Physics of Life Network 2 (PoLNet2)
Lead Research Organisation:
Durham University
Department Name: Physics
Abstract
The 'Physics of Life' is a current Grand Challenge research theme for EPSRC. It is a very fruitful interdisciplinary research field, and a strategic investment for the UK because of the potential our research base has to make leading contributions at or beyond the best efforts in the EU, USA and China, even though we lag behind these somewhat in investment. The strategic imperative arises from (i) the new techniques in experiment, theory and modelling from soft matter physics, instrumentation (especially imaging) and computational physics (including large data processing), together with (ii) a rich field of biological challenges that require physical methods to address at many length scales of biological systems from the molecular to population levels. This is even more true now than at the start of the first Network. Examples of (i) are: advanced AFM of membranes, high-resolution and 3D methods in optical microscopy, high-performance computing of complex molecular matter, the subfield of 'protein physics', field-theories of phase separation, coarse-graining in macromolecular matter, active soft matter, non-equilibrium thermodynamics. Examples of (ii) are: tissue growth and form, cell differentiation, cellular environment sensing, cell membrane rafts, evolutionary dynamics, fibrillar self-assembly, molecular motors.
Planned Impact
As well as academic beneficiaries and the UK research funding community, where constructive impact is anticipated, there is considerable impact anticipated in clinical research and in industry.
Major funders of clinical research including the Medical Research Council, Wellcome Trust, National Institute for Health Research (NIHR), Cancer Research UK and the British Heart Foundation increasingly recognise the key role that physics plays, not only in developing novel technologies, but also in bringing the physics paradigm to bear on major medical and biological research questions. This is exemplified by the NIHR Physical Sciences Oncology initiative (physics.cancer.gov) and the more recent Cancer Research UK Multidisciplinary Award Scheme.
There is also an increasing experience within related UK industry in a number of sectors (personal care, pharmaceuticals, medical engineering products, instrument manufacturing, etc.) that bringing the methodologies and techniques of physics together with biology can be transformation in developing new business and improving existing products.
A key feature of the translational strategy of PoLNet2 will be the inclusion of clinical research funders, clinical academics (drawing on their extensive clinical researcher networks funded by NIHR and others and institutes such as JIC and Crick) and industry. The intention is to develop translational research programmes linked to key themes in PoLNET2 including leveraging funding from industry for multidisciplinary focussed workshop events modelled on EPSRC practice and linked to cognate strategies (for example, Cancer Research UK "Grand Challenges")
Industry partners will be engaged by, building on existing industry networks where appropriate; for example, those available via the Innovate UK Precision medicine Catapult and the NIHR Health Technology and Diagnostic Evidence Cooperatives and Biomedical Research Centres (the latter with an estimated portfolio of more than 500 companies ranging from SMEs, biotech to major pharma and medical technology companies.
Major strategic infrastructure investments in linked and curated molecular and deep phenotypic data sets, including, for example, the MRC Centre for Medical Bioinformatics in Leeds and the Farr and Turing Institutes, offer the prospect of building and testing theoretical models developed by PoLNet2 partners.
Major funders of clinical research including the Medical Research Council, Wellcome Trust, National Institute for Health Research (NIHR), Cancer Research UK and the British Heart Foundation increasingly recognise the key role that physics plays, not only in developing novel technologies, but also in bringing the physics paradigm to bear on major medical and biological research questions. This is exemplified by the NIHR Physical Sciences Oncology initiative (physics.cancer.gov) and the more recent Cancer Research UK Multidisciplinary Award Scheme.
There is also an increasing experience within related UK industry in a number of sectors (personal care, pharmaceuticals, medical engineering products, instrument manufacturing, etc.) that bringing the methodologies and techniques of physics together with biology can be transformation in developing new business and improving existing products.
A key feature of the translational strategy of PoLNet2 will be the inclusion of clinical research funders, clinical academics (drawing on their extensive clinical researcher networks funded by NIHR and others and institutes such as JIC and Crick) and industry. The intention is to develop translational research programmes linked to key themes in PoLNET2 including leveraging funding from industry for multidisciplinary focussed workshop events modelled on EPSRC practice and linked to cognate strategies (for example, Cancer Research UK "Grand Challenges")
Industry partners will be engaged by, building on existing industry networks where appropriate; for example, those available via the Innovate UK Precision medicine Catapult and the NIHR Health Technology and Diagnostic Evidence Cooperatives and Biomedical Research Centres (the latter with an estimated portfolio of more than 500 companies ranging from SMEs, biotech to major pharma and medical technology companies.
Major strategic infrastructure investments in linked and curated molecular and deep phenotypic data sets, including, for example, the MRC Centre for Medical Bioinformatics in Leeds and the Farr and Turing Institutes, offer the prospect of building and testing theoretical models developed by PoLNet2 partners.
People |
ORCID iD |
| Tom McLeish (Principal Investigator) | |
| Martin Cann (Co-Investigator) |
| Description | Key findings have emerged for all workshops sponsored by PoLNet2. Detailed reports are available on the project website The grant has enabled substantial funding for UK Physics of Life to be prioritised by UKRI Strategic Research Funds. Seven. major awards started in 2019. This new funding has also enabled a third phase of PoLNet, starting in 2020. |
| Exploitation Route | New collaborative and interdisciplinary research in physics of life by the UK community. |
| Sectors | Agriculture, Food and Drink,Chemicals,Energy,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| URL | http://www.physicsoflife.org.uk/events.html |
| Description | The Physics of Life Network second phase has attracted industrial membership for the first time. Members are encouraged to conceive and co-sponsor workshops and sandpits that initiate fundamental research that is strategic to their business interest. In the past year Procter and Gamble have held a 2-day sandpit at Durham University gathering interdisciplinary research teams and questions together to address the issue of pollution in skin. Future workshops are planned with the industrial members. In the second phase of the Network a major impact on public policy has been realised. With the formation of UKRI, Physics of Life was chosen as one of the first round of Strategic Research Fund projects, and the Physics of Life Network (via the PI) asked to draft the internal RC case. This was awarded, releasing £30M funds to. 7 major projects in the first instance, and a further 3 year period or PoLNet |
| First Year Of Impact | 2019 |
| Sector | Chemicals,Healthcare,Government, Democracy and Justice |
| Impact Types | Societal,Economic,Policy & public services |
| Description | Institutional Co-funding |
| Amount | £4,000 (GBP) |
| Organisation | Durham University |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 09/2017 |
| End | 10/2017 |
| Description | PolNet2 |
| Organisation | University of Leeds |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | The network IS a partnership of universities and business in the UK - the coordinating partner administers the activities of the network such as workshops, sandpits and small research projects. |
| Collaborator Contribution | The other member universities contribute co-funding to the workshops that they host, thereby extending the reach of EPSRC funding |
| Impact | The outcomes of these collaborations are multi-disciplinary workshops on topics within the physics of life, outputs are in each case a full report, and increasingly full funding proposals to UK or international funding bodies. |
| Start Year | 2016 |
| Description | PolNet2 |
| Organisation | University of Surrey |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | The network IS a partnership of universities and business in the UK - the coordinating partner administers the activities of the network such as workshops, sandpits and small research projects. |
| Collaborator Contribution | The other member universities contribute co-funding to the workshops that they host, thereby extending the reach of EPSRC funding |
| Impact | The outcomes of these collaborations are multi-disciplinary workshops on topics within the physics of life, outputs are in each case a full report, and increasingly full funding proposals to UK or international funding bodies. |
| Start Year | 2016 |
| Description | Anti-microbial Resistance |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Quantitative approaches to antimicrobial resistance Satellite meeting of the 19th IUPAB congress and 11th EBSA congress Edinburgh International Conference Centre, 20th-21st July 2017 Organised by Rosalind Allen and Jamie Hobbs Antimicrobial resistance (AMR) is one of the most urgent emerging threats to global health. AMR has been estimated by the economist Jim O'Neill to have a potential cost of $100 trillion by 2050 if not addressed. Strategies to combat AMR include reducing the use of antibiotics in medicine and agriculture and increasing the pipeline of discovery of new antibiotics. Remarkably, many fundamental questions about how antibiotics work and how resistance emerges remain unanswered - we need to close this knowledge gap if we are to be able to rationally optimise antibiotic use. Quantitative science has a key role to play in this emerging field, just it has already come to have in many other fields of biology. This meeting aimed to strengthen the emerging UK and international research community working on quantitative approaches to AMR, and to discuss the most important priorities and requirements for future research in this field. Workshop presentations The interplay between antibiotic mechanism of action and the physiology of a bacterial cell formed one of the focuses of the meeting. For example, understanding quantitatively how translation works is a prerequisite for predicting how antibiotics that target bacterial ribosomes will act, and models for the physiology of individual ribosome targeting antibiotics (Scott) can, to some extent, predict what happens with combinations of such antibiotics (Kavcic). As another example, the physiology of cell size regulation also has intimate interplay with antibiotic action (Banerjee). Understanding the connection between bacterial physiology and antimicrobial action is important not just for conventional antibiotics but also for "natural" antimicrobials such as bacteriophage (Scott) and predatory bacteria (Sockett), both of which are promising alternatives to antibiotics for treating infections. Going beyond antibiotic mechanism of action, it is also important to understand quantitatively how bacteria evolve resistance to antibiotics. An important link exists between the steepness of an antibiotic's dose-response curve and the distribution of fitness effects of potential resistance mutations; moreover some mutations can slow the evolution of resistance (Bollenbach). In real clinical scenarios, antibiotic dosage changes in time; pulsed doses of antibiotics can select for bacteria that show tolerance rather than resistance; this may be a stepping stone on the pathway to evolution of resistance (Balaban). The mechanism by which resistance evolves may also have an interplay with bacterial physiology via the formation of filamentous cells, containing multiple potentially mutated chromosomes; recombination between chromosomes in filamentous cells could accelerate the evolution of resistance (Austin). Finally, horizontal gene transfer (HGT) is believed to be crucial in the spread of antimicrobial resistance. HGT can be observed on a single cell level using optical tweezers, and the ability (or not) of a strain to perform HGT may (or may not) be correlated to its success in evolving antimicrobial resistance (Maier). Detection of antimicrobial resistance is an important issue, from the molecular level to the level of infectious populations. On the molecular scale, new methods are being developed for visualising single molecules such as outer membrane pores, often implicated in AMR (Leake), for detecting changes in methylation of ribosomal RNA, also associated with AMR (Ranasinghe), and for imaging the detailed structure of bacterial peptidoglycan, which is crucial for understanding how cell wall-targeting antibiotics work (Turner). To be relevant in the clinic, quantitative approaches to AMR need to reach towards clinical practice. Exciting developments in this direction include achieving a better understanding of the dynamics of infection and co-infection of immune cells by Staphylococcus aureus (Foster), mimicking in the lab the effects of co-treatment of cystic fibrosis biofilm infections with tobramycin and bicarbonate (Gordon), and using molecular donors of the signal molecule nitric oxide to disrupt lung biofilms - an approach that is now in phase 2 clinical trials (Webb). Future physics of life research directions The discussion session on day 2 of the workshop produced the following ideas • Communication with clinicians and people from other disciplines is important and should be done early in a project. It would be good to have clinicians participating in future workshops. Interacting with clinicians can be challenging though (not least because they are very busy and often very focused). One solution can be to set up a lab in a hospital environment with direct access to both clinicians and clinical samples. • A gap exists between the lab experiments that many quantitative scientists in this field perform and clinical reality. Bridging this gap by studying the physics of animal models for infection could be a promising direction. • In the opposite direction, some argued for studying a bacterial model system even simpler than E. coli: such as a reduced genome strain. It is unclear how relevant to infection this would be though. • A common theme of many talks at the workshop was to understand how antibiotics work. While progress has been made on this for bacteria growing in liquid culture, much remains to be understood about how antibiotics act on biofilm infections. • High throughput analysis (e.g. screening of mutants, automated evolution experiments) is a promising direction that is only just starting to be exploited by physicists in this area. • Problems that can be studied on multiple scales are very attractive for a quantitative approach. One such topic is the bacterial cell wall (target of many antibiotics) - this topic poses interesting problems from the molecular (structure of peptidoglycan), to the cell-level (models for physiology of cell wall targeting antibiotics) all the way to the whole animal level (pharmacokinetics / pharmacodynamics of action of cell wall targeting antibiotics). • Extending existing imaging techniques (AFM, high resolution microscopy etc) to be able to perform in vivo imaging is an important goal. It is also important to make community-wide tutorial material available, such as you-tube videos on how to calibrate a super-resolution microscope. • Approach to fast diagnosis of bacterial infections is also a very important area where physicists can contribute, which was not covered in this meeting but could be included in future workshops. |
| Year(s) Of Engagement Activity | 2017 |
| URL | http://www.physicsoflife.org.uk/antimicrobial-resistance.html |
| Description | Biocomputation workshop |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Physics of Life Network Workshop on Biocomputation Organisers: Sarah Harris (Leeds), Susan Stepney and Agnes Noy (York), Viv Kendon and Dominic Horsman (Durham) The ability of living systems to store and process complex information in a manner that is responsive to the external environment has inspired the development of the multidisciplinary field of biocomputation, which aims to build computational devices using biomolecular systems. This workshop brought together researchers with interest interested in biocomputation with specialists in gene regulation, DNA mechanics, bioinformatics and computer science. The themes that emerged most strongly from the talks and discussion sessions at the meeting were the potential applications of biocomputation, the requirements for new computational languages and models, and the most challenging open questions in the field. Biocomputation: Its future potential. Biology provides a unique example of a naturally occurring information processing system. If we can understand how this is achieved biological information processing, then we should be able to mimic it synthetically. It is this challenge that defines the field of biocomputation. Three distinct strands in the field were articulated by Dr. Katherine Dunn during the workshop: i) Computing FOR biology - e.g. computer models of biological systems ii) Computing LIKE biology - e.g computational methods or algorithms that mimic biological systems, such as neural networks or evolutional algorithms and iii) Computing BY biology - e.g. using biological systems to build computers. This workshop focused on the third of these themes. To be most useful, biocomputation should exploit the many unique properties of biological systems compared to established computer hardware. Firstly, biocomputational devices have the potential to interact directly with existing biological systems in a manner that is not possible with non-organic technologies. In addition, the stochastic nature of biological interactions allows logical operations within a population of cells or synthetic biomolecular computational compartments to be performed in a probabilistic, rather than deterministic manner, which may offer opportunities for unique types of calculation that are impossible with existing solid state computational devices. Furthermore, biological systems can be inherently tolerant to noise, they can produce emergent behaviour from a set of simple rules and they can provide perform analogue computation, which is complementary to the digital logical operations performed by conventional computing. Biological systems. They are also are inherently "low power", which could solves one of the major global problems faced by the expansion of computing infrastructure on a global scale computing industry, while. Biological systems also have the the ability of biological systems to self-replicate, evolve and adapt , and they can adapt to changes in their environment, which provides both opportunities and challenges for the design of computing living systems that compute. Languages and models for biocomputation: How do we articulate the complex network of interactions between computing biological components? The explosion of biological online databases increasingly requires that this knowledge be represented in a standardised form, so that research communities, and now often increasingly data searching algorithms, can locate and process this information efficiently. For example, in the field of synthetic biology, the Internationally Genetically Engineered Machine (iGEM) project provide an online Registry of Standard Biological Parts, which is a standardised repository of genetic components that can be combined to build synthetic biology devices using a predefined set of assembly rules. The One of the challenges facing the biocomputation community is how to establish the appropriate set of rules for combining these and other components in practice, as current attempts frequently do not produce the expected behaviour once assembled into a larger system. For DNA-based computational engines, this is may be because the context and location of a given DNA sequence affects its output how it is processed. Understanding how the physical status of genes affects their regulation will be key to determining a successful set of design rules for biocomputational devices based on gene expression. Equivalent dependence on the physical location and environment of proteins in regulatory networks is also a limiting factor in understanding the function of cell signalling and metabolic pathways. Obtaining sufficient physical insight that the output from networked biological components can be predicted opens up the possibility of a semantic language for biology, in which the computational output from a given design can be demonstrated to have particular properties. Such a tool would be as valuable to our understanding of existing organisms as it would to the engineering of synthetic counterparts, because it would offer a method to integrate the individual biological components to form a holistic model of the overall outcome of the network, in an analogous manner to the compilation of computer code to generate an executable program. The invention of computational languages for synthetic and systems biology is an active area of community driven research. The Synthetic Biology Open Language (SBOL) for example, provides a vocabulary of schematic glyphs to represent genetic designs, whereas the Systems Biology Markup Language (SBML) is a machine-readable semantic language for model building and analysis of signalling and metabolic pathways and gene regulatory networks. Understanding and applications: What are the barriers to providing biocomputing technologies? One of the ultimate tests of understanding is our ability to engineer. An important role of synthetic biology is that it strongly tests our knowledge of living systems, and so exposes the areas where further research is most needed. As yet, the use of biology-based computational devices is limited to research laboratories, and no technologies are in widespread use. The barriers are primarily in understanding the complexity of biological systems with sufficient fidelity that we can create synthetic versions of them that are both sufficiently complex that they can be used for computation, but which still behave in a predictable manner. This is an exciting research challenge that should be a focus for multidisciplinary research at the Life Science Interface. Presentations • Overview of the Current State of the Art in Biocomputation: Successes and Challenges. Andrew Turberfield. • In Vivo Synthetic Computation. Rob Bradley. • How do living organisms process information? Charlie Dorman and Sean Colloms. • Measurement and Detection: What are the current technical limits to determining the output from biocomputation? Mark Leake and Massa Shoura • Languages and models for biocomputation: Katherine Dunn and Simon Hickinbotham • Applications of biocomputation: Angel Goni-Moreno |
| Year(s) Of Engagement Activity | 2017 |
| URL | http://www.physicsoflife.org.uk/biocomputation.html |
| Description | Engagement with industrial members of PoLNet2 |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Industry/Business |
| Results and Impact | Physics of Life Sandpit: 'Quantification of the migration of airborne particulates in tissue' 22nd and 23rd May, Ogden Centre for Fundamental Physics Organisers: Stefan Przyborski, Elena Lurie-Luke and John Girkin Present: Jim Thompson (P and G), Susan Forest (P and G), John Oblong (P and G) (via conference call), Isoken Igwekala-Nweke (P and G) (via conference call), Margarita Staykova (Durham University), Che Connon (Newcastle University), John Haycock (Sheffield University), Roy Harrison (University of Birmingham), Arto Maatta (Durham University), Ian Mudway (KCL), Laura Marshall (Royal Society for Biology), Karis Baker (Durham University), Tim Hawkins (Durham University), Heather Allinson (Durham University). Apologies: Andrea Jimenez-Dalmaroni (UCL), Barbara Maher (Lancaster University), Halim Kusumaatmaja (Durham University). The sandpit started with participant introductions using a one slide PowerPoint. Elena Lurie-Luke then briefly introduced the sandpit, recalling how it had come about from an initial idea to create a standard pollutant protection factor for skin (much like the SPF associated with sun cream). It had however since emerged that this idea is embroiled with complexity, not least because research has not yet determined how, and if, airborne pollution is able to breach the bodies' barrier to the external environment. As a result, it appears that this research void provides an ideal opportunity to gather a group of individuals (industry (P and G) and academia linked) to formulate a roadmap for investigating the impacts of airborne pollution on the skin. Susan Forest (P and G) gave a short presentation discussing the use of analytical measures of pollution and its experimental design. Particular mention was given to: • Methods of pollution collection e.g. past studies have utilised tape strips. • Determining what's in pollution, what components are particularly harmful and how these factors vary with geographic location. • Accounting for varying lengths of pollution exposure time, e.g. long term versus short term. • Defining experimental controls. John Oblong gave an overview of his work at P and G which has focused on the skin, and in particular, the impacts of UV and other environmental factors. An accumulating body of evidence is linking pollution to harmful effects on skin. Air pollution has been linked to the progression of several skin conditions such as atopic dermatitis, acne, hives, psoriasis as well as increased incidence of skin cancer. P and G have run several studies exploring the impacts of pollutants on skin. Specifically these studies have found that people living in polluted areas show significantly lower skin hydration, that diesel fumes, urban dust and cigarette smoke all cause skin inflammation and that significant changes in gene expression (COL5A) occur when the effects of UV light and pollution are combined, indicating particles may interact with UV to exacerbate adverse effects. P and G are currently planning to carry out further experiments to examine the impacts of pollution and UV on the skin by exposing cohorts to Beijing dust (by topical application onto the forearms of individuals). It is anticipated that the trial could take place by Dec 2017. Isoken Igwekala-Nweke gave an overview on the impacts of pollution on hair and the scalp. Consumers are linking increased pollution levels with diminished hair health; as judged by hair that feels and appears 'greasy and oily'. In vitro hair pollution simulations, run alongside Research Fellow Jennifer Marsh and P and G, have further verified these negative effects; post pollution exposure has led to SEM observation of particulates (with the majority being ~1-3µm in size) on the hair surface, gains in hair weight (particularly for frizzy hair) and an overall decrease in shine. Following the presentations, John Girkin chaired the remainder of the meeting to direct discussion towards formulating a roadmap for investigating the impacts of pollution on skin as directed by the gathered expertise. It was collectively agreed that very little is known about the impact of airborne pollution on the skin. There is a great deal of research that has been carried out on the systemic effects of pollution, via the lungs (c.f. Ian Mudway and Roy Harrison) but the impact on skin has remained understudied, despite a large body of research existing on the detrimental impacts of other environmental factors (e.g. UV and ozone). Ian Mudway suggested the group could take advantage of the wealth of research systematically tackling the impact of ozone (O3) on the skin. Similar methodological approaches could be used to question pollutant impact. Che Connon highlighted the need for the research to be hypothesis driven. It was collectively agreed that the group was working towards the hypothesis that air pollutants damage skin when combined with an activator (e.g. UV). Discussion therefore centered on the experimental design and set up that could test this hypothesis. In vivo and in vitro data were identified as the sources of data that could test this hypothesis. In vivo data could be shared through collaboration with P and G, who are currently planning a skin experiment based on individuals' exposure to Beijing air + UV (as discussed above). In vitro experiments would utilize the 3D skin models already well established in Stefan Przyboski's lab. One approach could be to simulate, as far as possible, the sets of conditions used for the P and G in vivo experiments. In any case, the design of the 3D skin model experiment clearly requires careful thought with clear justification of methodology. In this context, attention focused on the following points: 1. UV + airborne pollution: • The group discussed the importance of exposing 3D models simultaneously to UV light and airborne pollution, given the findings of the P and G research which implied airborne pollutant skin impact is enhanced with UV interaction (as presented by John Oblong; see above). It was agreed that incorporating UV into experimental design would be fairly straightforward; industrial standards and solar simulators already exist. • It would be important to include a control where UV is excluded. 2. Defining airborne particles of choice: • There are a number of pollutant possibilities and mixtures that could be used to test effects of exposure on skin models. The choice of airborne pollutants would be critical in determining both the success and impact of experiments, and therefore a careful review of the literature would be required. • It was agreed that pollutants should be representative of common ambient airborne pollutants in terms of both chemical composition and size. Ambient airborne pollution composition will however vary greatly according to geographic origin and so a clear justification of pollutant choices would be required. • One approach suggested was to focus on countries/regions where threats from pollution are perceived to be greatest (e.g. China; Beijing and Shanghai). In theory, samples of air could be collected from any geographic location and constituent particles identified through fractionation (Ian Mudway). One approach discussed was to use the same air that P and G's Beijing trials would utilize to provide a direct in vitro equivalent. • Roy Harrison suggested the following common pollutants would be important; ambient Particulate Matter (PM) including metals, combustion particles, organic compounds, inorganic compounds (ammonium sulphate, ammonium nitrate), ions, reactive gases and particlulate carbon. In the first instance, a divergent representation of pollutants should be tested on skin models with the aim to converge on those stimulating the greatest physiological response. Roy has an established engine lab where experiments could be carried out. • It was suggested that both the size and structural characteristics of pollutant particles are likely to be important factors in the ability to breach the skin barrier. - Ian Mudway cited research within the scientific literature, which demonstrates particles in the nanosize range, e.g. AuNP (1-6nm), are able to penetrate and disrupt the skin's lipid matrix (see Gupta and Rai, 2016). Among the air pollutants, particulate matter (PM) with aerodynamic diameter less than 2.5 µm (PM2.5) is considered the most detrimental to human health; it may be important to focus on these pollution components. - The characteristics of certain particle mixtures, such as those that are more reactive or contain abrasive components (e.g. combustion particles), may increase dermal penetration. Abrasive components may initiate mechanical micro damage. Stefan Przyboski and John Haycock discussed how mechanical motion could be incorporated into experimental design through flexing of skin models. 3. Mechanistic understanding of the interaction of particles with skin; • It is vital to understand the mechanistic interaction of pollution particles with the stratum corneum (sc) to inform understanding of potential routes of entrance and the extent of penetration into the epidermis and dermis. It was hypothesized that particle movement past the sc may occur via passive diffusion and phagocytosis. This aspect of experimentation would benefit from theoretical modelling; it was suggested that advice from Andrea Jimenez-Dalmaroni (who works in SMBP) should be sought. • Jim Thompson suggested skin condition might affect particle interaction with sc and absorption. For example, aged skin may be expected to provide less of a barrier than young skin. This could be tested by comparing skin models with cells both senescent and young. • P and G alerted the group to their relationship with 23 and me; the largest holder of personal genomic information. The company has characterized SNPs associated with human disease. It may be that genomic information derived from individuals' showing function defects in the skin barrier could be utilized to better understand the mechanistic interaction of particles with skin. 4. Identifying the skin's physiological response to pollution: • It was proposed that the range of skin cell physiological responses induced by pollution was likely to be wide, highly complex, time dependent and perhaps discrete. • A trawl of the occupational literature may help identify the possible expected responses. • Experimentation would utilize an array of standard methods to detect physiological response, these included: - Direct visualization: Using optical and fluorescence microscopy, optical coherence tomography, TEM, Raman spectroscopy, mass spec/imaging, - Tracking inflammatory biomarkers and chemical stress markers: e.g. cytokine secretion, ROS (tracked through spin traps), GSH and cell metabolic rates through metabolic assays. 5. Airborne particle exposure to skin in experimental set up: • Suggested modes of delivery for pollution particle exposure to skin models included: aqueous dispersion (when particles dissolve in water), aerosols, direct spread, ventilation and quantum dots. • Experimental design would have to account for varying exposure times (long versus short term), since pollution effects are likely cumulative. Skin models would use high temporal resolution, monitoring physiological responses of replicates at multiple time points. • Consideration of pollution concentration was required. There are pre-defined standards that could be used initially with effort later focusing towards the concentrations at which physiological responses are induced. A short talk was given by Heather Allinson (Durham Research and Innovation Service) on funding streams available for this type of project. The talk stimulated discussion on which RC would be most appropriate to direct a grant submission. The following research funding opportunities were specifically considered: - The Wellcome Trust seed awards in science (up to £200k, 2 yrs), see: https://wellcome.ac.uk/funding/seed-awards-science - NERC who's research area covers: Medical and Health interface; environment and health 'The relationship between environmental variables and human health. Sources, sinks and pathways of potentially harmful chemicals and organisms present in the natural environment that may have an effect on human health' see: http://www.nerc.ac.uk/funding/application/howtoapply/topics/ - The new EPSRC/BBSRC/MRC Technology Touching Life (TTL) whose aim is to 'foster interdisciplinary research into innovative and potentially disruptive technological capabilities that will drive world-leading basic discovery research in the health and life sciences.' John Girkin notified the group that he would be attending the first of the workshops discussing this new initiative in Birmingham on 6th June. John would explore the potential opportunities available. See: http://www.rcuk.ac.uk/research/xrcprogrammes/technology-touching-life/strategy/ - Global Challenges Research Fund, this funding avenue holds capacity for research and innovation between the UK and developing countries on the Official Development Assistance (ODA) list. It was discussed how collaboration could be sought with researchers from ODA countries affected by high levels of pollution e.g. India. It would be worthwhile considering this as a potential future funding option. See: http://www.rcuk.ac.uk/funding/gcrf/ - CRUK when considering the link between UV and pollutants and malignant melanoma. Actions: • KB to email Andrea Jimenez-Dalmaroni about modelling the movement of particles through stratum corneum [Post meeting note; KB actioned, Andrea met with KB and JG on 13th June to further discuss ideas]. • KB to check with Tom McLeish that Physics of Life seed corn money could be used to employ someone to carry out a literature review [Post meeting note: this is possible, Physics of Life will require a short write up of the sandpit and a summary for justification of spend. Up to £7K is in theory available from PoL with an additional £10K from P and G. A quick literature search reveals there are a number of recent, relevant reviews that would act as a useful starting points for further literature searches (see reference list below)]. • KB to collect ideas for the key questions requiring answers to direct an effective literature search [KB to action with above expenditure sign off]. • KB to arrange a shared drive folder where attending academics can upload their CVs and areas of expertise in support of the planned grant application. • SP to act as the academic lead in writing a grant application to the Wellcome Trust's seedcorn (>£200k). • JG to explore TTL plans. References: Gupta R. & Rai B. Penetration of Gold Nanoparticles through Human Skin: Unraveling Its Mechanisms at the Molecular Scale. J. Phys. Chem. B 120, 7133-7142 (2016). A series of reviews on the topic: Drakaki, E., Dessinioti, C., Antoniou, C.V. Air pollution and the skin. Front Environ Sci 2014; 2: 11. Kim K.E., Cho D., Park H.J. Air pollution and skin diseases: adverse effects of airborne particulate matter on various skin diseases. Life Sci. 2016;152:126-134. Koohgoli, R., Hudson, L., Naidoo, K., Wilkinson, S., Chavan, B., Birch-Machin, M.A. Bad air gets under your skin. Exp. Dermatol. 2016. Naidoo, K., Birch-Machin, M.A. Oxidative stress and ageing: the influence of environmental pollution, sunlight and diet on skin Cosmetics, 10 (2017), p. 4 Puri, P., Nandar, S.K., Kathuria S., et al Effects of air pollution on the skin: a review. Indian J Dermatol Venereol Leprol 2017;7:1-9. [Report written by Karis Baker, June 2016] |
| Year(s) Of Engagement Activity | 2017 |
| URL | http://www.physicsoflife.org.uk/events.html |
| Description | Nanofluidics in Biological Systems |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Title: Nanofluidics in Biological Systems Organiser(s): Kislon Voitchovsky Date and venue of Workshop: 13-15 September 2017, Durham University, Rochester Building, Physics dept. Summary of workshop (where relevant provide detail of key presentations): The workshop brought together about 40 participants from backgrounds across Physics, Chemistry, Engineering, Biology and Medical Sciences. Significantly, it allowed for senior researchers (Knowles, Keyser, Hobbs, Uchihashi) to discuss and share idea informally with younger scientists including postgraduate researchers. This was done both during the conference presentations and at socialising events. The presentations of Knowles, Hobbs, Conner, Hoogenboom and Uchihashi proved particularly stimulating and triggered many discussions. Emerging research questions: The participants to the workshop all work on different aspects of nanofluidics (in biological systems) embedded in Physics, Chemistry, Medical Sciences and Engineering. However, it was recognised that the research must be ultimately driven the big Biology questions. These questions often have multiple aspects, and relevance on multiple scales, and it is hence crucial to keep a constant and open dialogue between biologists, and the other disciplines. Some of the questions or themes identified at the workshop and that would be suitable for interdisciplinary research are: (i) The transport and dynamics of lipids in cells, including storage, droplets, bilayers and exchanges between all the them. (ii) Biological fibres: construction dynamics, repair and interactions with surfaces (keeping in mind the extraordinary abilities of the space bears) (iii) Nanochannels and water/solutes circulation throughout the body. Reported/Anticipated Outputs (e.g. papers, future proposals, key collaborative developments): Several participants have initiated collaborations from the discussions initiated at the workshop. These include: - A new collaboration between Dr Pillizota and Dr Voitchovsky on the dynamics of water flow through channels of Rhodobacter spheroids (Prof Hobbs as adviser). - A new collaboration between Prof Knowles and Dr Grellscheid on lipis nanodrops - A new collaboration between Dr. Lorentz, Dr Schlaich and Dr Voitchovsky to model nano-lubrication at bio-interfaces There was also a commitment to develop Nanofluidics as a scientific community. Through many of the presentations and discussions, it has become obvious that Nanofluidics is not just 'microfluidics but in smaller', but a whole field on its own, with applications ranging from biomolecular function, interface science, lubrication, nanotechnology, etc. Many of the concepts developed for tackling specific questions can be extended or adapted to other systems. The workshop showed that although it is a struggle, it is nonetheless possible to share ideas, models and questions between traditional field lines. Date of report: 9 January 2018 |
| Year(s) Of Engagement Activity | 2017 |
| URL | http://www.physicsoflife.org.uk/nanofluidics.html |
| Description | Physics of Life Town Meeting |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Physics of Life Town meeting summary: The first Physics of Life Town meeting took place at the Royal Society in London on October 2 with over 100 researchers registering for the event. The meeting was opened by network chair, Tom McLeish FRS, who introduced the plans, objectives and opportunities of PoLNET2 over the next 2.5 years. Plenary talks were given by Ben Simons (Cambridge University) and Helen Saibil FRS (Birkbeck College). The talk given by Ben Simons titled 'a unifying theory of branching morphogenesis', elegantly explained how branching morphogenesis follows simple conserved statistical rules in multiple organs. The talk perfectly described a physicist's approach to a biological problem. Ben's excellent paper on this topic was very recently published in Cell, see Hannezo et al., (2017) Cell, 171: 242-255.Helen Saibil's talk on '3D cry-electron microscopy of macromolecular machines' demonstrated the enormous power of this method for structural biologists. Helen detailed how her research has applied single particle analysis and tomography to macromolecular and cellular systems involved in protein folding and reversal of misfolding. It was fantastic to see that in the same week that Helen gave her talk to the Physics of Life the three biophysicists who developed cryo-electron microscropy were awarded the 2017 Nobel Prize for Chemistry! Procter and Gamble's Head of Global Life Sciences Open Innovation Elena Lurie-Luke flew in from Singapore to join the Physics of Life Town meeting and discuss how industry can interact with science research. Specifically, Elena used the example of a recent sandpit ran in collaboration with Physics of Life and P and G on examining the impact of airborne pollution on the skin Talks were also given by past recipients of PoLNET1's collaboration funding. Giovanni Sena (Imperial College, London) presented research on the use of a newly developed assay to image living roots in real time experiencing mechanical stress as they enter glass capillaries. Daniel Frankel (Newcastle University) discussed the presence of the extracellular matrix molecule, hyalouran, which may provide the secret to the naked mole rat's resistance to cancer. Daniel explained how he initiated an important collaboration for this project with Cambridge University's Ewan St John Smith via Tiwtter, promoting the use of social media! Finally, Rhoda Hawkins presented research on investigations on the mechanism of energy consumption in ATPase proteins. The Final session of the day saw 5 of the main science UK RCs (EPSRC, BBSRC, MRC, Wellcome and CRUK) present an overview on the opportunities available to interdisciplinary researchers. Specific mention was given to Technology Touching Life (the recent joint initiative between EPSRC, BBSRC and MRC) which will be of direct relevance to the Physics of Life community. Network members also had the opportunity to ask the panel of RC representative's questions and make suggestions related to their own experiences with interdisciplinary research. |
| Year(s) Of Engagement Activity | 2017 |
| URL | http://www.physicsoflife.org.uk/town-meeting.html |
| Description | Quantitative Methods in Gene Regulation IV |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Title: Quantitative Methods in Gene Regulation IV Organiser(s): Pietro Cicuta Date and venue of Workshop: 18-19 December 2017, Corpus Christi, Cambridge Summary of workshop (where relevant provide detail of key presentations): The 4th edition of Quantitative Methods in Gene Regulation 2-day meeting, held biannually, was very successful. 45 people attended an intense programme with 9 invited speakers (2 USA), 13 contributed speakers, short flash talks from all other contributors, and a general discussion on the state of the community and future directions. People attending represented a mix of physicists and biologists, including many international. We recognised a core of participants who have attended many of the previous meetings, but also many people attending this for the first time. We are very grateful for the sponsorship of PoL2, IOP, RSB and CNRS, which was essential to allow affordable conference charges and especially very low student rates. The meeting developed various scientific themes. One is the structure of chromosomes, which in different ways was the topic of both Mirny and Kleckner opening/closing lectures and other talks. The relation between chromosome structure, intended as its "polymeric" packing, with gene expression and other aspects of cell physiology, is clearly still an active area of both experimental and theoretical research. Many other talks also exemplified questions that call for joint forces from physical and life sciences, from antimicrobial resistance to quantitative analysis of energy production and metabolism in cells, from cell size regulation to epigenetics and the processes at play in development. The open discussion forum was extremely active: we asked ourselves about examples of best practice and strategies to promote inter-disciplinary activities and structures in our various institutions and countries. Examples of barriers. Ways in which we could community build and create effective research teams. Emerging research questions: We did not come up with a single research question, but rather the set of talks highlighted how statistical mechanics (and other physical mechanistic models) can have significant impact on understanding key biological processes. The (well known) challenges of this interdisciplinary activity are in two directions. (1) the physicist wants/needs to know or understand a reduced or well-defined system; this needs to be worked out and respect the possible great complexity of the actual living system. (2) the impact and insight provided by proper physical-based mechanistic models is only really evident, and its deep value can be exploited further, by researchers who understand the underlying physics, which is not normally the case with life scientists. These are the reasons why the two communities need sustained dialogue. Sometimes people will become cross-educated, other times research units will remain mixed, composed of experts from both areas. Reported/Anticipated Outputs (e.g. papers, future proposals, key collaborative developments): The meeting gave ample occasions of discussion and for people to meet. It is unclear how we can track down exact future outcomes. We know from this being a successful 4th edition, and from attendants asking for the series to be sustained, that this meeting has nucleated a lively community and serves as an important and unique reference point. We hope to run a 5th meeting in 2019. Date of report: 6/3/2018 |
| Year(s) Of Engagement Activity | 2017 |
| URL | http://www.physicsoflife.org.uk/qmgr.html |
| Description | Quantum Biology |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Report on the Surrey Workshop on Quantum biology This two-day workshop at the University of Surrey held over a Friday/Saturday (21,22 July 2017) was a satellite meeting to the Biophysics Congress that took place during the preceding week in Edinburgh, and which included a session on quantum biology (QB) convened and chaired by one of the workshop organisers (JAK). The workshop was funded by PoLNet2 (£4k) with a further £2k from the University of Surrey (split equally between the Faculty of Health and Medical Science and the Department of Physics). The motivation for the workshop was that the topic of quantum biology was listed in the PoLNet2 application as one of twelve topics that would benefit from having early-stage workshops in 2017 and 2018. Over the past few years, QB has grown from a speculative, some would even say controversial, field to one where exciting experimental and theoretical results are being explored and discovered. However, although there are a number of researchers working in the field in UK universities, the activity tends to be limited to one or two people here and there or as a side interest to other more mainstream (and better funded) research activities. The workshop brought together a programme of speakers from a wide range of backgrounds to discuss their work and to sharpen research questions and methodologies. Typically, such specialist workshops tend to be rather focused in their remit and scope and end up being a forum for specialists to update each other on their progress. While that type of meeting plays a vital role in research, it was not the purpose of this one. Instead, the organizers deliberately brought together a wide range of speakers and delegates from different fields: molecular biologists, synthetic biologists, biochemists, physical chemists, quantum physicists as well as stake holders and potential funders from dstl and the US Air Force Research Lab. This diversity meant that the nature of the talks and the ensuing discussions tended to be far wider than normal with a good deal of constructive criticism and advise. What emerged was two main issues surrounding the future of quantum biology as a viable and exciting new field of research: 1. The need to correctly define what 'quantum biology' is. The practitioners in the field would say they know - they would say it is the study of 'non-trivial' quantum effects and phenomena in biological systems. However, it is clear that no one working in the field would define themselves as a 'quantum biologist'. They are quantum physicists, molecular biologists, spectroscopists, physical chemists, etc. There was considerable discussion during the Saturday afternoon about whether the name should be changed, however no consensus was reach as to an alternative title. The problem is that much of the work in biophysics and biochemistry involves quantum mechanics in some form, whether it is modelling electronic distributions with techniques such as density function theory (computational biology) or quantum mechanisms in biomolecular bonds (quantum chemistry) or looking at theoretical models of quantum phenomena in biology such as in photosynthesis (quantum information theory). Is there then a need to have an umbrella term for anyone working on non-trivial quantum effects (long-lived coherence, tunneling, entanglement) in living systems? And if so, what are the benefits of doing so? 2. The 'So What?' question. This is the criticism usually leveled against the field by biologists and can be encapsulated as follows: a molecular biologist or biochemist might say 'yes, I agree that if you burrow down deep enough to the molecular and even atomic level, then you will hit the quantum domain. But these are incidental and will not have any bearing or measureable effect on the macroworld - the world of biological processes'. Their argument is that while quantum effects are surely always there at some level, they play no active role in the mechanics of life. One skeptical speaker stated that surely below the classical, deterministic nano-machinery inside cells is just thermodynamics. Needless to say, the workshop organisers did not agree with this view. A more valid criticism is that while in certain phenomena, such as proton tunneling in enzyme catalysis or energy transfer in photosynthesis, there is now well-established work suggesting quantum effects are non-trivial, many in the life sciences community (and indeed in the physical sciences) remain unconvinced that life has sought out these quantum mechanisms to give it an advantage. In which case, one might argue: so what if there is quantum mechanics buried underneath? However, the role of those working in the field of quantum biology is not to prove that quantum mechanics does indeed play a vital role in biology, but to investigate carefully whether or not it does. This is such an important and fundamental question that it needs to be addressed seriously. In terms of the workshop, one minor point to mention was that attendance on the Saturday was much depleted, which is understandable given this was the first weekend of the school summer holidays. The organisers appreciated the need to wait until the biophysics congress had ended on the Thursday, but in future they would avoid holding meetings that ran into weekends. As a concrete outcome, one of the organisers (JAK) has agreed to take on the task of putting together (coordinating) a white paper to address the above points, with input from interested workshop speakers and participants, and which can be presented to research councils to indicate the community's resolve and ambition in seeking funding sources. At the moment, the field suffers from not having an identifiable funding body that will take responsibility for the subject. It was also agreed that the organisers would potentially seek further funding from PoLnet2 in the form of a sandpit and/or pump-priming funds for further discussions and collaborations to clarify real challenges and research questions that could form the basis of grant proposals. Jim Al-Khalili 26 July 2017 |
| Year(s) Of Engagement Activity | 2017 |
| URL | http://www.physicsoflife.org.uk/quantum-biology.html |
| Description | Sandpit: How do ATPase proteins do work? |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Other audiences |
| Results and Impact | Organiser(s): Rhoda Hawkins, Martin Cann Date and venue of sandpit: University of Sheffield, 23/1/18 Emerging research questions: The small molecule adenosine triphosphate (ATP) is essential to life. It acts as the fuel or energy currency of the cell. The energy released in ATP hydrolysis provides the biochemical energy necessary for cellular processes. ATPases (adenosine triphosphatases) are enzymes that catalyse ATP hydrolysis. They use the energy released to drive further chemical reactions or perform mechanical work. Examples of ATPases include kinases, DNA motor proteins, transmembrane pumps, the protein synthesis/degradation machinery and cytoskeleton proteins such as actin and myosin that consume ATP to exert mechanical forces for transport, deformation and motility. A fundamental question is how does ATP binding and hydrolysis transfer energy to an ATPase protein to enable it to do work? This is a particularly pertinent question as ATPase proteins typically show a common protein fold at the ATP binding site. How can such a well conserved event at a common structural motif drive the enormous array of biochemical processes exemplified by ATPases? Surprisingly little is known about the details of the mechanism for this ubiquitous energy consumption process. The ubiquity of ATP means that this question underpins our knowledge of how biochemical systems function. A workshop from PolNet1 provided the framework for the research question and drove preliminary experiments to a point at which a discussion can be made concerning a full grant application. This sandpit brought together a group of physicists, chemists and bioscientists to discuss a multidisciplinary application to BBSRC to understand how ATP binding and hydrolysis transfer energy to an ATPase protein to enable it to do work. The following issues were considered 1. Where should a grant proposal be targeted? Agreed to send to BBSRC as it targets a biological question. 2. Should the proposal address both theory and experiment? Agreed that a theory/experimental proposal with 2xPDRA or 1xPDRA/1xTech would require significant investment of pump priming to provide preliminary theory to support such a large application. Preliminary experiments could conceivably be performed without pump priming although this was not ideal. 3. Was available pump priming sufficient to provide preliminary theory? It was agreed that pump priming could not provide the level of support required. 4. Can a smaller scale application to BBSRC be made? Agreed to write a small theory only proposal to BBSRC for 1xPDRA and 18 months. The aim of the proposal is to develop supporting theory for a larger 2xPDRA theory/experiment proposal in about 2020. The final outcome therefore will be an 18 month small-scale proposal to BBSRC with PI Rhoda Hawkins and Co-I Sarah Harris. We will aim for the April 2018 deadline. Reported/Anticipated Outputs (e.g. papers, future proposals, key collaborative developments): Proposal to BBSRC Date of report: 25/1/18 |
| Year(s) Of Engagement Activity | 2018 |
| URL | http://www.physicsoflife.org.uk/sandpits.html |
| Description | The Assembly, Dynamics and Organisation of Filaments and Cellular Responses |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Workshop Report: One of the most remarkable aspects of biology is the richness of behaviour in the cells and their components. It is this that makes the study of the cytoskeletal filaments and understanding their physical properties essential to appreciating how living systems communicate across scales. The cytoskeleton is a trans-cellular network of filaments that integrates individual cells into their respective tissues and helps coordinate the physiological responses of the organism. The filaments comprise individual proteins just a few tens of nanometers in length and yet these micron/mm/metres long filaments store, dissipate and channel the physical and chemical signals sensed by cells and tissues. The cytoskeleton is both an energy and an information dissipation/storage system for the cell. It is also a major structural asset essential to any tensegrity-based models of the cell and this workshop brought together biophysicists, cell biologists and modellers committed to revealing these biophysical properties. Detailing the assembly of intermediate filaments in vitro has proven a tough scientific problem that has spanned several decades, but of all the cytoskeletal elements, it is this filament system that stands apart from microtubules and microfilaments in their superior biomechanical properties, ability to fission and fuse and exchange subunits and assembly intermediates along the length of the filament. Workshop Presentations Although the initial stages of intermediate flament assembly are now reasonably well characterised, the detail of the filament itself and how to regulate the length and width as well as the internal structure are now key experimental goals. Native filaments present significant challenges to our understanding, as exemplified by the hagfish slime intermediate filaments. In these filaments, fusion of individual 10nm filaments to form micron wide filaments is observed, but by completely unknown mechanisms (Fudge). The potential socio-economic benefit of discovering the biophysical principles are very significant. Lessons from the ancient industries of rope making and weaving evidence the benefits of twisting multiple strands and/or braiding to increase strength. As well as changing the biophysical properties, the limit to the extent of the twist mediated by the ability of individual strands/fibres to slide and yet twisting several strands together can facilitate bending (Prior). So now the importance of understanding whether a filament is a collection of protofilaments or is a single entity becomes a critical question. What is clear is that the intermediate filament and its network of filaments in cells has incredible capacity to withstand stress and strain (Anders). Individually, filaments can be stretched to the (irreversible) point of undergoing alpha-helix to beta-sheet transition, suggestive of sliding mechanisms accompanied by irreversible secondary structure transitions at the extreme. Cation-assembled filament networks in vitro can withstand a 700% increase in strain, providing this is made in a step-wise fashion. This is accompanied by network softening and fluidisation arising from a loss of connectivity between filaments and finally the eventual rupture of the network. The filament network is considered as a mixed Maxwell and Kelvin-Voigt viscoelastic system so the creep and relaxation properties of the intermediate filament network are adequately explained. It is clear that as a network, intermediate filaments and their integration within the trancellular network provides a spectrum of biophysical properties. Two talks from Leube and Goldberg provided examples of these properties. At the nuclear membrane a supramolecular protein complex (LINC) physically connects the cytoplasmic and nuclear intermediate filament systems and we heard the complexity and functional diversity of the components that control, amongst other things, the spacing between the inner and outer nuclear membranes. Now of course in our reductionist world of science where every cell is a sphere this is a gift not to be ignored. Newtonian principles applied to understanding the regulation of enzymatic activity can now be applied to transcriptional regulation and mechanosensory systems of the cell - an impressive example of scaling indeed from atoms to whole animals - via the cytoskeleton! This included the dynamic behaviour of cytoplasmic filaments that supports both inward flow of polymer, with the necessary localized assembly and disassembly, as well as the positioning and complexity of a more stable filament network according to the functional requirements of the cell. It is this richness of behavior seen for intermediate filament networks and the fact that the transcellular network it forms exhibits such complex behavior in terms of forced oscillations and waves in response to external stimuli (physical and biochemical), their positioning and complexity in terms of bundles, nodes and integration within the cell, properties that likely have significant emergent potential, but as yet undiscovered because the imaging and modeling tools are still in development. The talk from Bromley and McLeish highlighted this richness in the intermediate filament assembly system. Their approach was synthetic biology based using synthetic polypetides based on coiled coil forming alpha-helices as biomimetics. Here it is clear that aspect of surface geometries and our current abilities to control width, length, subunit registration and uniform, apolar assembly are opportunities for future research. Amyloid fibre assembly (Auer) is related, but a far simpler assembly system compared to intermediate filaments albeit again using synthetic peptides. Modelling of this system to address the questions of nucleation, elongation and thickening of amyloid fibres helps inform amyloid network biomechanics. A step-wise nucleation process that is concentration/volume dependent offers new therapeutic opportunities has come about from simulation analytics. Modeling of the inward flow of keratin filaments (Portet) that accounts for the diffusion, active transport, assembly and disassembly of intermediate filament subunits and filaments is a complex multidimensional problem with potentially 36 different model outcomes. Selection is based on probability and from this a directed active transport model is favoured, where kinesin and dynein enter a tug of war to deliver the movement of intermediate filament particles. Interestingly the biomechanical properties of these particles and filaments affects the outcome of this motor protein tug of war. This is another example of the richness of the behavior in this filament system and why an interdisciplinary team approach is needed. Future Physics of Life Research Questions The workshop included several open discussions from which emerged a series of open questions concerning the ability of intermediate filament networks to self-organize, to store and channel biomechanical energy: • Do the compression/extension properties of individual filaments transfer to bundles and networks? • How do we explain how cell networks can soft with shear but not so with compression? Such questions will likely only be answered once we appreciate, understand and then mimic intermediate filament assemblies. The ability to design and fabricate a micron-sized, filament-like network would be a significant step to building and designing a synthetic cell. The advantages of a dynamic network with different assembly states would seem futurist, but filament fission and fusion is an energy independent process and therefore is matter of design, fortitude and vision for the experimentalist as such properties deliver a smart biopolymer that can tune itself to its environment and the changing physical demands. Here an appreciation and understanding of the 4 dimensional properties of a network (time and space dimensions) is an important experimental goal. How, for instance, the transcellular network of cells contribute to crowding and dragging properties and influence reaction rates / equilibrium constants is currently unexplored, but such a filament network is just a super-scaled catalyst for such reaction. The transcellular mimetic then facilitates reactions by creating nanodomains. How network mesh size influences reaction efficiency can be determined leading to the manufacture of substrate channeling systems using fabricated, synthetic filament networks so that we move artificial crowding agents into controlled and regulated mimics of the cytoplasmic space. In addition to the nanometer/micron scale of these cell-sized bioreactors, we could potentially polymerise the units into millimeter and meter sized bioreactors as the scaling properties are discovered and applied. This is another potential application in addition to potential dynamic, tunable mechanical properties, but illustrates the future for understanding the principles and physics of the transcellular intermediate filament network. |
| Year(s) Of Engagement Activity | 2017 |
| URL | http://www.physicsoflife.org.uk/filaments-and-cellular-responses.html |
| Description | The Structure and Properties of Mildly-broken Symmetries |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Title: The Structure and Properties of Mildly-broken Symmetries Organiser(s): Tom McLeish and Markus Hausmann Date and venue of Workshop: 4 - 5 October 2017, Institute of Advanced Study, Durham University Summary of workshop (where relevant provide detail of key presentations): The workshop was structured around a day from the perspective of physics, and second day from the perspective of cognitive neuroscience, exploring a wide gamut of questions around the special properties of near-symmetric systems. The programme included long discussion times and was as follows: Start Item 11:30 Registration and Coffee 12:00 Introduction: Tom McLeish 12:15 Frank Close (Physics, Oxford): The Asymmetric Universe - from unstable symmetry to stable unsymmetry 13:15 LUNCH 14:00 Ard Louis (Physics, Oxford): Does (near) symmetry spontaneously arise from the algorithmic nature of the world? 14:45 Amanda Nichols (Chemistry, Oklahoma) "Symmetry, Asymmetry, and the Explanatory Value of Aesthetic Properties Part 1" 15:30 Myron Penner (Philosophy, Trinity Western) "Symmetry, Asymmetry, and the Explanatory Value of Aesthetic Properties Part 2" 16:15 Refreshments 16:30 Panel Discussion 17.30 FINISH 19.00 Optional conference dinner at Lebaneat, Durham Thursday 5 October 2017 Start Item 09:00 Introduction by Markus Hausmann (Psychology, Durham) 09:15 Iain McGilchrist (Psychiatry, Oxford) "Asymmetry of the brain and asymmetry of the world" 10:15 Refreshments 10:45 Chris McManus (Psychology, UCL) "Near symmetry in bodies, brains and art" 12:15 LUNCH 13:00 Alain Goriely (Maths, Oxford) "Symmetry breaking in biological growth with applications to the brain" 13:45 Jonathan Heddle (Biotechnology, Krakow) "TRAPped in Space: Protein Nanocages with Unusual Structures" 14:30 Panel Discussion 15.00 Refreshments and close All talks were video-captured and will be made available after editing on the IAS website, and are already available to the speakers as they emerge, for use in further publications and proposals. Emerging research questions: What is the evolutionary route to near-symmetry, and what are the sensory advantages? Candidates are an ability to sense generalised-vectorial properties not sensible to a perfectly symmetric system, without acquiring structural disadvantages of poor symmetry. What would a generalises mathematical framework for near-symmetry look like? Is there a group-theoretic generator, a set of subgroups, that bridge from the discrete to continuous aspects of the problem? Are there particular enzymatic properties of near-symmetric molecules? Is specificity enhanced by a near-symmetric configuration, while e.g. maintaining a generalised adaptive fit? How can one characterise (including mathematically) near-symmetrical structures? How can we test and quantify the concept of mildly broken symmetry across all disciplines? What are the functional implications of mildly broken symmetrical structures? Why do we find near-symmetry structure attractive? Are mildly broken symmetries adaptive? How do symmetries and asymmetries develop? What can different disciplines learn from another about symmetry and asymmetry? Reported/Anticipated Outputs (e.g. papers, future proposals, key collaborative developments): An article about the findings and questions of the meeting has been proposed, and will follow in 2018. Possible research collaborations were discussed - Jonathan Heddle has made a return trip to Durham under the BSI to continue discussions. Sylvia Paracchini and Markus Hausmann have discussed the possibility of a joined grant application. Silvia Paracchini, Chris McManus, Iain McGlichrist and Markus Hausmann will attend the North Sea meeting on Brain Asymmetries in Dundee in August 2018. They will discuss the possibility of initiating a Laterality society (linked to the journal Laterality). In preparation of the workshop, Tom McLeish was invited by Markus Hausmann (book review editor LATERALITY) to review Frank Close's new book. The book review has now been published. Date of report: 9 Feb 2018 |
| Year(s) Of Engagement Activity | 2017 |
| URL | http://www.physicsoflife.org.uk/symmetry.html |