Improving computer modelling of cardiac properties by ditching the one-size-fits-all approach
A new approach to computer modelling has won the NC3Rs 2014 3Rs Prize. The work has been recognised for its potential to reduce the number of animals used in research, particularly in the safety assessment of new drugs.
For the first time since the prize was launched in 2005, the highest accolade has gone to a PhD student, Mr Oliver Britton, working with Professor Blanca Rodriguez, at the University of Oxford.
Mr Britton's winning paper describes using existing data to build a computer model of cardiac electrophysiology that incorporates variations in 'normal' heart properties that occur between individuals of the same species. Traditional modelling tends to ignore this, using averaged data instead. This new approach has the potential to make computer models that can more accurately identify drug compounds that could be toxic to the heart. Early identification would allow these compounds to be removed from the drug development pipeline before they reach the stage where regulatory animal studies are required. As confidence in the model grows, there could be potential for it to replace some in vivo studies altogether.
The computer model has also been developed into a user-friendly software package called Virtual Assay, which should increase industry uptake for use in drug safety testing, as it can be used without the need for specialist programming and modelling experience.
It is possible to use the modelling method to study variability in any biological system, increasing the potential of the model to reduce animal use.
Mr Oliver Britton, University of Oxford, said:
"It's great to have our research recognised as having a potential impact on the 3Rs, and winning the prize helps with publicising our work to the audience who might be interested in it. We plan to use the prize grant to apply our methodology in neuroscience, specifically pain research in humans, through a collaboration we have developed with an industrial partner. We will investigate how variability between individuals alters the response of different types of pain-sensitive neurons to drugs."
Three further papers were awarded highly commended status. A paper published in Nature Communications by Olivier Frey, from ETH Zurich in Switzerland, reports on a novel approach to culturing cells in vitro. Gaskill and Garner, both working in the US, have been commended for their study investigating the importance of nesting material and temperature for mouse welfare. AstraZeneca's study looking at the benefits of the microsampling technique for collecting blood from animals in toxicology studies was also recognised.
The international NC3Rs 3Rs Prize, sponsored by GlaxoSmithKline, is awarded to highlight an outstanding contribution to scientific and technological advances in the 3Rs in medical, biological or veterinary sciences. The prize, which will be awarded at an evening celebration in London in March, consists of an £18k award to be used to further the 3Rs potential of the study and a £2k personal award. Highly commended entries receive a £4k grant and £1k personal award.
Dr Steve Pyke, Senior Vice President Quantitative Sciences, GlaxoSmithKline said:
"GlaxoSmithKline is delighted to sponsor the NC3Rs Prize. We are really pleased that this year's winning authors come from academia and industry, and from Switzerland and the US as well as the UK, reflecting the inclusive and international nature of this important Prize."
Professor Ian Kimber OBE, 3Rs Prize panel chair, said:
"Mr Britton's paper really stood out to the panel because of the model's potential as a replacement for early-stage animal tests in drug safety studies, across a broad range of disciplines. The model has also been developed into a piece of user-friendly software, encouraging uptake and use by industry, which could have an important impact on the reduction of animals in research."
More information:
Laura McGuinness, Communications Officer, laura.mcguinness@nc3rs.org.uk
Notes for Editors:
About the NC3Rs:
The National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) is a leading independent scientific organisation dedicated to replacing, refining and reducing the use of animals in research and testing (the 3Rs). It supports the UK science base by driving and funding innovation and technological developments that minimise the need for animals in research and testing, and lead to improvements in welfare where animals continue to be used. It funds research, supports training and development, and stimulates changes in regulations and practice.
Primarily funded by Government, the NC3Rs is also supported by the charitable and private sectors. It works with scientists in universities and industry in the UK and internationally.
Further information can be found at: www.nc3rs.org.uk @nc3rs blog.nc3rs.org.uk.
About the 3Rs Prize:
The international NC3Rs Prize, sponsored by GlaxoSmithKline, is awarded to highlight an outstanding original contribution to scientific and technological advances in the 3Rs in medical, biological or veterinary sciences published within the last three years. The prize is part of our commitment to recognise and reward high quality research which has an impact on the use of animals in the life sciences.
The 3Rs prize is for a piece of primary research published in a peer-reviewed journal in the last three years and is open to any researcher, in academia or industry. The prize is awarded to the principal investigator, research team leader, or other nominated author. The Prize is open to international groups.
Applications are assessed by a dedicated Panel, which also selects the winner. Selection is based on the quality of the published research and its impact on the 3Rs.
About the winning papers:
Prize winner
Mr Oliver Britton – The University of Oxford
Britton O, Bueno-Orovio A, Van Ammel K, et al. (2013) Experimentally calibrated population of models predicts and explains intersubject variability in cardiac cellular electrophysiology. Proc. Natl. Acad. Sci. USA 110: E2098–2105 doi:10.1073/pnas.1304382110.
The authors have built a computer model of cardiac electrophysiology that incorporates natural variability. Normally when using a computer model to test how a drug might affect the heart, the effect of the drug on the heart is compared to an average profile of electrophysiology. But this average profile is not really representative of the whole population, where natural variations in heart properties occur from person to person. This new approach has the potential to make computer models that are far more powerful and more predictive of human response, and therefore a more viable alternative to using animals in research. This is the first time that natural variability has successfully been considered in such a model, and the methodology could be applied to other diseases. The methodology has also been developed into a user-friendly software package called Virtual Assay, which is a major facilitator for industry uptake, without the need for specialist programming and modelling experience. The authors are already planning to use the same methodology to build computer models for understanding pain and diabetes.
Highly commended
Dr Olivier Frey – ETH Zurich
Frey O, Misun PM, Fluri DA, et al. (2014) Reconfigurable microfluidic hanging drop network for multi-tissue interaction and analysis. Nat. Commun. 5:4250 doi:10.1038/ncomms5250
Frey’s paper reports on a novel approach to culturing multi-cellular spheroids in vitro. The work is a significant advance in engineering, which brings together the hanging drop method and microfluidics to substantially expand the experimental options for culturing spheroids. Growing cells using a hanging drop approach, means that 3D cell spheroids can be grown without the restriction that may be imposed by a scaffold or a dish. Microfluidic systems allow precise liquid handling including continuous medium and waste exchange, and also allow test substances, such as candidate drugs, to be run through the culture. This is the first time these two approaches have been combined, and the result holds real promise to bolster the predictivity of in vitro research. The microfluidic hanging drop network has already shown that spheroids of cells representing different organs can be inter-connected in physiological order and are able to communicate with each other via metabolite transfer. This is exciting as this capability is one of the first steps towards creating a multi-organ body-on-a-chip model.
Drs Brianna Gaskill and Joseph Garner – Purdue University and Stanford University
Gaskill B, Gordon CJ, Pajor EA, et al. (2012) Heat or insulation: Behavioral titration of mouse preference for warmth or access to a nest. PLoS ONE 7 (3): e32799 doi: 10.1371/journal.pone.0032799.
Mice are commonly housed at temperatures (20–24°C) which humans find comfortable for working in the laboratory. Mice become cold stressed below 30˚C, which can compromise many aspects of physiology and welfare. However, the amount of nesting material required to meet a mouse’s thermal needs has until now been unknown. In this study the authors found out where mice wanted to spend their time, based on combinations of temperature and nesting material. They found that mice prefer temperatures between 26–29°C, but shift from preferring a warmer temperature to a nest when provided 6-10g of nesting material. These results suggest that laboratory mice should be provided with no less than 6g of nesting material in order to build fully formed nests, but 10g or more may be needed to eliminate thermal stress. These results have the potential to positively impact the welfare of millions of laboratory mice all over the world.
Dr Nicola Powles-Glover – AstraZeneca UK
Powles-Glover N, Kirk S, Wilkinson C, et al. (2014) Assessment of Toxicological Effects of Blood Microsampling in the Vehicle Dosed Adult Rat. Regulatory Toxicology and Pharmacology. Apr; 68(3):325-31. doi:10.1016/j.yrtph.2014.01.001
It is a requirement in animal safety testing of new medicines that the blood concentration of the medicine is measured. Historically, large volumes of blood were required to detect the concentration of the medicine. This meant that for rat studies, separate groups of rats were used solely for measuring the concentration while other groups of rats were used to assess the effects of the medicine on the animal. Advances in the way that blood is analysed mean that, with the right analysis equipment, very small “microsamples” of blood are now sufficient. Taking a microsample of blood from a rat is a quicker, less stressful procedure than taking a larger volume. This paper provides the evidence that taking repeat microsamples does not adversely affect adult rats and therefore does not interfere with the ability to interpret these safety studies. This means that information about the drug concentration and its affects can be obtained from the same animal, allowing a direct link between drug concentration and effect. This is a major scientific improvement. It also means that far fewer rats are required on these safety studies. As a consequence of this work, whenever the sensitive analytical method is available, AstraZeneca now use microsampling routinely in all rat safety tests.
Provided by National Centre for the Replacement, Refinement and Reduction of Animals in Research
