Geometry as a key to the virosphere: Unmasking the fundamental roles of geometry in virus structure, evolution and pathology

Lead Research Organisation: University of York
Department Name: Mathematics

Abstract

Society faces major challenges from viral diseases. The recent Zika and Ebola outbreaks are only two examples of the devastating impact of viral illnesses on human health, and viral pathogens infecting agriculturally important livestock and plants simultaneously reduce food production and inflict great annual financial losses worldwide. Viruses, however, also have positive impacts on health and ecology. They balance and stabilise our gut microbiome, preventing serious illnesses such as certain autoimmune diseases, and influence our climate owing to their roles in carbon cycling in the oceans. It is therefore paramount to better understand virus structure and function across the entire virosphere in order to control, and even take advantage of, viruses in medicine and biotechnology.
I have demonstrated previously that mathematical approaches developed in tandem with experimentalists are drivers of discovery of functionally crucial structural viral features, revealing their novel functional roles in viral life cycles, and enabling their exploitation in therapy and biotechnology. Previously developed mathematical approaches were geared towards a specific major sub-group of the virosphere. In this research programme, I will both broaden and deepen the development of novel mathematical techniques. Working in close collaboration with leading experimental groups, at a larger scale, I will identify functionally important geometric viral features in a number of major groups of viruses. This will include: geometric strand assortment in multipartite viruses, such as the major agricultural pathogen Bluetongue virus; the assembly of retroviruses like HIV, with applications to the construction of virus-like particles from viral components as vectors for gene editing and therapy; and the structure and evolution of viruses important for the gut microbiome and marine ecology. By linking structural features with their functions, I will address open problems regarding drivers of evolution in one of the simplest yet most important groups of biological entities. This approach will unmask evolutionarily conserved functional features that can be used as novel targets in anti-viral therapy, for the development of novel safer vaccines or repurposed in bionanotechnology.

Planned Impact

Society faces major challenges from viral disease, and novel anti-viral targets and strategies are therefore urgently required. I have demonstrated previously that mathematical techniques and models, when developed in close collaboration with experiment, can act as drivers of discovery of such solutions. Indeed, together with experimental collaborators, I am a named inventor on three patents that exploit our discovery of an RNA-encoded virus assembly instruction manual in single-stranded RNA viruses.
In this research programme, I will tackle geometric challenges in viruses that are not amenable to the approaches developed previously, but that are expected to also have functionally important contacts between viral genome and capsid protein that could act as novel drug targets. Examples include the common cold virus and poliovirus. After cleavage of the major capsid protein, these viruses undergo structural transitions of their capsids concomitant with rearrangements of their genomes, as an essential step in becoming infectious. I will develop novel geometric approaches to characterise such contacts between viral genome and capsid in these viruses at a molecular scale, and develop models that enable us to study their functions. Please refer to the Statement of Support of my Project Partner Peter Stockley. I expect that further patents will arise from this work, with the potential of developing anti-viral drugs against viruses such as polio and the common cold virus, as well as a broad range of other viruses that are amenable to the techniques that we are developing in this programme. A further example is Bluetongue virus, an agriculturally important virus of ruminants for which my Project Partner Polly Roy is an internationally leading expert. The mathematical techniques that I am developing for this collaboration will potentially also apply to other multipartite viruses such as influenza and measles.
The mechanistic understanding of how structural features contribute to efficient formation of viral particles will moreover be used to design virus-like particles (VLPs) by repurposing viral components. This will enable the production of safe vaccines (noninfectious repurposed capsid shells, presenting neutralising viral epitopes to the immune system on the outer surfaces), which is of strong interest to the WHO Polio Eradication Initiative, and will contribute to the demand for ever more effective vaccines against larger numbers of pathogens.
VLPs derived from lentiviruses such as HIV, which are another focus of this research programme in collaboration with my Project Partner Greg Towers, have major potential applications in gene therapy, for example in the treatment of cancer. Insights from this research programme such as the cooperative role of the genome in assembly will make a significant contribution to the design of lentiviral VLPs by making their assembly more efficient, which is currently a bottleneck in the widespread therapeutic exploitation of these gene vectors.
Finally, my geometric understanding of phages and their roles in the gut will contribute to a better understanding of how the equilibrium between phages and bacteria can be rebalanced as a means to prevent severe illnesses such as some autoimmune diseases, and ultimately may also help understand the role of marine phages in carbon cycling, a process that is important for our climate.

Publications

10 25 50
 
Description In collaboration with Antoni Luque I have discovered a design principle for icosahedral structures that has solved several open problems in structural virology. It contains the seminal Caspar-Klug Theory as a special case. A paper reporting these results has been submitted to Nature Communications.

In collaboration with my PDRA Giuliana Indelicato I have developed a mathematical model of the structural capsid transitions in the common cold virus, that is an essential step in its life cycle and a prerequisite for infectivity of the virus.

I have developed a mathematical model of infectious interfering particles exploiting packaging signal mediated assembly.

Since the last reporting period, there has been significant interest in these results from the biological community, in particular for nanotechnology applications of (viral) protein containers, and several new collaborations have started as a result, as well as a number of high profile invitations to present this work as key findings at major international meetings. In addition, there has been strong interest from biophysicists studying virus (dis)assembly. We have been able to use the mathematical classification (corresponding to part I of the original proposal) to address fundamental open questions in the (dis)assembly of virus capsids as promised in part II of the original proposal. Progress so far fully addresses, and indeed exceeds, the items listed in the research programme.
Exploitation Route These results support the development of novel anti-viral strategies.

Most excitingly, recent developments enable us to repurpose the RNA encoded virus assembly manual for the improvements of vectors in gene therapy, allowing us to address a bottleneck in vector production. We are in contact with patent agents, and are considering setting up a spin-out company on the basis of these results.
Sectors Agriculture, Food and Drink,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL https://www-users.york.ac.uk/~rt507/
 
Description Public outreach: Results regarding the new design principle for icosahedral architectures developed in part I of my research programme have formed the basis of a collaboration with computer artists, who have used my models to render viruses in 3D, allowing the general public to experience viruses in a virtual reality (VR) environment. A VR presentation designed in collaboration with Prof William Latham from Goldsmiths and his team was shown after myIMA Gold Medal Award Lecture at the Royal Society in 2019. This has been further developed into a contribution to the arts exhibition "The State of Us" at The Lowry Gallery in Manchester ("Inside The HSV1, Herpes Simplex Virus in VR - Artistic variations" as part of the exhibition "The State of Us"; 9th November 2019 - 23rd February 2020), and is now on show at the Centre Pompidou in Paris (as part of the exhibition "DANS LE CADRE DE MUTATIONS / CRÉATIONS"; 26th February- 20th April 2020). Anti-viral intervention: Knowledge of the PSs in a viral genome not only allows us to inhibit virus assembly by blocking these vital contacts as described above, but it also makes it possible to improve on a bottleneck in the manufacturing of virus-like particles (VLPs), that are used for vaccination, drug delivery and gene therapy. In particular, all these technologies rely on the use of viral capsids as protein nanocontainer, to either present viral epitopes (see background section) or to deliver a cargo into a host cell. However, if viral protein containers are assembled in isolation without the presence of the viral genome, they tend to be less stable. Moreover, only a fraction of the particles contain the cargo as intended, requiring a costly sifting step to isolate the particles that have packaged cargo correctly. Based on our modelling and experimental work by our collaborators in Leeds we understand why this is the case: the packaging signals in viral genomes make the capsid shells more stable, and also are important for specific packaging of the correct cargoes [2]. Therefore, constructs mimicking the packaging signal distribution are required, as laid out in our patent ("Virus-Like Particles"; GB1708709.9). Industrial partners interested in vaccinology are interested in this technology, and I have been invited to present a talk to the development team of GlaxoSmithKline in Spring 2020 [3]. This has been scheduled to occur later in 2020. Gene therapy: Based on my mathematical results, I have recently developed algorithms that enable the synonymous recoding of any RNAs so that they present a distribution of packaging signals that enables more efficient packaging of these RNAs and capsid formation around them. In particular, via these recoding algorithms higher yields of correctly packaged particles are achieved, thus addressing the above-mentioned bottleneck in the manufacturing of VLPs for therapeutic purposes. I have recently won an award from the Centre for Future Health enabling me to work towards setting up a spin-out company that will offer such recoding services to industrial partners. Dr Keith Wreggett, managing director of InnoSpective Ltd and industrial advisor to the University is providing guidance in this process. He recognises the potential in "this unique knowledge and capabilities to develop novel therapeutic approaches in areas seen as very high value for investment by addressing clear unmet clinical need within and beyond viral infection".
First Year Of Impact 2019
Sector Education,Healthcare,Manufacturing, including Industrial Biotechology,Culture, Heritage, Museums and Collections,Pharmaceuticals and Medical Biotechnology
Impact Types Cultural,Societal,Economic

 
Title COMPOUNDS FOR TREATING HBV 
Description Disclosed are methods of treating hepatitis B virus (HBV) and inhibiting replication of HBV in a mammal comprising administering to the mammal in need thereof, e.g., administering a compound selected from the group consisting of compounds P1-P29 (as described herein), or a stereoisomer or a pharmaceutically acceptable salt thereof. For example, compound P1 has the following structure: (I) 
IP Reference WO2019241631 
Protection Patent application published
Year Protection Granted 2019
Licensed Yes
Impact The NIH has used this in order to identify small molecular weight lead compounds against viral targets, that are currently tested by expert groups.
 
Description BBC Documentary with Hannah Fry 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Contribution to a BBC Documentary with Hannah Fry: "Magic Numbers: Hannah Fry's Mysterious World of Maths", Episode 1 ("Numbers as God")
Shown 11th October 2018 at 3pm on BBC4 (https://www.bbc.co.uk/programmes/b0bn6wtp)
Year(s) Of Engagement Activity 2018
URL https://www.youtube.com/watch?v=cyvDG8qjt-M
 
Description Exhibition - Centre Pompidou in Paris 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Collaboration with computer artist William Latham from Goldsmiths and his team, rendering geometric models of virus architecture in a viral environment. Work displayed at the Centre Pompidou in Paris (as part of the exhibition "Dans Le Cadre De Mutations/Creations" 26th Feb - 20th April 2020
Year(s) Of Engagement Activity 2020
URL https://www.centrepompidou.fr/cpv/agenda/event.action?param.id=FR_R-f146fa16402582d562607c9d2cbeee3e...
 
Description Exhibition - The State of Us 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Collaboration with computer artist William Latham form Goldsmiths and his team, rendering geometric models of virus architecture in a viral reality environment. This work was exhibited at The Lowry Gallery in Manchester (Inside The HSV1, Herpes Simplex Virus in VR - Artistic Variatins as part of the exhibtion "The State of us" - 9th November - 23rd February 2020
Year(s) Of Engagement Activity 2020
URL https://thelowry.com/whats-on/the-state-of-us/
 
Description Guest Editor of a Special Issue on Medicine and Biology of Mathemetics Today 2019 with Ellen Brooks-Pollocks 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Guest Editor of a Special Issue on Medicine and Biology of Mathemetics Today 2019 with Ellen Brooks-Pollocks
Year(s) Of Engagement Activity 2019
URL https://ima.org.uk/12705/biology-and-medicine-editorial/
 
Description Invited Talk - Geometry as a key to the virosphere: Mathematics as a driver of discovery in virlogy and anti-viral therapy, Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited Talk - Geometry as a key to the virosphere: Mathematics as a driver of discovery in virlogy and anti-viral therapy, Oxford - October 2019
Year(s) Of Engagement Activity 2019
 
Description Invited Talk - Geometry as a key to the virosphere: Mathematics as a driver of discovery in virlogy and anti-viral therapy, Twarock, Edinburgh 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited Talk - Edinburgh - Geometry as a key to the virosphere: Mathematics as a driver of discovery in virlogy and anti-viral therapy, November 2019
Year(s) Of Engagement Activity 2019
 
Description Invited Talk - Geometry as a key to the virosphere: New Insights into Virus Structure, Assembly, Evolution and Therapy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited Talk - March 2019
Year(s) Of Engagement Activity 2019
URL https://www.nottingham.ac.uk/mathematics/events/cmmb/seminarcmmb12032019.aspx
 
Description Invited Talk - Gordon Conference on Physical Virology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited Talk - A Code Hidden Within a code: Deciphering RNA-Encoded Assembly Instructions in Viral Genomes for Applications in Bionantechnology and Anti Viral Therapy
Year(s) Of Engagement Activity 2019
URL https://www.grc.org/physical-virology-conference/2019/
 
Description Invited Talk - IMA Gold Medal Lecture, Royal Soceity 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Geometry as a Weapon in the fight against the viral disease
Year(s) Of Engagement Activity 2019
URL https://ima.org.uk/11396/ima-gold-medal-lecture-2019-geometry-as-a-weapon-in-the-fight-against-viral...
 
Description Invited Talk - Isaac Newton Institiute - Christmas Dinner 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact INI Christmas Dinner - Viral Tiling Theory and Beyond: Geometry as a Key to the Virosphere
Year(s) Of Engagement Activity 2019
 
Description Invited Talk - Viral gemome conformations and contacts across different life-cycle stages 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited Talk - 5-7 FEBRUARY 2020, BARCELONA, SPAIN, Novel Concepts in Virology
Year(s) Of Engagement Activity 2020
URL https://viruses2020.sciforum.net/conferences_files/265/customs/79a099de6c4be4a8c2eb08f5806e290b.pdf
 
Description Invited Talk - Visualising 3D structures 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited Talk - Visualising 3D structures - June 2019 - talk with William Latham (Goldsmiths)
Year(s) Of Engagement Activity 2019
 
Description Invited Talk - Visualising 3D virus structures - The Frances Crick Institute 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited Talk - Feb 2019 - Frances Crick Institute
Year(s) Of Engagement Activity 2019
 
Description Invited Talk Mathematical Virology: The Mathematics of Viral Geometry as a driver of discovery in virlogy and anti-viral therapy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited Talk - University of Leipzig - November 2019
Invited Talk Mathematical Virology: The Mathematics of Viral Geometry as a driver of discovery in virlogy and anti-viral therapy
Year(s) Of Engagement Activity 2019
 
Description Invited Talk Viruses and Geometry: Implications for virus assembly, evolution and therapy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited Talk - Gregynog 2019 -
Year(s) Of Engagement Activity 2019
URL https://gregynogwmc.github.io/Gregynog2019Timetable.pdf
 
Description Invited talk at the IMA Early Career Mathematicians' Autumn Conference, UCL, November 2018 - 'Viruses and Geometry: Mathematics enables discovery in virology and creates new opportunities in bionanotechnology and anti-viral therapy' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk title: Viruses and Geometry: Mathematics enables discovery in virology and creates new opportunities in bionanotechnology and anti-viral therapy
Year(s) Of Engagement Activity 2018
URL https://ima.org.uk/10273/ima-early-career-mathematicians-autumn-conference-2018/
 
Description Mathematics Today - Geometry as a Weapon in the Fight Against Viruses 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Mathematics Today Article - Geometry as a Weapon in the Fight against Viruses
Year(s) Of Engagement Activity 2019
URL https://www-users.york.ac.uk/~rt507/assets/files/Mathematics_Today_Twarock_2019.pdf
 
Description Plenary talk at Mathematics Professional Festival - for high school teachers, Department of Mathematical Sciences, University of Copenhagen, November 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Talk title: Viruses under the mathematical microscope: An opportunity to demonstrate the impact of mathematics in biology in the classroom environment
Year(s) Of Engagement Activity 2018
 
Description Seminar talk at the University of Nottingham, March 2019 - 'Viruses and Geometry: New Insights into Virus Structure, Assembly, Evolution and Therapy' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Talk title: Viruses and Geometry: New Insights into Virus Structure, Assembly, Evolution and Therapy
Year(s) Of Engagement Activity 2019
URL https://www.nottingham.ac.uk/mathematics/events/cmmb/seminarcmmb12032019.aspx
 
Description Talk at Maths Week Ireland, National Concert Hall Dublin, October 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Talk about my work and its applications in health to an audience of 16 year old transition year students (interlude between Junior Certificate and Leaving Certificate courses).
Year(s) Of Engagement Activity 2018
URL http://www.mathsweek.ie/2018/
 
Description Talk at The Roslin Institute, Edinburgh, November 2018 - 'An RNA-encoded virus assembly manual: mechanisms and consequences for viral evolution and therapy' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Talk title: An RNA-encoded virus assembly manual: mechanisms and consequences for viral evolution and therapy
Year(s) Of Engagement Activity 2018