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The Medical Innovators

Scientist by day, clinician by, well, day, too—and to that mix, add entrepreneur. How two original thinkers are devising solutions to complex health conditions

Photography by Curtis Lantinga

Dr. Victor Yang operates on David Spencer on Apr. 11, 2013. Spencer, who has since made a full recovery, had a rare condition that can lead to bleeding in the brain and brain damage.

Thomas Edison, a pioneer of the motion picture camera, electric light bulb and phonograph, famously said, "Discontent is the first necessity of progress. Show me a thoroughly satisfied man and I will show you a failure." Edison, who held 1,093 U.S. patents, was uncommonly prolific, but his dissatisfaction with the status quo is characteristic of all inventors. 

When Dr. Victor Yang was in the final year of his undergraduate engineering science studies, he was developing an imaging system for surgery to remove brain tumours. Although his system met the design specifications, it was cumbersome and unsuitable for the operating room (OR). When he asked how he might improve the design, Yang's mentor, a neurosurgeon, told him if he wanted to build something neurosurgeons would use, then he'd have to become one.

So he did.

"Engineers and clinicians speak different languages," says Yang, newly recruited as a senior scientist to the Brain Sciences Research Program at Sunnybrook Research Institute (SRI). "I'm happy to be the bridge, to help translate for each group, and articulate things that wouldn't have been [said] otherwise."

Yang is an engineer, physicist and neurosurgeon. He dedicates most of his time to research. One day a week, he treats patients with neurovascular conditions due to stroke at Sunnybrook Health Sciences Centre. On these days, he can be found dislodging a blood clot in the brain or neck artery, the cause of ischemic stroke. Or, you might find him in the OR, removing a tangle of abnormally formed blood vessels leading to hemorrhagic stroke, or bleeding in the brain.

He joined SRI for the opportunity to tether his research and clinical activity. Yang is designing an experimental OR at Sunnybrook in which surgeons can test new technologies, including ones he developed. He wants to maximize the OR's research potential while maintaining clinical functionality. "Even if you have motivated surgeons who want to be involved in engineering research, the moment you interrupt their workflow, this whole concept falls apart," he says. Thus, the experimental OR will be indistinguishable—at least superficially—from a typical OR.

Yang's area of expertise is biophotonics, the use of optical methods—light, basically—to study biological systems like people. He is developing technologies that harness the power of light to detect and diagnose disease, and monitor response to therapy.

His inventions are based on optical coherence tomography (OCT), which works in a similar fashion to ultrasound, but instead of sound waves bouncing back from tissue, light waves are reflected from tissue. These "echo" time delays of light are collected and analyzed. "We measure where they are coming from, how bright they are, and then we make a picture," says Yang, who is also an associate professor of surgery at the University of Toronto.

Optical coherence tomography, which images at the micron scale (one-thousandth of a millimetre), was developed for ophthalmology to allow doctors to see a patient's retina in detail, noninvasively. Scientists are now studying its potential for other uses. Yang adapted the Doppler technique used in ultrasound to study blood flow in large vessels, to OCT, to visualize the microvasculature, exquisitely small vessels of the circulatory system that are impossible to see noninvasively. These vessels—microns in diameter, 200 times smaller than the head of a pin—and their blood flow patterns can provide important clues in the progression of disease, Yang says.

In OCT, the Doppler effect is the ever-so-slight change in colour—one fraction in one trillion—that is observable when light is reflected from moving red blood cells. When red blood cells move toward the optical fibre, the light frequency is a little higher; when they move away from it, a little lower. Where Doppler OCT prevails over ultrasound is in its ability to detect the small frequency shifts generated by slow-moving red blood cells.

Dr. Victor Yang is designing an experimental operating room at Sunnybrook where he and other brain surgeons can test new surgical technologies.

"With Doppler OCT, red blood cell movement produces a larger frequency shift than that resulting from ultrasound, so it's easier to detect. The red blood cell is basically crawling, and you can see flow rate and measure it. We can actually see red blood cells moving to their neighbour positions; it's very sensitive," he says.

The resolution of Yang's Doppler OCT technology is seven microns, the size of a red blood cell. His team was the first to use Doppler OCT preclinically to study blood flow in the carotid artery, which delivers blood to the brain and head. At SRI, Yang will study plaque buildup in the carotid arteries of patients using a fibre optic catheter. He'll be looking for stroke-causing plaque lesions and their associated capillaries, which also supply blood to the carotid artery wall. He'll also use Doppler OCT to look for relationships between abnormalities in the retina and cerebrovascular disease in patients with dementia.

As Yang has also shown, the technology can detect cancers of the lung and gastrointestinal tract. He has used it to study small vessel characteristics associated with Barrett's esophagus, a precancerous lesion that leads to gastrointestinal cancer, and is working with the B.C. Cancer Agency to use Doppler OCT to assess microvasculature blood flow patterns in the lung for early detection of lung cancer.

In addition to seeing how cancer is progressing, Doppler OCT can be used to track if antiangiogenic therapy, which aims to stop new blood vessel formation in tumours, is working. "You want to monitor how tumour cells are growing, how they're getting their nutrients," says Yang. "Imaging these will allow you to assess whether you have the right treatment and the right response."

Another way in which Yang has been inspired by ultrasound is by applying the "multifoci" technique to create the world's first multibeam OCT system. Phased-array ultrasound uses a probe made of many small elements that send and receive high-frequency sound waves. A computer steers these sound waves and maps returning echoes to produce a cross-sectional image with multiple focal points. Similarly, Yang's multibeam OCT technology uses multiple emitters and receivers of light; compared to single-beam OCT, it enables greater depth of focus over a large field of view without sacrificing image resolution.

In 2007, Yang licensed this invention to Michelson Diagnostics, a British company. Dermatologists now use it to detect skin cancer and other abnormalities. He says he hopes it will be used to monitor response to treatments like radiation therapy, especially on delicate areas of the face where biopsy is undesirable.

Yang holds 15 patents, and says getting inventions to patients would be impossible without commercialization. "You have to commercialize [a technology], so that some company can manufacture, deliver and service it. Research groups are not designed to do that, and we shouldn't do that. We're best suited to discovery." He is working on a way to use the multibeam technique clinically in a neurosurgical endoscope, a device made of a long tube with a light and video camera at one end that allows doctors to see inside the body.

He says he's looking forward to marrying his two vocations at SRI. "We're hoping this will be a prescription for success for surgeon-scientists. Once the experimental OR is up and running, operating days will combine clinical [work] and research. In that case, I might be able to push the research component to 80% of my time," he says happily.

Clearing the way

On the day of our meeting, Dr. Bradley Strauss is one-half hour late. I arrive at his office to find he's been called into the catheterization lab for an urgent case. Strauss, a senior scientist in the Schulich Heart Research Program at SRI, still has his lab coat on as he apologizes for being late. As head of the division of cardiology and chief of the hospital's Schulich Heart Program, research and administration take much of his time, but he says his clinical work is critical. "I have many patients that I feel very close to, and who I like looking after."

Dr. Bradley Strauss, in his lab at Sunnybrook Research Institute, talks about a biological therapy he has developed to unclog blocked blood vessels of the heart.

Seeing patients is not only rewarding; it also informs his research. For more than a decade, Strauss has been developing a treatment for chronic total occlusions (CTOs) of the heart, where blood vessels have been completely blocked for three months or longer.

Cardiovascular disease is the number one killer in Canada. Coronary artery disease, narrowing of the arteries that supply blood to the heart, is its most common form. This narrowing is caused by atherosclerosis, a buildup of fatty materials and plaque on the inner walls of blood vessels. About 20% of patients with coronary artery disease have a CTO identified at coronary angiography, a type of X-ray to see inside blood vessels.

One treatment for this condition is angioplasty. Under X-ray guidance, doctors use a catheter to insert a guide wire into the blockage and inflate a balloon at its tip to crush the plaque and restore blood flow. Sometimes they insert a stent, a metallic mesh tube, to keep the vessel open. Most patients with a CTO are treated with drugs to manage chest pain, or if symptoms are severe, referred for bypass surgery. Medication is often ineffective and restricts patients' lifestyles. Although percutaneous, or through-the-skin, interventions are less invasive than surgery, and pose fewer risks of complications, they are attempted only in about 10% of all CTO cases. Doctors are reluctant to try interventions like inserting a stent for a few reasons. In addition to concern over prolonged radiation exposure, success rates of angioplasty for CTOs vary from 55% to 80%. Procedures usually fail because cardiologists cannot get the guide wire through the blockages, which are made mostly of collagen and are generally old and hard.

I was never as excited as the first time I saw the collagenase work.

It was against this backdrop that Strauss' invention was born. "It was always a great challenge to get the wire across when [the vessel] is totally blocked. There were so many times it failed. I had so many frustrations that I could not do it," says Strauss, who is also a professor at U of T.

Unwilling to accept defeat, he thought about how the materials that constitute these blockages could be used therapeutically. "I had done a lot of work with collagen and these collagenase enzymes, so I had a good understanding of the biology of it all. It just made sense to me: why don't you inject something to break down the collagen so you can get through the occlusion easier?"

An enzyme-based therapy to soften artery-clogging plaque seemed like a promising idea, but before he could test it Strauss had to develop experimental models. He then used an off-the-shelf enzyme mixture made from the bacterium C. histolyticum that degrades collagen, and injected it into the models—and waited.

Three days later, he had his answer.

"I couldn't believe what happened," says Strauss. "I was never as excited as the first time I saw the collagenase work. I thought I'd truly seen something unique."

He published preclinical results in 2003, by which time he learned the enzyme needed only 24 hours to work. He began to commercialize his invention, a process he found unfamiliar and at times overwhelming. "Doctors have no training in this. When I started, there were no mentors. I couldn't call up someone and ask, 'How do you do this?'"

It took several years for Strauss to test collagenase in patients. One hurdle was finding a manufacturer who could make a formulation pure enough to use in humans. He also had to obtain research ethics and regulatory approval, not to mention find money to do the work.

Through a grant, Strauss led a Phase 1 clinical trial, the first in humans. He recruited 20 patients; each had undergone one previous failed angioplasty. Strauss was eager to test the therapy in patients, but says the fear of causing harm weighed heavily upon him. "You have no idea what's going to happen. You're frightened because you don't want to make someone worse. Every time we changed the dose, I'd worry [about doing] something dangerous to someone."

Given he was testing the drug in patients with blockages that had already stymied doctors, Strauss set the crossing success rate at a modest 35%. To his delight, doctors got through blockages in 75% of patients. Moreover, they could trade stiff-tip guide wires—used routinely for CTOs for their increased probing force—for soft-tip guide wires in most procedures. At three months, there were no complications and patients reported less chest pain.

"I don't know if I can describe how wonderful it feels to think something you worked on did something profoundly important in someone's life. There are no words for it," Strauss says.

Interventional cardiologists Dr. Bradley Strauss and Dr. Harindra Wijeysundera stand in the catheterization lab moments after a failed angioplasty attempt. Strauss says such challenges underpin his motivation for developing a treatment to get through blocked blood vessels.

Immediately after the trial, he started Matrizyme Pharma to help bring the drug to market. It is difficult to license a new therapy, especially early on, because of financial risk. To this point, Strauss has taped to the back of his office door an email from a drug company executive, who, clinical trial results notwithstanding, says he remains skeptical of the enzyme's promise. "There are huge obstacles. This just reminds me of that," says Strauss, referring to the email. "You either give up, or try and draw some strength to say, 'They're wrong.' It gives me strength to know that I have to overcome huge challenges."

Strauss also notes that in his field, a play-it-safe mentality won't yield advances. "Interventional cardiology is by nature and historically a very innovative place. We're constantly doing new things to try and treat difficult coronary arteries easily. To put a stent into a patient for the first time, you have to be able to take risks. If you take a conservative approach, you won't improve things because you'll accept what's there," he says.

Matrizyme has raised the millions needed to do a Phase 3 randomized controlled trial, the gold standard of clinical testing. It will enrol 400 patients at 30 sites in North America. "We're going right for the big game," he says, smiling.

He hopes to complete recruitment within 18 months. The litmus test will be how patients feel immediately after the procedure and their quality of life two months later.

If results mirror the earlier ones, then it is likely that a large drug company will license collagenase, says Strauss. "It would be difficult for us to take it past this stage, because you really need to have a big sales force to show [the drug] to people all over the world. I expect that it will make its way across the globe, which is kind of neat. I can see that happening now; maybe I couldn't a few years ago. I feel pretty confident that we can do this."

Yang's research is funded by Brain Canada, Canada Foundation for Innovation, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada and the Ontario Ministry of Research and Innovation. Yang is also supported by the Canada Research Chairs program; he holds the Canada Research Chair in Bioengineering and Biophotonics

Strauss' research on collagenase was funded by the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, Reichmann Research Chair at Sunnybrook and St. Michael's Hospital Research Foundation. The Canada Foundation for Innovation and Ontario Ministry of Research and Innovation provided infrastructure support.