York viral biochemist aims to shoot more than the messenger

“Defeating some of the world’s most destructive and deadly viruses will require us giving their genetic complexity a lot more respect,” says viral biochemist Andrew White of York’s Department of Biology, who was awarded a Steacie Fellowship on Thursday by Science and Engineering Research Canada (NSERC).

Andrew White“Instead of thinking of viral RNA as a passive messenger of genetic information, we need to view RNA as a very active regulator of essential processes in the viral reproductive cycle,” says White, the Canada Research Chair in Plant Biotechnology and Structural Biology.

Right: Steacie Fellowship award winner Andrew White of York’s Department of Biology

The award was among six announced by David L. Emerson, minister of industry, and Tom Brzustowski, president of NSERC.

White’s research team has identified new types of ribonucleic acid (RNA) bridges, or riboregulators, that unite distant regions of the viral genome and work as a tag team to boost the production of viral proteins. His group has also produced the most advanced functional model for how RNA gates operate to cause the synthesis of specific viral messages. And, intriguingly, his team has discovered RNA switches which, through their structural changes, turn viral replication on or off.

White believes the uniqueness of these viral riboregulators makes them ideal targets for inhibiting viral infections. “The distinct structural features of these viral RNA elements should allow for the development of inhibitors that will specifically target the virus and not the infected cells,” he says.

The question of how many of the world’s most medically and agriculturally important viruses regulate their behaviour appears simple at first glance but it’s more than the viral proteins doing the job, says White. Most of these so-called positive-strand RNA viruses contain only a single molecule of ribonucleic acid. They include the largest group of crop-damaging viruses as well as such human pathogens as the SARS coronavirus, the West Nile virus and the Hepatitis C virus.

In the cellular context, RNA is viewed primarily as DNA’s handmaiden, a messenger carrying instructions from the nucleus to the cellular machinery that produces proteins. Likewise, biologists have traditionally viewed RNA viruses in the same way, believing that viral proteins are really calling the plays. Not so, says White. RNA is actually far more controlling than previously imagined. In fact, the viral genome is actually a collection of intelligent RNA sub-units that are responsible for regulating other molecules. “What’s now clear,” says White, “is that through various interactions or by changing shape, RNA elements actively regulate key steps in viral infections. They are the real conductors of the viral orchestra.”

White’s team is pioneering the identification and characterization of functional RNA sub-units in the Tomato bushy stunt virus, a positive-strand RNA virus. His research has shown that specific sections of RNA  play central roles in controlling key viral processes. These include the translation of viral proteins and the replication of the viral genome. The research has revealed that there are at least three major types of viral riboregulators: RNA bridges, gates and switches.

As part of his NSERC Steacie Fellowship research, White will continue a “search and discovery” mission to identify additional riboregulators in the Tomato bushy stunt virus and uncover new RNA elements in other viruses. Impressively, this research extends from the atomic level all the way to the greenhouse. In collaboration with colleagues in York’s Department of Biology, he’ll be using nuclear magnetic resonance spectroscopy to identify the atomic structures of various riboregulators. To see the impact of riboregulator function on the viral infection process, he’ll infect plants with genetically modified versions of riboregulators and monitor the spread of the infection and the development of symptoms.

The work will support the global effort to turn the table on viruses. One of White’s ultimate objectives is to gain control over riboregulators and put them to work in biotechnology. “Instead of having viruses hijack our cellular machinery to their ends, the goal is to use bioengineering to manipulate and control riboregulators so that certain viral processes can be refocused to beneficial applications,” says White.

For more information on his research at York, visit Andrew White’s page on the Department of Biology Web site.