Recent Discoveries and Research Initiatives at McGill

Drug Resistance Complicates River Blindness Fight

New findings by a McGill researcher may mean that a hard-fought 20-year battle with onchocerciasis, commonly known as river blindness, is about to get even tougher.

The study was led by Roger Prichard, James McGill Professor at the University's Institute of Parasitology, and shows a disturbing population boom among the parasitic worms that cause the disease in certain West African communities, in spite of traditional treatments. Ivermectin is the only widely available drug used to treat river blindness; an ivermectin-resistant parasite could spell disaster for people living in affected areas.

"We've found the first evidence of some resistance," reports Prichard, "where the adult parasites continue to reproduce and transmit the disease, and in some communities it seems to be getting worse."

The study, published in Lancet, followed 2,501 infected people in 20 communities around Ghana. Two McGill graduate students, Mike Y. Osei-Atweneboana and Jeff K. L. Eng, conducted the bulk of the research in partnership with local health authorities.

"This finding has important implications for this disease re-emerging and becoming a serious scourge," Prichard says. He warns that, if left unchecked, resistant parasites could wreak havoc in areas where widespread treatment had previously brought river blindness under control.

The disease is caused by blackflies commonly found in highly oxygenated, swift-moving water. In addition to irreversible blindness, it also causes itching so severe that excessive scratching often results in depigmentation and blotchy, leopard-like patterns on the skin.

The World Health Organization estimates that 99 per cent of the world's 18 million infected people are in Africa, with the remainder in Latin America and Yemen. Even when effective, ivermectin merely halts the progress of the disease without killing the adult parasites, and there is no vaccine. After trachoma, river blindness is the world's second leading infectious cause of blindness.

This research is funded by the UNICEF-UNDP-World Bank-World Health Organization Special Programme for Research and Training in Tropical Diseases, the Onchocerciasis Control Program, the African Program for Onchocerciasis Control, the Government of Ghana, the Canadian Institutes of Health Research and the Fonds québécois de la recherche sur la nature et les technologies.

Golden Lock

Margaret Lock, the Marjorie Bronfman Professor Emerita in Social Studies in Medicine, is the 2007 recipient of the Social Sciences and Humanities Research Council of Canada (SSHRC) Gold Medal for Achievement in Research. The Council's top award, representing $100,000 in research funding, recognizes her 30-year commitment to studying the relationships among culture, emerging bioscientific technology and the body. Lock has helped shape medical ethics policy and medical student education, with her work exploring the social implications of biomedical technologies such as organ transplants, reproductive technology and genetic testing. Her current research focuses on the social repercussions of advances in genetics, particularly in relation to Alzheimer's disease.

Protein Production Implicated in Host of Diseases

McGill researchers have uncovered the long-sought-after mechanism that controls the synthesis of the Bicaudal-C protein in fruit flies. Bicaudal-C is one of the estimated 77 per cent of genes implicated in human disease that have obvious counterparts in fruit flies, making this discovery an important step toward solving the mysteries of polycystic kidney disease, cancer and mental retardation in humans.

Paul Lasko, chair of McGill's Department of Biology, led a team of researchers from McGill and France's Centre national de la recherche scientifique. They discovered that Bicaudal-C controls how much protein particular messenger ribonucleic acid (messenger RNA) molecules can synthesize, thereby affecting embryo development in fruit flies. Insufficient Bicaudal-C in mother flies produces embryos with two posteriors and no anterior, while overexpression of Bicaudal-C produces embryos with no posterior. In mammals, the counterpart protein has been linked to polycystic kidney disease; in frogs, the same protein is required for embryonic kidney development.

Thus far, there have been no studies of the human counterpart of the Bicaudal-C protein. "We hope our study will guide people working on the human counterpart gene to look for the same type of function," says Lasko, "to find RNAs that are specific to kidney development. This protein is also related quite closely to the protein which leads to Fragile X, the most common mental retardation syndrome."

The team's findings were published in the November issue of the journal Developmental Cell.

This research was funded by the National Cancer Institute of Canada.

Quebec Discoveries of the Year: Controlling Messenger RNA, Breast Cancer Breakthrough

Two McGill research projects earned spots on Québec Science's prestigious Ten Discoveries of the Year list for 2007.

The magazine tipped its cap to McGill scientists who developed a novel system to study the control of genes in a test tube. Nahum Sonenberg, James McGill Professor of Biochemistry, Thomas Duchaîne, assistant professor in biochemistry at the McGill Cancer Centre, and research leaders and postdoctoral fellows Geraldine Mathonnet and Marc Fabian used microRNA (a class of tiny nucleic acids) to control messenger RNA in a test tube. Messenger RNA relays genetic coding information from DNA to a cell's ribosomes, where protein synthesis occurs; microRNA recently emerged as a major regulator of this "translation" process. This study—funded by CIHR, the Fonds de la recherche en santé du Québec and the Human Frontier Science Program—marks the first successful assessment of microRNA control of translation outside the confines of a living cell. Researchers will now be able to study the mechanisms by which they control the flow of genetic information and, therefore, protein expression. "These microRNA control 30 per cent of all genes in a body," says Sonenberg. "They are important to cancer development and progression. If we know how to control microRNA, we can control cancer and other diseases." The team (which includes collaborators at the University of Eastern Piedmont, Case Western Reserve University, Warsaw University and the Friedrich Miescher Institute for Biomedical Research) published their findings in the journal Science in July 2007.

Québec Science kudos also went to Dr. Michel Tremblay, director of the McGill Cancer Centre and the Jeanne and Jean-Louis Lévesque Chair in Cancer Research, for his discovery that 40 per cent of breast cancer cases in women present overexpression of the PTB1b gene. At normal levels, PTB1b's enzyme helps regulate cell growth and cell division, but too much PTB1b causes unchecked cellular growth. Eight years ago, Tremblay linked the gene to obesity and diabetes. Pharmaceutical companies are already doing human trials for PTB1b-suppressing drugs, leaving him optimistic that a breakthrough breast cancer drug may be on the horizon. "Adapting these compounds is all that is needed to attack breast cancer," he explains. Tremblay's research is funded by the Cancer Research Society, CIHR, the Weekend to End Breast Cancer and Rethink Breast Cancer.

Chairs Galore

In September and November 2007, Jim Prentice, the Canadian Minister of Industry announced the appointment of nine McGill University professors to the Canada Research Chairs (CRC) program:

• Tho Le-Ngoc, broadband access communications
• Stéphanie Lehoux, cardiovascular physiology
• Gergely Lukacs, molecular and cellular biology of cystic fibrosis and other conformational diseases
• Salah El Mestikawy, neurobiology
• Audrey Moores, green chemistry
• Vassilios Papadopoulos, biochemical pharmacology
• Thomas Quinn, soft tissue biophysics
• Amir Raz, cognitive neuroscience of attention
• Barbara Sherwin, hormones, brain and cognition

Seven McGill CRCs were renewed:

• Jorge L. Armony, affective neuroscience
• Michel Biron, Québécois and francophone literature
• Derek Bowie, receptor pharmacology
• Sylvain Coulombe, non-thermal plasma processing
• Elaine C. Davis, anatomy and cell biology
• Stephen M. Saideman, international security and ethnic conflict
• Thomas Schlich, history of medicine

The 16 CRCs have a value of $13.4-million. The Canada Foundation for Innovation will also invest over $2-million in infrastructure essential to the work done by the nine new Chairs. The Government of Canada created the CRC program in 2000; the program's goal is to help make Canada one of the world's top five countries for research and development by establishing 2,000 research professorships by 2008.

CIHR Kudos for TB Work

Michael B. Reed, assistant professor in the Faculty of Medicine, received the Peter Lougheed/CIHR New Investigator Award—Canada's Premier Young Researcher at the sixth annual Canadian Health Research Awards. CIHR, Canada's major federal agency responsible for funding health research, held the ceremony on November 20, 2007, in Ottawa. The award, given to a researcher at the beginning of his or her career, recognizes Reed's outstanding research on strain variation within the tuberculosis bacterium. Reed focuses on the unique attributes of the Beijing strain lineage that help it adapt to diverse environments within the human host; his research could potentially lead to improved treatment and risk identification.

The Royal Seven

Continuing McGill's long history of research excellence, seven of the University's researchers were recently feted by the Royal Society of Canada.

On November 17, 2007, the RSC presented two McGill faculty members with some of the most prestigious honours in their fields. In recognition of her cutting-edge work on neutron stars, pulsars and supernova remnants, Victoria Kaspi received the Rutherford Memorial Medal in Physics, which is awarded for outstanding research in any branch of physics. Kaspi is McGill's Lorne Trottier Chair in Astrophysics and Cosmology and Canada Research Chair in Observational Astrophysics. She and her team discovered more than 20 pulsars in a single Milky Way cluster, as well as the fastest-rotating pulsar known to science. Roderick Macdonald, the F.R. Scott Professor of Constitutional and Public Law at McGill, has been awarded the RSC's Sir John William Dawson Medal for his contribution to interdisciplinary research. Macdonald is generally regarded as one of Canada's most influential public intellectuals, and was among the first to explore law through disciplines as varied as philosophy, anthropology, literary theory, semiotics and history.

As well, five McGill researchers have been invited to join the RSC's ranks. The new fellows are:

• Hong Guo, professor in the physics department who achieved renown for his contributions in the theoretical and computational modeling of quantum transport in nanoelectronic systems;
• Michael J. Meaney, associate director of research at the Douglas Hospital Research Centre and one of the first researchers to identify the importance of maternal care in modifying the expression of the genes that regulate behavioural and neuroendocrine responses to stress;
• Morag Park, the James McGill Professor of Oncology and an international leader in understanding the mechanisms underlying the activation of human cancer;
• A. Patrick S. Selvadurai, William Scott Professor and James McGill Professor, who has profoundly influenced engineering modeling activities in nuclear waste management, soil-structure interaction and northern and environmental geomechanics; and
• Isztar I. Zawadzki, director of the radar observatory in the Department of Atmospheric and Oceanic Sciences and a major contributor to radar meteorology.

Acfas Honours

Four McGill researchers took home awards from the Association francophone pour le savoir's 63rd annual gala, held on October 11, 2007.

Donald L. Smith, James McGill Professor in the Faculty of Agricultural and Environmental Sciences and Chair of the Department of Plant Science, received the Prix Michel-Jurdant for his work in environmental science. Smith is the scientific director of the Green Crop Network, which unites leading Canadian scientists in the quest to develop crops that reduce carbon dioxide and nitrous oxide. Smith's recent work focuses on increasing the sequestration of carbon dioxide from the atmosphere into crop plants, a crucial tool for greenhouse gas management.

Physics professor Victoria Kaspi received the Prix Urgel-Archambault. In 2005, Kaspi and her team discovered the fastest-rotating pulsar known to science; the findings promise to yield important new information about the nature of one of the most mysterious forms of matter in the universe.

Internationally renowned for her work on regulating cerebral circulation, Édith Hamel received the Prix Adrien-Pouliot. Hamel is a neuroscientist at the Montreal Neurological Institute; by understanding the mechanisms of blood flow, she hopes to aid in the development of new drugs to decrease vascular head pain.

The Concours de vulgarisation de la recherche de l'Acfas recognized the work of Marie-Ève Brault. Brault is an anatomy and cell biology doctoral student at the Lady Davis Institute at the Sir Mortimer B. Davis Jewish General Hospital. In January 2008, her paper on the enzyme telomerase as it relates to aging and cancer appeared in the newspaper Le Soleil.

Founded in 1923, Acfas is a Quebec not-for-profit organization dedicated to promoting scientific activity, stimulating research and disseminating knowledge.

Stamping Out Superbugs

McGill researchers are one step closer to fighting bacterial infection—from the inside out.

Joint research between McGill and Oxford University uses population evolution and ecology to interpret the spread of bacteria such as Pseudomonas aeruginosa, dubbed "superbugs" for their tenacity. The team applied the "source-sink" theory to explain how antibiotics and disinfectants are failing in hospitals.

Andrew Gonzalez, Canada Research Chair in Biodiversity and associate professor of biology, explains that certain hospital environments, such as water reservoirs, represent excellent "source" areas for bacteria to thrive. It is the steady supply of bacteria from these source environments that allows them to infect humans. Antibiotics and hygienic practice, however, should make hospitals inhospitable "sinks" for bacteria: More microbes should drain from the "sink" than are replaced from the "source."

Yet superbugs thrive. The secret to their success: Superbugs need not wait for a fortuitous genetic mutation to adapt to hostile forces like antibiotics. "They can double their population very fast because useful DNA can be transferred quickly in a simple organism," says Gonzalez.

Within that transferred material, Albert Berghuis, Canada Research Chair in Structural Biology, and his research team in the Departments of Biochemistry and Microbiology & Immunology have observed how one superbug, Staphylococcus aureus, disarms the antibiotic Synercid using an enzyme that detoxifies quinupristin, one of the antibiotic's component drugs.

"It is only a matter of time before a superbug will be resistant to all antibiotics," warns Berghuis. His team will focus next on developing a compound to replace quinupristin in Synercid, and explore whether a similar modification in other drugs might further slow bacteria resistance.

"There is a small selection of drugs that still work against superbugs, but bacteria are very resourceful," says Berghuis. "What we observed is only one trick they use to develop resistance, but if we keep on winning these battles, I think we can stay ahead."

This research is funded by CIHR and the Canada Research Chairs program.

New Hope for Potential Parents

A new technique may improve the chances for women with cancer or ovarian disease to become mothers. At the 2007 meeting of the European Society of Human Reproduction and Embryology, Drs. Hananel Holzer, Ri-Cheng Chian and Seang Lin Tan from the McGill Reproductive Centre announced the birth of the first baby born from an egg matured and frozen in a test tube.

Twenty patients with polycystic ovarian syndrome (PCOS) underwent the IVF process at the McGill University Health Centre's Royal Victoria Hospital. PCOS is a hormone disorder that affects one in 10 women of childbearing age and is a leading cause of infertility.

Live births from frozen eggs aren't new. The McGill Reproductive Centre announced the first such birth in 2005; an egg which had already matured inside the ovary was removed, then frozen. The ovarian stimulation required for egg maturation, however, carries potentially serious side effects, especially for women with PCOS, making this new technique a significant breakthrough. The process may also be appropriate for patients who wish to preserve their fertility, but don't have time in the menstrual cycle to produce mature eggs before beginning cancer treatment or hormone stimulation is contra-indicated.

This research receives funding from CIHR, NSERC and Ton Yen General Hospital in Taiwan.

Prairie Prize to Epigenetics Explorer

Epigenetics researcher Michael Meaney (left) with former Alberta premier Peter Lougheed. Meaney is the inaugural recipient of the $100,000 AHFMR Lougheed Prize in fetal and early childhood development.
Darren Kemper, courtesy of AHFMR

Anybody who doubts the immense impact that moms can have on our lives need only visit Michael J. Meaney's lab. The associate director of research at the Douglas Institute Research Centre and a James McGill Professor of Medicine in the Departments of Psychiatry and Neurology & Neurosurgery, Meaney's research indicates that a mother's love not only soothes, it can effect changes in her offspring at the molecular level: Rat pups who receive plenty of grooming and other forms of TLC from their mothers tend to produce more receptors that control the production of stress hormones—and are therefore better equipped to deal with stress. These revelatory insights into the world of epigenetics (the study of changing gene function without changing the DNA sequence) was recently recognized by the Alberta Heritage Foundation for Medical Research, which named Meaney the inaugural recipient of the AHFMR Lougheed Prize in fetal and early childhood development.

The prize awards $100,000 to an outstanding biomedical or clinical researcher. The AHFMR will also provide support for a postdoctoral fellow from Alberta to work in Meaney's lab for up to three years. As the Lougheed Prize winner, Meaney will present public lectures in Alberta about his work and meet with scientists in the province who are also involved in child health research. The award is named after former Alberta premier Peter Lougheed, whose government created the AHFMR in 1980 with a $300-million endowment.

For more information about Michael Meaney's research, see "The Nurture of Things" in the Fall 2006 edition of Headway, archived at www.mcgill.ca/headway/fall2006.

New Impressions of Depression

Depression hasn't always been taken very seriously. People used to downplay it—nothing that a stiff upper lip and a carton of Häagen-Dazs couldn't cure—but two recent studies show how this profoundly debilitating and complex condition can influence, and be influenced by, how our bodies function.

According to a recent study co-authored by scientists from McGill and Université de Montréal, patients with coronary artery disease who are also experiencing depression or high levels of anxiety run twice the risk of suffering a repeated heart hospitalization. "On average, cardiac patients without these disorders had about a 13 per cent chance of a repeated cardiac event over two years, compared to 26 per cent of those with either major depression or generalized anxiety disorder," explains principal investigator Nancy Frasure-Smith, a professor with McGill's Department of Psychiatry and a researcher at the Montreal Heart Institute and the Centre Hospitalier de l'Université de Montréal.

The study, published in Archives of General Psychiatry, focused on patients with stable coronary artery disease—not those recently hospitalized for severe conditions such as a heart attack. "This is the first study to demonstrate that anxiety and depression can have a strong impact on people with stable coronary artery disease," notes Frasure-Smith's research collaborator, Université de Montréal psychiatry professor François Lespérance.

The research team interviewed more than 800 patients with stable coronary artery disease who were being monitored by a doctor. "Now that we know that anxiety and major depression are both markers of increased cardiac risk, it is imperative that these patients receive the best treatment for both their cardiac and psychiatric conditions," the study concludes.

In another recent study, also published in Archives of General Psychiatry, researchers at McGill's Montreal Neurological Institute have identified the neurological basis of depression in male athletes who have suffered concussions. In addition to other symptoms (such as attention and memory problems and fatigue), athletes recovering from concussive injuries frequently experience depression. While only about 5 per cent of the general public experiences serious depression, up to 40 per cent of head trauma patients may suffer from symptoms of depression.

"Until now, very little was known about the neurological basis of the depression frequently reported by athletes following concussion," says MNI neuropsychologist Alain Ptito, the lead investigator for the study. Ptito's team used functional MRI (fMRI), a computerized imaging technique that measures blood oxygen levels, to examine 56 male athletes, 40 of whom had concussions, and 16 who were concussion-free. Concussed athletes with depression presented with the same pattern of brain activation as that seen for patients with major depression, specifically in the dorsolateral prefrontal cortex and striatum and attenuated deactivation in medial frontal and temporal regions consistent with a limbic-frontal model of depression. The researchers suggest that symptoms of depression following head trauma may share the same underlying neural mechanism as major depression. Ptito believes this finding indicates a close link between the concussion-inflicted brain damage and post-concussion depression and has important implications for pharmacological and/or psychological treatments.

Frasure-Smith's research is supported by CIHR, GlaxoSmithKline, the Charles A. Dana Foundation, the Foundation of the Montreal Heart Institute, the Pierre David Fund and the Fondation du Centre Hospitalier de l'Université de Montréal. Ptito's study is funded by CIHR and the Fonds de la recherche en santé du Québec.

Diabetes and Cellular Sloth

A new study, led by Ciriaco A. Piccirillo of McGill's Department of Microbiology and Immunology and Centre for the Study of Host Resistance (McGill University Health Centre), proves a longstanding hunch that waning immunosuppressive T-cells, called regulatory T-cells, play a key role in the onset of type 1 diabetes. The team's findings were published in the January 2008 issue of the journal Diabetes.

Working with non-obese diabetic mice, Piccirillo's team discovered that the CD4+ T-cells, expressing the Foxp3 gene, which regulate autoimmune reactions, may lose their effectiveness and become "lazy" over time. These regulatory T-cells normally suppress various immune responses, but when they lose their potency with age they're no longer able to curb certain autoimmune responses—thus allowing the body to destroy insulin-producing beta islet cells in the pancreas.

The genetic and cellular mechanisms behind this immune system malfunction have long been a mystery. "For the last several years, it's been postulated that non-functional regulatory T-cells are the critical mechanism," says Piccirillo, who is the Canada Research Chair in Regulatory Lymphocytes of the Immune System, and a leader in this research area. "Now this study proves it."

Piccirillo says it's likely that certain genetic predispositions, possibly coupled with external environmental factors or infections, could alter regulatory T-cell function in susceptible individuals and trigger a full-scale diabetic autoimmune reaction in the pancreas. "Once they start," he says, "these immune responses are like a car without brakes."

Type 1 diabetes patients must regularly inject insulin to avoid potentially fatal diabetic shock; secondary health problems include blindness, heart attack and stroke. Piccirillo is optimistic that his team's discovery may lead to the development of new immune system-based therapies for the disease, and a host of other autoimmune and chronic inflammatory disorders. "We believe that these regulatory T-cells may represent a kind of master switch, and by understanding how they are made, how they function and how they survive, we may be able to stop disease from occurring."

This research is funded by CIHR and the Canadian Diabetes Association.

Changing the Look of Malaria

The optical effect called third harmonic generation causes malaria secretions to glow blue in infected blood cells (left), promising a faster, more efficient diagnosis than traditional microscopy imagery (right).
Courtesy of Paul Wiseman

The traditional wisdom on malaria: quick to contract, slow to detect. A new invention, however, promises to change at least part of the malaria rulebook by giving the disease a colourful makeover.

Technicians currently detect malaria in the clinic by staining slides of blood smears with giemsa dye, which marks the DNA of the malaria parasites. They then painstakingly examine the stained blood samples under an optical microscope. The process is laborious—technicians manually count all the visibly infected blood cells to determine if the count exceeds the detection limit—and requires a very specific skill set. A research team led by Paul Wiseman of McGill's Departments of Physics and Chemistry, however, has developed a faster, more user-friendly technique. The new process relies on a known optical effect called third harmonic generation; THG causes hemozoin, a crystalline substance secreted by the malaria parasite, to glow blue when irradiated by an infrared laser.

In a study published in Biophysical Journal, the researchers say the new technique could eliminate the need for specialized training, slides, staining and microscopes—spelling the welcome end of a labour- and time-intensive process. Moreover, the faster a person is diagnosed with malaria (first symptoms don't appear until 10 to 15 days after infection), the faster they can get treatment; early treatment not only prevents complications, it dramatically reduces the risk of death.

Each year, upward of 500 million people contract the malaria parasite—principally spread by the female anopheles mosquito—and one to three million die from the resulting disease. Most of the fatalities are concentrated in sub-Saharan Africa, where diagnosis is often stymied by a dearth of trained personnel and equipment. The disease is also found in parts of Asia, Europe, Latin America and the Middle East.

Wiseman and his colleagues now hope to adapt existing technologies, including fibre-optic communications lasers and cell sorting technology, to quickly move the technique from the laboratory to where it's needed most. "We're imagining a self-contained unit that could be used in clinics in endemic countries," he says. "The operator could inject the cell sample directly into the device, and then it would come up with a count of the total number of existing infected cells without manual intervention."

This research is funded by the Natural Sciences and Engineering Research Council of Canada, the Network of Centres of Excellence—Canadian Institute for Photonic Innovations, CFI and CIHR.