Last week brought excitement and disappointment in approximately equal measures for my research on tracking nanoparticles [see ‘Slow moving nanoparticles‘ on December 13th, 2017 and ‘Going against the flow‘ on February 3rd, 2021]. The disappointment was that our grant proposal on ‘Optical tracking of virus-cell interaction’ was not ranked highly enough to receive funding from Engineering and Physical Sciences Research Council. Rejection is an occupational hazard for academics seeking to win grants and you learn to accept it, learn from the constructive criticism and look for ways of reworking the ideas into a new proposal. If you don’t compete then you can’t win. The excitement was that we have moved our apparatus for tracking nanoparticles into a new laboratory, which has been set up for it, so that we can start work on a pilot study looking at the ‘Interaction of bacteria and viruses with cellular and hard surfaces’. We are also advertising for a PhD student to start in September 2021 to work on ‘Developing pre-clinical models to optimise nanoparticle based drug delivery for the treatment of diabetic retinopathy‘. This is an exciting development because it represents our first step from fundamental research on tracking nanoparticles in biological media towards clinical applications of the technology. Diabetic retinopathy is an age-related condition that threatens your sight and currently is managed by delivery of drugs to the inside of the eye which requires frequent visits to a clinic for injections into the vitreous fluid of the eye. There is potential to use nanoparticles to deliver drugs more efficiently and to support these developments we plan that the PhD student will use our real-time, non-invasive, label-free tracking technology to quantify nanoparticle motion through the vitreous fluid and the interaction of nanoparticles with the cells of the retina.
Last week I wrote about research we have been carrying out over the last decade that is being applied to large scale structures in the aerospace industry (see ‘Slowly crossing the valley of death‘ on January 27th, 2021). I also work on very much smaller ‘structures’ that are only tens of nanometers in diameter, or about a billion times smaller than the test samples in last week’s post (see ‘Toxic nanoparticles?‘ on November 13th, 2013). The connection is the use of light to measure shape, deformation and motion; and then utilising the measurements to validate predictions from theoretical or computational models. About three years ago, we published research which demonstrated that the motion of very small particles (less than about 300 nanometres) at low concentrations (less than about a billion per millilitre) in a fluid was dominated by the molecules of the fluid rather than interactions between the particles (see Coglitore et al, 2017 and ‘Slow moving nanoparticles‘ on December 13th, 2017). This data confirmed results from earlier molecular dynamic simulations that contradicted predictions using the Stokes-Einstein equation, which was derived by Einstein in his PhD thesis for a ‘Stokes’ particle undergoing Brownian motion. The Stokes-Einstein equation works well for large particles but the physics of motion changes when the particles are very small and far apart so that Van der Waals forces and electrostatic forces play a dominant role, as we have shown in a more recent paper (see Giorgi et al, 2019). This becomes relevant when evaluating nanoparticles as potential drug delivery systems or assessing the toxicological impact of nanoparticles. We have shown recently that instruments based on dynamic scattering of light from nanoparticles are likely to be inaccurate because they are based on fitting measurement data to the Stokes-Einstein equation. In a paper published last month, we found that asymmetric flow field flow fractionation (or AF4) in combination with dynamic light scattering when used to detect the size of nanoparticles in suspension, tended to over-estimate the diameter of particles smaller than 60 nanometres at low concentrations by upto a factor of two (see Giorgi et al, 2021). Someone commented recently that our work in this area was not highly cited but perhaps this is unsurprising when it undermines a current paradigm. We have certainly learnt to handle rejection letters, to redouble our efforts to demonstrate the rigor in our research and to present conclusions in a manner that appears to build on existing knowledge rather than demolishing it.
Coglitore, D., Edwardson, S.P., Macko, P., Patterson, E.A. and Whelan, M., 2017. Transition from fractional to classical Stokes–Einstein behaviour in simple fluids. Royal Society open science, 4(12), p.170507.
Giorgi, F., Coglitore, D., Curran, J.M., Gilliland, D., Macko, P., Whelan, M., Worth, A. and Patterson, E.A., 2019. The influence of inter-particle forces on diffusion at the nanoscale. Scientific reports, 9(1), pp.1-6.
Giorgi, F., Curran, J.M., Gilliland, D., La Spina, R., Whelan, M.P. & Patterson, E.A. 2021, Limitations of nanoparticles size characterization by asymmetric flow field-fractionation coupled with online dynamic light scattering, Chromatographia, doi.org/10/1007/s10337-020-03997-7.
Image is a photograph of a fast flowing mountain river taken in Yellowstone National Park during a roadtrip across the USA in 2006.
Today is ‘This is Engineering’ day organised by the Royal Academy of Engineering to showcase what engineers and engineering really look like, celebrate our impact on the world and shift public perception of engineering towards an appreciation that engineers are a varied and diverse group of people who are critical to solving societal challenges. You can find out more at https://www.raeng.org.uk/events/online-events/this-is-engineering-day-2020. I have decided to contribute to ‘This is Engineering’ day by describing what I do on a typical working day as an engineer.
Last Wednesday was like many other working days during the pandemic. I got up about 7am went downstairs for breakfast in our kitchen and then climbed back upstairs to my home-office in the attic of our house in Liverpool [see ‘Virtual ascent of Moel Famau’ on April 8th, 2020]. I am lucky in that my home-office is quite separate from the living space in our house and it has a great view over the rooftops. I arrived there at about 7.45am, opened my laptop, deleted the junk email, and dealt with the emails that were urgent, interesting or could be replied to quickly. At around 8am, I closed my email and settled down to write the first draft of a proposal for funding to support our research on digital twins [see ‘Tacit hurdle to digital twins’ on August 26th, 2020]. I had organised a meeting earlier in the week with a group of collaborators and now I had the task of converting the ideas from our discussion into a coherent programme of research. Ninety caffeine-fuelled minutes later, I had to stop for a Google Meet call with a collaborator at Airbus in Toulouse during which we agreed the wording on a statement about the impact our recent research efforts. At 10am I joined a Skype call for a progress review with a PhD student on our dual PhD programme with National Tsing Hua University in Taiwan, so we were joined by his supervisor in Taiwan where it was 6pm [see ‘Citizens of the World’ on November 27th, 2019]. The PhD student presented some very interesting results on evaluating the waviness of fibres in carbon-fibre composite materials using ultrasound measurements which he had performed in our laboratory in Liverpool. Despite the local lockdown in Liverpool due to the pandemic, research laboratories on our campus are open and operating at reduced occupancy to allow social distancing.
After the PhD progress meeting, I had a catch-up session with my personal assistant to discuss my schedule for the next couple of weeks before joining a MS-Teams meeting with a couple of colleagues to discuss the implications of our current work on computational modelling and possible future directions. The remaining hour up to my lunch break was occupied by a conference call with a university in India with whom we are exploring a potential partnership. I participated in my capacity as Dean of the School of Engineering and joined about twenty colleagues from both institutions discussing possible areas of collaboration in both research and teaching. Then it was back downstairs for a half-hour lunch break in the kitchen.
Following lunch, I continued in my role as Dean with a half-hour meeting with Early Career Academics in the School of Engineering followed by internal interviews for the directorship of one of our postgraduate research programmes. At 3.30pm, I was able to switch back to being a researcher and meet with a collaborator to discuss the prospects for extending our work on tracking synthetic nanoparticles into monitoring the motion of biological entities such as viruses and bacteria [see ‘Modelling from the cell through the individual to the host population’ on May 5th 2020]. Finally, as usual, I spent the last two to three hours of my working day replying to emails, following up on the day’s meetings and preparing for the following day. One email was a request for help from one of my PhD students working in the laboratory who needed a piece of equipment that had been stored in my office for safekeeping. So, I made the ten-minute walk to campus to get it for her which gave me the opportunity to talk face-to-face with one of the post-doctoral researchers in my group who is working on the DIMES project [see ‘Condition-monitoring using infra imaging‘ on June 17th, 2020]. After dinner, my wife and I walked down to the Albert Dock and along the river front to Princes Dock and back up to our house.
So that was my Engineering Day last Wednesday!
The DIMES project has received funding from the Clean Sky 2 Joint Undertaking under the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 820951. The opinions expressed in this blog post reflect only the author’s view and the Clean Sky 2 Joint Undertaking is not responsible for any use that may be made of the information it contains.
During the lock-down in the UK due to the coronavirus pandemic, I have been reading about viruses and the modelling of them. It is a multi-disciplinary and multi-scale problem; so, something that engineers should be well-equipped to tackle. It is a multi-scale because we need to understand the spread of the virus in the human population so that we can control it, we need to understand the process of infection in individuals so that we can protect them, and we need to understand the mechanisms of virus-cell interaction so that we can stop the replication of the virus. At each size scale, models capable of representing the real-world processes will help us explore different approaches to arresting the progress of the virus and will need to be calibrated and validated against measurements. This can be represented in the sort of model-test pyramid shown in the top graphic that has been used in the aerospace industry [1-2] for many years [see ‘Hierarchical modelling in engineering and biology’ on March 14th, 2018] and which we have recently introduced in the nuclear fission  and fusion  industries [see ‘Thought leadership in fusion engineering’ on October 9th, 2019]. At the top of the pyramid, the spread of the virus in the population is being modelled by epidemiologists, such as Professor Neil Ferguson , using statistical models based on infection data. However, I am more interested in the bottom of the pyramid because the particles of the coronavirus are about the same size as the nanoparticles that I have been studying for some years [see ‘Slow moving nanoparticles’ on December 13th, 2017] and their motion appears to be dominated by diffusion processes [see ‘Salt increases nanoparticle diffusion’ on April 22nd, 2020] [6-7]. The first step towards virus infection of a cell is diffusion of the virus towards the cell which is believed to be a relatively slow process and hence a good model of diffusion would assist in designing drugs that could arrest or decelerate infection of cells . Many types of virus on entering the cell make their way to the nucleus where they replicate causing the cell to die, afterwhich the virus progeny are dispersed to repeat the process. You can see part of this sequence for coronavirus (SARS-COV-2) in this sequence of images. The trafficking across the cytoplasm of the cell to the nucleus can occur in a number of ways including the formation of a capsule or endosome that moves across the cell towards the nuclear membrane where the virus particles leave the endosome and travel through microtubules into the nucleus. Holcman & Schuss  provide a good graphic illustrating these transport mechanisms. In 2019, Briane et al  reviewed models of diffusion of intracellular particles inside living eukaryotic cells, i.e. cells with a nuclear enclosed by a membrane as in all animals. Intracellular diffusion is believed to be driven by Brownian motion and by motor-proteins including dynein, kinesin and myosin that enable motion through microtubules. They observed that the density of the structure of cytoplasm, or cytoskeleton, can hinder the free displacement of a particle leading to subdiffusion; while, cytoskeleton elasticity and thermal bending can accelerate it leading to superdiffusion. These molecular and cellular interactions are happening at disparate spatial and temporal scales  which is one of the difficulties encountered in creating predictive simulations of virus-cell interactions. In other words, the bottom layers of the model-test pyramid appear to be constructed from many more strata when you start to look more closely. And, you need to add a time dimension to it. Prior to the coronavirus pandemic, more modelling efforts were perhaps focussed on understanding the process of infection by Human Immunodeficiency Virus (HIV), including by a multi-national group of scientists from Chile, France, Morocco, Russia and Spain [12-14]. However, the current coronavirus pandemic is galvanising researchers who are starting to think about novel ways of building multiscale models that encourage multidisciplinary collaboration by dispersed groups, [e.g. 15].
 Harris GL, Computer models, laboratory simulators, and test ranges: meeting the challenge of estimating tactical force effectiveness in the 1980’s, US Army Command and General Staff College, May 1979.
 Trevisani DA & Sisti AF, Air Force hierarchy of models: a look inside the great pyramid, Proc. SPIE 4026, Enabling Technology for Simulation Science IV, 23 June 2000.
 Patterson EA, Taylor RJ & Bankhead M, A framework for an integrated nuclear digital environment, Progress in Nuclear Energy, 87:97-103, 2016.
 Patterson EA, Purdie S, Taylor RJ & Waldon C, An integrated digital framework for the design, build and operation of fusion power plants, Royal Society Open Science, 6(10):181847, 2019.
 Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, Cuomo-Dannenburg G, Thompson H, Walker PGT, Fu H, Dighe A, Griffin JT, Baguelin M, Bhatia S, Boonyasiri A, Cori A, Cucunubá Z, FitzJohn R, Gaythorpe K, Green W, Hamlet A, Hinsley W, Laydon D, Nedjati-Gilani G, Riley S, van Elsland S, Volz E, Wang H, Wang Y, Xi X, Donnelly CA, Ghani AC, Ferguson NM, Estimates of the severity of coronavirus disease 2019: a model-based analysis., Lancet Infectious Diseases, 2020.
 Coglitore D, Edwardson SP, Macko P, Patterson EA, Whelan MP, Transition from fractional to classical Stokes-Einstein behaviour in simple fluids, Royal Society Open Science, 4:170507, 2017.
 Giorgi F, Coglitore D, Curran JM, Gilliland D, Macko P, Whelan M, Worth A & Patterson EA, The influence of inter-particle forces on diffusion at the nanoscale, Scientific Reports, 9:12689, 2019.
 Gilbert P-A, Kamen A, Bernier A & Garner A, A simple macroscopic model for the diffusion and adsorption kinetics of r-Adenovirus, Biotechnology & Bioengineering, 98(1):239-251,2007.
 Holcman D & Schuss Z, Modeling the early steps of viral infection in cells, Chapter 9 in Stochastic Narrow Escape in Molecular and Cellular Biology, New York: Springer Science+Business Media, 2015.
 Braine V, Vimond M & Kervrann C, An overview of diffusion models for intracellular dynamics analysis, Briefings in Bioinformatics, Oxford University Press, pp.1-15, 2019.
 Holcman D & Schuss Z, Time scale of diffusion in molecular and cellular biology, J. Physics A: Mathematical and Theoretical, 47:173001, 2014.
 Bocharov G, Chereshnev V, Gainov I, Bazhun S, Bachmetyev B, Argilaguet J, Martinez J & Meyerhans A, Human immunodeficiency virus infection: from biological observations to mechanistic mathematical modelling, Math. Model. Nat. Phenom., 7(5):78-104, 2012.
 Bocharov G, Meyerhans A, Bessonov N, Trofimchuk S & Volpert V, Spatiotemporal dynamics of virus infection spreading in tissues, PLOS One, 11(12):e)168576, 2016.
 Bouchnita A, Bocharov G, Meyerhans A & Volpert V, Towards a multiscale model of acute HIV infection, Computation, 5(6):5010006, 2017.
 Sego TJ, Aponte-Serrano JO, Ferrari-Gianlupi J, Heaps S, Quardokus EM & Glazier JA, A modular framework for multiscale spatial modeling of viral infection and immune respons in epithelial tissue, bioRxiv. 2020.