by JASON GONDZIOLA

Web-spinning herbivores. Cells encouraged to kill themselves. Bacteria that eat poison and poop out water and air. These are not your typical business products. Then again, biotechnology is not your typical business.

Still largely financed by speculative investment, biotechnology is intimately tied to a new breed of ethics that says it’s okay to tinker with the basic components of life, and this new and controversial industry has found a home in Montreal, now one of the 10 largest clusters in North America. The city’s 300 biopharmaceutical companies account for nearly half of all Canadian activities in the sector, employing over 18,000 people.

Unlike other major centres, where biochemical manufacturing is more prevalent, Montreal’s biotech sector tends to focus on research and new product development. The following is a glimpse into some of the stranger and more innovative projects in the city.

PCB-eaters

The old adage that history catches up with you is especially true of toxic waste; decades of environmental neglect have filled our seas and soil with a whole slew of poisonous and carcinogenic materials, such as polychlorinated biphenyls, or PCBs.

PCBs are a complex group of industrial chemicals that were banned in the 1970s. They are carcinogenic, neurotoxic immunosuppressants that don’t kill, per se, but rather instigate slow and widespread systematic degradation from within. Nasty stuff.

Chemically, PCBs are composed of a pair of carbon rings, known as a biphenyl group, with chlorine attached at various positions along the rings. This configuration makes them highly stable, which is good for industrial applications, but horrible for organisms and the environment. The longevity and stability of PCBs, along with their tendency to produce toxic by-products, have made incineration and containment the most common treatment methods.

However, the discovery of bacteria that eat biphenyls has led to research that could find an organic cure for this inorganic problem. Researchers from Queen’s, Institut Armand Frappier, the University of British Columbia and Concordia are investigating the use of bacterial enzymes to degrade PCBs.

"These organisms use biphenyl as their energy source and their carbon source," says Justin Powlowski, a biochemist at Concordia. "The limitation is that they have a fairly narrow range."

Researchers are trying to change that. Enzymes collected from around the world are being investigated to determine their specific tastes for certain PCB configurations, or congeners. The ultimate goal of the project is to create a generic group of enzymes capable of digesting a large variety of PCBs.

"The idea is that we could genetically engineer the organisms to accept a broader range of congeners and PCBs," says Powlowski. The waste products from these enzymes are carbon dioxide, water and chloride, all of which are harmless to living organisms.

As it stands, the research is without a method of application, but future uses may involve the customized creation of an organism that uses these enzymes to break down PCBs in contaminated areas.

"If you have a spill in the environment into the soil, it can spread out a lot," he says. "That can be difficult to treat using chemical processes. We could inoculate the soil with these organisms and they could take care of it."

Silky milk

Altering enzymes seems tame when compared to the work going on at Nexia. Pushing the frontier of recombinant DNA technology, Nexia’s scientists have inserted DNA from spiders into a breed of African dwarf goats. The result? Goats that produce spider silk proteins in their milk.

The move to this dairy medium came out of commercial necessity; spiders don’t take well to domestication. Unlike their silk-producing vermiform counterparts, spiders are aggressively territorial, so whereas silkworms live in close quarters and produce silk, spiders devour each other. Traditionally, this has made large-scale spider silk production difficult, if not impossible.

Other scientists attempted spider silk production in bacterial colonies, but this only yielded a sludge that bore little resemblance to the desired product. The silk extracted from this murky medium was substandard in strength and elasticity, the most important traits of quality spider silk.

"There are some molecules that are just too complex," explains Nexia CEO Jeffrey Turner, a former McGill professor. "They can’t be made with bacteria."

Researchers turned their attention to one of nature’s most successful protein exporters: the mammary gland. "Milk is a really complex fluid that evolved to carry large amounts of protein," says Turner. "Every mammal makes milk, so you’ve got a rich diversity to choose from."

The team looked into a number of different species, including mice and dairy cattle. Mice were ideal candidates because they were easily modified, but made very little milk. "There are no commercial mouse cheeses," Turner jokes. Cows, on the other hand, made a lot of milk, but were difficult to modify. Nexia settled for the goat: milkier than the mouse and simpler than the cow.

Using spider genes isolated at the University of Wyoming at Laramie, Nexia has produced transgenic goats that are capable of breeding. Thus far, two generations of stable spider-goats have been produced. The resultant milk is indistinguishable from its non-modified counterparts, but beneath the silky white veneer is, well, silk.

Termed BioSteel, the resulting proteins are spun into thread and will be used to make medical sutures, surgical meshes, technical sporting gear and lightweight body armour. But it doesn’t stop with silk.

Capitalizing on the success of their transgenic goats, Nexia is now developing anti-nerve-gas agents, under contract from the U.S. Army. They will make use of the same technologies as their BioSteel program, substituting genes that will code for the anti-nerve-gas agent for the silk genes.

Simpler solutions

Not all of the city’s work revolves around altering existing organisms to suit our needs. Some of the research in the Montreal area is made possible because of the genetic uniqueness of Quebec’s francophone population, where nearly 70 per cent of the current gene pool is derived from some 2,500 original founders.

"It’s a relatively new founder population," says Simon Pimstone, president and chief operating officer of Xenon Genetics, a B.C.-based company that conducts founder population research in Montreal. "That’s very important for a geneticist. In essence, what that means is that the population is sufficiently the same but also sufficiently different."

Statistically, there are enough people in Quebec that most diseases will exist within the population without a wide range of differing genetic causes. For example, of the more than 500 mutations or variants in the BRCA1 gene, a cause of breast and ovarian cancer, only four are found in French Canadians. Quebec’s low genetic variability immensely simplifies gene discovery and mapping.

Locating genetic causes for disease is done through a complex process of elimination. Using founder populations, a collection of afflicted individuals is gathered and compared against a healthy group from the same population.

"We have ways in which we can actually scan the chromosome to see which part of it looks different," says Pimstone, adding that it’s like creating a genetic roadmap. "You’ll find that certain places on that roadmap look different between the affected and non-affected people."

This is why founder populations are so useful: there are fewer differences between roadmaps. Geneticists can easily isolate the different regions and then sequence the DNA, base-pair by base-pair. An analysis is given, examining the proteins involved and finding suitable candidates for disease cause.

Xenon has excelled at this, discovering more genes associated with human disease than any other company in the world, according to Pimstone. He sees the current disease-mapping race as being analogous to the activities of old world explorers.

"They raced around the world to lay claim to various lands," he says. "What researchers are doing is kind of the same thing, with respect to new genes. That’s why competition is so fierce, because there are significant opportunities for those who can make these discoveries and translate them into new and improved therapies for diseases."

Cure-all peptides

However, not every biotech company is interested in tracing genetic causes of disease. Some, like Theratechnologies, are looking to find ways to treat the disease by imitating natural substances in the body.

Their lead product treats sleeping disorders, chronic obstructive pulmonary disease, hip fractures in the elderly, and may be effective in treating pre-Alzheimer’s patients. All of this from a single molecule: the peptide.

"A peptide is a small protein," explains Thierry Abribat, vice-president and chief scientific officer. "The difference is that you don’t need to genetically engineer this kind of peptide. You can produce it with classical chemistry."

Peptides regulate many physiological functions in the human body, but in and of themselves make poor medications because they are only active for a few minutes in their natural form. Thera’s research and development platform is focused on countering this.

TH-GRF, Thera’s main product, is a synthetically fortified form of Growth Hormone-Releasing Factor (GRF), a regulatory peptide that controls secretions of the growth hormone in humans.

"We take natural peptides as they exist in the organism and we stabilize them, because peptides are very fragile molecules," says Abribat. "Natural GRF has a half-life in [blood] serum of less than 10 minutes. In our compounds, it has a half-life of two to four hours." Thera has created a molecular shield that prevents the breakdown of their GRF compound, giving it a longer active life.

Not only is the drug long-lived, it’s potent. TH-GRF is currently in phase two human clinical trials, with promising results at only one milligram per day (compare to a 325 mg dose of acetaminophen in regular Tylenol). Currently, TH-GRF can only be administered via injection, but Thera is planning to release a patch-like delivery system, similar to those used by smokers, when the drug hits the markets.

Inhibiting the inhibitor

If you can’t treat the disease, you can always kill the affected cells.

Enter apoptosis, a cell-death process that leads to the removal of dead or disorderly cells from the body. Apoptosis is a natural and vital function of any healthy organism, and is also used as an emergency response in case of infection by disease. Cells that have been compromised are given the message to self-destruct, but in certain diseases, like cancer, this doesn’t occur.

The responsible mechanisms were unknown until founder population research at the University of Ottawa led to the discovery of the IAPs, a gene family that inhibits apoptosis. This work led to the formation of Aegera Therapeutics, which now owns patents for five of the eight known IAPs and has a strong focus on cancer research.

"IAPs are actually over-expressed in many cancers," says John Gillard, chief scientific officer. "It’s a very simple way in which a cancer cell can avoid killing itself. A cell with that much damage to its gene would normally trigger an apoptotic response."

Aegera’s technologies revolve around creating IAP antisense compounds, complementary molecules that deactivate the IAP gene family. In this case the medication would stop the IAPs from inhibiting cell death. The end result is a biological double-negative: Aegera’s medication inhibits the inhibitor.

Because cancer cells have higher metabolisms than their non-malignant cousins, they would take up more of the medication. "It has such a high metabolic rate that it has a tremendously enhanced uptake," says Gillard. "You get concentration that occurs there."

With the cancer cell’s resistance weakened, treatment would then involve standard chemotherapy, with the added benefit of needing smaller chemo doses. Ideally, the cancerous cells would die quietly and without a fight.

Lots of competition

Most of these projects have not yet been translated into viable products. This is typical of biotechnology, where investment periods run long, risks are high, and competition is fierce. The playing field is full of aggressive companies who are daily trying to woo investors and venture capitalists with their promises of cures to come.