New York: A team led by Dan Jacobson of the US Department of Energy's Oak Ridge National Laboratory recently used the Summit supercomputer to analyse genes from cells in the lung fluid of nine Covid-19 patients compared with 40 control patients.
The computational analyses, published in the journal eLife in July, suggest that genes related to one of the body's systems responsible for lowering blood pressure -- the bradykinin system -- appear to be excessively 'turned on' in the lung fluid cells of those with the virus.
Based on their analyses, the team believes that bradykinin -- the compound that dilates blood vessels and makes them permeable -- is overproduced in the bodies of Covid-19 patients.
They believe that related systems either contribute to overproduction or cannot slow the process.
Excessive bradykinin leads to leaky blood vessels, allowing fluid to build up in the body's soft tissues.
Much attention has focused on what's known as the cytokine storm, a severe reaction in which the body releases an excess of cytokines, a variety of small proteins that help regulate the immune system.
Jacobson's team thinks a bradykinin storm may instead be to blame for much of the viral pathogenesis.
If the team's disease mechanism model is accurate and substantiated by experimental analysis, it may mean that existing medicines could be repurposed to slow the pathogenesis of Covid-19.
This would require extensive clinical trials of drugs currently used to treat other bradykinin-related conditions.
"If we can block this pathogenesis in severe patients, we can keep the human response from going overboard and give their immune system time to fight off the virus so they can recover," Jacobson said.
The bradykinin storm could explain the wide variety of symptoms experienced by Covid-19 patients, such as muscle pain, fatigue, nausea, vomiting, diarrhea, headaches, and decreased cognitive function.
Similar symptoms are also experienced by patients with other bradykinin-related conditions such as hereditary angioedema, a genetic condition that is characterised by episodes of severe swelling throughout the body.
"This is one of those rare times where you can really tie everything back to a eureka moment," said Jacobson.
"I was looking at data, and I suddenly saw some very distinct patterns happening in the pathways of the renin-angiotensin and bradykinin systems. That led us to do a deep dive of the gene families of the blood pressure regulatory system."
The renin-angiotensin system, or RAS, and bradykinin pathway regulate blood pressure and fluid balance in the body.
Using the Summit and Rhea supercomputers at the Oak Ridge Leadership Computing Facility, the team compared the genes of COVID-19 patients against a control group and analysed population-scale gene expression data -- 17,000 samples from uninfected individuals -- to see which genes were normally co-expressed, or turned on or off at the same time.
Summit is currently the most powerful supercomputer in the US, with a theoretical peak performance of 200 petaflops, or 200 quadrillion calculations per second.
Jacobson and his colleagues required the power of Summit to run 2.5 billion correlation calculations that helped them understand the normal regulatory circuits and relationships for the genes of interest.
With Summit, the team completed the calculations in one week rather than spending months doing them on a desktop computer.
The team also uncovered that an enzyme that forestalls the bradykinin cascade -- the angiotensin-converting enzyme, known as ACE -- was less expressed in Covid-19 patients.
At least 10 existing drugs are known to act on the specific pathways Jacobson's team studied, but large-scale clinical trials are needed to determine whether they might be effective at treating Covid-19.
The team also used the Compute and Data Environment for Science, or CADES, at ORNL to determine which genes in the RAS-bradykinin pathways have vitamin D binding sites.
The results of their analyses might help scientists determine through experimentation which parts of these pathways could potentially be influenced by vitamin D.
Because vitamin D helps regulate the RAS and vitamin D deficiencies have already been associated with more severe illness in COVID-19 patients,
It is another molecule worth further study, said Jacobson.
