Channel changer

Prof. Terry Snutch turns the channel on calcium

by Charles Ker
Staff writer

Picture Hunched over a rack of tiny test tubes, Ellie Mathews clones a calcium channel as Sting croons I'm So Happy through an overhead speaker. Life is good in Biological Sciences Lab 3459.

Mathews, a die-hard Montreal Canadiens (Habs) fan, wears a Habs hat, shirt and carries 3-D hockey cards of Saku Koivu and other Canadiens stars in her back pocket. She is a dedicated young scientist and a walking torment to mentor Terry Snutch.

"I was born in Ontario and my father was a devoted Leafs fan," says Snutch, whose office lies directly across from Mathews' workstation. "Even though I've been in Vancouver all these years, the Toronto Maple Leafs seem part of my genetic makeup."

It seems also that Snutch, a professor in UBC's Biotechnology Laboratory, is genetically predisposed to ground-breaking science.

Mathews is one of two graduate students, six post doctoral fellows, two undergraduates and two technicians currently following Snutch on his quest for, and an understanding of, calcium channels in the human body.

Essentially, Snutch investigates how calcium gets in and out of the brain's 100 billion nerve cells, or neurons, and triggers electrical and chemical signals en route. Calcium acts as the messenger between neurons that control skeletal, heart and smooth muscle contraction, hormone secretion and all electrical signaling in the central nervous system. That's the good news.

The bad news is that too much calcium entering a cell, through so-called calcium channels, can be toxic.

Snutch's research during the last seven years has led to some startling breakthroughs.

"When we first started this work, people didn't know how many calcium channels were in neurons," says Snutch, who has cross-appointments in the departments of Zoology and Psychiatry. "They knew if you poked an electrode into a cell you could detect channels opening and closing but nobody knew how many channels there were or how they worked."

Snutch has since identified and cloned five genes encoding the proteins (channels) that regulate calcium entry into brain cells. It turns out that some of these genes are also turned on in the heart. In fact, Snutch believes that there may be as many as a dozen types of calcium channels, controlling different functions, in different parts of neurons and in different types of cells.

His discovery has opened up a huge new field for pharmaceutical companies, which, with the help of Natalie Dakers and others in UBC's Industry Liaison Office, have beat a path to the molecular neurobiologist's door.

Two of the channels cloned by Snutch are the target of drugs currently given to treat cardiovascular disorders including hypertension, angina and certain arrhythmias. Migraine headaches and some forms of epilepsy are two other disorders shown to involve calcium entry into cells.

Snutch says approximately 50,000 Canadians suffer from strokes each year, 15,000 of whom die. The remainder, he adds, are left with varying degrees of disability as cells are killed by a flood of calcium in the stroke's aftermath.

"If you want to design a drug that will block calcium coming into cells to prevent injury from stroke, then you want to block a specific type of channel," says Snutch. "Similarly, if you want a drug that is going to interact with channels involved in migraines, you don't want a drug that will effect other channels that are busy controlling important functions elsewhere."

Snutch's challenge was to simplify the process whereby each of the brain's 100 billion neurons simultaneously transmit thousands of electrical signals in tens of milliseconds.

Unfertilized eggs from the South African clawed toad provided the simplified model he needed to study calcium channels individually outside the body.

One floor up in Snutch's second lab, post doctoral fellow Kathy Sutton oversees what appears to be a most delicate operation. Two electrodes -- looking like needles dentists use to freeze gums -- are trained on a small tray under a microscope. A glance through the lens shows that the electrodes are stuck into a single frog cell which has been injected with the gene for a particular calcium channel.

Sutton explains that after the frog cell is injected with the cloned DNA, it is left for five days to manufacture the protein in its own membrane. "Then," says Sutton, "we shock the membrane, the protein opens and we have a functioning calcium channel. The frog eggs don't know that they are not a nerve cell, and we get them to act like one."

The next step is to introduce potentially useful drugs or different serums from patients with particular diseases that are thought to effect calcium channels and see what happens to the calcium current.

Snutch's pioneering process enables scientists to study channels and all their properties outside the brain and use this information to design or look for drugs that can either block or excite certain channels by themselves without risk of effecting other channels.

Back in room 3459, Snutch hauls out a shoebox filled with cone snail shells and holds up a Conus geographus specimen. He warns that handling a live specimen on a beach in its native home of Micronesia would result in certain death within two hours.

One of 500 species of hunting cone snails, the geography cone snail paralyses its prey by injecting a toxic venom that blocks one of the channels Snutch has cloned. The channel in question is required for electrical signaling in all nerve cells. Disrupting calcium flow through it leads to suffocation.

Snutch also discovered that the snail toxin blocks other channels involved in strokes and pain transmission. A drug company in the U.S. has taken this information and is developing a pain reliever reported to be a thousand times more sensitive than morphine.

Snutch says the drug may eventually help ease chronic pain among AIDS and terminally ill cancer patients.

Since his arrival at UBC in 1989, Snutch has accepted a steady stream of provincial, national and international research awards. These include: Killam Research Prize (1991); Alfred Sloan Research Fellowship (1991-93); International Research Scholar, Howard Hughes Medical Institute (1991-96); Outstanding Academic Alumni Award, Simon Fraser University (1994); Medical Research Council of Canada Scientist Award (1995-2000); and the 1996 International Albrecht Fleckenstein Award.

When he isn't doing award-winning research, Snutch does confess to having another obsession.

For three years he's been trying to catch and spay the den mother of a burgeoning cat population living under a hut behind the Biological Sciences building. The blue russian has managed so far to evade Snutch and the three-metre-long extension net he keeps in the corner of his office.

"She's up to two littters a year and the campus is being overrun," says Snutch, who has already adopted three of her kittens.

And then, of course, there are his beloved Toronto Maple Leafs, currently last in their division. On this matter, Snutch says, "all my channels are firmly closed."