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The wonder cell: Scientists hope to harness stem cells in a war against debilitating diseases
By Margret Brady The Ottawa Citizen
Sunday, November 2, 2003
In a quiet lab at the Ottawa Hospital Research Institute, Michael Rudnicki places a small glass dish under a microscope. It illuminates clusters of cells resembling pimpled jellyfish blobs you might find on a beach at low tide. But these are mouse stem cells, incubated at 37 C, the normal body temperature of mice and men. They have been nourished in a sea of mouse embryonic cells, that provide nutrition and other forms of support.
They may not look like much, but stem cells may turn out to be the most useful weapon in our medical armoury. They are versatile and expected to have the ability one day to cure major neurodegenerative illnesses such as Parkinson's, restore vision and regenerate muscle tissue and skin.
Canadian scientists such as Rudnicki, a biologist who is director of the institute's molecular medicine program, are at the forefront of worldwide stem-cell research. Over the past decades, Canadian researchers have achieved breakthroughs in stem-cell biology that define the concepts and methodologies used today.
Yet despite the promise such research holds, the ethical debate over the use of human embryonic stem cells in medical research is blocking investigation in Canada and abroad. Many scientists are concerned that doors to research are being closed with undue haste. Certainly some research programs around the world are being derailed by a mishmash of pending laws and regulations related to stem-cell research.
In Canada, the much-delayed federal Bill C-13, which deals with human reproduction, cloning and human embryonic research, is one of the most hotly debated pieces of legislation in recent memory. "There are a lot of positive things about the legislation," says Rudnicki. "However, a regulatory framework already exists through the Canadian Institutes of Health Research (CIHR)." The bill, which was approved by the House of Commons last week but still faces opposition in the Senate, is overly restrictive of research, Rudnicki believes.
"Canadian scientists are not doing bandit science such as Dolly-the-sheep cloning in humans," he says. "Current cloning technology doesn't even work in primates. If it did work, what woman would want to gamble with a one-in-300 chance of success versus using a donor sperm? Cloned children would have health problems, die early and trigger wrongful life suits."
The Criminal Code is a heavy hammer for regulating scientific experiments, although controversial work should be carefully regulated, he says. "We need flexibility. We don't even know what next year's experiments will be."
Provisions in the legislation parallel existing CIHR guidelines. Under Bill C-13, federal funds will be allowed for research on "existing embryonic stem-cell lines" (established banks of living embryonic stem cells) and new stem-cell lines derived from excess embryos produced through fertility treatments.
However, therapeutic cloning (the cloning of an embryo to derive stem cells for therapeutic applications) and the creation of embryos solely for research purposes would be prohibited, provisions Rudnicki finds too constraining. The legislation also bans research combining human and animal stem cells and embryos.
By comparison, U.S. guidelines restrict federal funding to research on existing embryonic stem-cell lines. Privately funded research in the U.S. has no such restrictions. For example, privately funded U.S. researchers conduct therapeutic cloning, and develop stem-cell lines from embryos remaining after infertility treatments. They can also combine human stem cells with animal embryos and vice versa.
"Countries have different social and cultural environments and different histories of research," says Janet Ros-sant, an expert on mammalian development who chaired CIHR's Working Group on Stem Cells that provided recommendations for research guidelines in Canada in 2002. "It's very hard to come up with internationally acceptable guidelines," she says. Britain, for example, has a liberal environment for stem-cell research, but legislation in Austria and Germany is very restrictive.
A Pollara poll conducted from Sept. 29 to Oct. 2 showed broad public support in Canada for embryonic stem-cell research and for its federal funding. Still, a vocal group of federal MPs dubbed the "God Squad" object to the legislation because embryos are destroyed in the process of harvesting the cells.
"A moral argument must be countered with another moral argument," says Rudnicki. "If your child is dying of a lethal genetic disease and you have the tools to cure the child, how can you stand there and deny that child the opportunity?"
For sufferers of many diseases, such research is the only hope.
Human development begins with a single fertilized egg called a zygote. When that egg begins to divide, stem cells are formed with the potential of developing into a complete organism. These are called totipotent stem cells. Soon, the egg forms a round ball of cells called a blastocyst, which contains pluripotent stem cells that can turn into any body tissue. These cells evolve into stem cells that create more specific cell types. These are called multipotent because they can form many but not all body tissues. For example, neural stem cells will generate different types of brain cells, and muscle stem cells make muscles.
The stem cells become more rigid and set in their ways as they age, just as most people do. As development and formation proceeds, cells have a smaller repertoire.
It was believed that pluripotent stem cells were lost soon after birth, but researchers, including several Canadians, have discovered pockets of them in adult muscle, bone, brain, liver and skin. These are loosely termed adult stem cells.
"It looks like some adult cells have more flexibility than once thought, although it remains very controversial," says Rudnicki, whose work focuses on the potential of muscle stem-cell therapies for degenerative neuromuscular diseases.
In June, Rudnicki and his colleagues published a paper in the journal Cell that garnered international attention. Based on work with stem cells from adult muscle tissue in mice, the team found that proteins important in embryonic development stimulate adult muscle stem cells to participate in the repair process. The stem cells from injured muscle tissue proliferated and generated new muscle cells.
"What our work clearly demonstrates is that there is a normal role for adult stem cells and they are responsible to a large degree for muscle regeneration," says Rudnicki.
Using adult stem cells effectively gets around the ethical debate. Also, using a patient's own skin cells, for example, minimizes immune rejection problems.
However, adult stem cells have major disadvantages. They are rare, difficult to isolate and tricky to grow in vitro (outside the body). Although most Canadian research involves adult stem cells, the research community generally considers embryonic stem-cell research crucial.
"In a couple of years, we will know a lot more about the value of embryos for research," says Ronald Worton, CEO and scientific director of the Ottawa Hospital Research Institute, the research arm of the Ottawa Hospital and the University of Ottawa faculties of medicine and health sciences. "It may turn out that embryonic stem cells are far better at repairing and regenerating tissue than adult stem cells."
A vast amount of research must be done to determine how the molecular mechanisms controlling stem cells work.
"If you are going to put stem cells in somebody's brain to correct Parkinson's disease, you want to be sure that they make neurons and not bone," says Worton, a biophysicist and biochemist who is also the scientific director of the Ottawa-based Stem Cell Network. "In other words, stem cells have the potential to do more harm than good if they are not adequately controlled."
Canadian Research
Canadian stem-cell pioneers James Till and Ernest McCulloch deserve a Nobel Prize for their work at the University of Toronto, says Rudnicki. In 1963, they proved that stem cells were multipotent when they showed that transplanted bone marrow cells could produce different types of blood-forming cells. This was a discovery of the highest magnitude. In 2002, the journal Nature Immunology identified 35 of the most significant stem-cell papers published in the last half of the 20th century. Almost half were by Canadians and nine were co-authored by Till, a specialist in biophysics and cellular biology.
The Canadian Stem Cell Network, formed in 2001, is part of the federal government's Network of Centres of Excellence program. More than 60 leading scientists from across Canada form the network that focuses on major stem-cell issues such as ethics and stem-cell manipulation and growth.
The network has identified four major diseases where a co-ordinated research effort could make a major impact -- Parkinson's disease, juvenile diabetes, hemophilia and stroke.
"The stem-cell network couldn't happen in the U.S.," says Dr. Lawrence Rosenberg, a top stem-cell researcher at McGill University in Montreal.
"The advantage we have is we talk to each other. We're less suspicious of our colleagues."
Fetal Development
Janet Rossant, senior investigator at Toronto's Samuel Lunenfeld Research Institute, is one of Canada's leading researchers on embryonic stem cells in mice. Her lab studies mouse cells during very early stages of development when they start to become embryonic as well as trophoblast stem cells that make the placenta. Embryonic stem cells are pluripotent, which can make any body tissue, whereas trophoblasts are specialized.
"We are trying to understand the genes that make embryonic stem cells different from trophoblast stem cells so we can understand more about embryonic stem cells and how to keep them pluripotent," says Rossant.
"We have a lot of clues but we don't understand all of those processes, particularly how to make pluripotent cells differentiate into bone or muscle or heart in a reproducible way."
Problems in early pregnancy often result from problems in the placenta, which is why Rossant is particularly interested in the trophoblast stem cells. In humans, many embryos are lost before they attach to the uterus. Miscarriages often occur without women knowing. Problematic placenta development is also linked with inadequate fetal nourishment and pre-eclampsia or hypertension, a dangerous condition for pregnant women.
The lab's studies on the biology of embryonic stem cells promise to lead to a better understanding of adult stem cells and how to make stem cells into therapeutic agents.
Juvenile Diabetes
Canada has a stellar history in diabetes research dating back to the Nobel prize-winning discovery of insulin by Frederick Banting and Charles Best in 1921. In 2000, Canadian diabetes researchers made international headlines with the Edmonton protocol announcing pancreatic cell transplants that stimulated insulin production in diabetics.
About eight per cent of the Canadian population is diabetic and each year 50,000 Canadians die of the disease and its complications. Diabetes occurs when the pancreas doesn't produce enough insulin to break down blood sugars.
Juvenile or Type 1 diabetes affects about five per cent of diabetics. This strikes at a much earlier age than Type 2 diabetes and is more severe. Type 2 diabetes, often caused by obesity, is rising in Canada and has reached epidemic proportions within the aboriginal community.
"Some of the best investigators in diabetes and stem-cell research are in Canada," says McGill University's Dr. Lawrence Rosenberg, who leads an eight-city Canadian Stem Cell Network team seeking a cure for the disease.
"It is clear that taking insulin for 30 or 40 years is a treatment and not a cure. It is also an issue of quality of life."
In the 1980s, Dr. Rosenberg discovered that a gene could be switched on to trigger the growth of insulin-producing cells or islets. His research underlies the development of an experimental drug that causes the body to create new islets. The drug is undergoing clinical testing in the U.S.
Diabetes can be treated with a pancreatic transplant, an operation with many potential complications. The Edmonton protocol cell transplant is less invasive than a full organ transplant but results are not as good. Both procedures depend on organ donations.
"There are not enough organs to go around," says Ron Forbes, president of the Juvenile Diabetes Research Foundation (JDRF) in Markham For two million Type 1 diabetics in North America, 2,000 pancreases might become available for transplants each year. JDRF North America has committed $25 million to stem-cell research over five years and that amount is expected to increase substantially.
Dr. Rosenberg says some sort of cellular therapy is the best hope for diabetics. "That's why we need to find alternate sources of cells," he says. "I think within two years we will have identified stem cells to grow new islets."
Deborah Gibson's son was diagnosed with Type 1 diabetes at age three. He is now 11. "Eight years ago we thought we were on the cusp of a breakthrough," the Brampton woman says. "There needs to be acceptance for unrestricted research in this area. Our medical systems are crumbling under the financial burden caused by medical complications that diabetics, like my son, suffer. Research into prevention and cure is a better way to funnel the money."
Parkinson's Disease
As a sculptor and a neurosurgeon, Dr. Ivar Mendez of Dalhousie University in Halifax is interested in the head outside and within. Three years ago, the Bolivian-born chief of neurosurgery at the university's medical school and the Queen Elizabeth II Health Sciences Centre began transplanting fetal neurons into the brains of patients with Parkinson's disease. The treatment was developed in Sweden but modified in Halifax.
Parkinson's is a progressive neurological disease that affects more than 150,000 Canadians. It is caused by the loss of dopamine, a chemical that helps control muscle movement. The cells that produce dopamine degenerate and die and the brain is literally starved of the vital chemical, triggering symptoms such as tremors, slowed movements and loss of motor control. The debilitating progression of the disease can be seen in Pope John Paul II, for example.
Dopamine tablets, commonly used to treat Parkinson's, gradually lose effectiveness. Also, they cause side effects such as uncontrollable wriggling movements. This symptom can be seen in Canadian actor Michael J. Fox, who has raised spectacular sums of money for research on the disease. Fox is convinced that stem-cell research will result in a cure for Parkinson's within a few years.
While fetal cell transplants are effective -- patients have begun to walk again without braces and canes -- the treatment is not ideal, says Dr. Mendez. Aside from ethical concerns about the use of tissue from abortions, fetal tissue supplies are limited. Also, there is a risk of infection and the need for immuno-suppression drugs which, in themselves, are toxic.
Parkinson's is an ideal candidate for cell restoration because it involves only one type of cell, says Dr. Mendez, who leads the Stem Cell Network's Parkinson's team. The most promising potential therapies will involve adult stem cells, he says.
The team includes Sam Weiss, a University of Calgary scientist who discovered stem cells in the adult brain, and Freda Miller of the Hospital for Sick Children in Toronto, who isolated stem cells in human skin. Other key players are the University of Toronto's Derek van der Kooy, who has done groundbreaking work on retinal stem cells, and the University of Calgary's Leo Behie, who is developing ways to produce standardized stem cells in large quantities.
"We have all the elements of the puzzle," says Dr. Mendez, who is also the chair of the new Brain Repair Centre located at Dalhousie University's medical school. This month, the centre is opening a stem-cell research laboratory dedicated to brain repair, including Parkinson's, stroke and spinal cord injury.
"Canada is a powerhouse in stem-cell research," he says. "We might be the first in the world to successfully transplant stem cells into Parkinson's patients."
Hemophilia
Queen Victoria's nine children and grandchildren were the kings and queens of Europe. They formed a powerful royal dynasty, but one with an insidious and fatal genetic flaw -- hemophilia. By means of strategic arranged royal marriages with members of the British royal family, the royal houses of Spain, Germany and most famously, Russia, were all affected by the bleeding sickness.
Today, the inherited disorder, which prevents proper blood clotting, affects about 2,750 Canadians. Hemophiliacs -- and most of these are men -- lack a gene that creates a clotting protein. In hemophilia A, the more common form of the disease, the protein is called factor VIII.
"Hemophilia is a superb paradigm for the new genetic technologies," says Dr. David Lillicrap, a professor of pathology and molecular medicine at Queen's University in Kingston. "Genetic technology has led to a greater understanding of the disease, its prenatal diagnosis and potentially its treatment."
Dr. Lillicrap heads the Stem Cell Network hemophilia team that is researching three adult stem cells that might be suitable for gene therapy. The Queen's lab is studying stem cells used in forming the blood vessel linings. Labs at McGill University and the University of Toronto are examining different types of bone marrow cells.
The concept of gene therapy as a treatment for hemophilia is simple although its implementation is not. The missing gene could be inserted into a hemophiliac's stem cells and re-implanted. The first stumbling block is finding the perfect candidate cell.
Although the disease is relatively rare, Canada spends $120 million a year on its treatment. Factor VIII injections, now prepared from replicating DNA rather than blood transfusions, are safe and effective. However, they are costly and inconvenient -- particularly for patients with a severe hemophilia which causes frequent spontaneous internal bleeding.
"You can just wake up in the morning, turn over in bed and have a bleed into your knee or hip," says Dr. Lillicrap.
Hemophilia occurs naturally in dogs, cats, sheep and horses, and Queen's has a large hemophiliac dog colony as well as genetically modified mice. Because dogs are closer in size to humans than mice, they are good animal models for pre-clinical testing.
"As you know, we are not there yet," says Dr. Lillicrap, who believes that gene therapy for hemophilia will be a reality within the decade. However, the cost of gene therapy is not yet known. "Everyone's hedging their bets," he says.
Stroke
Up to 50,000 Canadians suffer a stroke each year and more than 300,000 Canadians are stroke survivors. Stroke can have debilitating and long-lasting effects, including loss of muscle control, speech and memory. In conjunction with the Canadian Stroke Network, the Stem Cell Network has formed a team of 25 scientists to try to find if adult stem cells can contribute to recovery of function after a stroke.
The project will compare the effectiveness of adult stem-cell transplants with the stimulation of stem cells already resident in the brain. The team is comparing adult skin, bone marrow and brain stem cells to see if these can be turned into brain cells that can be successfully implanted in the brain.
Sam Weiss of the University of Calgary co-leads the project with Freda Miller of Toronto's Hospital for Sick Children. His lab is treating experimental animals who have had strokes with growth factors and hormones.
"There is very positive preliminary evidence that we can get some recovery of function through stimulation with growth factors," he says.
"It's an area of research with tremendous potential," says Paul Morley, deputy scientific director for the Ottawa-based Canadian Stroke Network.
While most stem-cell scientists support the federal government's Bill C-13, the legislation is a compromise because it will not allow the creation of embryos for research purposes. However, the legislation will buy time for researchers to assess the viability of embryonic stem cells as effective medical tools.
"We also know that peoples' views change over time," says Worton of the Ottawa Hospital Research Institute. The institute is opening a $40-million stem cell and genomics research facility on the General Hospital campus in 2005. "Think of the reaction around the world to the first test-tube baby," he says. "Now we have test-tube babies by the tens of thousands."
Literature and, more recently, film have often portrayed scientists as coldly clever, amoral and oblivious to the consequences of their research. Scientists can be eccentric, says Worton, but they are seldom mad. "At the end of the day, we go home to our families or go watch our kids play baseball, just like everyone else," he says. "We want to find cures for diseases. What's mad about that?"
Margret Brady is an Ottawa science writer.
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What are stem cells?
Human and animal bodies are composed of more than 200 types of cells with the same basic structure, such as a nucleus and a porous membrane, but with different shapes and functions. Virtually all cells divide and reproduce themselves. Stem cells are the master dividers and seemingly divide indefinitely. They are like blank pages -- not performing a terminal function like red blood cells or nerve cells. Stem cells can be coaxed to become certain types of specialized cells by adjusting the solution in which they grow.
They require a "soup of the right proteins and growth factors," says stem-cell expert Janet Rossant, an authority on mammalian development. They are called stem cells because they act as a stem for all future growth for tissues, somewhat like a plant. "They have the capacity to keep dividing and making copies of themselves but at the same time they can bud off specialized cells," says Rossant.