Computational modeling of retinal development

Lead Research Organisation: Newcastle University
Department Name: Institute of Neuroscience

Abstract

The development of retinal tissue is based on the well-orchestrated interaction between genetic programs and environmental cues. Genetic instructions produce certain factors, such as extracellular substances, which conversely influence gene expression. Insights into this dynamic, developmental process are of high medical relevance. For instance, a better understanding of the developmental programs of precursor cells would support stem cell-based treatments for the repair and regeneration of the injured or diseased retina. Also, elucidating how neurodevelopmental diseases give rise to severe malformations and impaired function would help devise new clinical approaches to counteract disease progression.

The retina is an ideal candidate for investigating neural development. Because of its peripheral location, it is one of the best-studied parts of the central nervous system (CNS), with much experimental data publicly available (e.g. the synaptic connectivity between individual cells or reconstructions of neuronal morphologies). Additionally, its organisation is simpler as it is composed of only 3 cell layers, in contrast to the 6-layered mammalian neocortex. Furthermore, there is a basic consistency of the retina across species, and so the insights on the retina for specific species are very relevant also for others.

Computer simulations bridge the gap between theory and experiment by providing an alternative way of investigating complex systems, and allow bringing together different lines of research into one coherent framework. However because of limitations in computing performance, models of retinal development have remained on a rather abstract level, and do not incorporate detailed neuronal structure and function.

Here I propose to investigate retinal development based on a novel Neuroinformatics approach, using state-of-the-art software and hardware technology. I want to simulate retinal development by taking into account detailed physical interactions. These comprise mechanical forces between neurons and the secretion and detection of substances in 3D space. I will assess the accuracy and biological plausibility of the simulations with datasets from a number of studies on retinal structure and function. Also, this work will take into account gene expression data obtained from cultures of human stem cells for the growth of transplantable, retinal tissue. By following this detailed simulation approach, I want to derive experimentally testable predictions on the effects of alterations during specific stages of retinal development. These are the main questions that I would like to address in this research:

- How does, starting from a few precursor cells, retinal lamination occur? Here I will incorporate knowledge from gene expression data obtained from cultures of human stem cells. This analysis will allow me to relate these to the interaction with the physical patterning.
- How do neurons develop their structure within the laminated retina? This question requires the investigation of how different developmental cues (e.g. extracellular substances, electrical activity) shape neuronal morphologies.
- How do neurons coordinate their developmental behavior, giving rise to the experimentally measured synaptic connectivity? Again, this problem requires the modeling of dynamic interactions between neurons.

Overall, this project addresses the problem of how bottom-up genetic and top-down developmental processes produce retinal structure. I aim at a detailed computational model of retinal development, offering an in-silico approach for understanding the rise of retinal diseases and putative new treatment routes.

Technical Summary

The proposed research aims at a computational characterization of retinal development. I want to simulate the growth of the structural development of the retina, by incorporating results from different studies into a coherent framework. This detailed approach enables a mechanistic explanation for how retinal tissue develops from a few precursor cells, which has high relevance for stem cell-based treatments. This work will use genetic data obtained from retinal differentiation of human embryonic and induced pluripotent stem cells, from the collaboration with Prof. Lako. This is a unique dataset because the samples will be taken at different stages during retinal development. The fact that these are human cells renders these data highly relevant for medical purposes. Based on these data, gene regulatory dynamics will be inferred and related to the structural changes. This model will support the generation of tailored, multilayered neural retinas for drug discovery purposes, disease modeling and transplantation.

Leveraging modern computer hardware and software, this Neuroinformatics project will incorporate very elaborate mechanisms. In contrast to existing approaches to model retinal development, physical forces will be taken into account to simulate cell interactions. The production, diffusion and detection of extracellular substances will enable the modeling of the guidance of neuronal growth processes. Also, the interaction between anatomical and electrophysiological development will be investigated. For example, dendritic growth can depend on electrical activity, as supported by experimental data. Importantly, the simulation is such that every cell behavior is based on information that is available at the location of the process in question. Overall, this detailed and mechanistic model of retinal development will generate experimentally testable hypotheses, and will account for findings such as the specificity of synaptic connections between neurons.

Planned Impact

This project is relevant from a number of perspectives, and will have a wide range of beneficiaries (in addition to the academic beneficiaries):

1) Medical applications

Eye health is a major determinant of quality of life. Worldwide, approximately 39 million people suffer from blindness. In the UK alone, the total cost of visual impairment in 2008 has been estimated to be approximately £22 billion (Access Economics, 2009), with an increasing trend. Computational modeling of retinal development has high relevance for the treatment of visual impairment or blindness. Regenerative medicine for the replacement of cells that have been lost, e.g. in retinal blindness, offers promising approaches for treating disorders of the eye. However, the generation of laboratory grown synthetic retina is currently in its infancy. Quantitative models on the relevant developmental mechanisms, and of how and when they shape retinal tissue would help researchers to generate customized retinal tissue in vitro, which could be used in transplantations. Furthermore, elucidating the mechanisms of retinal development will improve our understanding of neurodevelopmental disorders. Such insights into how and when the wrong execution of developmental processes generates associated malformations will support treatments to counteract the disease.

2) Industrial High-Performance Computing (HPC)

This project will benefit from a collaboration with CERN openlab, aiming at a novel software framework for conducting large-scale simulations using hybrid cloud computers. By simulating the computationally very challenging problem of retinal development, my work will demonstrate the power and efficiency of this particular approach. The same software structure can in principle be used for a wide variety of HPC applications, such as for example simulations for industrial engineering.

3) Influence on Society

I am deeply committed to communicating my work to the general public. Since my work will be based on very detailed models in 3D, the results of this project can brought across in an easily understandable way. Visualizations of the simulations are often aesthetically appealing (e.g. my publication in the journal Cerebral Cortex was illustrated on the cover). I will upload results on a personal website and Youtube, in order to bring my research closer to the public. See also "Pathways to Impact" for further information on my plans for public engagement.

4) Animal use in research

Computer simulations provide a third scientific way, in addition to theory and the traditional experimental method. Already now, it has become possible to do experiments in computer simulations that would not be feasible otherwise. Ultimately, with more detailed and accurate models of a system, it will become possible to conduct medical research and development in computer simulations, and so decrease the use of animals in medical research. For example, predictions on highly probable complications or low information gain could be used in order to improve the efficacy of animal experimentation.

Publications

10 25 50
 
Description Faculty of Medical Sciences & MRC Proximity To Discovery Industrial Strategy Challenge Fund
Amount £17,500 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2018 
End 08/2018
 
Description Innovation Fellowship: Computational modelling of cryopreservation of biological tissue
Amount £502,399 (GBP)
Funding ID EP/S001433/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 06/2018 
End 06/2021
 
Title BioDynaMo software 
Description The BioDynaMo software platform is a computational research tool to simulate biological dynamics, in particular the development of biological tissues. 
Type Of Material Improvements to research infrastructure 
Year Produced 2017 
Provided To Others? Yes  
Impact While the software is under ongoing development. The research tool has led to a number of student projects (on the undergraduate, graduate and doctoral levels), and constitutes an important part of the currently ongoing Innovation Fellowship ("Computational modelling of cryopreservation of biological tissue") of the PI. 
URL https://biodynamo.web.cern.ch/
 
Title Cancer growth model 
Description We have made publicly available code that uses our previously created BioDynaMo software to simulate cancer growth. 
Type Of Material Computer model/algorithm 
Year Produced 2020 
Provided To Others? Yes  
Impact This code further supports our associated scientific publication and also promotes the BioDynaMo software, which stems from the BioDynaMo software collaboration that I initiated and lead. 
URL https://figshare.com/articles/Supplementary_Material_-_Code/9725135
 
Description BioDynaMo collaboration: a software platform for computer simulations of biological dynamics 
Organisation European Organization for Nuclear Research (CERN)
Department CERN - Other
Country Switzerland 
Sector Academic/University 
PI Contribution I am the leader of this collaboration, aiming at the efficient implementation of a software platform for simulations of agent-based biological dynamics. I organize weekly Google Hangouts meetings, and I also organised a plenary meeting with the consortium in 2017. Moreover, I consult/guide two programmers (one PhD student and one Master student) who are based at CERN openlab (Geneva, Switzerland), to provide them with important information on the biology of their programming work. My PhD student Jean de Montigny uses BioDynaMo for his research, and also helps with the implementation. My previous postdoctoral supervisor Prof. Marcus Kaiser is also involved, advising on the scientific aspects of the project.
Collaborator Contribution Until now, most of the programming work was done by the collaborators at CERN openlab. They work and consult on the IT aspects, and regularly communicate with me in this collaboration.
Impact The source code is freely available in a github repository, which can be reached via the biodynamo website. Moreover, we published a book chapter [1] and a conference paper [2], where the project is described in more detail. [1] Bauer, R., Breitwieser, L., Di Meglio, A., Johard, L., Kaiser, M., Manca, M., Mazzara, M., Rademakers, F., Talanov, M. and Tchitchigin, A.D., 2017. The BioDynaMo Project: Experience Report. In Advanced Research on Biologically Inspired Cognitive Architectures (pp. 117-125). IGI Global. [2] Breitwieser, L., Bauer, R., Di Meglio, A., Johard, L., Kaiser, M., Manca, M., Mazzara, M., Rademakers, F. and Talanov, M., 2016. The biodynamo project: Creating a platform for large-scale reproducible biological simulations. arXiv preprint arXiv:1608.04967. The BioDynaMo collaboration is multi-disciplinary, involving the fields of Biology, Neuroscience and Computer Science.
Start Year 2015
 
Description Collaboration with GE Healthcare 
Organisation GE Healthcare Life Sciences
Country United Kingdom 
Sector Private 
PI Contribution We make use of the Asymptote VIA Freeze freezer in our research, and mention this on conferences and scientific meetings. Moreover, we have regular meetings with Asymptote Ltd. (based in Cambridge) where we update each other. Moreover, I apply for research funding (PhD studentships) in collaboration with Asymptote.
Collaborator Contribution They lend us an Asymptote VIA Freeze freezer for research purposes.
Impact - Oral presentations at Society for Cryobiology Meeting in San Diego, USA - Two poster presentations at Society for Cryobiology Meeting 2019 in San Diego, USA - A poster presentation at Society for Low Temperature Biology Meeting 2019 in Sevilla, Spain The collaboration is multi-disciplinary, i.e. it involves computer science, physics and biology.
Start Year 2017
 
Title BioDynaMo software license 
Description The BioDynaMo software platform is a computational research tool to simulate biological dynamics, in particular the development of biological tissues. 
IP Reference  
Protection Copyrighted (e.g. software)
Year Protection Granted 2016
Licensed Yes
Impact While BioDynaMo has been and still is under development since the start, the research platform has played and is currently playing a crucial role in a number of student projects (on the undergraduate, graduate and doctoral levels), and constitutes an important part of the currently ongoing Innovation Fellowship ("Computational modelling of cryopreservation of biological tissue") of the PI.
 
Title BioDynaMo software 
Description The BioDynaMo software platform is a computational research tool to simulate biological dynamics, in particular the development of biological tissues. 
Type Of Technology Software 
Year Produced 2016 
Open Source License? Yes  
Impact While BioDynaMo has been and still is under development since the start, the research platform has played and is currently playing a crucial role in a number of student projects (on the undergraduate, graduate and doctoral levels), and constitutes an important part of the currently ongoing Innovation Fellowship ("Computational modelling of cryopreservation of biological tissue") of the PI. 
URL https://biodynamo.web.cern.ch/
 
Description BioDynaMo Agent-based modelling meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact I organised a meeting related to the BioDynaMo collaboration that I lead. Members of the collaboration and delegates from industry and representatives of schools were present. We agreed to co-organise a student summer school for biomedical informatics in the future together.
Year(s) Of Engagement Activity 2019
 
Description Co-organization of an international conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I co-organized an international conference named "Computational Neurology 2017" together with colleagues at Newcastle University. Over 110 participants attended this international conference, among them senior and well-established PIs from well-known universities. During this 2-day conference, we had a number of discussions, and contributed to cultivating a network of academics working on clinically relevant computational models of neural tissue. A poster session also added to interactive and stimulating discussions.
Year(s) Of Engagement Activity 2017
URL https://conferences.ncl.ac.uk/compneurology/
 
Description Holmes lecture for pupils 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I presented at the Holmes Public Lecture Series for 10- to 14-year-olds. The purpose was to bring vision research closer to pupils, and teach them about various vision-related topics. The pupils were extremely interactive and I received only positive feedback.
Year(s) Of Engagement Activity 2018
URL http://www.ncl.ac.uk/events/noticeboard/item/thewindowstothesoul-humanvision.html
 
Description Press release about recent scientific publication 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This press release was about a second recent scientific study that we published. The press release was done via the Online News Service EurekAlert. Multiple people that I know told me that they saw this article, and I was asked whether I would be interested to give a talk to give more information about this work.
Year(s) Of Engagement Activity 2020
URL https://eurekalert.org/pub_releases/2020-02/nu-csf020620.php
 
Description Press release on a recent study 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This was a press release about a recent study that we published in the Science News Service Eurekalert. Several individuals approached me and asked me questions after publication of this press article.
Year(s) Of Engagement Activity 2020
URL https://www.eurekalert.org/pub_releases/2020-01/nu-pit012920.php
 
Description Talk at CERN Knowledge Exchange Event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact I gave a talk at the CERN Knowledge Exchange Event in Daresbury (UK), to an audience consisting mainly of industry delegates collaborating with CERN. This gave rise to a number of members of the audience asking me for more information.
Year(s) Of Engagement Activity 2019
 
Description Talk at a conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact I gave a talk at the "Big Data in Medicine: Challenges and Opportunities" meeting at CERN, Geneva (Switzerland). The talk was well-received and connected me to medically relevant industrial players.
Year(s) Of Engagement Activity 2019
URL https://indico.cern.ch/event/800343/
 
Description Talk at a public event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Study participants or study members
Results and Impact I gave a presentation at a UK Biobank Participant event with over 200 attendees. This sparked questions and discussion afterwards, and the responsible organisors reported that this significantly supported the interaction with the participants.
Year(s) Of Engagement Activity 2019
URL https://www.ukbiobank.ac.uk/newcastle-participant-event-16-september-2019/
 
Description Talk at conference organised by student society (King's College London) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact The King's College London Neuroscience Society organised a conference ("Seeing is Believing: Advances in Neuroimaging:) where I gave a talk. A number of students asked for more information about my computational methodology, and might use it in their future work too.
Year(s) Of Engagement Activity 2019