The Research File

Research giant vs "the antigen from hell"

Shedding light on some molecular mysteries

By Joshua Karpati

The University of Toronto's Faculty of Medicine is something of a colossus among academic research institutions in Canada. With eight affiliated teaching hospitals, and subject fields stretching from biomedical engineering to nutrigenomics, there's an extraordinary wealth of research riches.

PRION DISEASES
The range of topics studied at the U of T is so vast, and varied, that it's easy to lose sight of their more relevant work. Take prions, for example. These shape-shifting infectious entities have enjoyed a relatively low profile in the past. But the infections in which prions have been implicated, including mad cow disease, are becoming less obscure.

Dr Neil Cashman, a princi- pal investigator at U of T's Centre for Research in Neurodegenerative Diseases and professor in the Department of Medicine, has recently published groundbreaking work on prions in Nature Medicine. Until recently, all assays of prion levels in the brain depended on measurements of their protease resistance. According to Dr Cashman, this resistance doesn't reveal all prions, and there's a likelihood of some lurking infectious agents being missed. His solution was to try "a novel pathway, a sub-molecular approach." He dubbed this the "side chain accessibility hypothesis."

"The structure of a protein is based on a 3D folding of its amino acid chains. When folded, some of the chains are buried in the interior. We hypothesized that some of these would become exposed on the surface of the misfolded protein," explains Dr Cashman. The geometrical re-alignment of these destructive proteins offers a rare opportunity to make them susceptible to antibodies. We search for an antibody binding site that appears on the molecular surface of malformed proteins." The side chain being exploited in this method is extremely small ? just three linked amino acids.

Why hasn't this approach been tried before? "The best labs in the world have tried to raise antibodies to prions but it's very hard to get the immune system to react. It's the antigen from hell."

This novel approach opens the door to improved diagnostics and vaccines. Dr Cashman is currently conducting a number of trials, including one in which mice are inoculated with prions of sheep scrapie (essentially mad sheep disease) and another major vaccine trial using 'bovinized' mice, ? those expressing bovine forms of prions. It will be at least five years before we see the human vaccine.

HUMAN GENOMICS
Dr Stephen Scherer, Professor of Molecular and Medical Genetics, recently won the prestigious Steacie Prize for contributions to the field of human genomics. U of T researchers have won the award four times out of the last five years. "Our group is one of the few in the world that studied the human genome early on from its highest order structure of chromosomes through to its simplest form of linear DNA sequence," notes Dr Scherer. He and his group have helped map or discover over 20 disease-causing genes, many located on human chromosome seven. "The most exciting times are ahead," says Dr Scherer, "because genomics now provides an avenue for unifying natural scientists together in order to provide solutions to complex biomedical problems, once considered unsolvable."

STEM CELLS
Dr Freda Miller, cross-appointed between the Faculty of Medicine and the Hospital for Sick Children Research Institute, has detailed how stem cells can be derived from adult skin, and how they then can differentiate into primitive nerve cells. This discovery, in addition to its possible impact on treatment of neurodegenerative diseases, could allow the bypassing of the ethically contentious issue of harvesting stem cells from human embryos.