FLC | Sandia scientists' COVID-19 work takes CRISPR beyond DNA editing

Sandia scientists' COVID-19 work takes CRISPR beyond DNA editing

May 14, 2020

Genetic sequencing tools and CRISPR-based technology help scientists thoroughly probe the most micro happenings inside of cells in multi-dimensional ways—and researchers at Sandia National Laboratories are now putting them to use against COVID-19.

Biochemist Joe Schoeniger and virologist Oscar Negrete recently briefed Nextgov on their team’s long-term vision and efforts to genetically engineer antiviral countermeasures that could help curb the novel coronavirus and other future outbreaks.

“There's huge open questions about mitigating this thing as it goes on as a phenomenon all around the world,” Schoeniger explained. “And that's a reason why we need to vigorously pursue lots of avenues."

Using CRISPR (short for Clustered Regularly Interspaced Short Palindromic Repeats) technologies, researchers can essentially alter the nucleic acids that make up cells. The tech enables experts to home in on particular DNA and RNA sequences and manipulate genes or control gene expression to combat viruses and help human bodies withstand infection.

“You can do all kinds of things with that,” Schoeniger said.

From their homes and inside the New Mexico-based lab, the team is tapping into advanced genetic resequencing tools to address the present pandemic, but the efforts were not initially ignited by COVID-19. Negrete and Schoeniger have been studying emerging infectious diseases for years, including the zoonotic Nipah virus and Ebola virus. Negrete noted several significant commonalities between those viruses and the coronavirus exist: They likely emerged from bats, they have spillover events that can lead to outbreaks, and they also all have well-defined host factors, as well as defining targets that could be used for therapeutic interventions.

“And that is the key sticking point that we've been thinking about for a long time—it’s how do we create rapid countermeasures that could basically target a family of viruses instead of just one,” he said.

Backed with funding from the Biological Technologies Office in the Defense Advanced Research Projects Agency (DARPA), the researchers were already fervently working to deploy CRISPR and other technologies to conduct studies addressing a broad class of viruses on their radar, and particularly using Ebola as a model. But as the reality of the novel coronavirus’ threat surfaced in late January, the team members opted to pivot their work to focus on the latest global health threat.

Still funded by DARPA, Negrete said the current, more COVID-19-focused project encompasses three overall components. The first is ultimately exploring “new technologies, like CRISPR” as a novel antiviral countermeasure approach to targeting a broad spectrum of viruses, as opposed to one strain. Though most immediately associate CRISPR with editing DNA, the scientists emphasized that “the CRISPR toolbox is much bigger than that,” and their specific work is much more about responsible programmability inside human cells.

“Basically you don't really have to cut DNA or make permanent rearrangements and mutations, you can use [CRISPR] as a toolbox to harness gene regulation methods—you could up and down regulate genes of interest,” Negrete explained. “And so what we really want to do with CRISPR is reprogram the cells to block infection.”

This essentially entails using the technology to upregulate or downregulate important proteins that are involved with virus infection. Once that works in a cell culture and dish, the next component scientists will pursue is how to safely translate it into humans. The delivery of such biological treatments is an area that is also undergoing rapid development, Negrete noted. One of those delivery methods is a nucleic acid vaccine.

“Instead of making components of the virus, purifying them, then injecting them into humans, you're sending in the code—messenger RNA—into the cells and you make your own body produce the antigens of the virus to stimulate the immune response,” he said. "So can we incorporate that CRISPR delivery, those methods, to inhibit virus infection with nucleic acid delivery technology, [and] we make ourselves reprogram them to defend against viruses, so that speeds up the process.”

In their original Ebola virus research, some of the early cells infected by the virus were liver cells. Working in collaboration with Lawrence Livermore National Lab, the team used delivery vehicles that can be injected intravenously. Now, the team is looking to apply that same approach to countering the coronavirus and effectively switching the delivery efficacy to lungs—the main targets of the latest viral threat—to see if there’s a new host protein worth addressing.

The researchers are currently leading proof-of-concept trials for an antiviral that they hope could be customized to specific viruses, including the coronavirus. Though further testing and study is needed, if it works, this would keep medical professionals from scrambling to create new countermeasures for each outbreak or pandemic that occurs. And Sandia's gene-focused research will continue, even if or after the coronavirus has been controlled.

“We have a big-picture problem, which is that we keep having outbreaks of emerging illnesses,” Schoeniger said.

He added that while some of the work has been managed and maintained remotely, certain studies just can’t be done alone at home. The lab imposed comprehensive measures to ensure the safety of those who enter it, and the scientists added that all researchers are trained not to touch their faces while working. Generally, they wear a great deal of protective equipment in facilities regardless of the pandemic; working with viruses inherently requires strong protection.