by Neil Morris
She doesn't expect to find Ponce De Leon's Fountain of Youth, but Dr. Eugenia Wang would like to slow down some of the ravages of aging. Specifically, the McGill University scientist hopes to unravel part of the mystery behind why some body cells that should not die do and why some that should die won't.
"Five years ago, very few had even heard the word apoptosis or knew how to spell it. Now it's the central activity in the whole field of aging research," says Wang, who is Director of the Bloomfield Centre for Research in Aging in the Lady Davis Institute for Medical Research of the Jewish General Hospital and Associate Director of the Division of Geriatric Medicine and Aging in McGill's Faculty of Medicine.
Apoptosis is the process of programmed cell death. In effect, it means that each cell in the body has a program to kill itself at some point. As Wang sees it, this whole process is under genetic control such that specific genes, when activated, can either kill a cell or protect it from death. There are thus killer genes and survivor genes. If the process is functioning properly--that is, destroying cells that pose a threat to the body and saving those that are essential and cannot be replaced--then neither cancer nor neurodegenerative diseases like Alzheimer's should exist.
In cancer, cells have become resistant to death and replicate in an uncontrolled fashion. In neurodegenerative diseases, essential brain neurons, which are incapable of reproducing, die. The same happens in heart diseases where cardiac muscle cells cannot proliferate. Why do cells that are essential die, and cells that should die, namely cancer cells, survive? Why haven't the survivor and killer genes done their respective jobs in the appropriate cases? Cancer, cardiovascular and neurodegenerative diseases are primarily age dependent, says Wang. In the case of cancer, it can be hypothesized that a series of "bad hits," beginning with inheriting one or two, and later compounded by the effects of other factors like stress, poor nutrition or smoking, set the stage for a potential cancer to strike around the age of 60.
"My rationale is that if I can remove one of those hits, while it won't cure cancer, it may just gain us valuable time before another hit builds up again. If we can compress mortality to gain time, as well as enhance the quality of life during that time, we have added functional life expectancy for the elderly, even if we haven't cured anything."
Wang says that "eliminating some of the hits" will, in many cases, require modifying lifestyles, but manipulating the action of genes also holds great promise. Using cultured cell model systems, she has identified several of the genes responsible for determining whether a cell should continue to multiply or stop and die.
"Because the decision to live or die or self-propagate is a fundamental guideline by which body tissues can maintain their proper functional state, the identification of genes that control the decision process opens the door to future pharmacological or genetic therapy in age-dependent diseases like Alzheimer's disease and cancer, where the incidence increases with age."
Wang and her team are asking several questions, among them: Is the prevalence of Alzheimer's disease among the elderly due to the premature death of essential neurons, and if so, can we identify the specific death genes responsible for it and deactivate their unwanted killing action?
Along the same line, is the increased cancer incidence among the elderly a result of cells self-propagating unchecked, therefore producing more cells than are needed and eventually creating a tumour mass which obstructs normal tissue function? In an attempt to answer these questions, Wang and her team have been concentrating on the identification of genes that control replicative status, as well as the molecular program dictating whether individual cells live or die. They have focused on three possible growth-arresting genes: statin, terminin and S1. Of the three, S1 is the most characterized in terms of its molecular and tissue-specific properties. Her team has found it expressed only in brain, heart and muscles, tissues that possess a tightly controlled program of differentiation. They have identified statin, a protein related to the halting of cells from further replication. The presence of this protein has been found to be a powerful negative indicator for tumour malignancy and a determining factor for predicting long-term survival rates for breast cancer.
Terminin has been shown to be a marker for cellular death, and one specific form of it, known as Tp30, is found only in cells that are dying.
In Wang's opinion, application of this knowledge may be useful in a wide spectrum of disease incidence, where cell death is considered to be an important cellular event-either good for the organism, in the case of cancer therapy targeted to get rid of diseased cells, or bad for the organism, as in the case of neurodegeneration, when functional cells are lost.
She explains that senescent fibroblasts-cells that should die but won't-are sitting ducks for mutations and genetic insults and represent a "time bomb" for possible transformation into cancer cells or some other problem in time. She hypothesizes that resistance to apoptosis is due to a blockage in the intracellular pathway that relays the signal for cell death.
"If we can identify the site of this blockage, we may be able to remove it and triage cells to the apoptotic route and death. In the case of cells that have become cancerous but won't die, removing even half of them would help gain time for an individual," says Wang. "If we can delay and compress mortality, we give a great many people added functional life while at the same time saving government billions in health care costs." she says.
Born in Chungking, China, Wang obtained her PhD from Case Western Reserve University. Before moving to Montreal, she was an assistant professor at Rockefeller University. Besides her research endeavours, Wang holds a Medical Research Council operating grant, as well as two National Institutes of Health grants, including a prestigious NIH MERIT Award given to individuals who have had significant track records and contributions to their chosen field of research and have scored outstanding on grant applications.
It is becoming increasingly difficult to obtain research grants today, and Wang, who is a member of the public information committee of the American Society for Cell Biology, believes scientists must make a better effort to inform ordinary Canadians who provide the research dollars of biomedical research accomplishments and the benefits they have brought about in diagnosis, prevention and treatment of disease.
"The scientific community traditionally has chosen to hide its light under a bushel, and if we continue to do this we do so at our peril," she says, adding that the public has to be told that "we're not Frankenstein working on some esoteric problem in a mouldy lab, but on problems that directly affect the health and lives of living people."
A member of the Council of NIH's National Institute on Aging and the review committee of the American Federation for Aging Research, Wang devotes much of her spare time to evaluating grant applications, including some from MRC. "There is a great deal of talent out there and some truly outstanding research proposals," she says. But the competition is intense and because of funding shortages many deserving applicants cannot be funded.
Wang knows from personal experience how painful it can be not to receive a grant, but she says she learned from the experience.
"Whenever you are refused a grant you want to ask why, and there is usually a solid reason for it. It may take you some time to figure it out. When I was refused a renewal of my very first grant, I came to realize that I hadn't been concentrating and hadn't really asked myself what the most important question was that I should be asking.
"I always tell young investigators about my [grant] failures," she says. But she also tells them that this experience marked a milestone in her research career and gave her a jump-start for the future. "After I saw and understood the reviewers' suggestions and realized that they were correct, it sharpened my focus. Without that experience and what it did for me, I think I would probably be doing pedestrian research today."
This article has been excerpted with permission from the Medical Research Council publication MRC Communiqué, Winter/Spring 1996.