Drawing breath You probably know kids like these: Ashley is the one left behind in the mad rush down the street to catch the ice-cream vendor. She ends up sitting on the curb trying to catch her breath. Michael is the one who caught the same cold everyone else had, but he was off school for more than a week. You heard later that he had even been rushed to the hospital These are the kind of children who inspire Edmonton pediatrician Dr. Darryl Adamko. “Kids are suffering from asthma. As a doctor, it’s hard to see this, day after day. I started to wonder why common viruses—the kind that give most people a simple cold—can make asthmatics so sick.” Eosinophils This is the question Dr. Adamko explores as a Heritage Clinical Investigator. He suspects that a type of white blood cell called an eosinophil is at the heart of the problem. Eosinophils release certain proteins that kill the cells lining the airways and cause inflammation. But eosinophils are not all bad. Dr. Adamko has shown that a certain protein released by eosinophils can kill some viruses. “In asthma, the problem is that there are so many eosinophils, they are in the wrong places, and they are releasing so many different proteins. As a result, they’re doing more harm than good.” Dr. Adamko’s particular research focus is to discover just how eosinophils are activated to release proteins. He has shown that eosinophils release proteins in response to viral infection only in the presence of T cells, which are white blood cells critical to the immune response. This suggests there is some kind of signalling mechanism between T cells and eosinophils. Understanding this pathway could lead to a new target for asthma drugs. “Right now I’m not after targets. I’m trying to understand how things work,” says Dr. Adamko. “That’s what I like about research. You have an idea, you test it out, see if you’re right. The ideas build on each other.” The U of A Dr. Adamko notes that the University of Alberta is one of the best places in the world to work on eosinophils. His office is across the hall from that of Heritage Scientist Dr. Redwan Moqbel, an international authority on the immunobiology of eosinophils and their role in airway damage in asthma. Dr. Moqbel conducts basic research on the proteins released by eosinophils, as well as applied research on ways to block their release. For example, he recently began a new research program into how an eosinophil-derived enzyme may be involved in switching the immune system’s “normal” pattern of fighting infection to the allergic pattern of response in asthmatics. Dr. Moqbel is convinced that this switch, a key immunological event, could be diverted back to the appropriate immunological response. “We’re benefiting from and are a part of a worldwide research effort on asthma,” Dr. Moqbel says. “So much more is known than when I began 27 years ago. This is a very exciting time in eosinophil and asthma research.” In another new project, Dr. Moqbel is using nuclear magnetic resonance (NMR) to detect eosinophil “fingerprints” in asthma. Because NMR can identify tiny amounts of certain markers of inflammation in human fluids such as saliva, it may be possible to distinguish among different types of asthma and thus offer treatment that is customized to the patient. To further this research, Dr. Moqbel and his collaborators at the Canadian National High Field NMR Centre and the University of Alberta Hospital are in the process of establishing the Pulmonary Health Institute at the University of Alberta. “There’s great potential for the development of individualized, precise diagnosis and therapies for asthma and airway inflammation,” says Dr. Moqbel. “Our objective is to treat the patient rather than the umbrella disease because asthma is a complex of varied syndromes.” He expects this non-invasive NMR technique to have applications beyond asthma to chronic obstructive pulmonary disease (COPD) and pneumonia. New partnerships That’s important because these are some of the major respiratory diseases the world is facing, says Dr. Dean Befus, the AstraZeneca Canada Inc. Chair in Asthma Research at the University of Alberta. “Lung diseases account for a lot of the suffering in this world, and yet many of them do not have a high profile.” Dr. Befus notes that in Alberta alone, about 200,000 people have asthma. By 2020, it’s expected that COPD will be the number-three cause of death in the world. Tuberculosis still kills 3 to 5 million people a year. Lung cancer continues to have one of the poorest survival rates of all cancers. Cystic fibrosis is the most common fatal genetic disease. Infectious diseases of the lungs, such as community-acquired pneumonia, are on the rise. And new diseases are emerging, such as SARS and strains of avian influenza that can infect humans. Concerns about the increasing toll of respiratory disease on society have led to new partnerships among researchers and healthcare professionals. Dr. Befus is a good example. One of Canada’s foremost asthma researchers (his work focuses on the basic mechanisms of allergic inflammation), Dr. Befus is also the director of the Alberta Asthma Centre. Established in 1993, the Centre is dedicated to asthma-related health promotion. Recognizing the need for even greater collaboration and interaction, Dr. Befus was recently involved in establishing the COPD and Asthma Network of Alberta (CANA), a province-wide respiratory disease network of healthcare professionals, industry, government, and public representatives. “The responsibilities for COPD and asthma have been quite fragmented,” explains Dr. Befus. “Now there’s a groundswell of interest in sharing resources and strengthening networks. By working together, we can facilitate the flow of patients through the healthcare system, give consistent messages to patients, and champion causes in an organized manner. This isn’t basic research, but it is a critical part of the overall effort to find better ways to help people with respiratory diseases.” Collaboration Collaboration is also vital to the work of Heritage Senior Scholar Dr. Gregory Funk, a basic scientist who studies the neural control of breathing during the perinatal period (i.e., just before and after birth). He came to the University of Alberta from New Zealand in 2003. Dr. Funk was attracted by the opportunity to work with a group of basic and clinical respiratory researchers in Alberta, including Heritage Scientists Dr. Klaus Ballanyi and Dr. John Greer, and Heritage Clinical Investigator Dr. Bernard Thébaud—all from the University of Alberta and all members of the Perinatal Research Centre—and Heritage Scholars Dr. Richard Wilson and Dr. Marc Poulin at the University of Calgary. “Being able to join a dynamic group such as this is an incredible and rare opportunity,” says Dr. Funk. “AHFMR funding has enabled us to come together in Alberta. Real support for generating such an interactive environment is extraordinary. Researchers often lament their lack of local collaborators. I’m spoiled for choice.” Dr. Funk’s interest lies in establishing how the respiratory rhythm is generated by regions in the brainstem, as well as how that rhythm is transformed into proper breathing by motor neurons that drive the muscles. If the rhythm-generating system becomes unstable, it can actually stop for variable periods (central apnea). If the activity of muscles that keep the airway open and pump muscles—such as the diaphragm—is unbalanced, negative pressure can actually block the airway (obstructive apnea). Neurochemical signals are crucial to keeping the breathing systems in proper balance. This balance is particularly fragile during the perinatal period, when all systems are changing dramatically. Dr. Funk wants to understand what these chemicals are, what they are doing, and how they interact with other neurochemicals to control breathing. Control of breathing One of Dr. Funk’s collaborators is Heritage Scholar Dr. Richard Wilson, a physiology professor at the University of Calgary. Dr. Wilson also studies the neuronal control of breathing, examining fundamental mechanisms as well as doing more applied research. In 2003, Dr. Wilson’s team discovered an important role of the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) in the regulation of breathing. They investigated why mice lacking this peptide are more likely to die suddenly about two weeks after birth. This phenomenon is strikingly similar to sudden infant death syndrome (SIDS)—the sudden and unexpected death of an apparently healthy human infant, whose death remains unexplained even after a complete investigation. SIDS peaks in infants 2 to 4 months old, and is rare before 1 month and after 12 months of age. In addition to his basic research on the physiological effects of PACAP, Dr. Wilson is also collaborating with Dr. Torben Bech-Hansen at the University of Calgary to examine whether defects in the gene that codes for PACAP are present in the DNA of babies who have died of SIDS. “This is expensive, time-consuming research because PACAP works in a complicated pathway, and we don’t know exactly where in this pathway defects might be,” says Dr. Wilson. “There’s certainly no guarantee of success, but this is where our basic research is pointing, and we would be negligent not to explore this avenue. SIDS education programs, promoting such recommendations as putting babies to sleep on their backs and reducing their exposure to cigarette smoke, have reduced the SIDS death rate by 50% and continue to be our most valuable weapon against SIDS. However, research is the key to eliminating SIDS.” Enthusiasm for research is the hallmark of the Alberta scientists who are studying the respiratory system. They take nothing for granted. “Breathing is one of our most robust behaviours—it continues even in very sick humans and animals,” says Dr. Wilson. “Breathing is quintessential to human health and well-being, yet we still don’t know much about its fundamental mechanisms. That’s what makes research in this area so fascinating. There’s always something new to learn.” Credentials and publications Heritage Clinical Investigator Dr. Darryl Adamko is an assistant professor in the departments of Pediatrics and Medicine (Division of Pulmonary Medicine) at the University of Alberta. His research is also supported by the Hospital for Sick Children Foundation. Heritage Scientist Dr. Redwan Moqbel is director of the University of Alberta’s Pulmonary Research Group and a full professor in the departments of Medicine and Medical Microbiology and Immunology. He is the current president of the International Eosinophil Society. His research is also supported by the Canadian Institutes of Health Research (CIHR), the Alberta Lung Association, Merck Frosst Canada Ltd., the University of Alberta Hospital Foundation, and the Endodontic Endowment Fund of the Department of Dentistry at the University of Alberta. Dr. Dean Befus is the AstraZeneca Canada Inc. Chair in Asthma Research and a full professor in the Department of Medicine at the University of Alberta. He is also director of the Alberta Asthma Centre. His research is supported by CIHR, the National Institutes of Health (NIH) in the United States, and the Alberta Lung Association. Heritage Senior Scholar Dr. Gregory Funk is an associate professor in the Department of Physiology at the University of Alberta, a member of the Perinatal Research Centre, and adjunct associate professor in the Department of Physiology at the University of Auckland, New Zealand. His research is also supported by CIHR, the Canada Foundation for Innovation (CFI), the Alberta Science and Research Authority (ASRA), the Health Research Council of New Zealand, and the Marsden Fund. Heritage Scholar Dr. Richard Wilson is an assistant professor in the Department of Physiology and Biophysics at the University of Calgary. His research is also supported by the Calgary Health Region, the Heart and Stroke Foundation, CIHR, and NSERC (Natural Sciences and Engineering Research Council of Canada). Selected publications Adamko DJ, Fryer AD, Bochner BS, Jacoby DB. CD8+ T lymphocytes in viral hyperreactivity and M2 muscarinic receptor dysfunction. American Journal of Respiratory and Critical Care Medicine 2003 Feb 15;167(4):550-556. Logan MR, Odemuyiwa SO, Moqbel R. Understanding exocytosis in immune and inflammatory cells: the molecular basis of mediator secretion. Journal of Allergy and Clinical Immunology 2003 May;111(5):923-932. Gilchrist M, Hesslinger C, Befus AD. Tetrahydrobiopterin, a critical factor in the production and role of nitric oxide in mast cells. Journal of Biological Chemistry 2003 Dec 12;278(50):50607-50614. Parkis MA, Feldman JL, Robinson DM, Funk GD. Oscillations in endogenous inputs to neurons affect excitability and signal processing. Journal of Neuroscience 2003 Sep 3;23(22):8152-8158. Cummings KJ, Pendlebury JD, Sherwood NM, Wilson RJA. Sudden neonatal death in PACAP-deficient mice is associated with reduced respiratory chemoresponse and susceptibility to apnoea. Journal of Physiology 2004 Feb;555(1):15-26.