A team of researchers led by Dan Jacobson at the Oak Ridge National Laboratory (ORNL) employed powerful supercomputers to analyze vast troves of data in a bid to better understand COVID-19. The team used data analytics and explainable AI tools via ORNL’s Summit and Rhea supercomputers. The group produced a mechanistic model for COVID-19 that could possibly point to targeted therapeutics. They include, among others, Danazol, Stanozolol, lcatibant, Ecallantide, Berinert, Cinryz and Haegarda.
A Systems Approach
The ORNL team used the Summit and Rhea supercomputers driven by Systems Biology Frameworks to analyze and better understand the underlying mechanisms for how the body responds to SARS-CoV-2. If this approach turns out to be correct, significant time and capital can be preserved in the effort to repurpose existing FDA approved therapies to at least treat the most severe of COVID-19 cases. The study results were published in eLife.
Some Preliminary Findings
The team discovered that the bradykinin system could potentially be involved with much of the viral pathogenesis associated with COVID-19. A peptide that actually manages blood pressure and is involved with the triggering of inflammation, bradykinin in greater numbers can dilate blood vessels, making them more permeable. Furthermore, if excessive amounts are produced, blood vessels can start leaking, leading to a fluid buildup spilling into adjacent tissues.
According to Jacobson in a recent Forbes piece, “What we’ve found is that the imbalance in the renin-angiotensin system (RAS) pathway that appeared to be present in COVID-19 patients could be responsible for constantly resensitizing bradykinin receptors. So, this imbalance in the RAS pathways will take the brakes off the bottom of the bradykinin pathway at the receptor level. In addition, the downregulation of the ACE gene in COVID-19 patients, which usually degrades bradykinin, is another key imbalance in the regulation of bradykinin levels. We have also observed that the key negative regulator at the top of the bradykinin pathway is dramatically down-regulated. Thus, you likely have an increase in bradykinin production as well, stopping many of the braking mechanisms usually in place, so the bradykinin signal spirals out of control.”
Hence an incredible crunching of data led the team to uncover that gene expression modifications likely to trigger creation of bradykinin. Moreover, those enzymes that can help the body breakdown these peptides are decreased in expression. The result could be a significant accumulation of bradykinin, hence leading to blood vessel leakage.
Vitamin D Link
As Vitamin D helps to regulate the RAS pathway, the ORNL team also investigated connections between vitamin D binding sites and RAS-bradykinin genes. Interestingly, the team observed that those with severe COVID-19 often experience deficiencies with vitamin D.
The researchers found a link to Vitamin D, as Jacobson notes in the Forbes article, “The Vitamin D link was an interesting one that affects the very early steps of the RAS pathway. It is simply one component involved in a complex system, and we’re probably going to have to target multiple treatments across the entire system to break the cascade. One single intervention alone is probably not going to solve it. But if we can understand all the different components and target those collectively, I think we can have a better shot at it.”
Now that the team was on to the bradykinin storm hypothesis, based on the data generated, the ORNL team generated in their analysis a number of potentially existing FDA, reusable drugs such as Danazol, Stanozolol, lcatibant, Ecallantide, Berinert, Cinryze and Haegarda. These drugs could possibly be used to reduce the high bradykinin signaling in a bid to stop bradykinin escalation.
In parallel, the ORNL team has an ongoing study to analyze the entire SARS-CoV-2 virus from a “systems biology” approach—they believe that any attempts to control or reduce SARS-CoV-2 will require a strategy combining therapies.
The ORNL team along with partners at the U.S. Department of Veterans Affairs, Yale University, Cincinnati Children’s Hospital and the Versiti Blood Research Institute, the University of Kentucky, and the Cincinnati Children’s Hospital continue to proceed, leveraging supercomputing and explainable AI to conduct studies that offer a more comprehensive and holistic point of view with an emphasis of superior understanding of the body’s mechanisms in a bid to discover more economical and beneficial ways to introduce therapies.
Dan Jacobson, Chief Scientists for Computational Systems Biology