Tomorrow's Health, Today's Research

Dr. Francis Choy

Professor, Biology Department
Coordinator for Gaucher Disease research in Western Canada
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Phone: (250) 721-7107
Department Page
Research area: genetics and enzymology of Gaucher disease and other lysosomal storage diseases
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Research profile:

The heartbreak of tracking rare lethal mutations

Dr. Francis Choy studies the biochemistry and genetics of inherited diseases. It’s an emotional job, given the impact of the diseases on the patients he studies.

Part of his job consists of assisting doctors from around the world screen patients (and sometimes fetuses) for certain rare genetic mutations. He also helps diagnose genetic diseases in children. He loves the relief he sees on the faces of expectant parents when he can tell them their offspring will be fine, but not every couple is so lucky. He has corresponded with some families for years, and in one case, even lobbied a drug company to give free treatments worth millions of dollars to help alleviate symptoms.

Choy currently focuses on three metabolic disorders that profoundly affect children: Gaucher disease, Sanfilippo syndrome and glycine encephalopathy.

Originally from Hong Kong, Dr. Choy went to McMaster University and then McGill University in the early 1980s for his post-doctoral fellowship training. He began with an interest in lysosomes, which are organelles that clean up and digest worn out materials in the cell. That interest led to researching Gaucher disease, which is caused by a mutation in a lysosomal enzyme called glucocerebrosidase.

Gaucher disease is rare, but relatively frequent in Jews of Eastern European descent. People without glucocerebrosidase can’t digest old membrane lipid, which leads to fatty buildups in many organs. In Canada, anyone with a history of Gaucher disease is offered genetic screening, which is somewhat controversial because historically it has been hard to predict how an infant will be affected. Depending on the exact mutation (or combination of mutations) the symptoms vary dramatically. Some children don’t survive their second birthday; others have neurological involvement that can lead to mental retardation; and others have mild manageable symptoms. Dr. Choy has helped link certain mutations to the more serious disease, and link others to the mild form – a crucial distinction when screening patients, including prenatal diagnosis in fetuses. This information is also important for the B.C. government, who consult Choy to predict who might benefit from an enzyme supplement treatment. The progress of Type 1 Gaucher disease (which is non-neurological, but includes symptoms of bone pain and fractures, and liver and spleen problems) can be halted if patients inject glucocerebrosidase.

While this treatment is very effective, the problem is the cost: as much as $4 million a year per patient. The treatment is covered in B.C. for some patients, but Choy knows families outside B.C. who have lost children because they couldn’t afford the drug. In fact, few patients are treated.

One reason for the high cost is that standard methods to purify human enzymes in large scale don’t work with glucocerebrosidase. Standard methods involve cloning human proteins into bacteria, which can be grown in large quantities for mass production. However, this doesn’t always work because of post translational modifications (modifications to lysosomal enzyme proteins that happen in higher life forms such as humans, but not bacteria). Although there have been many attempts by Choy and other researchers to clone and produce glucocerebrosidase into a more sophisticated, yet cheap, system, nobody has had any success at making an active protein.

This means the enzyme has to be produced in hamster tissue culture cells, a pricey procedure. Another option is to purify the enzyme from placentas, but it can take up to 50,000 placentas to treat one patient for a year – clearly not an option.

One avenue Choy’s lab is pursuing is to track post-translational modifications of glucocerebrosidase to try and figure out what is needed for an active enzyme.

Meanwhile, his lab continues to improve and develop new genetic and biochemical tests for inherited diseases. One of his grad students, Agnes Zay won the Lieutenant Governor’s silver award for her master’s thesis on glycine encephalopathy, a lethal disease caused by an inability to break down glycine.

Glycine is normally broken down by a complex of four proteins, and a mutation in one of three proteins in the complex will cause the disease. Zay was the first to successfully clone and produce the H-protein of the complex in yeast, enabling researchers to purify it in large quantities, a necessary step towards developing a cheap biochemical assay to diagnose glycine encephalopathy.

Like Gaucher disease, glycine encephalopathy can be very serious. It can lead to early infant death or severe seizures and mental retardation. So while Zay was surprised that she won the award because she thought it would go to a “sexier” area of science, the impact of her work and others in Choy’s lab is immediate. Zay’s assay will mean pre-natal screening will become available. As Choy says, “what is the use of research if it doesn’t improve the quality of human life.”