In a technical tour de force with potentially profound implications for the study of emerging diseases, researchers have built the largest-ever self-replicating organism from scratch.
The organism is a virus based on genome sequences taken from a bat-borne version of SARS, a lethal respiratory disease that jumped from animals to humans in 2002. The synthetic virus could help explain how SARS evolved, and the same approach could be used to investigate other species-hopping killers.
“This gives us a system to more quickly answer the questions of where a virus came from, of how to develop vaccines and treatments for a brand-new virus that leaps to humans like SARS did,” said Vanderbilt University microbiologist Mark Denison.
Just a decade ago, artificially constructed viruses seemed like science fiction. But the field of synthetic biology has progressed with extraordinary rapidity. Six years ago, polio became the first virus to be synthesized. Three years ago, biologists reconstructed an influenza strain from the 1918 epidemic, in the process discovering what made it so lethal. The synthetic SARS virus is even more complicated than either of those creations. And as such research has progressed, concerns have intensified over viruses jumping from animals to people, then spreading rapidly through a globalized world of international travel and migration.
In some cases, scientists might — as with SARS — suspect the identity of the original animal virus, but not understand the murky process by which it became infectious in humans. In other cases, they might want to know what is needed for an existing animal virus to enter people. But it’s not always easy to study viruses: many are impossible to grow in a lab, or known from just a few wild samples. That’s when synthetic viruses could be useful.
“It can be very hard to study where a virus originally came from,” said Denison. “If you start from where you think the virus was, and let the virus tell you where it’s going, then you learn a tremendous amount about viral evolution and movement.”
In the case of SARS, which killed nearly 800 people before being contained, scientists think it came from bats, but have been unable to keep the bat version alive in laboratory cell cultures.
Denison’s team used the genetic sequence of bat SARS to build the virus. Bat SARS doesn’t normally infect people, but the researchers added a critical tweak: a gene present only in the human version of the virus. The new version flourished in human cell cultures, suggesting that a mutation in the gene, known as Bat-SRBD, was responsible for SARS’ lethal spread.
The new virus did not kill mice, however. Other genetic differences between the synthetic and natural strains can now be studied to learn what makes SARS so virulent, said Denison, and the technique applied to other viruses similar to SARS. These include the Ebola, Hanta, Nipah and Chikunguya viruses, all of which originated in animals and are lethal to people.
“You could get to a point where, within a couple weeks of an epidemic being identified, you’ve already grown and generated viruses for the study of immune response,” said Denison.
Whether the technique is useful elsewhere remains be seen, but “there’s a good possibility” that it will, said Peter Palese, a Mount Sinai Medical Center microbiologist. Palese edited the paper, published today in the Proceedings of the National Academy of Sciences, but was not involved in the research itself.
Even if it’s experimental, he said, researchers need to try.
“If we were successful with conventional approaches,” said Palese, “then they would have worked already.”
Synthetic recombinant bat SARS-like coronavirus is infectious in cultured cells and in mice [PNAS]
Image: Synthetic SARS virus (tagged with fluorescent green protein) growing in mouse respiratory tissue / PNAS
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