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What’s Inside Basic research: the foundation for medicine DNA damage Curiosity Cell sorting Sorting Lipids Domains Bacteria Infection Crucial work T cells The good and bad Clinical uses Sidebar: The mechanics of osteoporosis Research Views Responding to the reader Fatigue and illness Adolescent nutrition and lifestyle Learning to walk...again At the Forefront Researchers in the making Heritage Youth Researcher Summer (HYRS) Program 2006 Reader Resources Basic research: the foundation for medicine The pages of this magazine regularly feature stories on research related to cells, molecules, proteins, lipids, and genes—things not only invisible to the naked eye, but also, for many of us, difficult to grasp as concepts. “What does this work have to do with my health?” a reader may ask. “How will this research translate to better treatments for cancer, Alzheimer’s, heart disease, or the many other serious illnesses that take a toll on our lives?” This type of work is called basic research. It is the study of a research question or area which may have no immediate clinical application—the pursuit of knowledge for the sake of knowledge. Yet basic research has proven essential time and again, resulting in vital medical advances. Penicillin, for example, was discovered by a scientist who noticed that a mould had dissolved the bacteria growing in a petri dish. Some 15 years later, that mould had been isolated and was being used clinically to treat infections. Such a delay between breakthrough and clinical use is a feature of basic research, Heritage Scientist Dr. Susan Lees-Miller explains. “I don’t think people realize how long science takes. We’re talking 5 to 10 years before finding out that something might have therapeutic potential, and then another 5 to 10 years to actually find out if it will be useful in the clinic. And the answer may turn out to be no. But along the way, we’ve generated all of this other information. You never know if what you’re working on will turn into something useful. That’s why funding basic, curiosity-driven research is so important: It is the foundation from which all of the more clinical and translational projects derive.” DNA damage After nearly 15 years of work at the University of Calgary, Dr. Lees-Miller has contributed substantially to this groundwork. She studies how cells detect DNA damage caused by radiation and how they respond to it. This area is clinically relevant, because at least half of all cancer patients receive radiation therapy. And, while radiation has been used to treat people for many years, it is only in the past 10 years or so that we have gained an understanding of how radiation-induced DNA damage is detected and repaired in these cells. Dr. Lees-Miller draws an analogy here: “If your car breaks down, there is no point in changing the tire if the thing has run out of gas. If you want to manipulate this process to kill cancer cells more effectively, you have to know how it works.” The application of radiation in cancer treatments involves a gene known as ataxia-telangiectasia mutated (ATM)—a major player in detecting and repairing DNA damage. It turns out that ATM is deleted or mutated in 20% to 50% of mantle cell lymphoma cases (a fairly common non-Hodgkin’s cancer that mainly affects men in their 60s). That information may allow researchers to predict how the cancer cells will respond to radiation. If ATM is not present to mend the radiation damage, therapy could be designed to target the backup repair pathways, and lower doses of radiation might be sufficient to destroy the cancer cells. Curiosity “What drives basic scientists is this curiosity—how does the cell function, how does it carry out all these complex roles?” says Dr. Lees-Miller. “Although I’m certainly a basic scientist at heart, my field has matured enough so that we’re ready to start asking more clinical and translational questions.” She points to mantle cell lymphoma to illustrate her point. “Before we knew that ATM was deleted in this lymphoma, and before we knew ATM’s function, there was no way we could come up with ideas on how to target those pathways. But with 10 to 15 years of basic science telling us how that protein functions, we can start to kill cancer cells more efficiently by targeting different pathways, instead of treating all cancers one way. You can’t make those kinds of hypotheses or do those kinds of experiments unless you have the basic research behind you.” Cell sorting University of Alberta Heritage Scientist Dr. Paul Melançon agrees. “We never quite know where the next penicillin or the next dramatic improvement in health will come from,” he says. “But I don’t think about this every day. Like most scientists, I want my work to be relevant to human health, but that is not what drives day-to-day experiments. I want to figure out how things work. I am fascinated by the complexity of the cell. How is it possible that all of these molecules sort themselves out to yield the intricate organization we observe under the microscope?” Dr. Melançon focuses his studies on the Golgi complex, one of the so-called organelles (compartments) of the cell. He explains that this organelle plays a key processing-and-sorting role in the cell, acting like its central post office. A lot of material goes in, becomes modified, and comes out bound for different destinations. Sorting Dr. Melançon investigates the physical means by which the Golgi complex accomplishes this function. Sorting is performed by special proteins that re-order content, as well as produce the small carriers that ferry cargo between places in the cell. The particular protein he studies ensures that the material goes to the Golgi complex and is sorted away from the other material. “This is a key step,” he emphasizes. “There is a significant number of human diseases, many of them genetically inherited, whose molecular basis originates at this sorting step. Recent studies revealed that even Alzheimer’s disease involves processing enzymes that are sorted at this step. It may well be that as we better understand the regulation of this quality control, we will be able to collaborate on better treatments of Alzheimer’s and other disease.” Lipids AHFMR Scholar Dr. Elmar Prenner shares this fascination with the intricate workings of the cell membrane and its many functions. His research in the University of Calgary’s Faculty of Science focuses on the role of lipids in biological membranes. Lipids are water-insoluble fatty substances that provide a structural framework for the cell, forming a stable barrier by shutting out water. Dr. Prenner points out that, while a lot of current research focuses on various cellular proteins, the biological role of lipids is much less understood. “Lipids exist in various ratios, depending on cell type or cell substructures,” he states, “and these ratios may have a role.” He explains that the two major components of mammalian cells (phosphatidylcholine and sphingomyelin) combine with cholesterol to form lipoproteins. Different lipoprotein subclasses transport cholesterol in the body and vary significantly in their lipid ratios. Dr. Prenner’s laboratory investigates whether these ratios play a role in how the lipids and proteins interact to form lipoproteins. Domains In addition, some lipids form distinct “islands” called domains, or even more complex structures called lipid rafts which involve proteins. “Lipid rafts play a role in signalling but also provide docking points for pathogens from outside the cell,” he says. Recently Dr. Prenner’s group managed to image very distinct domains of membrane proteins on their own. Some of Dr. Prenner’s other recent work has involved a class of lipids called ceramides that act as intracellular signals but also form membrane domains. Ceramide content is increased in Alzheimer’s disease and has been shown to promote the progression of the disease. However, the binding of a protein called apo E to ceramide domains helps prevent atherosclerosis (hardening of the arteries). Dr. Prenner points out that his research, while very basic in nature, may contribute to a better understanding of the role of lipids in diseases such as atherosclerosis or Alzheimer’s. Bacteria Instead of the internal complexities of the cell itself, AHFMR Scholar Dr. Tracy Raivio at the University of Alberta focuses on external threats to the cell: bacteria. Bacteria are everywhere; and because they can live in very different environments (E. coli, for example, can live not only in our gut but also in food and water), they have to be able to change their physiology to adapt. Gene expression (the process by which a gene is switched on) changes each time a bacterium moves to a different environment. “What we want to know is, how does the bacterium know it’s in a different environment, and how does it transduce that into a change in gene expression?” To address these questions, Dr. Raivio looks at one particular pathogen called enteropathogenic E. coli. She explains that this form of E. coli is not a big health threat in North America; it mainly infects infants in developing countries. However, the pathogen uses infection mechanisms that mimic those in the other types of E. coli and such other disease-causing organisms as Salmonella, Shigella, and Yersinia. Infection When they infect a host cell, these bacterial pathogens produce a set of proteins called virulence factors, which allow them to cause the symptoms of infection. Almost all of these virulence factors are found in the envelope (the outermost compartment) of the bacterium or are secreted across the envelope. Dr. Raivio focuses on envelope stress responses, bacterial signal pathways that recognize changes in the bacterial envelope. Some changes causing proteins to misfold in the envelope activate something called the CPX pathway. “One of our theories is that the CPX stress response might be involved in sensing when these virulence determinants are expressed, and in helping to fold them and make sure they’re functional,” says Dr. Raivio. She hopes that, based on this work, a new antimicrobial drug targeting this pathway could some day be developed to treat these pathogens. Crucial work While that kind of application for such basic research may be very far away, Dr. Raivio gives a very good example of how seemingly obscure research can uncover information crucial to human health. During her post-doctoral work at Princeton, Dr. Raivio worked down the hall from a scientist named Dr. Bonnie Bassler, who studied particular marine bacteria that live in squid. When the bacteria reach a certain density they give off light—a symbiotic relationship that helps the squid hide its shadow as it hunts on moonlit nights. With no obvious human application to the work in sight, Dr. Bassler identified the mechanism the bacteria use to sense their own numbers so they can regulate the amount of light emitted according to bacterial cell density. It turns out that this number-sensing mechanism is found in many pathogens, enabling them to sense when their numbers are great enough to overpower a host. It was a landmark discovery that provided information crucial to finding new ways to help fight deadly bacteria. “Basic research is very important and is often in danger of being neglected,” summarizes Dr. Raivio. “There is always a push to fund things for which the human application is really obvious. And that’s understandable because the money comes ultimately from the public. But you never know from where the next flash of insight to help make our lives better will come. I don’t think we are smart enough to know exactly which area of science we need to study to do the things we want to do for humanity, so it is really important to fund basic research in a lot of different areas. Often an application for human health will spring from something that nobody would have seen coming.” T cells AHFMR Scientist Dr. Chris Bleackley elaborates with another example. “Just about every drug currently out there has been developed on the basis of basic research,” he points out, explaining that many of the newer therapies have been created through genetic engineering. This allows researchers to design and make novel proteins as potential drugs and is based on something called restriction enzymes. These enzymes were discovered over 30 years ago by scientists doing basic research in bacteria. “This was something which, on the face of it, had no clinical relevance whatsoever, [but which] is now used extensively,” says Dr. Bleackley. Recent examples include Herceptin for treatment of breast cancer, Enbrel for arthritis, and human insulin for diabetes. Dr. Bleackley’s own groundbreaking work also has the potential for many applications. His research focuses on cells called cytotoxic lymphocytes, also known as killer T cells. Millions of these T cells circulate in an inactive state in our bodies. During an immune response stimulated by a virus, for example, T cells reproduce until there are billions of them; they destroy the virus-infected cell, and then they start dying themselves until a baseline level of inactive cells is reached, and the immune system goes back to a resting stage. The good and bad T cells protect us from viruses and bacteria, and they are involved in the destruction of cancer tumour cells. That’s their good side. The bad side is that T cells can react against the healthy cells of the body, leading to autoimmune diseases such as diabetes and rheumatoid arthritis. Dr. Bleackley wants to understand how these cytotoxic T cells work at the molecular level in order to influence the activity of the cells. In other words, if someone’s immune system is not functioning well enough to destroy a tumour cell, the cytotoxic T cells could be stimulated to help. Or the T cells could be deliberately suppressed to prevent rejection in a patient who has received an organ transplant. “The basic hypothesis is that if you can understand these cells, you can influence their activity either up or down for therapeutic value,” he says. Dr. Bleackley has already contributed a great deal to our understanding of how the T cells work. In 1986, he discovered that killer T cells express a family of molecules called granzymes when activated. When the killer cells interact with a tumour or a virus-infected cell, the granzymes are transferred into the tumour cell and flick a molecular switch causing the tumour cell to die by a process known as programmed cell death (apoptosis). “We’re starting to now get into why some tumours do not die when the switch is flicked,” he says. “It turns out they are able to express molecules that can block this cell death.” Clinical uses Dr. Bleackley collaborates with a number of colleagues to pursue the many potential clinical uses for his work. Working with Dr. Phil Halloran at the University of Alberta, Dr. Bleackley looks at using molecular tools to study kidney-transplant rejection. He also works with a geriatrician at the University of British Columbia to study influenza in elderly patients who don’t respond as well as they should to vaccines. And with Edmonton Protocol pioneer Dr. Ray Rajotte, he investigates molecules that could be mobilized to suppress rejection of islet transplants in diabetes treatment. “I have a great interest in seeing the molecular tools we’ve developed used in clinically relevant situations,” says Dr. Bleackley. But these clinical uses may still take many years. “The human body is incredibly complicated, and it can take a long, long time to understand it at the molecular level,” explains Dr. Bleackley. In the first place, the science discovery stage may take a long time. Then a compound developed from this discovery must go through a series of clinical trials that also take a long time. But the results may change lives. “Many people have been cured of many different things through the benefits of basic research,” emphasizes Dr. Bleackley. “It is fundamentally important for the future of human health.” Dr. Susan Lees-Miller is an AHFMR Scientist and a full professor in the Department of Biochemistry and Molecular Biology in the University of Calgary Faculty of Medicine. In addition to Heritage support, she receives funding from the Canadian Institutes of Health Research (CIHR), the Alberta Cancer Board, and the National Cancer Institute of Canada (NCIC). Dr. Paul Melançon is an AHFMR Scientist and a full professor in the Department of Cell Biology in the University of Alberta Faculty of Medicine and Dentistry. His research is supported by CIHR and the Human Frontier Science Program. Dr. Elmar Prenner is an AHFMR Scholar and an assistant professor in the Department of Biological Sciences in the Faculty of Science at the University of Calgary. His research is supported by the Natural Sciences and Engineering Research Council of Canada (NSERC). Dr. Tracy Raivio is an AHFMR Scholar and associate professor in the Department of Biological Sciences in the University of Alberta Faculty of Science. In addition to AHFMR support, she receives funding from CIHR and NSERC. Dr. Chris Bleackley is an AHFMR Scientist and full professor in the Department of Biochemistry at the University of Alberta. He is a Canada Research Chair in Molecular Biology and an International Research Scholar of the Howard Hughes Medical Institute. His research is also supported by CIHR and NCIC. Selected publications Goodarzi AA, Jonnalagadda JC, Douglas P, Young D, Ye R, Moorhead GBG, Lees-Miller SP, Khanna KK. Autophosphorylation of ataxia- telangiectasia mutated is regulated by protein phosphatase 2A. EMBO Journal 2004 Nov 10;23(22):4451-4461. Dunphy JL, Moravec R, Ly K. Lasell TK, Melançon P, Casanova JE. The Arf6 GEF GEP100/BRAG2 regulates cell adhesion by controlling endocytosis of beta1 integrins. Current Biology 2006 Feb 7;16(3):315-320. Raivio TL. Envelope stress responses and Gram-negative bacterial pathogenesis. Molecular Microbiology 2005 Jun;56(5):1119–1128. Veugelers K, Motyka B, Frantz C, Shostak I, Sawchuk T, Bleackley RC. The granzyme B-serglycin complex from cytotoxic granules requires dynamin for endocytosis. Blood 2004 May 15;103(10):3845-3853. Sidebar The mechanics of osteoporosis Basic science is not just cellular-level research. Ask Heritage Scholar and mechanical engineer Dr. Steven Boyd. The University of Calgary researcher studies bone architecture to determine the causes of bone loss in diseases such as osteoporosis. Dr. Boyd uses micro-CT (computer tomography) to obtain images of the bones of mice and rats. By means of x-ray technology, his scanner captures high-resolution images which are then processed by computer to create very accurate three-dimensional pictures of the bone. Dr. Boyd studies the effects of exercise and various drugs on the progression of osteoporosis; the scanner allows him to see exactly which part of the bone is thinning. He also examines the influence of different genetic traits on bone. “The tools that we develop for basic research with animals translate directly for use on humans,” he says. Translation In fact, Dr. Boyd is doing the translating. He also examines the structure and mechanics of human bones using another micro-CT scanner at the University of Calgary Faculty of Kinesiology. This machine is the only one in Canada (and one of only four in North America) used to scan humans. “It’s very exciting because, for the first time, this machine allows us to measure 3-D bone architecture in people,” says Dr. Boyd. The bone architecture that concerns him most is that of the wrist. “The bottom line in osteoporosis is fracture,” says Dr. Boyd. A fracture of the wrist is usually an early warning sign of the disease and can forecast increased risk for future hip and spine fractures. “So we want to know what changes happen to the wrist, and how these relate to fracture.” While Dr. Boyd’s second micro-CT is a research scanner that likely won’t be found in clinical use soon, he is quick to emphasize the relevance of his work to human health. “Basic research is important because it allows us to explore effects of osteoporosis treatments in detail before they’re ready for the clinic.” AHFMR Scholar Dr. Steven Boyd is an assistant professor in the Department of Mechanical and Manufacturing Engineering at the Schulich School of Engineering, with a joint appointment in the Faculty of Kinesiology at the University of Calgary. His research is also supported by CIHR, NSERC (Natural Sciences and Engineering Research Council of Canada), and the Canada Foundation for Innovation. Selected publication Boyd SK, Davison P, Müller R, Gasser JA. Monitoring individual morphological changes over time in ovariectomized rats by in vivo micro-computed tomography. Bone. Prepublished online 2006 June 6; doi: 10.10.16/j.bone-2006-04-017. Back to Top