New technique to study Coronaviruses raises safety risks

Coronaviruses have already caused three major disease outbreaks, including the Covid-19 pandemic that hit most countries in the world.

However, scientists claim that those pathogens are difficult to grow in the labs, making it difficult for them to study them to come up with countermeasures.

Reporting in ‘Nature’, scientists said they have equipped human cells with custom-designed receptors that these viruses can bind to and use to sneak inside cell.

The study uses “cutting-edge work at the intersection of virology, immunology, biochemistry, molecular modelling, and cell biology,” says Arturo Casadevall, a microbiologist and immunologist at the John Hopkins Bloomberg School of Public Health, who was not involved with the work.

The darker side of this approach, however, could be many more studies of newfound coronaviruses, and therefore, a greater risk of accidentally infecting lab workers or even triggering an outbreak, critics say. But the authors recognise that concern, says study leader Huan Yan of Wuhan University.

“Overall, we believe that the advantages of using  (this strategy) outweigh the potential risks associated with these research activities.”

The paper’s authors include scientists in the United States and Switzerland, and also China’s Shi Zhengli, whose former lab at the Wuhan Institute of Virology has been accused for causing Covid-19 pandemic.

Beyond the Covid-19 pandemic, coronaviruses were also behind the 2003 worldwide epidemic of severe acute respiratory syndrome (SARS), triggered by a virus now named SARS-CoV, and Middle East respiratory syndrome, a disease transmitted primarily by camels that burst onto the scene in 2012 and still sickens people.

There are thousands of other coronaviruses in nature, most of them likely living in bats. In most cases, scientists have only detected these viruses’ genomes, or part of them, but they haven’t isolated the actual virus itself. And even if they could, such viruses are challenging to grow in the lab.

To enter a cell, so-called “spike” proteins on the surface of a coronavirus, which give it the characteristic crown like appearance, must latch onto a matching receptor on a cell, like a key fits into a lock.

 Scientists have identified only a handful of coronavirus receptors so far, including angiotensin-converting enzyme 2 (ACE2), the most important receptor for SARS-CoV, SARS-CoV-2, and several other coronaviruses. ACE2 is widely found on lung cells, for example, explaining some of the respiratory symptoms the viruses produce.

When researchers have a coronavirus’ genomic sequence, they can produce its spike protein. Yan, whose group specialises in receptor biology, wondered whether these spike proteins could help him build receptors from scratch, using a variety of building blocks, and stick these artificial receptors into the membranes of human or animal cells.

To do this, the team constructed “scaffolds” from parts of known coronavirus receptors, including ACE2. Then they attached customised “virus-binding domains”—the part of a receptor that matches the spike protein—to the scaffold.

 The scientists used a variety of techniques to optimise both scaffolds and virus-binding domains. Some of the best functioning receptors, it turned out, were the ones in which the virus-binding domain were so-called “nanobodies”, smaller versions of regular antibodies that attached to the spike protein.

Such studies might help develop new anti-virals and vaccines, says Yan, who adds that the technique could also provide new insights into viral invasion mechanisms and the precise roles receptors play. His team is exploring whether the strategy can be applied to other kinds of human viruses and has already obtained “some promising results,” he says.