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The increasing number of viral outbreaks in recent decades poses a clear threat to our well-being, as well as often provoking severe economic consequences. However, the rapid evolution of technology means that we are now able to detect and track the genetic mutations of these viruses with much greater accuracy. This is useful for mapping the spread of the virus and developing effective strategies for managing and controlling emerging epidemics.
The PATHPHYLODYN project, funded by the European Research Council, brought together an interdisciplinary group to look specifically at the combined evolutionary and ecological dynamics of infectious diseases, particularly viruses. A key aspect was the development and application of new mathematical, computational and statistical methods to analyse the vast and increasing amount of genetic data available on these diseases.
Drawing on theories from phylogenetics (the relationship between organisms based on their evolutionary similarities and differences), phylodynamics (the study of the interaction between epidemiological and pathogen evolutionary processes), molecular evolution and population genetics, the project created a new suite of analytical methods. This will open up new avenues of research and make it much easier to exploit the explosive growth in genetic data on biological diversity across many disciplines.
‘Changes in genome-sequencing technology have dramatically reduced the cost of this sequencing and the speed and ease of generating virus genome sequences,’ explains principal investigator, Professor Oliver Pybus, from the University of Oxford in the UK.
‘We were early adopters of nanopore sequencing, which enables direct real-time sequencing of DNA or RNA. This has freed up the whole area of genomic sequencing making it more portable, more immediate and less centralised. Our challenge is how to make best use of this vast new source of data,’ Pybus adds.
Managing vast datasets
PATHPHYLODYN was initially conceived as a methodological approach to develop new tools for managing the rapidly increasing volume of data being generated. The researchers have, however, had the opportunity to directly apply these new methods within the context of several public health crises occurring during the project’s lifetime. These included the Zika virus epidemic in South America in 2015-2016, the 2016 yellow fever outbreak in Brazil and, recently, the COVID-19 pandemic currently making a massive global impact.
‘This has meant that our work was more focused on areas of direct practical importance than originally anticipated,’ Pybus continues. ‘Theories were developed by working closely with colleagues in public health, which has increased the project’s impact. I would say that we have brought the field of genomic phylodynamics closer to public health and raised awareness of the considerable power of these approaches,’ he adds.
The scope of PATHPHYLODYN was very broad and multidisciplinary and generated over 100 research papers in a wide range of areas, including new methods for estimating, from very large sets of virus genomes, how fast viruses are adapting and evolving. These techniques have already been applied to important human viruses including HIV, influenza and COVID-19.
Tracking the spread of COVID-19
‘Several methods developed under PATHPHYLODYN have been used to study the COVID-19 virus – for example, to measure virus dispersal both within and among countries, including China and the UK, and to understand how the virus evolves through time,’ Pybus continues.
Tools such as the TEMPEST software, also developed by the team and their collaborators, have been widely cited and applied to hundreds of virus outbreaks worldwide. Another piece of software – SERAPHIM – has been used to look at the spread of coronavirus in both Belgium and Brazil. This tool was specifically designed to understand how viruses spread geographically through space by considering the factors influencing spatial spread.
Mapping Zika, yellow fever and HIV
Using a technique called phylodynamic analysis, researchers collect and sequence the genomes of many samples of a given microbe and scour them for tiny substitutions in their DNA or RNA. By tracking those genetic shifts, they can reconstruct a rough picture of a pathogen’s passage through a population and detect turning points along the way. This proved extremely useful in the analysis of the 2015 Zika outbreak where it was key in helping to reveal the origins of the epidemic and track its subsequent spread through South America, Central America, the Caribbean and the USA. It was also fundamental in tracking and understanding the unprecedented yellow fever outbreak in Brazil.
Furthermore, the project researched how human immune responses and virus populations respond and adapt in response to each other, including insights into how antibodies diversify and change within the course of an infection. This was useful, for instance, in understanding reactions to treatments used in HIV infection.
PATHPHYLODYN has helped create a number of new and very useful computer code and software packages which are now openly available to other researchers worldwide. These tools will allow them to ask new questions about the evolution of pathogens and strengthen global and national readiness to address these emerging infectious disease threats.