The Ongoing Evolution of Genomics at McGill
It is 1957. Charles Scriver is a resident at the Children’s Medical Center at Harvard. A woman brings in her four-month old daughter who is having seizures that do not respond to epilepsy medication. The distraught woman says tearfully, “It’s happening again.” Her first child died of a mysterious convulsive disorder and she is worried her second child will meet the same fate.
“To have a child die from an illness that nobody understood, and then to have it appearing again is a pretty frightening thing,” says Scriver, BA’51, MDCM’55, DSc’07, looking back on one of the pivotal moments in his lauded career.
It will be another 15 years before the first gene is sequenced. Whatever ails Scriver’s patient seems very likely to be hereditary. But doctors have no way of diagnosing what exactly is wrong, and even if they could, what then? You can’t do much about the genes you were born with.
Or can you?
“These changes are fundamental”
Tour the McGill University and Génome Québec Innovation Centre in 2011 and you will see large DNA sequencing machines, such as the Applied Biosystems 3730xl DNA Analyzer, which was a frontline tool in the Human Genome Project during the 1990s and analyzes 96 samples in parallel. Sitting next to these are the latest-generation machines, which can sequence millions of samples in parallel. In under a decade, technology has evolved that quickly.
On February 14, several floors below these labs, the Centre is celebrating a momentous day. The internationally renowned genomicist, Mark Lathrop, has been recruited back to his native Canada to become director of the Innovation Centre. He delivers a speech to leaders from McGill and the Quebec government, as well as journalists and Innovation Centre investigators. Among them is Ken Dewar, the Centre’s acting scientific director, who was a co-author of the landmark February 15, 2001, Nature publication on the Human Genome Project.
“Genomics represents a change in the way we approach biology,” Lathrop states from the podium. “Yes there have been impacts,” he adds emphatically. “The molecular basis for human disease is now much better understood. Genetic mutations underline 2,000 single-gene disorders. Just in the way we can now classify and diagnose disease – these changes are fundamental and important.”
This kind of genetic understanding of disease wasn’t available in 1957 when Scriver was trying to save a mother’s second child from a likely death. But he made a fortuitous discovery anyway. After returning home from the hospital, he picked up a pediatrics journal he subscribed to. “Here was this article about a convulsive disorder in infancy that responded to Vitamin B6.”
He went back on rounds the next day and gave Vitamin B6 a try. It worked. The infant girl’s seizures stopped. But why exactly? That would not be explained until 2010, when Peter Clayton of University College London identified an enzyme deficiency in the brain as the cause of seizures of this kind. Vitamin B6 restored the balance.
The treatment had actually preceded the diagnosis by half a century. With this case, Scriver had helped dash the notion that biology is destiny. You could do something about genes. You could change their environment.
Genetics comes of age
Scriver came back to McGill from Harvard. At that time, he says “medicine had little interest in genetics.” However, he found a kindred spirit in F. Clarke Fraser, MSc’41, PhD’45, MDCM’50, DSc’10, who built McGill’s department of genetics in the 1950s. Fraser was a pioneer in the study of the genetic basis of birth defects and established Canada’s first pediatric medical genetics department at the Montreal Children’s Hospital. In 1961, Scriver founded the DeBelle Laboratory in Biochemical Genetics at the Children’s to study genetic disorders in children and went on to convince the provincial government to set up the Quebec Network of Genetic Medicine. Between them, the two colleagues and friends ensured the future of the field at McGill and in Quebec.
David Rosenblatt, BSc’68, MDCM’70, the current chair of McGill’s Department of Human Genetics, recalls the palpable excitement he found at Scriver’s lab when he arrived in 1967. “Scriver and Fraser were extremely talented, very outward-looking people,” he says. “If someone came out with outlandish ideas, Fraser would ask, ‘Is that possible?’” Rosenblatt’s very first publication with Scriver was in Nature. Careers don’t start much more auspiciously than that.
The future is here
With the pioneering work that built the impressive genetics infrastructure of Quebec and McGill today, have we arrived at the era of personalized medicine – that oft-cited concept of tailoring therapies to a patient’s DNA? “We are very much there,” says Rosenblatt “but it will still take time and patience to integrate the complexity.”
Ken Dewar explains “First you have to get the knowledge, then you have to get the understanding and then you have to get the wisdom.” He gives the example of Clostridium difficile, the bacteria which several years ago fatally spread through Quebec hospitals. Dewar’s sequencing of the bacteria helped deliver a good chunk of the “knowledge.” The “understanding” will be in figuring out how, on a molecular level, C. difficile thrives at the patient’s expense. The final step, “wisdom,” is taking advantage of that understanding to develop an intervention that can ultimately stop or control C. difficile.
Personalized medicine, then, requires the marshalling of significant resources because geneticists and genomicists must turn their efforts to the thousands of diseases still out there. Some of the most notorious ones, lung cancer and cardiovascular disease, have been the subject of Mark Lathrop’s prolific research career.
As the February 14 press conference draws to a close with almost 100 government officials, VIPs, Faculty alumni, researchers and friends looking on, Lathrop leaves the crowd with this final thought: “We at McGill, and in Quebec, have a very strong potential to be among the leaders of the new wave of genomics.”
If the new wave is as revolutionary as the last half-century has been, the infant girl that Scriver saved will ultimately be joined by millions of patients whose DNA will show the way to life-saving treatments.
[Laurence Miall + Maria Turner]