The Miracle Workers

It is as if Frederick Banting and Charles Best set the momentum for medical research at the University of Toronto and the pace hasn’t slowed since. The discovery of insulin in 1922 by Banting and Best (along with J.J.R. Macleod and J.B. Collip) was perhaps Canada’s most dramatic medical breakthrough of the past century. Judging by recent discoveries by U of T researchers such as Tak Mak, Lap-Chee Tsui, Peter St George-Hyslop and Josef Penninger, U of T is helping to set the direction of medical science in the 21st century, too.

The Faculty of Medicine can lay claim to countless research firsts. Take a look at the partial list of breakthroughs over the past 20 years that follows and you will encounter, for example, Robert Salter (MD 1947), an orthopedic surgeon whose innovative work has improved lives everywhere. One of Salter’s numerous surgical procedures carries his name: the Salter innominate osteotomy repairs congenital dislocations of the hip in young children. He also found that bones, cartilage, tendons and ligaments in joints could be stimulated to repair themselves with a gentle movement called continuous passive motion.

Philip Seeman, professor of pharmacology and psychiatry and holder of the Anne and Max Tanenbaum Chair in Neuroscience, was described by the selection committee for the Killam Prize for Health Sciences as one of Canada’s most important neuroscientists. His discoveries regarding dopamine receptors have allowed researchers to begin to unravel the mysteries of schizophrenia and have led to ways to diagnose the disease more precisely.

Michael Sefton (BASc 1971), professor of chemical engineering and applied chemistry and director of U of T’s Institute of Biomaterials and Biomedical Engineering (IBBME), discovered a way in 1997 to trigger the growth of new blood vessels, which will help speed the healing of wounds and aid in the growth of artificial organs for transplant. In the field of tissue engineering, he is leading an effort to develop procedures that could enable nerve regeneration, artificial skin and cornea replacement. He also co-ordinates an international group of scientists for the Living Implants from Engineering project that is focusing on organ transplants. John Davies, a professor of biomaterials in the Faculty of Dentistry and head of the bone interface group at IBBME, developed a biodegradable foam that can be used as a scaffolding for bone growth and could lead to new ways to reconstruct bone surgically. In 1998, his experiment to investigate how bone cells interact in space was sent on a space shuttle mission.

Molecular biologist Tony Pawson is recognized worldwide for uncovering some of the mechanisms used by cells to communicate with each other. This work has given researchers the clues they need to find out how cells grow, react with hormones and become cancerous. With more than $300 million a year in research funding, U of T scientists are laying a large part of the groundwork for what will become the advanced technologies of the 21st century.

1981
• Harald Sonnenberg and others discover the atrial natriuretic factor, a hormone secreted by the atrium of the heart that is believed to have an effect on salt balance and blood pressure regulation.
• Griffith Pearson and Joel Cooper perform the world’s first single lung transplant.
• Tak Mak and others identify the T-cell receptor gene, a major advance in understanding the human immune system.
• Ronald Worton and others locate the gene responsible for Duchenne muscular dystrophy.
• Joel Cooper performs the world’s first successful double lung transplant.

1988
• Alan R. Hudson and Susan E. Mackinnon perform the world’s first sciatic nerve transplant on a nine-year-old boy.

1989
• Lap-Chee Tsui, Manuel Buchwald and Jack Riordan isolate the gene that causes cystic fibrosis.
• Menashe B. Waxman and others develop the tilt-table test, which identifies people who lose consciousness as a result of fainting, as opposed to seizures, heart-rhythm disturbances or narrowed heart valves.

1990
• Donald W. Killinger and others discover that the distribution of body fat has an effect on the activity of human sex hormones. Abdominal body fat causes greater production of androgens, and fat on the lower body is linked to increased levels of estrogen.
• Anthony Pawson discovers that cancer cells will grow without the stimulation of the SH2 domain, an element that allows cell proteins to interact and transmit growth signals.
• Anthony Pawson identifies how cell receptors transmit signals instructing cells to change. This leads to new cancer drugs.

1991
• Philip Seeman identifies two new dopamine receptor proteins, D4 and D5, thus allowing for the development of more effective and safer medicines for treating psychosis, schizophrenia and possibly cocaine addiction.
• Mladen Vranic discovers new mechanisms involved in regulating glucose turnover, a key to understanding the development and treatment of diabetes.

1992
• Mary Hannah and others complete the Canadian post-term pregnancy trial and discover that a policy of inducing labour is best for both mother and baby when pregnancy is overdue by more than one to two weeks.
• Peter St George-Hyslop identifies a defective gene on chromosome 14 that may be responsible for familial Alzheimer’s disease.

1993
• Philip Seeman discovers that the D4 receptor, one of the five known types of brain cell receptors for the chemical dopamine, is six times more abundant in people with schizophrenia than in others.
• Terry Delovitch and others discover that a naturally occurring hormone, interleukin-4, which is produced by white blood cells, halts attacks on insulin-producing pancreatic cells and may protect children from developing insulin-dependent, or juvenile, diabetes.

1994
• Using a powerful atomic-force microscope, Cynthia Goh and others obtain revealing new images of the clusters of protein threads characteristically found in the brain neurons of Alzheimer’s patients.
• David Jenkins discovers that diets high in soluble fibre reduce blood cholesterol levels, even after significant dietary reductions in saturated fat and cholesterol have been achieved.
• Steven Narod and others discover the BRCA1 gene, which is suspected of causing two to four per cent of breast cancers and five to 10 per cent of ovarian cancers.
• Endel Tulving and others prove that different areas of the brain are activated when different types of memory are engaged.
• Brenda Andrews and others discover a new member of the kinases enzyme family responsible for controlling cell division in yeast. This affords insight into the aging process and diseases like cancer, which are linked to uncontrolled cell division.

1995
• A. Venket Rao and Mi-Kyung Sung discover that saponins, a natural compound found in soybeans, inhibit colon-cancer cell growth in tissue culture.
• Peter Wells and others discover a link between DNA repair and birth defects in mice.
• Colopath, a rapid, non-invasive screening test invented by George Krepinsky and others for the early detection of colorectal cancer, is granted a U.S. patent.
• Steven Narod and others discover a second gene for hereditary breast cancer (BRCA2).
• Peter St George-Hyslop and others identify the defective gene responsible for early onset Alzheimer’s, a rare but extremely aggressive form of the disease. The genes are so dominant that an inheritor is virtually destined to get the disease by age 50, even as early as 25.
• Peter St George-Hyslop and others identify a second gene responsible for the early onset of a less severe form of Alzheimer’s disease.

1996
• Mary Hannah and others complete the International Term PROM Study and discover that inducing labour with intravenous oxytocin is advisable when membranes are ruptured at term but labour has not started spontaneously.
• Luc De Nil and others discover a genetic basis for stuttering, which was previously assumed to result from emotional or psychological difficulties.
• Bibudhendra Sarkar develops an effective treatment of Menkes disease, a fatal genetic neurological disorder caused by defects in copper transport, required by many life-sustaining enzymes.
• Jeff Wrana and others identify a gene implicated in the development of colon cancer.
• Don Low and others develop a method to identify those at greatest risk of developing the severe invasive group A streptococcal (flesh-eating) disease.
• Brenda Gallie and others develop a new therapy for retinoblastoma, a cancer of the eye that leads to blindness. It is the first major new treatment of retinoblastoma in 35 years.
• Using X-ray crystallography, James Rini discovers a critical feature of e-cadherin, a cell membrane protein that suppresses cancer cell invasion.
• Robert Salter discovers a method of regenerating joint cartilage in severely damaged knee joints.
• Michael Moran and others discover that the GRB2 protein acts as a kind of on-off switch for cell growth and cell division. This lays the groundwork for drugs to prevent the growth and division of cancer cells.
• John Dick and others identify a bone marrow cell that produces blood in the human body, a significant step toward new therapies for blood diseases.
• Dan Drucker and others discover that the hormone Glucagon-like Peptide2 (GLP-2) can stimulate the growth of the lining of the small intestine. This could help patients with severely compromised intestinal functions.
• Manuel Buchwald and others identify and clone oneof the genes of Fanconi anemia, a rare but serious genetic disorder.
• Lap-Chee Tsui, Stephen Scherer and Elena Belloni identify a gene that causes cyclopia, a disfiguring disease affecting the fetal development of the forebrain and mid-face.
• Shoukat Dedhar and others discover ILK, a protein kinase. This illuminates new aspects of cell adhesion and demonstrates that an integrin-associated protein may cause tumours.

1997
• Brenda Andrews and others discover a new link between cell regulators that could lead to improved treatments for cancer.
• Ren-Ke Li demonstrates that cell transplantation can improve cardiac function and that transplanted cardiomyocytes survive in myocardial scar tissue and form a cardiac tissue that improves heart function.
• Roderick McInnes and others identify a gene whose mutations cause an inherited degenerative disease called cone-rod dystrophy, which leads to blindness.
• Christopher Feindel develops a new technique of preserving hearts for transplantation.

1998
• Thomas Wolever and others develop a more accurate test for detecting glucose intolerance, which improves diabetes screening.
• Michael Sefton and others initiate the Living Implants from Engineering (LIFE) project, an international research effort to create tissue-engineered organs. The initial effort is directed toward hearts.
• Choy Hew and others identify an antifreeze protein in some Arctic fish that plays a role in preventing damage by cold temperatures and may prove useful in cell and organ preservation.
• John Davies and others create “living bone” by growing human cells in biodegradable polymeric foam.
• John Dick and others discover a new stem cell in human blood that provides insight into the mechanics of the blood system.
• Stephen Scherer and others identify a gene responsible for Lafora disease, one of the most severe forms of epilepsy.

1999
• Lewis Kay receives the Steacie Prize for his work in nuclear magnetic resonance (NMR) spectroscopy, a process allowing for the sophisticated analysis of the interaction of molecules. More than 200 labs around the world currently use the NMR methodology developed by Kay.
•Tak Mak and others discover that Interleukin-13 growth cells facilitate the development of Hodgkin’s disease.
• Josef Penninger and Young-Yun Kong discover how the OPGL gene triggers osteoporosis.
• Josef Penninger identifies a link between heart disease and chlamydia pneumoniae, a bacteria associated with pneumonia and bronchitis.
• Lap-Chee Tsui and others identify a region on chromosome 19 containing a gene that modifies the severity of cystic fibrosis.
• José L. Perez-Velazquez and others unravel one aspect of human seizures. By determining patterns of brain activity, researchers can forecast seizures and manipulate them with electric stimulation.
• Ulrich Krull develops a DNA hybridization detection system that provides on-the-spot screening for fungal and bacterial infections and diseases such as AIDS and hepatitis.

2000
• Emanuela Mundo and others identify a genetic variable in individuals with obsessive-compulsive disorder, which may provide insight into its cause and treatment.
• Roderick McInnes and others identify retinal stem cells in the adult eye, a discovery that opens the door for retinal regeneration as a possible cure for damaged or diseased eyes.
• Josef Penninger and others discover a protein that suppresses colorectal cancer in mice and human cell cultures.
• Geoff Clarke and others demonstrate that mutant genes that lead to inherited neurodegenerative conditions like Parkinson’s disease confer a constant risk of programmed cell death.
• Peter St George-Hyslop and others announce that a new Alzheimer’s vaccine is ready for human testing.
• Janet Rossant is elected to the Royal Society in recognition of her work on the genetic control of normal and abnormal development in the early mouse embryo that provides insight into what can go wrong in early pregnancy.
• Reza Emami develops a software program that can look at a virus or tumour and identify the genes that have an impact on the infected cell.
• Mary Hannah and others complete the International Term Breech Trial and discover that delivery by caesarean section is best for breech babies at term and does not increase the risk for the mother.
• Tony Miller, Cornelia Baines and others report results from the Canadian National Breast Screening Study for women age 50 to 59.

2001
• Josef Penninger and others identify the CD45 protein, a switch that turns off hormones and proteins that control the human immune system.

Josef Penninger
Type in “Josef Penninger” when doing an Internet search and you’ll be bombarded with hundreds of listings. They are all for the U of T associate professor of medical biophysics and immunology, who this year announced that he and his colleagues had discovered a protein, CD45, that acts as an on-off switch for the immune system. The finding may be pivotal in the quest for treatments for diseases in which the immune system is acting too aggressively – such as arthritis, Type 1 diabetes and some kinds of cancer.

In 1999, Penninger and his research team at the Amgen Research Institute in Toronto discovered OPGL, a gene that causes the destruction of bone tissue, leading to severe osteoporosis. The team found that diseases that cause inflammation in the body (for example, arthritis) and activate the immune system initiate an attack against the bones. A natural blocker of OPGL is undergoing human clinical trials in the United States.

That same year, Penninger also found a causal link between chlamydia pneumoniae and heart disease, and last year, he and his lab found a protein that suppresses colorectal cancer in mice.

Lap-Chee Tsui

The Sept. 8, 1989, edition of the journal Science included three scientific papers announcing the discovery of the cystic fibrosis (CF) gene. All three had the name of Lap-Chee Tsui on them. Tsui (pronounced “Choy”), geneticist-in-chief at the Hospital for Sick Children and a professor of molecular and medical genetics, along with an international team of researchers, had just made a huge impact on genetics research.

Since then, genetic tests have been developed for the disease, and researchers are on the path to finding new treatments. In 1999, Tsui and his colleagues found the location of a gene that affects the severity of CF in individuals.

In November 1996, Tsui and his team identified a gene that causes a disfiguring disease in unborn infants known as “cyclops syndrome,” which produces deformations of the forebrain and mid-face. He is also involved in the mapping of the gene responsible for Tourette’s syndrome. Last year he became president of the Human Genome Organization (HUGO), which co-ordinates 1,000 scientists working on the Human Genome Project.

Tak Mak
When Tak Mak, director of the Amgen Institute in Toronto, puts his mind to a problem, great things happen. Indeed, the whole field of immunology was advanced by his discovery of how T-cells work. For years researchers knew that T-cells were the tiny guards in our blood that recognize and attack invaders such as bacteria and viruses, but nobody knew how they did their job. Mak, a professor of immunology who had been working with viruses, turned his attention to T-cells.

On March 8, 1984, two independent papers appeared in the journal Nature announcing the discovery of the T-cell receptor. The lead author of one of them was Tak Mak. Finding the receptor was pivotal to understanding how T-cells recognize what is foreign or native to the body.

In 1999, Mak and colleagues found interleukin-13, a cell that fuels the growth of cancerous cells in Hodgkin’s disease. He continues basic research in cell biology at the Ontario Cancer Institute in Toronto.

Peter St George-Hyslop
As a boy, Peter St George-Hyslop, a neurologist at Toronto Western Hospital and director of U of T’s Centre for Research in Neurodegenerative Diseases, was clearly ahead of his class. Shortly after his family moved to Ottawa from Britain and the young St George-Hyslop started Grade 9, his teachers realized he needed to be advanced to Grade 12. The pattern has continued throughout his adult career. The soft-spoken neurologist has garnered numerous accolades, including the gold medal from the Royal College of Physicians and Surgeons of Canada.

The recognition is well deserved. There are four known genes linked to early-onset Alzheimer’s disease, and St George-Hyslop has found two of them. Both were discovered in 1995 within an astounding two months of each other. The first gene is associated with the most virulent form of early onset Alzheimer’s, while the second is linked to a less severe, inherited form of the disease. He and his team recently developed a vaccine for Alzheimer’s, now ready for human tests.