Using little proteins to accomplish big things

Canada is making strides in medical research thanks to the delicate art of protein engineering.

Researchers at the Protein Engineering Network of Centres of Excellence (PENCE), are working to improve the effectiveness of medication, develop new vaccines, and tailor carbohydrates to reduce the cost of developing drugs — all by tweaking tiny proteins.

Proteins, the small building blocks of cells, have countless functions and there are millions of them floating around in the human body.

"Disease usually involves proteins. Knowing the structure and function of proteins enables us to develop drugs to treat disease," explains Dr. Robert Hodges, network leader for PENCE. He says changing a protein's function in the slightest way can yield incredible results.

Protein Engineering involves either creating new proteins from scratch — an experimental new area of research for the future — or modifying existing proteins. PENCE currently has 28 projects under way, most in the biomedical area.

With over 250 scientists from 14 universities, hospitals, and government laboratories, and 40 industrial partners, the NCE funds going to PENCE result in an average annual investment in research and development of $4.2 million. Most PENCE researchers also receive separate grants from the Natural Sciences and Engineering Research Council and/or the Medical Research Council to support research projects complementary to their PENCE work.

In one exciting new project, researchers at the University of Alberta are using protein engineering to develop two vaccines against ventilator-associated pneumonia (VAP), a potentially fatal disease that affects roughly 20 per cent of patients in intensive care units.

The most common cause of VAP is PSEUDOMONAS, a common organism found in water, soil, vegetables, etc. It only becomes dangerous when a person is injured and their bodily defences are down.

"But for the bug to make you sick, it's got to stick to your cells," explains Randy Irvin, professor of medical microbiology and immunology at the University of Alberta. "What we are doing is creating vaccines that will recognize the bug and prevent it from sticking."

VAP caused by PSEUDOMONAS kills an estimated 60,000 people in North America every year and this highly resistant disease adds over $5 billion a year in health care costs across North America. These new vaccines have the potential to significantly reduce health care costs and save thousands of lives.

The new vaccines are being developed by PENCE, in association with the Canadian Bacterial Diseases Network, both of which are funded by the federal Networks of Centres of Excellence. Extensive tests on animals have shown near perfect results and the vaccines are now being commercialized by Cytovax, an Alberta-based company. Clinical trials are expected to begin on human test subjects by fall 1998.

A slightly different approach to protein engineering is being used in research on modifying hemoglobin — a protein responsible for the delivery of oxygen in the blood. PENCE researchers are devising ways to use hemoglobin as a way of delivering medication more effectively.

The research is still in an early stage, but the goal is to use hemoglobin to deliver drugs that otherwise would not be tolerated or effective. This could minimize the side effects of many medications, allow doctors to safely give patients larger doses of a drug and control its delivery, and even reduce the length of many treatments.

Hemoglobin drug delivery could be a revolutionary new way to treat illnesses like cancer, colitis and multiple sclerosis — diseases for which medications are often difficult to use effectively. Researchers say it might particularly benefit chemotherapy patients since the hemoglobin could deliver oxygen, which enhances the effectiveness of radiation therapy, as well as supplying medication.

"If you deliver a cancer drug and oxygen together then you have a bomb directed at the tumour," says Dr. Ronald Kluger, professor of bio-organic chemistry at the University of Toronto. "The body doesn't see hemoglobin as foreign so it won't be attacked the way other proteins are."

Several aspects of Dr. Kluger's research have been licensed to Hemosol Inc., a Canadian biotechnology company that is looking at the possibility of taking the research further.

"If you could use hemoglobin to better deliver medication safely and cost-effectively, then you would open up a considerable market — world-wide," says Anthony Magnin, senior vice-president of Hemosol Inc. But he adds that pre-clinical trials will be needed to determine any future direction the work may take.

Steve Withers is also hoping to bring his research into clinical trials. The University of British Columbia chemistry professor has found a cheaper way of synthesizing carbohydrates that will allow them to be used to develop various new drugs and therapies.

Chemically altered carbohydrates have long been touted as excellent test subjects for anti-viral and anti-bacterial drugs and vaccines. But they have always been far too expensive to be used in industrial quantities for clinical trials.

Now, through protein engineering, Withers has figured out how to change the function of a certain enzyme (a kind of protein that causes a reaction) so that it will build up a sugar instead of breaking it down.

This discovery means they can lower the cost of producing carbohydrates by over a thousand fold. It now costs $2,872 for one gram of the sugar needed to make a certain carbohydrate. Withers says he could probably produce it for $1 per gram.

"We hope this will make a whole range of drugs accessible that weren't accessible before," says Withers. "By reducing the cost of producing these sugars, you open the door to a whole bunch of solutions to diseases you couldn't even consider before."

Withers says his research group is now looking into the next phase — commercializing their work. They have applied for patents and are searching for commercial partners.

According to network leader Dr. Robert Hodges, Canada has the potential to be a world leader in protein engineering and government support is essential for this to happen. The federal government supports PENCE research through their NCE program, which is jointly funded by NSERC, MRC and the Social Sciences and Humanities Research Council.

"Our scientists are internationally competitive and have won many awards, including Dr. Michael Smith's 1993 Nobel prize for site-specific mutagenesis (manipulating DNA to produce a desired protein); and new products are being developed all the time," says Dr. Hodges. "The future of Canada's economy depends on job creation in high-tech and biotech areas. The contributions of protein engineering will improve the quality of life for Canadians."

For more information please visit the PENCE Web site.