Jane Finlayson

Time to rewrite the textbooks? Research redefines how stem cells make blood

sgupta — Thu, 05 Nov 2015 12:56:02 +0000

Time to rewrite the textbooks? Research redefines how stem cells make blood sgupta Thu, 11/05/2015 - 07:56

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“Think of it as moving from the old world of black-and-white television into the new world of high definition,” Professor John Dick says (photo courtesy UHN)

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Discovery reveals that we've been wrong about how human blood is made

Stem-cell scientists led by the University of Toronto's Dr. John Dick have discovered a completely new view of how human blood is made, upending conventional dogma from the1960s.

The findings, published online Nov. 5 in the journal Science, prove “that the whole classic ‘textbook’ view we thought we knew doesn’t actually even exist,” says Professor Dick, the principal investigator.

Dick is senior scientist at Princess Margaret Cancer Centre, University Health Network (UHN), and a professor in the department of molecular genetics at �Թϱ��.

“Instead, through a series of experiments we have been able to finally resolve how different kinds of blood cells form quickly from the stem cell – the most potent blood cell in the system – and not further downstream as has been traditionally thought,” says Dick, who holds a Canada Research Chair in Stem Cell Biology and is also director of the Cancer Stem Cell Program at the Ontario Institute for Cancer Research.

Below, Dick talks about the research

The research also topples the textbook view that the blood development system is stable once formed. Not so, says Dr. Dick. “Our findings show that the blood system is two-tiered and changes between early human development and adulthood.”

Co-authors Dr. Faiyaz Notta and Dr. Sasan Zandi from the Dick lab write that in redefining the architecture of blood development, the research team mapped the lineage potential of nearly 3,000 single cells from 33 different cell populations of stem and progenitor cells obtained from human blood samples taken at various life stages and ages.

“Our discovery means we will be able to understand far better a wide variety of human blood disorders and diseases”

For people with blood disorders and diseases, the potential clinical utility of the findings is significant, unlocking a distinct route to personalizing therapy.

Dick says: “Our discovery means we will be able to understand far better a wide variety of human blood disorders and diseases – from anemia, where there are not enough blood cells, to leukemia, where there are too many blood cells. Think of it as moving from the old world of black-and-white television into the new world of high definition.”

There are also promising implications for advancing the global quest in regenerative medicine to manufacture mature cell types such as platelets or red blood cells by engineering cells (a process known as inducing pluripotent stem cells), says Dick, who collaborates closely with Professor Gordon Keller of the department of medical biophysics at �Թϱ�� and a director of UHN’s McEwen Centre for Regenerative Medicine.

“By combining the Keller team’s ability to optimize induced pluripotent stem cells with our newly identified progenitors that give rise only to platelets and red blood cells, we will be able develop better methods to generate these mature cells,” he says. Currently, human donors are the sole source of platelets – which cannot be stored or frozen – for transfusions needed by many thousands of patients with cancer and other debilitating disorders.

Today’s discovery builds on Dick’s breakthrough research in 2011, also published in Science, when the team isolated a human blood stem cell in its purest form – as a single stem cell capable of regenerating the entire blood system.

“Four years ago, when we isolated the pure stem cell, we realized we had also uncovered populations of stem-cell like ‘daughter’ cells that we thought at the time were other types of stem cells,” says Dick. “When we burrowed further to study these ‘daughters’, we discovered they were actually already mature blood lineages. In other words, lineages that had broken off almost immediately from the stem cell compartment and had not developed downstream through the slow, gradual ‘textbook’ process.

“So in human blood formation, everything begins with the stem cell, which is the executive decision-maker quickly driving the process that replenishes blood at a daily rate that exceeds 300 billion cells.”

For 25 years, Dick’s research has focused on understanding the cellular processes that underlie how normal blood stem cells work to regenerate human blood after transplantation and how blood development goes wrong when leukemia arises. His research follows on the original 1961 discovery of the blood stem cell by Princess Margaret Cancer Centre scientists Dr. James Till and the late Dr. Ernest McCulloch, which formed the basis of all current stem-cell research.

The research published today was funded by the Canadian Institutes for Health Research, Canadian Cancer Society, Terry Fox Foundation, Genome Canada through the Ontario Genomics Institute, Ontario Institute of Cancer Research, a Canada Research Chair, the Ontario Ministry of Health and Long-term Care, and The Princess Margaret Cancer Foundation.

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Researchers show how a molecule can cause cancer

sgupta — Fri, 06 Jul 2012 10:37:46 +0000

Researchers show how a molecule can cause cancer sgupta Fri, 07/06/2012 - 06:37

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Dr. Tak Mak's research shows for the first time how a molecule known as a metabolite causes cancer

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A team of international researchers led by �Թϱ��’s Dr. Tak Mak has demonstrated how a molecule produced by a genetic mutation can cause leukemia – raising hope scientists can prevent the disease by blocking the mutation.

“For the first time, we have demonstrated how a metabolite can cause cancer,” says Professor Mak of the Princess Margaret Cancer Centre, University Health Network. “This sets the stage for developing inhibitors to block the mutation and prevent the production of this disease-initiating enzyme.”

Published July 4 in Nature, the research shows how a metabolite - a molecule which is produced by a mutated metabolic enzyme - can cause one of the most common types of leukemia in adults.

In the lab, Mak’s team genetically engineered a mouse model with the mutation in its blood system to mimic human acute myeloid leukemia (AML). They discovered that the gene mutation launches the perfect storm for the metabolite to trigger the blood system to increase the stem cells pool and reduce mature blood cells in the bone marrow.

The resulting condition creates a situation with similarities to myelodysplastic syndrome – one of the precursors to this type of leukemia.

“This is one of the most common mutations in AML,” says Mak. “We also found that it is the common mutation in about 40% of a specific type of lymphoma.”

The mutation is also known to be involved in about 70-90% of low-grade brain cancers (glioblastomas gliomas) and a variety of other cancers.

Mak, a professor in the Departments of Medical Biophysics and Immunology at �Թϱ��, is an internationally acclaimed immunologist renowned for his 1984 discovery of cloning the human T-cell receptor. His research team included scientists at Weill Cornell Medical College, New York City, and Agios Pharmaceuticals, Cambridge, Massachusetts.

The connection between cancer and metabolism has fascinated Mak and scientists at Agios; they were the first to identify the metabolite in research published in Nature (2009) and The Journal of Experimental Medicine (2010).

The metabolite is a by-product of a gene mutation of an enzyme initially discovered in brain cancers in 2008 by American scientists at Johns Hopkins in Baltimore and subsequently also linked to leukemia.

Mak’s interest in the blood system began as a young researcher three decades ago with Drs. Ernest McCulloch and James Till, the acclaimed “fathers of stem cell science” at Ontario Cancer Institute, the research arm of Princess Margaret Hospital, whose 1961 discovery of stem cells launched the new field. Today, Mak is Director of The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital.

Mak’s research was funded by grants from the Canadian Institutes of Health Research, the Ontario Ministry of Health and Long-Term Care and the Terry Fox Foundation. His research is also supported by The Princess Margaret Hospital Foundation.

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Drug treatment delays progression of prostate cancer

sgupta — Tue, 24 Jan 2012 11:17:44 +0000

Drug treatment delays progression of prostate cancer sgupta Tue, 01/24/2012 - 06:17

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Professor Neil Fleshner led the clinical trial showing that the drug dutasteride helps slow prostate cancer's progression. (UHN photo)

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Localized cancer responds to dutasteride

Treatment with the drug dutasteride (Avodart) and regular monitoring delays the progression of low-risk, localized prostate cancer, according to the results of a three-year clinical trial conducted by the University of Toronto’s Dr. Neil Fleshner.

The research also shows that the treatment reduces anxiety, said Fleshner, a professor of surgery and head of the Division of Urology at the University Health Network. The findings are published online Jan. 23 in The Lancet.

“The results prove that using active surveillance [regular monitoring] plus dutasteride is a viable, safe and effective treatment option for men who often undergo aggressive local treatment despite low risk of dying from the disease,” said Fleshner, who also holds the Love Chair in Prostate Cancer Prevention Research

“This is very good news for men with low-risk disease because aggressive treatment can have a major impact on their quality of life, with risks of impotence and incontinence.”

The three-year clinical trial enrolled 302 men between the ages of 48 and 82 diagnosed with low-risk localized prostate cancer and regularly monitored for clinical changes – a treatment option called “active surveillance”. In the trial, participants were randomized 1:1 to receive dutasteride or a matching placebo daily. The men also underwent biopsies at 18 months and three years.

The study showed that fewer men treated with dutasteride saw their cancer spread – 38 per cent compared with 48 per cent who received the placebo. As well, the final biopsies showed the men treated with the drug were cancer free – 36 per cent for the placebo group compared with 23 per cent for those taking the drug.

“The drug, currently commonly used to treat enlarged prostate, works by inhibiting the male sex hormone that causes the enlargement in the first place,” said Fleshner.

Fleshner noted that a small percentage of men reported drug-related side effects. including sexual difficulty with either desire or erections (five per cent), or breast tenderness or enlargement (three per cent).

“It’s important to realize that these drugs have been around for almost 20 years in clinical practice to treat enlarged prostates and so we have a wealth of knowledge about their side effects, which are reversible if the drug is stopped,” said Fleshner.

Participants were also assessed for cancer-related anxiety and the men on dutasteride reported feeling much less anxious because their biopsies and PSA blood test values improved, added Fleshner. (PSA – or prostate-specific antigen – is a blood test used to help diagnose prostate cancer.)

The Canadian Cancer Society estimates 25,500 new cases of prostate cancer will be diagnosed this year and that 4,100 men will die from the disease.

The clinical research was funded by GlaxoSmithKline. Fleshner is affiliated with The Campbell Family Cancer Research Institute at Princess Margaret Hospital and his research is also supported by The Princess Margaret Hospital Foundation.

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Combination treatment improves survival rate for prostate cancer

sgupta — Fri, 04 Nov 2011 09:16:26 +0000

Combination treatment improves survival rate for prostate cancer sgupta Fri, 11/04/2011 - 05:16

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November has become Movember, a time to grow mustaches in support of prostate cancer research. (Photo from Movember Foundation)

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