License? | Yes |
| Impact | unknown |
| URL | https://github.com/CellBranch/CellBranch |