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Past Winner
2003 NSERC Doctoral Prize

David Vocadlo

Organic Chemistry

The University of British Columbia

David Vocadlo
David Vocadlo

Dr. David Vocadlo entered the University of British Columbia (UBC) aiming to be an architect; to design the buildings that we live in. He left in 2001 having developed groundbreaking insights into the function of enzymes — molecules that are among the key building blocks of life.

"I think about design at an atomic level. And I like to look at biological problems," says Dr. Vocadlo, winner of a 2003 Natural Sciences and Engineering Research Council (NSERC) Doctoral Prize, one of Canada's premier graduate student awards.

If DNA is the blueprint of life, enzymes, a type of protein, are the workers. Without them, the biochemical reactions that constitute life would grind to something much slower than a snail's pace. That's because most of the myriad chemical reactions that take place in our bodies, and in all living things, are catalyzed by these molecular movers and shakers.

"Enzymes permit life to occur on the time scale that we are familiar with," says Dr. Vocadlo, now a postdoctoral fellow at the University of California, Berkeley. "So a major question is how enzymes work so amazingly fast — breaking a bond in a few milliseconds that might only have a 50 per cent chance of breaking down in a half-million years."

His doctoral work substantially clarified the general catalytic mechanism for a key group of enzymes called glycosidases. When we eat pasta or potatoes, glycosidases work on a carbohydrate such as starch by breaking the links between the many constituent sugar units that make it up, liberating them for use by our bodies.

"Understanding how catalysis works in these specific cases is the first step in being able to make 'designer' enzymes, one of the holy grails of bioengineering," notes Dr. Vocadlo, whose doctoral work was under the supervision of UBC's Dr. Stephen Withers, a veteran researcher in the field of carbohydrate processing enzymes.

Dr. Vocadlo's study of five specific glycosidases involved the use of an impressive range of analytical tools. These included mass spectrometry to assess how much various enzymes weighed at different points in a reaction, chemical synthesis of alternative forms of carbohydrates to test their rates of reaction, and X-ray crystallographic analysis (done in collaboration with a British colleague) of intermediary enzyme reaction structures.

The general understanding of glycosidase activity that emerged from this intensive research pointed to a problem with the text book explanation of the functioning of an iconic glycosidase known as hen egg white lysozyme.

"I realized that if indeed hen egg white lysozyme uses the mechanism the text books described, it wasn't really a paradigm, but a paradox," recalls Dr. Vocadlo of his awareness that he was on route to tipping over a scientific apple cart.

Hen egg white lysozyme was the first enzyme whose three-dimensional structure was determined. It was groundbreaking biochemical work in the 1960s: the description developed then of how the enzyme functioned became dogma in biochemical education. However, in work published in Nature in 2001, Dr. Vocadlo demonstrated that the lysozyme reaction is actually different than previously thought. He and Dr. Withers are now working with several scientific publishers to revise their text books.

Dr. Vocadlo is currently continuing his exploration of enzymes, but this time turning the tables to look at the way that sugars modify the structure and function of proteins. And he's doing so with eyes wide open to possibility.

"Not everything in a textbook is necessarily correct or the final word," cautions Dr. Vocadlo. "We need to keep questioning things, that's part of science."