Photo Courtesy: National Institute of Allergy and Infectious Diseases

Did the SARS-CoV-2 virus emerge in the human population spontaneously or was it engineered in a laboratory? Several months into this pandemic, there are still many more questions than answers about this stealthy new coronavirus that has commandeered the world stage. Its ability to enter a human population for the first time and spread quickly and with such unpredictable outcomes has led to many conflicting theories and suspicions about its origins.

“People are hungry for basic information to dispel the rumors that are out there,” says Benhur Lee, MD, Professor of Microbiology and Ward-Coleman Chair in Microbiology at the Icahn School of Medicine at Mount Sinai.

In March, Jillian Carmichael, PhD, a postdoctoral fellow in Dr. Lee’s lab, created a blog to address the misinformation and confusion about the COVID-19 disease caused by the virus that she was seeing on social media. In addition, “I was getting so many questions about SARS-CoV-2 from friends and family that I couldn’t answer them all. I decided to reach out to my virology colleagues for help.”

Together with Christian Stevens, an MD/PhD student in the Lee lab, Dr. Carmichael launched a science-communications blog. Since then, they have worked with a team of graduate students and postdoctoral fellows to parse through reams of studies to create an ongoing series of posts that educate the public about what is plausible and what is not based on their knowledge of science and virology, in particular. Their posts have received traffic from more than 100 countries.

One persistent rumor they sought to demystify for the public was whether SARS-CoV-2 could have been deliberately engineered.

“While nothing is impossible in science, there are some things we do know, and it is very unlikely that SARS-CoV-2 could have been designed in a lab,” says Mr. Stevens, who helps engineer viruses in Dr. Lee’s lab. “We have a natural hypothesis that fits all the evidence so far.”

There are two ways to engineer something in biology, Mr. Stevens says. You take what you know works and piece it together so that it works in a new way. Or, you simulate the way nature does it and tweak it in order to make improvements.

“When the exact parts of the SARS-CoV-2 virus are plugged into a computer model, they look like they’re going to perform really badly,” he says. “The computer would tell you this is a terrible idea, try something better. A human would have been unlikely to rationally design this.”

In January, when the Chinese government released the virus’ genome, which showed its similarity to a virus from a horseshoe bat, researchers gained a better understanding of its makeup. They found that no prior studies existed to explain the way in which this new virus worked, and two distinct features made the theory supporting its natural evolution more likely.

First, a piece of the virus’ spike protein—called the receptor-binding domain (RBD)—provides the virus with an exceptional ability to attach to the ACE2 protein located on the outer surface of cells in various organs. Second, the backbone of the virus—its overall molecular structure—differed substantially from other coronaviruses and mostly resembled related viruses found in bats. If SARS-CoV-2 had been deliberately engineered in a laboratory it would have been constructed from a virus that was known to cause disease, and these did not.

In addition, the SARS-CoV-2 virus has features that would make it difficult to engineer in a lab. The RBD on the spike protein closely resembles that found in a coronavirus in pangolins—an animal also called a “scaly anteater” that is one of the world’s most trafficked. The theory that a bat virus mixed with, potentially, a pangolin virus, mutated, and then jumped to humans continues to make the most sense.

Then, he says, there is the virus’ biological makeup. It has a polybasic cleavage site, which appears to give it the ability to connect to many different tissue types in the human body. While additional testing is needed, early indications are that SARS-CoV-2 does hit many areas of the body in addition to the lungs. By comparison, previous coronaviruses all had monobasic cleavage sites that connected to fewer tissue types. And last, but not least, the virus has O-linked glycans, which may function to shield the virus from the immune system. This means that in order to develop, the virus probably would have needed a human immune system, something unlikely to have been engineered in cell culture.

On the flip side, says Mr. Stevens, there is plenty of evidence to support the premise that the virus emerged naturally and jumped into humans either already possessing the tools it needed to mutate and begin infecting them quickly, or acquiring these tools soon after landing in the human population.

To learn more about SARS-CoV-2, please go to the Lee lab’s science blog and subscribe for updates.

Benhur Lee, MD, Professor of Microbiology and Ward-Coleman Chair in Microbiology

As governments make plans to reopen their economies and seek reliable ways to ensure their populations can get back to work safely, high-quality antibody testing has emerged as the only way to truly determine which individuals may be protected against the SARS-CoV-2 virus that causes COVID-19. Microbiologists at the Icahn School of Medicine at Mount Sinai have created tests that are answering that need.

A team of scientists led by Benhur Lee, MD, Professor of Microbiology and Ward-Coleman Chair in Microbiology, has developed an assay that tests the quality of an individual’s antibodies to see whether they strongly neutralize the SARS-CoV-2 virus.

Using technology that differs from the more commonly used ELISA method of testing for antibodies, Dr. Lee’s lab has built an identical replica of the outer portion of the SARS-CoV-2 virus, or a pseudo virus. This replica allows researchers to see how well the antibodies from recovered patients actually block SARS-CoV-2 from entering into cells and effectively stop the infection in its tracks. Such neutralizing action provides confirmation that an individual is protected against the virus.

Using the ELISA test and the pseudo virus test together shows how well antibodies that bind to the spike protein also correlate with virus neutralization, says Dr. Lee. The two-step process can provide governments and institutions with a critically important starting point in effectively determining which individuals have been exposed to the virus and carry neutralizing protection.

There are still many unknowns. While the scientific community at large agrees that immunity to the SARS-CoV-2 virus offers protection from re-infection, there is no firm understanding of how long that immunity will last. In addition, researchers do not know whether there is a threshold or level at which antibodies correlate with immunity.

“The gold standard in determining whether someone carries neutralizing antibodies is by using a live virus to test their serum after it has been drawn,” says Dr. Lee. “But this is not scalable for the hundreds of thousands of samples that will need to be tested. So what we developed is a safe surrogate that represents the real virus and can be automated with high-throughput testing in scientific facilities used by many governments and universities around the world.”

Dr. Lee says his pseudo virus assay is essentially a bridge between the binding capability of the ELISA test and the “gold standard” of live-virus neutralization, which requires laboratories to carry a higher, biosafety-level-3 (BSL 3) designation, allowing them to work with dangerous or potentially lethal agents. The pseudo virus can be handled in more commonplace biosafety-level-2 (BSL 2) laboratories that are designated for working with milder agents.

The new pseudo virus can serve as a platform for creating and optimizing potential vaccine designs, generating monoclonal antibodies, and screening anti-viral peptides—all of which would be used to treat or prevent COVID-19.

Government health agencies and universities in the United States and around the world have been sending formal requests to use Dr. Lee’s assay, and he says he will look to them for feedback on how well it is working. “We’re spending time investing in quality control,” he says. “It is important that when we send out this test it works the way we say it works.”