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Grudge Match against COVID-19 Enters Year Three

Scientists continue their battle against COVID-19, but they won’t secure a complete victory without a change in strategy.
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Two years ago, on January 10, 2020, Eddie Holmes, PhD, a virologist and evolutionary biologist at the University of Sydney, tweeted that the first draft sequence of “the coronavirus associated with the Wuhan outbreak” was available on the website Virological.org. The sequence was made possible through the work, and willingness to share, of Yong-Zhen Zhang, PhD, a virologist at Shanghai’s Fudan University.

Since then, scientists have tirelessly studied the “novel coronavirus” SARS-CoV-2 while drawing on decades of research into SARS-CoV (the cause of the 2003 SARS outbreak), HIV, and other viruses. Science has been “amazingly responsive” to the pandemic, Francis Collins, MD, PhD, the outgoing director of the National Institutes of Health told MSNBC.

The growing body of scientific literature on COVID-19 offers corroborating evidence. There are currently 206,544 results for COVID-19 and 128,335 results for SARS-CoV-2 in PubMed, and thousands more studies posted on the preprint servers bioRxiv and medRxiv. From cryogenic electron microscopy to genome sequencing, the techniques of basic research have been crucial to the development of Food and Drug Administration–authorized vaccines and drugs that have saved thousands of lives.

As Carl Sagan wrote in The Demon-Haunted World, “There is a constant battle between microbial measures and human countermeasures. We keep pace in this competition not just by designing new drugs and treatments, but by penetrating progressively more deeply toward an understanding of the nature
of life—basic research.”

With COVID-19, keeping pace has been surprisingly difficult in some respects. Policymaking has been inconsistent, and authoritative messaging has been shouted down by misinformation. Through it all, the scientific community has remained steadfast in opposing COVID-19. However, as a new year begins, the competition with COVID-19 is starting to drag into overtime: the opposition has a seemingly endless bench of substitutes, and sections of the crowd are vocally rooting for the wrong side.

This tweet by Eddie Holmes, PhD, a virologist at the University of Sydney, heralds the release of the first SARS-CoV-2 genome sequence, a sequence that had been generated by virologist Yong-Zhen Zhang, PhD. Zhang’s openness in sharing the sequence allowed scientists around the world to expedite the development of COVID-19 countermeasures. In the United States, where the sequence became available on a Friday evening, vaccine developers began downloading and utilizing the sequencing data by Saturday morning.

With flying colors

What scientific feats over the past two years have done the most to fight COVID-19? There can be little doubt about the top three. First, there is the rapid development of efficacious mRNA vaccines by Pfizer/BioNtech and Moderna. Some would go so far to suggest that mRNA vaccines represent the biggest scientific accomplishment of the century.

Second, according to many experts, is an increase in collaboration across scientists’ traditional silos. Last May, Nevan Krogan, PhD, professor of cellular and molecular pharmacology, director of the Quantitative Biosciences Institute (QBI) at University of California, San Francisco, stressed the importance of collaboration. Discussing the effort that went into constructing a SARS-CoV-2 protein interaction map and its role in identifying 10 repurposed drugs that inhibit viral replication, Krogan said it was “amazing how fast science can move when we all work together”—unlike anything he had experienced before in his career.

Third is the authorization or approval by the Food and Drug Administration of multiple antiviral drugs for the treatment of COVID-19 patients. Because viruses are notoriously elusive targets in drug discovery, the development of these treatments is an impressive triumph.

Building the toolbox

Laboratory work on SARS-CoV-2 is complicated by the need for biosafety level 3 (BSL-3) facilities. This requirement significantly limits the range of experiments that can be run. “Even though we are lucky to have BSL-3 facilities,” notes Inna Ricardo-Lax, PhD, a postdoctoral fellow in the Rockefeller University laboratory of virologist Charles Rice, PhD, “we have to limit ourselves to certain kinds of experiments, and a lot more labor and time are spent on the experiments that we run.”

Inna Ricardo-Lax, PhD
While pursuing her postdoctoral degree at the Rockefeller University, Inna Ricardo-Lax, PhD, has been leading a project to create versions of SARS-CoV-2 that are noninfectious. These replicons can be used as an alternative to SARS-CoV-2 in assays, such as assays for testing potential drug candidates.

Some researchers have focused on developing tools that would make it easier to work on SARS-CoV-2 without BSL-3 facilities. Ricardo-Lax, for example, led a study published in late 2021 in Science describing the generation of a replicon, or self-replicating RNA, that can be used to study the virus. Ricardo-Lax and colleagues constructed SARS-CoV-2 replicons that lack the spike protein, and thus cannot assemble infectious virus.

Another issue according to Ricardo-Lax is that SARS-CoV-2’s large genome—roughly three times longer than the average RNA virus—makes it “very hard” to construct a virus clone or replicon. Standard cloning methods fall short, she notes, and more sophisticated strategies are needed, such as constructing the genome in yeast cells from multiple DNA fragments.

Group dynamics

Although many scientists have worked diligently to chip away at SARS-CoV-2’s armor, other efforts have been more collective in nature. These efforts include the rapid gathering and analysis of large data sets, and the sharing of results with the community.

One need look no further than the Global Initiative on Sharing Avian Influenza Data (GISAID), an organization founded in 2008 to promote the sharing of viral genomic data. Originally, GISAID was focused on influenza; today, it is focused on SARS-CoV-2. As of December 2021, the GISAID website contained more than 6 million sequences of the SARS-CoV-2 genome. In related work, the team at the open-source resource Nextstrain.org uses the differences in SARS-CoV-2’s genomic sequences—submitted to GISAID from around the world—to track, analyze, and garner information about the virus’s transmission, evolution, and spread.

Other examples of team science are the herculean, collaborative efforts underway to understand the host’s response to the viral infection. The COVID-19 Host Genetics Initiative has organized an enormous worldwide collaboration of researchers. The goal is to bring together the human genetics community to “generate, share, and analyze data to learn the genetic determinants of COVID-19 susceptibility, severity, and outcomes.” A similar effort is the COVID Human Genetic Effort—an international consortium aiming to discover the human genetic and immunological bases of the various clinical forms of SARS-CoV-2 infection.

Reaching the limits

It is not easy to predict what 2022 will bring. Much of the pandemic’s course depends on whether the existing vaccines will hold up to the onslaught of new variants—including the latest variant, Omicron. Unless the percentage of vaccinated people around the world increases significantly, it is safe to say that 2022 will bring a deeper familiarity with the Greek alphabet and more of the same troubles we’ve been suffering the past two years—more shutdowns, more illnesses, and more unnecessary deaths.

With scientists working around the clock and SARS-CoV-2 data pouring out of laboratories, discoveries abound. But “scientia potentia est” (knowledge is power) is limited by adoption. The rejection of science—and the fruits of its labor—is a problem that cannot be fixed at the laboratory bench.

Collins said on MSNBC that the scientific community has underestimated the degree to which the anti-vaccination movement would blunt the effectiveness of the scientific advances that have been made. Collins suggests that people who understand the facts should become “ambassadors” because outreach is not the work of one organization alone. Together, he said, we have to figure out a way to get back to making decisions based on facts and evidence, not rumors and conspiracies.

Sagan would doubtless concur. In The Demon Haunted World, he writes: “Like it or not, we are stuck with science. We had better make the best of it. When we finally come to terms with it and fully recognize its beauty and its power, we will find, in spiritual as well as in practical matters, that we have made a bargain strongly in our favor.”

The post Grudge Match against COVID-19 Enters Year Three appeared first on GEN - Genetic Engineering and Biotechnology News.

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