(Toronto, January 18, 2001) - The role of a gene that acts as the off switch for several disease signals including cancer, heart disease and autoimmune diseases has been discovered for the first time by researchers at Princess Margaret Hospital's Ontario Cancer Institute with colleagues at Toronto General Hospital and the Amgen Research Institute.
Researchers discovered the role of a key protein called CD45 which is responsible for regulating how the body's cells respond to developmental signals and manage functions such as the growth of red and white blood cells, the regulation of viral infections and heart disease. The finding paves the way for future research into how to turn off the cellular signals that trigger various diseases and is reported in today's issue of Nature. The research was funded in part by Amgen, the Canadian Institute for Health Research, the Heart and Stoke Foundation and the National Cancer Institute of Canada.
The discovery could lead to a much more targeted way to control diseases such as cancer, diabetes and heart disease by turning off the communications signals that order the immune system to go on the offensive, according to senior author and world expert on inflammation and autoimmune disease Dr. Josef Penninger, an immunologist at Princess Margaret Hospital's Ontario Cancer Institute and the AMGEN Institute and a member of the Departments of Medical Biophysics and Immunology at the University of Toronto. Dr. Penninger is also the federally appointed Canadian Research Chair in Cell Biology.
The signaling system's Holy Grail
"Although the attack signal is a good thing when the body is invaded by disease, you must have a way to call in the troops once the enemy has been defeated," said Dr. Penninger. "Otherwise the immune system continues fighting and, after it destroys the invader, it goes after healthy cells and results in diseases such as diabetes, multiple sclerosis, heart disease or even cancer. Our cells rely on the delicate balance of communications signals to grow normally and produce blood cells. However, when a signal cannot be stopped, the cells overgrow and we run into trouble. We have discovered that it is CD45 that sends the `cease fire' signal to cells. This is the Holy Grail of the body's cellular signaling system."
According to one of the paper's coauthors Dr. Peter Liu, a cardiologist at Toronto General Hospital and Director of the Heart and Stroke/Richard Lewar Centre of Excellence at the University of Toronto, a thermostat provides a good analogy. "In your home, you need to be able to turn on the heat when you need it and you need a corresponding switch that turns off the heat when you don't. Otherwise your house overheats and eventually burns down," explained Dr. Liu. "Likewise, the body maintains itself by regulating the signals that control and balance all cellular functions. We must have an on switch to activate the body's response to infection, but the off switch is just as important. Without it, the body continues to attack itself leading to a number of diseases. Essentially, we have discovered the off switch that shuts down those disease signals."
A Eureka moment
CD45 has been extensively studied for over a decade and it was widely accepted in the scientific community that its function was well understood. Dr. Penninger said the most exciting thing for him in this study was proving the field wrong.
"For me, this is what makes science so exciting," said Dr. Penninger. "This finding will affect an entire paradigm shift in how science looks at cellular signaling. This was definitely a Eureka moment, in which we discovered an entirely new function of a gene science had assumed was all figured out."
The next step will involve the research team looking for ways to restore the function of missing or damaged CD45 in search of a way to essentially shut down cell growth in cancer and autoimmune diseases. In the current study, Dr. Penninger and his team, in particular Drs. Takehiko Sasaki and Junko Irie-Sasaki, two post-doctoral fellows, found that CD45 controlled the development of virus-induced heart disease. Mice without CD45 did not develop heart disease. And because CD45 stops the body's immune system from attacking foreign invaders, the discovery also has potential for finding effective ways to prevent the body's rejection of donated organs or bone marrow in transplantation.
According to Dr. Liu, most of the drug treatments we use to manage or treat diseases today work on the "on switch", which works very well for acute diseases. However, with an aging population, more and more people are affected by chronic diseases such as diabetes, arthritis, cancer, obesity and heart disease, all of which result from growth or inflammation that is left "on" and cannot be turned off. "Because of this discovery, we can begin developing drug treatments that may someday turn off many of the chronic diseases that affect a very large population of our society," said Dr. Liu.
Princess Margaret Hospital, a teaching hospital of the University of Toronto, has achieved an international reputation as a global leader in the fight against cancer and is considered one of the top comprehensive cancer research, teaching and treatment centres in the world. PMH is a member of the University Health Network, which also includes Toronto General Hospital and Toronto Western Hospital. Toronto General Hospital has a long established tradition of excellence in cardiovascular care and research. The AMGEN Research Institute is an integral part of AMGEN, the world's largest biotechnology company and an innovative and pioneering world-wide organization dedicated to the research and development, manufacture and marketing of human proteins for therapeutic use, using recombinant DNA technology.
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