Blood disorders

02
Dec 2015
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Dr. Sheila Singh

Dr. Sheila Singh

Solving the Christopher mystery

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Dr. Sheila Singh is driven to know why one Christopher died when the other thrived.

About 20 years ago, while in her third year of a residency rotation and working in pediatric neurosurgery at Toronto’s SickKids Hospital, Dr.…

Dr. Sheila Singh is driven to know why one Christopher died when the other thrived.

About 20 years ago, while in her third year of a residency rotation and working in pediatric neurosurgery at Toronto’s SickKids Hospital, Dr. Singh was assigned two five-year-old boys. Both were named Christopher. Both had medulloblastoma, the most common kind of childhood brain tumour.

“I took care of them hour to hour, day to day. They both got the same surgery, the same chemo, the same radiation. In all clinical ways, the tumours were identical.  One Christopher did very well and was cured. The other died. I had this huge epiphany in that moment:  I realized that even if I did neurosurgery for the rest of my life, I would never figure out why one Christopher survived and one died.”

Dr. Singh realized that, along with being a brain surgeon, she needed to understand the molecular and cellular biology of brain tumours.  She entered the Surgeon Scientist Program at the University of Toronto where, while still a PhD student working in Dr. Peter Dirks’ lab, she was lead author on the 2004 Nature paper that identified human brain tumour initiating cells.

Since returning to her native Hamilton in 2007, Dr. Singh has worked as a pediatric neurosurgeon at McMaster Children’s Hospital while doing complementary research with Mac’s Stem Cell and Cancer Research Institute.

“There’s a bridge that connects the Children’s Hospital on the fourth floor to where my lab is and I go back and forth.  When I have a whole week of clinical work, where I’m covering emergency operations on call and doing clinics, you see everything that the children go through.  When I go back to the lab, I’m filled with clinical questions: Why did this happen to this child? It’s gratifying to have this research lab where I can bring questions to a useful end.”

In her research, Dr. Singh uses preclinical mouse models of brain cancer to improve treatments for her patients.

“We’ve developed ways of adapting the therapies that we use on children for immune-deficient mice. We transplant the human tumours into the mice and treat them with the exact same chemotherapy or radiation protocols that the children get. So I can profile — in a personalized medicine way — what’s going on with each child’s tumour. That’s the aim of these preclinical models: to model what’s going on in the patient in a faster, higher-throughput way. I’m hoping that one day we will have a model that will allow us to feed back to the patient:  ‘You have this cell population that’s going to escape radiation, so you are going to need this added drug to help you with your therapy.’”

Another approach is to take a sample of the child’s tumour cells and test the use of various compounds to defeat them. “We have a compound screening and drug screening program at the Institute.  So we can take the patient’s cells and screen them against libraries of thousands and thousands of compounds. Theoretically, we can find something that will work better as a therapy.”

Regardless of the approach, hers is the opposite of ivory tower, research-for-research-sake activity.  It is all patient-driven.

“You see a lot of things in pediatric neurosurgery and all of them — good and bad — inspire my research.  And every person who works with me has a direct connection to the ‘Why?’ of research.  Very often patients and their families will come for a tour of the lab and my people get to meet them.  There is a real connection. People in my lab work twice as hard because they have that direct motivation.”

On a personal level, doing research has made her a more patient person.

“Surgeons — we’re activists. We like to say, ‘OK, we’ll take that tumour out and you’ll feel better.’ But research requires long-term thinking.  Research forces me to be patient, have vision and plan in the long term. I’m not a patient person, but I’m learning.”

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17
Nov 2015
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From right, Will Wang, Caroline Brun, Dr. Michael Rudnicki and Dr. Nicolas Dumont

From right, Will Wang, Caroline Brun, Dr. Michael Rudnicki and Dr. Nicolas Dumont

Canadian reseachers deliver another game-changer

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Within the space of two weeks, two Canadian scientists have unveiled game-changing research into stem cells — providing further proof of Canada’s prominent position in the field.…

Within the space of two weeks, two Canadian scientists have unveiled game-changing research into stem cells — providing further proof of Canada’s prominent position in the field.

On November 5th, the University of Toronto’s Dr. John Dick published a paper in Science that has researchers around the world rethinking how human blood gets made.  Dr. Dick’s team showed that the traditional understanding of blood production is wrong and that stem cells drive production of different kinds of blood cells much earlier than previously thought. This has huge implications for future treatments for blood-based cancers. We blogged about it here.

Yesterday came news that a University of Ottawa team led by Dr. Michael Rudnicki published a paper in Nature Medicine that could completely alter perceptions on how Duchenne muscular dystrophy happens — linking it to intrinsic defects in the function of muscle stem cells.

Affecting about one in about 3,600 boys, Duchenne muscular dystrophy occurs when genetic mutations deplete production of dystrophin protein, causing muscles to deteriorate.

According to an Ottawa Hospital Research Institute release, dystrophin was thought to be a simple structural protein found only in muscle fibres. The Ottawa team discovered that muscle stem cells also express the dystrophin protein. Without it they can produce only one-tenth the number of muscle precursor cells needed to generate functional muscle fibre.

Dr. Nicolas A. Dumont and Yu Xin (Will) Wang are co-lead authors on the paper. that also showed that dystrophin is a key piece of the molecular machinery that enables muscle stem cells to function.

“Muscle stem cells that lack dystrophin cannot tell which way is up and which way is down,” said Dr. Rudnicki. “This is crucial because muscle stem cells need to sense their environment to decide whether to produce more stem cells or to form new muscle fibres. Without this information, muscle stem cells cannot divide properly and cannot properly repair damaged muscle.”

Dr. Rudnicki was featured in many news reports about the discovery, including this feature by CBC.

 

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27
Feb 2015
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What is Denis-Claude Roy excited about?

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Recently, we asked several of Canada’s leading stem cell scientists to tell us about what they think will be the next big thing in regenerative medicine.

Recently, we asked several of Canada’s leading stem cell scientists to tell us about what they think will be the next big thing in regenerative medicine. Where do they see things going? What are they excited about? For today’s instalment, we interviewed Dr. Denis-Claude Roy, Director of the Centre de recherche de l’Hôpital Maisonneuve-Rosemont and a full professor at the Université de Montréal. Dr. Roy is Chief Executive Officer of CellCAN Regenerative Medicine and Cell Therapy Network. Asked about what he sees developing in the field of stem cells and regenerative medicine he provided the following highlights of his work and others.

In our work with blood-based cancers like leukemia and lymphoma, we have developed a protocol for stem cell transplantation for people who don’t have a matched donor. We are able to do mismatched stem cell transplants, or what’s called haploidentical stem cell transplantation. This means that in place of being fully compatible (with the donor cells), a patient can be 50% compatible and still get a transplant.

Normally (such a transplant) would kill the patient, but we’ve developed a strategy to eliminate the cells that cause Graft Versus Host Disease (GVHD) and attack the patient. GVHD is probably the biggest problem associated with stem cell transplantation. Instead of having the patient develop GVHD or treating the patient with drugs to prevent it from occurring, we treat the cells in the lab and eliminate those that cause GVHD. So, we’re able to do stem cell transplants without immune suppression and the patient won’t have to take immuno-suppressor drugs for the rest of their lives.

We’re very excited about this. Our first study included 19 patients and we have had extremely good results. The patients had few infections and low relapse rates. A second study on another 23 patients, part of an international study, is currently led by our centre. To date, patients are again doing very well.

We’re also starting a clinical trial using a molecule called UM171 that was developed by Dr. Guy Sauvageau (Université de Montréal) to expand umbilical cord blood stem cells while maintaining their properties. Right now, donated umbilical cords have too few cells to treat adults. One donation provides enough cells to treat a child, but not enough for a normal size adult. Currently for an adult, we have to use two donations and that presents immune issues and is very expensive. We want to ramp up the number of stem cells from umbilical cord donations for those patients that have a match but not enough cells. We can grow the cells in the lab to have enough for the transplant.

This will allow us to select from our larger pool of umbilical cord blood donations and therefore improve the match, which should result in decreasing the number of complications associated with transplants and make it possible for more people to get them. This could also accelerate engraftment, shortening the time for the cells to engraft, which would decrease risk associated with the procedure.

The the use of stem cells in cardiac treatments is also starting to gather momentum. Dr. Duncan Stewart (University of Ottawa) has a trial (using genetically modified stems to repair heart damage) that is going very well. I am also working with Dr. Nicolas Noiseux (Université de Montréal) on activating stem cells before they are infused into the heart. He is studying a number of molecules to activate the cells before they are injected. The idea is to repair the hearts of patients who have poor cardiac function.

We will also be starting a trial using cells from the immune system to target leukemia. They are specific, acting like missiles, which will select and kill leukemia cells. Dr Claude Perreault (Université de Montréal) is developing a series of new targets. A new clinical trial is likely to start in the Fall.

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13
Feb 2015
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Tricky science made simple, Valentine’s edition

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When we think of Valentine’s Day, we think of hearts. And when we think of hearts, we think of their life-sustaining role of pumping blood.…

When we think of Valentine’s Day, we think of hearts. And when we think of hearts, we think of their life-sustaining role of pumping blood. But where does that blood come from? How does it get made?

A great resource to find answers to those questions and understand the role of stem cells in blood formation is now available. “What is a hematopoietic stem cell?” narrated by Dr. Connie Eaves is the latest video in Stem Cell Shorts series that explains how hematopoietic stem cells (HSCs) produce new blood cells.

Contained in the bone marrow, HSCs can produce new blood cells or regenerate the blood production system. In fact, bone marrow transplants have treated patients with a variety of blood cancers and disorders, including multiple myeloma, leukemia and lymphoma for decades.

Dr. Eaves, a professor in the Department of Medical Genetics at the University of British Columbia, is a leader in the field of hematopoietic stem cell biology. Her work has led to advances in treatment for leukemia. Currently, she is researching the unique properties of normal and cancerous stem cells in a variety of tissues to improve treatments for breast cancer and leukemia.

The new video, produced by Ben Paylor, a PhD candidate at the University of British Columbia, and Dr. Mike Long, a post-doctoral fellow at the University of Toronto, is co-sponsored by the Canadian Stem Cell Foundation and the Stem Cell Network.

All the videos — including “What is a stem cell?” narrated by Dr. Jim Till, “What are embryonic stem cells?” voiced by Dr. Janet Rossant, “What are induced pluripotent stem cells?” narrated by Dr. Mick Bhatia, “What is stem cell tourism?” voiced by Prof. Timothy Caulfield, “What is a cancer stem cell?” narrated by Dr. John Dick, “What is a retinal stem cell?” voiced by Dr. Derek van der Kooy and “What is a hematopoietic stem cell?”  – are now available on the Foundation’s You Tube channel. Click here to view them.

The final instalment of the series,“What is a neural stem cell?” narrated by Dr. Sam Weiss, will be released soon. Stay tuned!

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04
Feb 2015
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‘Cancer is not beyond us’

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Today is World Cancer Day. Under the tagline “Not beyond us,” the campaign’s goal is to raise awareness about the leading cause of death in Canada.…

Today is World Cancer Day. Under the tagline “Not beyond us,” the campaign’s goal is to raise awareness about the leading cause of death in Canada. Cancer is responsible for 30% of all deaths.

This year’s global campaign encourages prevention, early detection, treatment and care. Its message is a simple one: solutions to fight cancer are within our reach.

Stem cells represent a valid treatment option for certain types of blood cancers and solid tumours, and there is hope that more stem cell therapies for cancer will be available in the near future.blood

Canadian scientists are at the forefront of cancer research.  One of the major contributions to the field comes from Dr. John Dick, senior scientist at Princess Margaret Cancer Centre and the McEwen Centre for Regenerative Medicine in Toronto. He was the first to isolate cancer stem cells — in leukemia in 1994 and in colon cancer in 2007. Recently, he and his team found a way to disarm a gene called BMI-1 that regulates colorectal cancer stem cells.

But there is potential to do more. The Canadian Stem Cell Strategy & Action Plan, could lead to novel treatments for cancer. In fact, the goal of the Strategy is for Canada to lead the way in delivering five to 10 safe and effective treatments for chronic diseases within 10 years.

By making stem cell research a national priority Canada has the potential to show that cancer is “not beyond us.”

 

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06
Jan 2015
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Researchers find many cancers are ‘bad luck’

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Credit: C. Tomasetti, B. Vogelstein and illustrator Elizabeth Cook, Johns Hopkins

We all know that unhealthy lifestyles and genetics increase the risk of developing cancer, but a new study suggests that hereditary or environmental factors are not the primary cause of two-thirds of cancer types.…

Credit: C. Tomasetti, B. Vogelstein and illustrator Elizabeth Cook, Johns Hopkins

Credit: C. Tomasetti, B. Vogelstein and illustrator Elizabeth Cook, Johns Hopkins

We all know that unhealthy lifestyles and genetics increase the risk of developing cancer, but a new study suggests that hereditary or environmental factors are not the primary cause of two-thirds of cancer types. Instead, misfortune plays a large part.

According to the study, published in Science and widely reported on in the media, 65% of adult cancers are mainly due to “bad luck,” or random genetic mistakes that occur during the process of cell division in the body.

“All cancers are caused by a combination of bad luck, the environment and heredity, and we’ve created a model that may help quantify how much of these three factors contribute to cancer development,” DrBert Vogelstein of the Johns Hopkins University School of Medicine said in a media release.

Cell division is constantly happening in the body to replace old cells. Sometimes genetic mutations occur during the process. As might be expected, the risk of mistakes increases with the increased number of cell divisions. Drs Vogelstein and Cristian Tomasetti, analyzed the total number of stem cell divisions in 31 tissue types during an individual’s lifetime, excluding breast and prostate cancers. They estimated that 22 cancer types were a result of genetic mutations occurring during the normal cell division process and could not be avoided. These include leukemia, pancreatic, bone, ovarian and brain cancers.

“If two-thirds of cancer incidence across tissues is explained by random DNA mutations that occur when stem cells divide, then we should focus more resources on finding ways to detect such cancers at early, curable stages.” said Dr. Tomasetti in a report by The Telegraph carried in the National Post.

According to the researchers, other cancers, such as colorectal, skin and lung cancers are heavily influenced by genes and exposure to cancerous agents, such as smoking for lung cancer, UV exposure for skin cancer and poor diet for colorectal cancer.

Does the new finding mean we should abandon our efforts to prevent cancer? Not at all.

“Everything we know about altering lifestyles to prevent cancer from the environmental point of view we absolutely need to continue doing. If anything our finding puts more stress on the need to spend even more money on early detection,”  Dr. Tomasetti told Time magazine.

“About half of all cancers can be prevented through healthy living and healthy public policies,” Gillian Bromfield of the Canadian Cancer Society said in a statement. “We encourage Canadians to lower their risk of cancer by not smoking, eating well, being active, sitting less, maintaining a healthy body weight, limiting alcohol, being safe in the sun and avoiding indoor tanning.”

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18
Dec 2014
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Saying goodbye to Professor Donald Metcalf

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The world of haematology research is mourning the loss of one of its giants, Prof. Donald Metcalf, who has died at the age of 85.…

The world of haematology research is mourning the loss of one of its giants, Prof. Donald Metcalf, who has died at the age of 85.

A native of New South Wales, Australia, Prof. Metcalf received a Carden Fellowship in cancer research at Melbourne’s Walter and Eliza Hall Institute of Medical Research in 1954.

Starting from an interest in leukemia, Prof. Metcalf focused his research on blood cell production. Following the findings of Canada’s Drs. James Till and Ernest McCulloch, who first isolated stem cells in 1961, Prof. Metcalf and his team discovered colony-stimulating factors (CSFs), hormones that regulate white blood cell production.

The discovery of CSFs has had a significant impact on the recovery of cancer patients after chemotherapy. The injection of CSFs can reduce susceptibility to life-threatening infections by increasing the number of blood cells responsible for fighting those infections.

“Over the past 20 years, more than 20 million cancer patients have been treated with CSFs and, as a result, have been given the best possible chance of beating their cancer. There can be no greater legacy for a medical researcher.” according to a tribute by Prof. Douglas HiltonDirector of Walter and Eliza Hall Institute Of Medical Research, and Profs. Warren Alexander and Nicos Nicola, Heads of Institute’s Division of Cancer and Haematology.

Despite many opportunities across the world, Prof. Metcalf spent 60 years as a Carden Fellow at the Institute, even after his official retirement in 1996. He received several Australian and international awards for his work. Among these were the Companion of the Order of Australia (1993), the Albert Lasker Award for Clinical Medical Research (1993) and the Robert Koch Prize (1998).

Diagnosed with pancreatic cancer in August, Prof. Metcalf, also known as “the father of modern haematology,” performed his last experiment in October and died surrounded by his family on Monday.

 

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24
Oct 2014
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Tricky science made simple, part IV

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Back in June, we announced the release of another StemCellShorts video: “What is a cancer stem cell?” narrated by Dr.

Back in June, we announced the release of another StemCellShorts video: “What is a cancer stem cell?” narrated by Dr. John Dick. Stem Cell Shorts is a series of about-a-minute-long informative videos produced by Ben Paylor, a PhD candidate at the University of British Columbia, and Dr. Mike Long, a post-doctoral fellow at the University of Toronto.

Dr. Dick, senior scientist at Princess Margaret Cancer Centre and the McEwen Centre for Regenerative Medicine, was the first to isolate cancer stem cells — in leukemia in 1994 and in colon cancer in 2007. Recently, he and his team found a way to disarm a gene called BMI-1 that regulates colorectal cancer stem cells.

The new video is co-sponsored by the Canadian Stem Cell Foundation and the Stem Cell Network.

All the videos — including “What is a stem cell?” narrated by Dr. Jim Till, “What are embryonic stem cells?” voiced by Dr. Janet Rossant, “What are induced pluripotent stem cells?” narrated by Dr. Mick Bhatia, and “What is a cancer stem cell?” — are now available on the Foundation’s You Tube channel. Click here to view them.

Another instalment, “What is a retinal stem cell?” narrated by Dr. Derek van der Kooy, will be released soon.

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24
Apr 2014
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Gene that regulates leukemia will take time (and patience) to tame

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While patience is a virtue for most of us, it is an absolute prerequisite for stem cell researchers.

The recent news that scientists have identified a gene called BRG1 that appears to regulate leukemia stem cells marks an important advance in understanding the dread disease.…

While patience is a virtue for most of us, it is an absolute prerequisite for stem cell researchers.

The recent news that scientists have identified a gene called BRG1 that appears to regulate leukemia stem cells marks an important advance in understanding the dread disease. It also signifies years of work by the team led by Dr. Julie Lessard at the Institute for Research in Immunology and Cancer (IRIC) of Université de Montréal.

“About four years,” says Dr. Lessard, pictured left, one of Canada’s leading researchers in the field of hematopoiesis — the art of blood production.

Using mice as subjects, Dr. Lessard’s team found that removing the BRG1 gene left the leukemia stem cells and progenitors unable to survive, divide and make new tumors, permanently shutting down the cancer.  But while they are delighted with their findings, the researchers know they are in for many more years of work.

“We need to identify BRG1 inhibitors that will work in vitro (in test tubes and Petri dishes) and in vivo (with animals and humans),” says Dr. Lessard. “We believe that it is the ATPase activity that is the essential function we need to target for potential drug development, so that’s what we’re going after.”

In essence, that means finding small molecules that can stifle BRG1, the research equivalent to finding a needle in a haystack. Fortunately, IRIC is equipped with computer-driven high throughput screening to search their library of about 120,000 molecules for one that will do the trick. “We are hoping we can get there in the coming years,” she says.

Dr. Lessard’s findings further strengthen Canadian leadership in the field of stem cells and hematopoiesis. It was two Ontario Cancer Institute researchers — Drs. James Till and Ernest McCulloch — who first proved the existence of stem cells in the early 1960s while trying to find new treatments for leukemia. Dr. John Dick, of Toronto’s University Health Network, first identified tumour-initiating cancer stem cells in 1997.

What’s particularly intriguing about Dr. Lessard’s findings is that shutting down the BRG1 gene only appears to affect leukemia-generating stem cells. “Its function in the normal stem cell is rather modest. So you can take the gene out of leukemic cells and it will shut them down without shutting down the other stem cells you need to continue growth.”

While Dr. Lessard is excited about this project, she’s realistic about the amount of time and work involved.

“First of all, we have to have a very solid preclinical product to test in animals.  We think that a therapeutic window must exist. And this is what makes this study more interesting. It will be very exciting to explore in the coming years.”

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13
Feb 2014
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Our gold medal stem cell scientists

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While Canada’s athletes continue to pile up medals at the Winter Olympics in Sochi and prove their prowess on ice and snow, our stem cell scientists are demonstrating that they too are the best in the world.…

While Canada’s athletes continue to pile up medals at the Winter Olympics in Sochi and prove their prowess on ice and snow, our stem cell scientists are demonstrating that they too are the best in the world.

On the same day that 1,000-metre speed skater Denny Morrison came off the bench (courtesy of team mate Gilmore Junio surrendering his spot) to win silver, Dr. John Dick’s team at the University Health Network in Toronto showed the world what the origins of leukemia look like, publishing their findings in the prestigious journal Nature. That news comes hard on the heels of fellow UHN researcher Dr. Gordon Keller’s discovery of a key regulator that controls the formation of blood-forming stem cells, published in the top-tier Cell.

Both papers represent advances in how we understand and may someday treat disease. Without wanting to sound over-the-top patriotic, both prove that, as a nation, we continue to do outstanding work in the field founded by two Canadians — Drs. James Till and Ernest McCulloch — more than 50 years ago.

Essentially, Dr. Dick has identified a “pre-leukemic stem cell” that appears to initiate acute myeloid leukemia (AML) and, because chemotherapy doesn’t eradicate it, allows the disease to come back. Readers of this blog will recall that Dr. Dick was the first in the world to identify cancer stem cells. He proved that just as stem cells produce millions of specialized cells to build and repair tissues and organs (while also renewing themselves), cancer stem cells drive the production of millions of tumour cells (while also replicating themselves).

“What we found is the first normal cell, the cell of origin, that actually sets off the of cascade events, which is going to ultimately lead to leukemia,” Dr. Dick explains in the UHN video above. “So, one of the direct implications and benefits of our findings is that we should be able to detect leukemia before it arises. And, by identifying patients like that earlier, we should be able to follow them and introduce therapy an earlier stage.”

It should be pointed out that this is very early-stage work. To have application in cancer prevention or care, scientists must find a drug that can target a mutation in the gene called DNMT3 that causes these pre-leukemic stem cells to develop. Such a drug would have to be rigorously tested, something that could take years. But it’s still a very important advance.

“What’s John’s given us is something to go after before the disease gets out of hand,” says Dr. Mick Bhatia, Director of the McMaster Cancer and Stem Cell Biology Research Institute. “That’s a huge gift. It’s like stories about the unicorn. He has identified it, now we have to figure out how to capture it. What we have to grapple with is: ‘Are these pre-leukemic cells targetable?’ ‘Can you diagnose them?’ and ‘Can you shut them down before they become leukemic?'”

In his discovery, Dr. Keller, Director of the McEwen Centre for Regenerative Medicine, identified a key regulator controlling the formation of blood-forming stem cells in the early embryo. He focused on retinoic acid, which is produced from vitamin A and is vital in growth. His team demonstrated that the retinoic acid signalling pathway is critical to making blood-forming stem cells. In experiments with mice, the researchers found that blocking the pathway blocked the formation of blood-making stem cells. Activating it pathway set off an upsurge of blood-forming stem cells.

“Our findings have identified a critical regulator for directing pluripotent stem cells to make blood-forming stem cells, bringing us one step closer to our goal of developing a new and unlimited source of these stem cells for transplantation for the treatment of different blood cell diseases,” says Dr. Keller in Medical News Today.

This discovery is also early-stage work, but also very important, says Dr. Bhatia.

“He is capturing a pathway that is critical for when the first blood stem cell is born and how it makes copies of itself — the self-renewal process. That is going to be instrumental in how we move forward clinically.”

While neither finding is a cure for cancer, both are important steps forward on the path to get there. To push the Olympics analogy a bit further, this is like winning a preliminary competition that allows you compete in the medal round.

Except this is not a game and in this medal round, the prize is much more precious than gold.

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