In February, as the new coronavirus swept across China, a scientist named Sai Li set out to paint its portrait.
At the time, the best pictures anyone had managed to take were low-resolution images, in which the virus looked like a smudge.
Li, a structural biologist at Tsinghua University in Beijing, joined forces with virologists in Hangzhou who doused the viruses with chemicals to render them harmless. Li and his colleagues then concentrated the virus-laden fluid from a quart down to a single drop.
Li froze the drop in a fraction of a second. If he made the slightest mistake, ice crystals could spear the viruses, tearing them apart.
Li placed the smidgen of ice into a cryo-electron microscope. The device fired beams of electrons at the sample. As they bounced off the atoms inside, Li’s computer reconstructed what the microscope had seen. He could see thousands of coronaviruses packed in the ice. They were beautifully intact, allowing him to inspect details on the viruses that measured less than a millionth of an inch. “I thought, I was the first guy in the world to see the virus in such good resolution,” Li recalled.
Over the following weeks, Li and his colleagues pored over the viruses. They inspected the proteins that studded its surface and they dove into its core, where the virus’ strand of genes was coiled up with proteins.
Thanks to the work of scientists like Li, the new coronavirus, known as SARS-CoV-2, is no longer a cipher. They have come to know it in intimate, atomic detail. They have discovered how it uses some of its proteins to slip into cells and how its twisted genes commandeer our biochemistry. They have observed how some viral proteins throw wrenches into our cellular factories, while others build nurseries for making new viruses. And some researchers are using supercomputers to create complete, virtual viruses that they hope to use to understand how the real viruses have spread with such devastating ease.
“This time is unlike anything any of us has experienced, just in terms of the bombardment of data,” said Rommie Amaro, a computational biologist at the University of California, San Diego.
Earlier this year, Amaro and other researchers directed much of their attention to the proteins, called spikes, that stud the virus’ surface. Spike proteins have an essential job to play: They latch onto cells in our airway so the virus can slip inside. But the spike protein is not sharp, narrow or rigid. Each spike protein snaps together with two others, forming a tuliplike shape.
The genes of the new coronavirus are arrayed on a molecular strand called RNA. On Jan. 10, Chinese researchers published its sequence of 30,000 letters. That genetic text stores the information required for a cell to make the virus’ proteins.
But the genome is more than a cookbook. The strand folds into a complex tangle. And that tangle is crucial for the virus’ exploitation of our cells. “You have a lot more information stored in how it’s shaped,” said Sylvi Rouskin, a structural biologist at the Whitehead Institute.
Rouskin led a team of scientists who mapped that shape. In a high-security lab at Boston University, her colleagues infected human cells with the viruses and gave them time to make thousands of new RNA strands. Tagging the genetic letters on the strands with chemicals, Rouskin and her colleagues could determine how the strand folded in on itself.
In some places it only formed short side-loops. In other places, hundreds of RNA letters ballooned out into big hoops. By comparing millions of viral genomes, Rouskin and her colleagues discovered places where the virus slips from one shape to another. Studies suggest these knots allow the virus to control our ribosomes, the tiny cellular factories that pump out proteins.
After the virus enters a human cell, our ribosomes attach to its RNA strands and glide down them like a roller coaster car running along a track. As the ribosomes pass over the genetic letters, they build proteins with corresponding structures. Scientists suspect that the loops of RNA may throw the roller coaster car off its track and then guide it to a spot thousands of positions away.
Other loops force the ribosome to back up and then move forward again. This hiccup can cause the virus to make entirely different proteins from the same stretch of RNA.
The viral proteins that spew out of our ribosomes fan out across the cell to carry out different tasks. One of them, called Nsp1, helps seize control of our molecule machinery.
Joseph Puglisi, a structural biologist at Stanford University, and his colleagues mixed Nsp1 proteins and ribosomes in test tubes. They found that the proteins slipped neatly into the channels inside the ribosomes where RNA would normally fit. Puglisi suspects that Nsp1 stops our cells from making proteins of their own — especially the antiviral proteins that could destroy the virus.
While Nsp1 is manipulating ribosomes, other viral proteins are busy making new viruses. A half-dozen different proteins come together to make new copies of the virus’ RNA. Together, the proteins and RNA spontaneously turn into a droplet, akin to a blob in a lava lamp.
Physicists have long known that molecules in a liquid spontaneously form droplets if the conditions are right. But only in recent years have biologists discovered that our cells regularly make droplets for their own purposes. They can bring together certain molecules in high concentrations to carry out special reactions, shutting out other molecules that cannot enter the droplets.
Richard Young, a biologist at the Whitehead Institute, and his colleagues have mixed together SARS-CoV-2 proteins that build new RNA along with RNA molecules. When the molecules assemble, they form droplets. The virus likely gets the same benefits as the cell does from this strategy. Young was not surprised by his discovery. “Why wouldn’t viruses exploit a property of matter?” he said.
Already the new pictures of SARS-CoV-2 have become essential for the fight against the virus. Vaccine developers study the virus’ structure to ensure that the antibodies made by vaccines grip tightly to the virus. Drug developers are concocting molecules that disrupt the virus by slipping into nooks and crannies of proteins and jamming their machinery. “There are probably a lot of Achilles’ heels,” Gladfelter said.