On March 1st 2020, the total number of people in the UK known to have died from COVID-19 was three. By March 15th that number had risen to 76.
The following day, March 16th, a multidisciplinary team at the University of Southampton led by Tristan W. Clark and Diana Baralle secured approval from the South Central – Hampshire A Research Ethics Committee to conduct a research trial investigating this alarming new pathogen.
A week later, as the total number of deaths in the UK surpassed 800, the UK government announced the first nationwide lockdown.
Background
Dr Jenny Lord is a Senior Research Fellow at the University of Southampton. She studies rare diseases using genomic sequencing technologies, and she played a key role in the study led by Clark and Baralle.
“COVID happened and we saw an opportunity to do some interesting research”.
That research1, which saw the University of Southampton joining the global effort to understand and combat COVID-19, was a collaborative enterprise involving 20 academics with a range of research interests, including molecular biology, proteomics, immunology, genomics, and biotechnology.
“This was before there were any treatments, any vaccines, anything like that, and Tristan Clark and Diana Baralle thought that taking RNA samples from these patients would be potentially useful”.
RNA, in the simplest possible terms, performs the complex logistics involved in carrying out the instructions given by DNA. It carries the blueprints from genes in the genome to cellular machinery that turns those instructions into proteins.
The modus operandi of viruses like COVID-19 is to infiltrate and exploit this process. Having entered the body, coronaviruses bind with healthy target cells using distinctive spike proteins. They hijack the cells’ own machinery to create new viral particles, and spread through replication.
How the Study Worked
The COV-19POC (point of care) study involved comparing the RNA of COVID-19 patients with the RNA of influenza patients.
“They took samples from around 80 patients that had COVID, and they already had samples from patients that had been in hospital with flu”. These were collected between 2017 and 2019 for an earlier POC study.
After removing outliers from the cohort, along with those subjects who failed quality control, the team was left with 83 influenza patients and 78 COVID-19 patients, of whom 16 died within 30 days of hospital admission, underlining the urgency of the project.
“At the time we didn’t know anything about how COVID was affecting people, what the immune response was like … so we sent off the samples and got RNA sequencing data back”.
The team used this data to carry out a couple of different analyses, the first of which involved comparing patients who had influenza with those who had COVID-19. The result was significant. “We found … differences in the way the immune system was activated by different viruses”.
Secondly, the team examined the ways in which RNA profiles differed between COVID patients with favourable outcomes and those who died, identifying certain markers in the particularly severe cases. “Inflammation for example was a lot higher in the patients that ultimately went on to die”.
Broadly speaking, the human body has not one but two immune systems working in parallel: innate, which responds quickly but without precision; and adaptive, which takes longer to respond but tends to be more powerful.
“Influenza cases had a much higher activation of the innate immune system, whereas COVID patients had a much higher activation of the adaptive immune system, where the body recognises specific pathogens and targets them”.
Dr Lord and her colleagues found that a slower adaptive immune response was strongly predictive of mortality, because it allowed the innate immune system to overproduce an inflammatory protein called cytokine, resulting in the dreaded cytokine storm.
Therefore, the likelihood of a patient surviving their brush with COVID-19 might be established by examining distinct prognostic immune signature genes.
Testing for these genes upon admission might help clinicians, explains Dr Lord, “by flagging patients that need more intensive intervention or that might benefit from early ventilation versus patients that don’t need such intensive care”.
How HPC Helped
It is estimated that the human genome, uncoiled into a continuous string of DNA, would stretch to the moon and back 150 times.
While this piece of trivia doesn’t bear directly on the COV-19POC study, it illustrates the sheer volume of data involved in genetic research. The work, says Dr Lord, was “very computationally intensive, and needed … a lot of processing power. Having Iridis meant that we could get the results that we needed quickly”.
Naturally, it would have been practically impossible to store and work on this data using ordinary PCs.
“It would have taken years rather than a couple of months”.
Dr Jenny Lord
But processing power was not, perhaps, the greatest advantage offered by HPC. The COV-19POC study is testament to the power of interdisciplinary scientific research, and the collaboration relied heavily on Iridis’s ability to store a vast quantity of data in a shared repository.
“We used a lot of different methods. There were a few different groups across the university that contributed, and having Iridis was really really useful because it meant that we could store all of the data centrally … all of the different research groups could work on it at the same time”.
In this way, high-performance computing can play an important role in collaborative and interdisciplinary research.
“The way that it facilitated the sharing of the data was really crucial”.
Dr Jenny Lord
Accessing HPC
Dr Lord is a computational biologist, with a great deal of experience using high-performance computers in her research – but it’s worth stressing that she acquired most of her programming knowledge on the job.
“I made a few attempts to learn programming when I didn’t really need to use it, learning the theory, doing little exercises, but it never really clicked until I actually found uses for it in my own work”.
Like learning a language, coding is a skill that anybody can acquire with some practice.
Iridis-5 is available to academics in every faculty and school, and the University of Southampton employs a team of specialist HPC Research Software Engineers (RSEs) whose job it is to help scholars not only use high-performance computing effectively, but also to identify potential new applications of this powerful new tool.
For more information, including details on how to get help from the HPC
RSEs free of charge, see: https://rsg.southampton.ac.uk/hpc
- https://www.frontiersin.org/articles/10.3389/fimmu.2022.853265/full ↩︎