Stories about: blood disorders

Medical milestone: Making blood stem cells in the lab

blood stem cells
The gradation of pink-to-blue cells illustrates the transition from hemogenic endothelial cells to blood progenitor cells during normal embryonic blood development. Daley, Sugimura and colleagues recreated this process in the lab, then added genetic factors to produce a mix of blood stem and progenitor cells. (O’Reilly Science Art)

Pluripotent stem cells can make virtually every cell type in the body.  But until now, one type has remained elusive: blood stem cells, the source of our entire complement of blood cells.

Since human embryonic stem cells (ES cells) were isolated in 1998, scientists have tried to get them to make blood stem cells. In 2007, the first induced pluripotent stem (iPS) cells were made from human skin cells, and have since been used to generate multiple cell types, such as neurons and heart cells.

But no one has been able to make blood stem cells. A few have have been isolated, but they’re rare and can’t be made in enough numbers to be useful.

Now, the lab of George Daley, MD, PhD, part of Boston Children’s Stem Cell Research program as finally hit upon a way to create blood stem cells in quantity, reported today in Nature.

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Discovering a rare anemia in time to save an infant’s life

Illustration of the erythropoietin hormone. A newly-discovered genetic mutation, which switches one amino acid in EPO's structure, resulted in two cases of rare anemia.
An illustration showing the structure of a cell-signaling cytokine called erythropoietin (EPO). It has long been thought that when EPO binds with its receptor, EPOR, it functions like an on/off switch, triggering red blood cell production. New findings suggest that this process is more nuanced than previously thought; even slight variations to cytokines like EPO can cause disease.

While researching a rare blood disorder called Diamond-Blackfan anemia, scientists stumbled upon an even rarer anemia caused by a previously-unknown genetic mutation. During their investigation, the team of scientists — from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, the Broad Institute of Harvard and MIT and Yale University — had the relatively unusual opportunity to develop an “on-the-fly” therapy.

As they analyzed the genes of one boy who had died from the newly-discovered blood disorder, the team’s findings allowed them to help save the life of his infant sister, who was also born with the same genetic mutation. The results were recently reported in Cell.

“We had a unique opportunity here to do research, and turn it back to a patient right away,” says Vijay Sankaran, MD, PhD, the paper’s co-corresponding author and a principal investigator at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “It’s incredibly rewarding to be able to bring research full circle to impact a patient’s life.”

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Rare blood disorder sideroblastic anemia slowly reveals its genetic secrets

congenital sideroblastic anemia
Regardless of the gene, all patients with sideroblastic anemia have sideroblasts: red blood cell precursors with abnormal iron deposits in mitochondria, shown here ringing the cell nucleus. (Paulo Henrique Orlandi Mourao/Wikimedia)

A decade ago, Brooks McMurray’s routine check-up was anything but routine. The suburban Boston boy’s spleen was enlarged. His red blood cell count was low and the cells were very small and very pale, which suggested a serious iron deficiency anemia. The family pediatrician referred McMurray, now a 19-year-old college freshman, to Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

There hematologists discovered the boy had unexpectedly high iron levels. Together with pathologist Mark Fleming, MD, DPhil, they solved the mystery. McMurray has congenital sideroblastic anemia, an inherited blood disorder so rare that fewer than 1,000 cases have been reported worldwide. Iron was getting stuck in the wrong place in the precursor red blood cells developing in his bone marrow.

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Rainbow-hued blood stem cells shed new light on cancer, blood disorders

color-coded blood stem cells
These red blood cells bear color tags made from random combinations of red, green and blue fluorescent proteins. Same-color cells originate from the same blood stem cell (Nature Cell Biology 2016, Henninger et al).

A new color-coding tool is enabling scientists to better track live blood stem cells over time, a key part of understanding how blood disorders and cancers like leukemia arise, report researchers in Boston Children’s Hospital’s Stem Cell Research Program.

In Nature Cell Biology today, they describe the use of their tool in zebrafish to track blood stem cells the fish are born with, the clones (copies) these cells make of themselves and the types of specialized blood cells they give rise to (red cells, white cells and platelets). Leonard Zon, MD, director of the Stem Cell Research Program and a senior author on the paper, believes the tool has many implications for hematology and cancer medicine since zebrafish are surprisingly similar to humans genetically.

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Tool helps interpret subtle DNA variants from genome-wide association studies

Genome-wide association studies are huge undertakings that compare the genomes of large populations. They can turn up thousands to tens of thousands of genetic variants associated with disease. But which GWAS variants really matter?

That question becomes exponentially harder when the variants lie in the vast stretches of DNA that don’t encode proteins, but instead have regulatory functions.

“It’s hard to know which hits are causal hits, and which are just going along for the ride,” says Vijay Sankaran, MD, PhD, a pediatric hematologist/oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and an associate member of the Broad Institute.

Reporting in Cell, Sankaran’s team and two other groups at the Broad Institute describe a new tool that can looks at hundreds of thousands of genetic elements at once to pinpoint variants that truly affect gene expression or function. Called the massively parallel reporter assay (MPRA), it could help reveal subtle genetic influences on diseases and traits.

In Sankaran’s case, the MPRA is helping him understand how common variants contribute to blood disorders in children. “Most of the common variation is just tuning genetic function,” he says. “Just slightly, not turning it on or off, but actually just tuning it like a dimmer switch.”

The above video explains how the assay works – via DNA “barcodes.” Read more on the Broad Institute’s blog, Broad Minded.

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Stuart Orkin honored for his lifetime research on blood development

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Presenter Bill Evans, IBM Watson Health and Stuart H. Orkin, MD

When colleagues describe Stuart H. Orkin, MD, associate chief of hematology/oncology at Boston Children’s Hospital and chair of pediatric oncology at Dana-Farber Cancer Institute, the words “immeasurable,” “vanguard” and “mentor” quickly roll off the tongue.

In honor of his 35-year career and commitment to blood cell research, Boston Children’s Hospital presented Orkin with the 2015 Lifetime Impact Award, during Boston Children’s Global Pediatric Innovation Summit held this week. The award recognizes a clinician and/or researcher who has significantly impacted pediatric care through practice-changing innovations or discoveries and made extraordinary and sustained leadership contributions in health care throughout his or her career.

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Hematologist Vijay Sankaran receives Boston Children’s Hospital Rising Star Award

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Before an audience of several hundred luncheon attendees, physician-scientist Vijay G. Sankaran, MD, PhD, received Boston Children’s Hospital’s 2015 Rising Star Award — recognizing the outstanding achievements of an up-and-coming innovator under the age of 45 in pediatric health care.

Sankaran, a board-certified pediatric hematologist/oncologist with Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, conducts innovative research on red blood cell disorders such as Diamond-Blackfan anemia, sickle cell disease and thalassemia.

The Rising Star Award and companion Lifetime Impact Award ceremony were held at the hospital’s Global Pediatric Innovation Summit + Awards on November 10.

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The costs of quiescence, for cars and blood cells

Old car aging blood cell hematopoietic stem cell blood disorder Derrick Rossi
Like an old, unused car, our aging blood stem cells can accumulate damage over time that they can't fully repair.

My first car was my grandfather’s 1980 Chevrolet Malibu. For about two years before my family gave it to me, it sat unused in Grandpa’s garage—just enough time for all of the belts and hoses to rot and the battery to trickle down to nothing.

Why am I telling this story? Because it’s much like what happens to the DNA in our blood-forming stem cells as we age.

Hematopoietic stem cells (HSCs) spend very little of their lives in an active, cycling state. Much of the time they’re quiescent or dormant, keeping their molecular and metabolic processes dialed down. These quiet periods allow the cells to conserve resources, but also give time an opportunity to wear away at their genes.

“DNA damage doesn’t just arise from mistakes during replication,” explains Derrick Rossi, PhD, a stem cell biology researcher with Boston Children’s Hospital’s Program in Cellular and Molecular Medicine. “There are many ways for damage to occur during periods of inactivity, such as reactions with byproducts of our oxidative metabolism.”

The canonical view has been that HSCs always keep one eye open for DNA damage and repair it, even when dormant. But in a study recently published in Cell Stem Cell, Rossi and his team found evidence to the contrary­­—which might tell us something about age-related blood cancers and blood disorders.

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Is obesity on the rise among children with sickle cell disease?

Obese child on a scale
Obesity is more common in sickle cell disease than thought. Why?

Ask many doctors about their image of a child with sickle cell disease (SCD), and they’ll describe a short, skinny child, perhaps almost malnourished. For decades, that image was accurate.

That perception needs to change, though. A group of sickle cell specialists from hospitals in New England—members of the 11 institutions in the New England Pediatric Sickle Cell Consortium (NEPSCC)—recently made a surprising observation: Nearly a quarter of children with SCD are overweight or obese. The question is, why?

The answer may start with their red blood cells (RBCs).

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Customized cell therapy for untreatable diseases: Your tax dollars at work

Leonard Zon (top) and Massachusetts Lt. Governor Timothy Murray in the Stem Cell Program's zebrafish facility. (Courtesy MLSC)
Ed. Note: Leonard Zon, MD, is founder and director of the Boston Children’s Hospital Stem Cell Program, which yesterday was awarded $4 million by the Massachusetts Life Sciences Center to build the Children’s Center for Cell Therapy.

As a hematologist, I see all too many children battling blood disorders that are essentially untreatable. Babies with immune deficiencies living life in a virtual bubble, hospitalized again and again for infections their bodies can’t fight. Children disabled by strokes caused by sickle cell disease, or suffering through sickle cell crises that drug treatments can’t completely prevent. Children whose only recourse is to risk a bone marrow transplant—if a suitably matched donor can even be found.

Over the past 20 years, my lab and that of George Daley, MD, PhD, at Boston Children’s Hospital have worked hard to give these children a one-time, potentially curative option—a treatment that begins with patients’ own cells and doesn’t require finding a match.

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