When Dr. Lorrie Kirshenbaum decided to investigate how genes affect the life and death of heart cells, he came up with a novel approach to study the problem.
First, he developed a virus. Nothing too serious - just a run-of-the-mill cold virus.
Then he took the gene in question and inserted it into the virus. Once that was done, he dropped the gene-carrying bug into the heart tissue of a lab rat.
Through this process, which Kirshenbaum pioneered in 1993, he was able to observe how genes affect heart cells. In fact, this technology allowed Kirshenbaum to be among the first investigators to manipulate adult heart cells with certain genes that promoted DNA synthesis and cell growth. He has also used this approach to genetically engineer heart cells with special genes that make them resistant to injury and death after heart attack. In effect, he created a new theatre in which to study heart disease and, perhaps, how to cure it.
Now, nearly 20 years later, the gene-in-a-virus technique is helping Kirshenbaum take another major step towards his ultimate goal. Earlier this year, he announced that he had identified a series of genes that switch on when the heart muscle is deprived of oxygen.
The discovery is an intriguing one. Learning how to prevent the genes from switching on when starved of oxygen could lead to new treatments to prevent damage to heart muscle cells during heart attacks, says Kirshenbaum, who is the University of Manitoba's Canada Research Chair in Molecular Cardiology at St-Boniface Hospital Research. It could also open the door for new approaches to treating cancer.
"What we discovered was that the genetic pathway that gets switched on in the heart when the cells are deprived of oxygen is the same as the one that gets switched off in cancer cells," says Kirshenbaum, who is also a professor in the Departments of Physiology and Pharmacology and Therapeutics at the University of Manitoba's Faculty of Medicine. "So this research could have a major impact in the treatment for both diseases."
Kirshenbaum's ongoing investigation into the life and death of cells is considered world-class, and is just one example of the leading edge research taking place in Manitoba today. Everywhere you look, researchers working in the lab or out in the community are pushing the boundaries of knowledge in their respective disciplines as they map a path for the future of health care.
In doing so, today's researchers are building on the legacies of a previous generation of Manitoba research icons, people like Drs. Bruce Chown and John Bowman, who developed a cure for Rh disease, and Dr. Joseph Doupe, who is credited with transforming the University of Manitoba's medical school following the Second World War by emphasizing the importance of research in the delivery of care.
But while the quest for knowledge may be as old as the test tube itself, there are important differences in the way researchers go about their work today, says Dr. Peter Nickerson, Associate Dean (Research) for the University of Manitoba's Faculty of Medicine.
For example, researchers now have access to an array of technologically advanced tools to help them explore whole new frontiers of medicine, including molecular biology, proteomics and stem cell research. "Compared to the tools that we had then, the tools we have now are unbelievably more sophisticated," says Nickerson, who is also a member of the Manitoba Health Research Council's Board of Directors.
He cites the case of American researcher Craig Venter who decided about 10 years ago to map the human genome. "That whole exercise took about a year," he says. Now, with the acquisition of the latest technology in the form of the AB 5500 XL gene sequencer, "We can do that in a week. It's an explosion of capacity and speed that is generating genetic data in a way we never could do before."
Another example is the QStar Elite mass spectrometer, used by scientists to analyze the makeup of proteins. The instrument is based on a design developed by a group led by Dr. Ken Standing, professor emeritus, and Dr. Werner Ens, professor, in the Departments of Physics and Astronomy at the University of Manitoba. "The earlier versions of the mass spectrometer would take days and give us a low level of resolution (of a protein). Now that we have much more sophisticated machines, they are able to go through the analysis much faster and with a much higher level of sensitivity. We're able to detect low-level proteins that, before, we didn't even know were there."
Nickerson likens advances in research techniques to exploration of space. "It's like looking at the moon through binoculars 50 years ago, and now you have the Hubble telescope," he says. As a result, scientists are better able to piece together how cells, proteins and genes interact with each other in the human body. "And it is through that interaction that we are able to actually think about how we might modify that interaction… so that in the case of cancer, you shut off cancer growth, or in the case of auto-immune disease, you shut off the auto-immune process, and have healing and recovery of normal function. In that sense, it is a new world," says Nickerson.
Kirshenbaum's work is a case in point. In order to carry out his research, he first needed to develop the technology or technique of dropping the gene into a virus. Then, using a number of highly sophisticated molecular biology techniques coupled with a laser scanning fluorescence microscope, he was able to see where the genes he introduced into the heart cells were located and their effects on cell growth.
Kirshenbaum and his team of 10 researchers, comprised of students, post-doctoral trainees, and research associates, are not the only ones coming up with new answers to old problems. Within the last few years, the University of Manitoba's Faculty of Medicine has opened, directly or in partnership with other groups, a number of labs to explore new fields of medical research. They include:
The Regenerative Medicine Program
Headed by Dr. Geoff Hicks, this lab includes eight principal investigators, 36 graduate students, 20 technologists and 10 post-doctoral fellows. The objective is to develop stem cell therapies to treat conditions ranging from cancer to spinal cord injury.
The Manitoba Centre for Proteomics and Systems Biology
Led by Dr. John Wilkins, this lab has seven principal investigators and about 35 support staff. It was created to study proteins, the biochemical compounds that essentially build every living cell. Understand how proteins operate and you can gain new insights into what happens when cells become infected or diseased.
These groups represent a new wave of research that is emerging in Manitoba, all of it aimed at developing better care for people in Manitoba and beyond.
One of the province's more established research groups can be found at the Manitoba Institute for Child Health. As the Director of Research, Dr. Terry Klassen heads one of the largest research organizations of its kind with more than 200 affiliated principal investigators. He says the impact of research on patients can be seen every day. "When you look at our major themes of Biology of Breathing and the Diabetes groups, what you'll find is leading researchers and clinicians tackling major health problems that have a tangible benefit to care here in Manitoba," says Klassen, who is also Associate Dean (Academic) and professor of Pediatrics and Child Health at the University of Manitoba's Faculty of Medicine. "Asthma and diabetes are both huge issues in Manitoba, and we've been able to bring together the basic bio-medical researchers and clinicians caring for these children."
In health research parlance, the idea of gathering researchers from different backgrounds under one roof is known as "clustering." For example, the Biology of Breathing group at MICH includes experts from completely different backgrounds who are all working on different problems. But working side by side has its benefits. Simply put, they feed off each other's passion, experiences and wealth of expertise.
As evidence of this, Klassen cites the work of Dr. Richard Keijzer, who came to work at MICH from the Netherlands because it offered him the opportunity to run a research lab and still see patients.
As a pediatric surgeon, Keijzer performs minimally invasive laparoscopic procedures on newborn babies. But he also conducts important research on lung development problems of the fetus in utero. His experimental techniques will someday lead to a less invasive treatment for what's referred to as a "diaphragmatic hernia," a developmental defect in utero that causes the lungs of newborns to be malformed, leading to lifelong breathing problems.
Keijzer's innovative research involves nano-technology. Together with Dr. Malcolm Xing, he developed a treatment for the disorder using nanoparticles - which are essentially engineered molecules - that has already shown promise in the lab. A cure is likely still a number of years away, but in the meantime, Keijzer carries on as a pediatric surgeon, helping to improve outcomes for mothers and newborns. "He (Keijzer) is a clinician who brings a very important skill to the province," explains Klassen. "By recruiting him, with a strong commitment to research, the kids in Manitoba now benefit."
Working alongside Keijzer, who was recently named the U of M's Thorlakson Chair of Surgical Research, are Xing, an assistant professor in the Department of Mechanical and Manufacturing Engineering at the University of Manitoba's Faculty of Engineering, and an expert in bio-engineering and nano-medicine, and Dr. Andrew Halayko, Canada Research Chair in Airway Cell and Molecular Biology at the University of Manitoba, Head of the Biology of Breathing Group, and a leader in personalized medicine and lung disease.
While they're all focused on their own specific research, their work frequently intersects. For example, if Halayko is trying to figure out how to regenerate lung tissue, he may seek out the experience of Keijzer, who treats pediatric patients with lung disorders. Or Xing may develop a new form of fibre that can serve as a framework to create living airway tissue in a lab that Keijzer and Halayko can use in their research. "That's the very essence of clustering," says Klassen.
The Manitoba Health Research Council, which already plays an important role in helping to fund new research in Manitoba, sees merit in supporting the clustering concept. As Nickerson explains, efforts are underway to develop core strengths throughout the research community that can be bolstered through additional funding and recruitment. "For us to be successful, for us to compete for federal funding, for grant funding, and investment by industry, we have to be focused. And focus means getting groups of people to cluster together and say, 'We're going to work on a challenge; this is going to be our focus.'"
In addition to the Biology of Breathing group, Nickerson says there are many other examples of clustering going on in Winnipeg's research community. The Cardiac Sciences group at St-Boniface Research, which includes Kirshenbaum, is one example. The HIV research group at the National Microbiology Laboratory, which includes Drs. Frank Plummer and Keith Fowke, is another. "We clearly have strengths, areas where we have well-established groups leading in their area and who are successful at getting grant funding," says Nickerson.
The concept of clustering can also be used to link researchers in different organizations. Take, for example, a project touted by the MHRC that involves people from the University of Winnipeg, Health Sciences Centre and the Winnipeg Health Region. As Dr. James Currie, Dean of Science at the University of Winnipeg, explains, scientists in the university's Physics Department are working with staff from HSC and the Region on a new method of producing medical isotopes that doesn't require a nuclear reactor.
"We are creating medical isotopes using a linear accelerator," Currie says. Someday, their work may lead to a replacement for the isotopes produced at Chalk River, the aging nuclear reactor in Ontario. This new method will produce little waste - unlike a nuclear reactor. Currie calls it a "green way" of producing the isotopes necessary for medical imaging used in mapping cancerous tumours and other disease. Demand for isotopes is high all over the world, so it's likely that innovation here in Winnipeg will benefit health care everywhere.
The U of W is also home to several other MHRC-supported researchers, including those working in the field of environmental science. "Dr. Charles Wong is a Canada Research Chair in Environmental Toxicology," Currie says, adding that Wong has recently received an MHRC establishment grant. He is studying the persistence and fate of man-made chemicals on the environment - a subject obviously critical to human health." Normally, when people think of the MHRC, they might think of medical school," Currie says. "But here's a chemist who is also in the Department of Environmental Studies and Sciences."
The idea of clustering is not limited to the hard sciences. As Nickerson points out, community health research has become an increasingly important component of health research overall. "There are researchers who are looking at how social environments affect health," he says. "How do they put people at risk for disease? If you can prevent those situations, then you can prevent diseases from occurring in the first place."
He points to the example of the Diabetes Research Envisioned and Accomplished in Manitoba (DREAM). This group of researchers, scientists and medical doctors is working with community outreach workers and others to tackle the growing problem of Type 2 diabetes among young people, mostly in northeastern Manitoba. In addition to the lab work that will help identify biomarkers that may signal the early warning signs of Type 2 diabetes, other members of the team are looking at how other factors, such as physical activity, sleep, diet and stress may affect a child's health. "Why is health care so expensive? Because we are reacting all the time to the diseases we are presented with as opposed to investing in prevention. Those investigations are looking at how to help people avoid (developing disease) in the first place," says Nickerson.
Beyond Winnipeg, MHRC is also supporting health-care research focused on rural areas. "Historically, most of the funding that has been provided by MHRC is for researchers based in Winnipeg, primarily for the University of Manitoba," says Dr. Dean Care, acting Vice-President, Academic Provost at Brandon University. But in the last few years, researchers at Brandon University's Faculty of Health Studies have received MHRC funding, which is then used to leverage more funding from the national fund providers, such as the Canadian Institutes for Health Research.
Care is a member of the research team that has received funding from MHRC. The team is studying the health of rural post-secondary students at Brandon University and the University of Saskatchewan campus in Prince Albert. The goal is to identify ways to help students avoid developing unhealthy behaviours. Like the saying goes, an ounce of prevention is worth a pound of cure.
The student health study is just the beginning. "The 'M' in MHRC stands for Manitoba, but it has been seen as the Winnipeg Health Research Council," Care says. "Today, this funding support means there is more than just lip service being paid to rural areas, and we see ourselves as part of the future of health-care research. That's very encouraging."