The study involved the first-ever use on an infectious disease of a new research technique called chemical genetics. Every virus presents scientists with a new kind of genetic code—the challenge is to figure out how to decipher it to gain a fuller understanding of how the virus works and how to combat it. In the past, such research was often slow and laborious. But thanks to chemical genetics—which allows scientists to quickly test how a new virus reacts with thousands of different chemicals—viruses that might have remained indecipherable for years can now be at least partially unlocked in months or even weeks. "Instead of testing out keys in a lock one by one, it's like trying out 50,000 keys all at once," says Yuen.
The point of both chemical and classical genetic research is to figure out which genes do what—in effect, to learn to read an organism's genetic language. In classical genetics, scientists usually mutate an organism, see how its functions have changed (a mutated virus might no longer be infectious) and then work back and identify which gene mutated. If a mutated virus loses its ability to infect a cell, then that gene probably has something to do with infectivity. In chemical genetics, explains Dr. Richard Kao, the lead researcher on the HKU study, scientists try do the same by testing thousands upon thousands of chemicals on virus samples. The vast majority won't have any effect, but a handful will. Researchers can then take those virus samples and use further tests to figure out which viral gene has been affected by which chemical. "If we discover that interfering with a certain gene stops the virus from replicating, then we know that gene's function likely has to do with replication," says Kao, a biochemist who brought his passion for chemical genetics to HKU from Harvard University, where the process was first pioneered in the early 1990s.
In HKU's SARS study, Kao and his colleagues filled the tiny wells of a small, waffle-like board with samples of the coronavirus cultured in cell lines. Microscopic amounts of different chemical compounds were introduced into each separate well using a $180,000 machine called an automated high-throughput screening platform. Once the chemicals had time to interact with the virus, scientists could examine the results with an inverted microscope. The process was repeated until all 50,240 compounds in their chemical library had been tested, which took a few months. "You'd think it'd be tedious work, but it's really not that bad," says Kao. If the chemical failed to interfere with the virus, as was the case with most of them, researchers would easily see evidence of unchecked infection in the cell lines. But about 1,000 compounds seemed to slow the virus, and 104 of those all but stopped infection. It stood to reason that those compounds were hitting the viral genetic pathways that were most important for infectivity.
With help from their collaborators at the Aaron Diamond AIDS Research Center in New York, Kao and his colleagues discovered that one of 104 compounds inhibited a kind of viral processing inside the cell, six inhibited viral replication and 18 seemed to prevent the virus from entering the cell in the first place. (Kao says further work will be needed to figure out which viral genes the remaining 78 compounds affect. One of them seems to affect both processing and replication.) A number of these compounds could form the basis for promising anti-SARS drugs, and HKU plans to begin animal-testing some of the most effective compounds soon. But the real value of the study is the clearer picture it offers of the SARS virus and the blueprint it provides for research responses to any future emerging diseases, like avian flu. "We can react more rapidly, and we can find new drugs that specifically target the disease," Kao says. "If there's a new virus, we can jump onto this."
Around HKU, that's a question of when, not if. HKU's work on SARS and bird flu has helped transform a regional university into a world player in disease research, and its staff understand that they are part of a vital bulwark. "Hong Kong is a very strategic place to be for emerging-infectious-disease work," says Yuen. And when the next would-be superbug pops up, at least scientists will have one more arrow in their quiver.