Health

PROTEIN POWER

Canadians are pioneers in the quest to develop better drugs faster

DANYLO HAWALESHKA February 18 2002
Health

PROTEIN POWER

Canadians are pioneers in the quest to develop better drugs faster

DANYLO HAWALESHKA February 18 2002

PROTEIN POWER

Health

Canadians are pioneers in the quest to develop better drugs faster

DANYLO HAWALESHKA

In a closely guarded room in an industrial complex by Toronto’s international airport, racks stacked with hundreds of powerful central processors stand erect like faceless sentinels. The rush of air from the massive computer’s cooling system fills the bungalow-sized space with a loud drone. Scientists call this towering number cruncher Inukshuk, the Inuktitut word for stones stacked to resemble a human being. It’s a fitting nickname for what’s billed as Canada’s largest supercomputer. Inukshuks symbolize persistence in a harsh environment, and this one is analyzing the biological nuts and bolts of life. It’s part of the international, high-stakes race by pharmaceutical companies to cash in on proteomics, the study

of the proteins in the human body.

Inukshuk the supercomputer belongs to MDS Proteomics Inc., one of dozens of Canadian pioneers exploring a biological frontier on a scale never before possible. Built by IBM, Inukshuk can perform 400 billion operations per second. Its 80-terabyte archive is so big it could store the text from all the books, newspapers, scholarly journals, mass-market periodicals and newsletters printed in the world over the course of five years. In the process, Inukshuks cascading electrons churn out a lot of heat, says Michael Moran, chief scientific officer at MDS. “If the ventilation system failed,” he says, “the temperature would rise so high, things in this room would literally start melting.”

The large-scale study of proteins is just as hot. Canada ranks among the world’s

leaders (some say it’s the leader)—a nice scientific (and commercial) turnaround after the country largely missed the boat on mapping the human genome. From the genome’s 30,000 genes, many international scientists have turned their attention to the proteome, a vast collection of all the body’s proteins. No one really knows how many there are—estimates vary from 100,000 to 300,000. But with the genome sequence as their guide, and supercomputers to do the laborious data analysis 24-7, proteome scientists are picking apart the body’s proteins. Their goal is to develop better pharmaceuticals faster in a race to treat cancer, AIDS, diabetes and a host of other ailments.

Before the mapping of the genome, it would take, on average, about 10 years of research and clinical trials to have a new

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drug tested and approved for human consumption. Now, supercomputers scan the genome and use it as a template to quickly assemble protein fragments for analysis. With proteomics, drug development times could be cut by about a third, estimates David Wishart, a protein biochemist in the faculty of pharmacy and pharmaceutical sciences at the University of Alberta in Edmonton. That’s because researchers can use the supercomputers to determine if a potentially useful drug would be toxic or ineffective, or would trigger unacceptable side effects. That way the process avoids clinical trials with drugs that are sure to be therapeutic duds.

Still, it’s important to keep proteomics and the potential for rapid drug development in perspective. “It’s not going to lead to cures for everything instantly,” says Wishart. “It just means we now have tools that allow us to do this more quickly than we did in the past—thousands of times more quickly.”

To date, all the drugs in the world target about 500 proteins, crippling, curbing or otherwise altering their performance in the body to elicit a desired therapeutic response. With proteomics, researchers are trying to figure out what the other hundreds of thousands of proteins do so they can engineer new drugs, with fewer side effects. Quite simply, scientists are “digitizing biology,” says Clarissa Desjardins, executive vice-president of business development for Montreal-based Caprion Pharmaceuticals Inc. Like MDS, Caprion has formed its own supercomputing alliance —in its case with Sun Microsystems Inc.—and entered a new world of research. “It used to be enough to study one or two proteins in a scientist’s career,” says Desjardins. “Now were studying tens of thousands of proteins, many of them seen for the very first time.”

Why the fascination? It has to do with the critical roles that proteins play in the body. They act as enzymes to catalyze chemical reactions, as hormones to elicit a cellular response, or as carriers, such as hemoglobin which transports oxygen around the body. These versatile organic molecules are made of one or more amino 1 acid chains. Genes determine the order in I which the amino acids are linked together,

I acting like a blueprint that cells use to asI semble proteins required for normal cell 1 function. Once the chain is built from the

plans outlined by genes, proteins can undergo many structural transformations as the cell further refines its work. Chains of amino acids coil and fold in on themselves to form protein structures which, if magnified, look something like popcorn.

When corrupted by disease, bad proteins can kill. Not surprisingly, targeting them has enormous pharmaceutical potential. First, companies try to identify proteins of medical interest. Using supercomputers, they scour electronic databases containing a digital catalogue brimming with millions of chemical compounds with the potential to act as drugs. Their hope is to find one that attacks the offending protein with the requisite medical malice. It might work this way, says Moran at MDS: a cancer cell could have a unique protein straddling its membrane that plays a key role in its unrelenting, lethal growth. If scientists can identify that protein, they can engineer a drug to bind to it to disrupt its function. “Knock it out,” says Moran, “and you knock out the cell.”

In many respects, these are still early days for proteomics. Last month, MDS published a research paper in the British journal Nature on its examination of more than 600 protein complexes in yeast cells. Using Inukshuk as well as state-of-the-art mass spectrometers which analyze streams of vaporized protein fragments, MDS researchers were able to track new as well as previously known proteins. They drew a detailed map showing the proteins as dots and using red lines to connect those that came in contact with each other. With each protein typically interacting with many others, the connections were so numerous and complex that the diagram resembles a ball of densely packed red twine.

The study made an important point. It proved MDS could crunch large volumes of biological data, and that it was ready to tackle human protein analysis, says David

Thomas, chairman of the biochemistry department at McGill University and an expert in protein interactions for the Montreal Network for Pharmaco Proteomics and Structural Genomics, which is trying to map all the proteins within human cells. The Nature paper, says Thomas, “is an impressive technological tour de force.”

Not surprisingly, it takes a lot of money to do this sort of work. And Canada hasn’t always been good at providing it. That has changed since the creation in 2000 of Genome Canada. Marc LePage, the notfor-profit funding agency’s executive vicepresident of corporate development, says it has so far backed proteomics work to the tune of $72.1 million. Now Genome Canada is evaluating grant applications for 66 project proposals. At stake is a $330million cash pool for basic research, half from Genome Canada, the rest in matching grants from provinces, industry and non-profit foundations. “If you’re going to be a leader in proteomics,” says LePage, “that’s the price of leadership.”

Canada has many leaders. In addition to MDS and Caprion, they include Integrative Proteomics Inc. in Toronto and Vancouver’s InterOmex Biopharmaceuticals Inc. and Xenon Genetics Inc. As well, five of the top eight pharmaceutical companies in the world use proteomics hardware and software built by CRS Robotics Corp., headquartered in Burlington, Ont. Late last month, that company unveiled a new lab automation system designed to cut drug discovery times by 20 per cent or more. Speaking of the industry as a whole, Caprions Desjardins expects to see some very successful enterprises. “Multi-billiondollar proteomics companies,” says Desjardins, “will be created in the process.” And some expensive flops. Many companies are competing for public attention, hoping to attract the millions of dollars they need through initial stock offerings. Buyers beware, cautions U of A’s Wishart. Proteomics is a business in which companies play the odds, using supercomputers to churn out perhaps 1,000 potential drug candidates over the course of about five years. Of those, only a handful are likely to make it to market. It’s always been tough to find new drugs. “The field is littered with the carcasses of would-be drug companies,” says Wishart. Success will require determination, as well as science as rock solid as any Inukshuk. ESI