Innovation Fellowship: Computational modelling of cryopreservation of biological tissue

Lead Research Organisation: Newcastle University
Department Name: Sch of Computing

Abstract

The preservation of organs and biological tissue is currently in its infancy. The lack of preservation capacity results in 2/3 of donor hearts and 4/5 of lungs being rejected for transplant for logistical reasons. Current estimates of the incidence of diseases that could be treated by on-demand organ replacement amount to several millions in the United States and Europe combined. Hence, advances in biological tissue preservation would revolutionize medicine and biotechnology. Moreover, since synthetic tissue growth is time and labour intensive, such advances would also enable large-scale drug-screening and toxicology testing using organoids grown from human stem cells.

Cryopreservation, where very low temperatures are used, is a standard procedure for the preservation of embryos, oocytes and sperm. It allows tissue availability on demand (as opposed to waiting several months for fresh culture), allows economies of scale to reduce costs, facilitates quality control, and prevents wastage. However, state-of-the-art freezing and thawing techniques lead to tissue damage in anything larger than 1-3mm3. Above-freezing storage times of human organs range from approximately 3 to 24 hours - depending on organ - before becoming unviable.

Currently, cryopreservation is mainly an experimental process, and lacks a guiding computational component. The control of the spatial influence of cryoprotectant agents, their administered quantity, and the timing of induced temperature changes remain largely subject to a black-box approach. However, with the advent of modern computing technologies, the automated analysis of large datasets and detailed computer simulations have become possible.

In this fellowship, I aim at the computational analysis and modelling of cryogenic processing, to provide a systematic framework that generates novel protocols. Physical processes, such as the diffusion of chemicals, mechanical interactions, heat transfer and ice propagation will be incorporated in 3D computer models. This implementation will benefit from the BioDynaMo collaboration with CERN openlab, which aims at a cloud-based software platform for computer simulations of biological tissue dynamics. Cells will be modelled in an agent-based approach. Overall, this computational model will be able to predict tissue-specific cryogenic processing methodologies to ensure optimal tissue viability.

This fellowship will initially focus on the retina, which is part of the central nervous system, and is particularly well-suited because its function can be assessed relatively easily and cost-effectively. Mouse retinal tissue will be used as the model system, because of the consistency of retinal structure across vertebrates. Additionally, retinal organoids, which were synthetically grown in culture in the lab of Prof. Majlinda Lako, will be used. After successful retinal cryopreservation, other tissues (e.g. mouse kidney and cortex) will be cryogenically processed to demonstrate the power of the research approach. Asymptote Ltd (GE Healthcare) will provide expertise, equipment and support for the freezing and thawing processes, hence adding to a prestigious network of well-established collaborators for this fellowship.

Different cryopreservation protocols will be applied to generate samples for computational analysis. Serial block-face scanning electron microscopy, immunocytochemistry, quantitative polymerase chain reaction and multi-electrode array recordings will be used to quantify damage to the tissue after thawing. Based on these data, a 3D computational model will be informed to generate optimal cryogenic processing parameters. Ultimately, this fellowship will allow me to become an international leader in cryopreservation. I will also pursue commercial activities based on the research results. To this end, the computational approach will be used for consulting purposes, e.g. for pharmaceutical, cosmetics or cryopreservation companies.

Planned Impact

This fellowship has a wide range of beneficiaries, including industrial and academic stakeholders.

Quality of life. This research will advance cryopreservation of organs and organoids. Ultimately, the wider public will benefit from such progress: firstly, more donated organs will become available. According to NHS Blood and Transplant, about 500 people died last year in the UK while waiting for a transplant. Moreover, pharmaceutical companies will be able to test drugs and potentially toxic substances on tissues grown from human stem cells, which will facilitate the development of novel drugs and cosmetic products. Importantly, this research will benefit the UK medical supply chain in accordance with the Industrial Strategy Green Paper.

Industrial stakeholders. Currently, the preservation of many biological tissues is very limited, and so tissue availability for drug-screening, disease modelling or substance safety evaluation is highly constrained. The possibility to scale up such in-vitro studies is of great interest to the industry (e.g. pharma and cosmetics companies). The project partner Newcells Biotech already has links with multiple companies interested in cryopreservation (Roche, Novartis, Bayer, etc.), and will provide support to bring the research results to the market. Software enabling automated tissue analysis and prediction of viable cryogenic protocols is a likely candidate product. Moreover, it is anticipated that consulting based on computational modelling can be commercialized. This commercialization will be supported by presentations at conferences, publications and a website. Routes to commercialisation will be identified in regular meetings with members of the university's enterprise services and the Director of Business & Engagement. Moreover, a workshop on cryopreservation will facilitate the dissemination of the research results to relevant companies.

The project partner Asymptote will support this fellowship with modern equipment, including a freezer (worth £20,000) and a thawer (worth £9,500). In return, advances in the cryogenic processing will benefit Asymptote because its equipment will gain further application areas, and its economic competitiveness will be fostered.

Computational biologists. This fellowship will lead to at least five publications in high-impact journals. Hence, future computational modelling efforts where biological tissue dynamics are modelled will be facilitated. Importantly, such models are relevant for a wide range of topics. For example, in an EPSRC project (EP/K026992/1) where I worked as an RA, normal and abnormal brain development was modelled. The computational approach taken in this fellowship will facilitate such biology research.

Animal welfare. Based on the computational model developed in this fellowship, promising experimental protocols will be identified, while protocols that would likely yield bad outcomes can be discarded. Hence, the number of mice required for cryopreservation research will be reduced. Also, this research will support tissue engineering research. Ultimately, human tissues grown from stem cells will strongly decrease the use of animals for pharmaceutical research.

Societal impact. It is crucial that more people become aware of the fact that millions of people die each year, because of a lack of transplantable organs. To raise awareness of this problem, I will regularly publish my results on a website for the fellowship and present my findings to a wide audience. Importantly, the computer simulations in this research often yield aesthetically pleasing animations. For example, a publication of mine was featured on the Cerebral Cortex journal cover, and a video has attracted almost 10,000 views on YouTube. Since such animations are often easily understandable by the general public, I will show my results via various channels (YouTube, website, public talks, etc.) to raise public awareness for the lack of donated organs.
 
Description We have managed to cool down retinal tissue to subzero temperatures, and thaw it. Our results suggest that the tissue is indeed at a high quality after this process.
Exploitation Route The outcomes of this funding could have many biomedical applications. For instance, the availability of transplantable tissues could benefit various patients. Moreover, pharmaceutical companies could benefit from the availability of large numbers of biological tissues for drug development.
Sectors Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology

 
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 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