The National Institutes of Health maintains a library of drugs, the Clinical Collection, that are safe for humans but failed in clinical trials or didn’t make it to the market for other reasons. These compounds, numbering 450 to date, are just sitting on the shelf, waiting for a researcher to identify a disease process they might treat.
Repurposing such drugs could potentially save the pharmaceutical industry time and money. Getting a new drug from R&D to market currently takes $2 to 3 billion and 13 to 15 years. In contrast, some estimate that repurposing a safe drug could cost just $300 million and take just 6.5 years.
Pfizer, one of the biggest pharma companies in the world, saw the appeal. It just launched SpringWorks Therapeutics, a mission-driven company dedicated to reviving shelved drugs to treat underserved diseases. In its pipeline are experimental therapies to treat four diseases that currently have no cure.
One of the earliest-stage candidates is senicapoc. …
Porphyrias, a group of eight known blood disorders, affect the body’s molecular machinery for making heme, which is a component of the oxygen-transporting protein, hemoglobin. When heme binds with iron, it gives blood its hallmark red color.
The different genetic variations that affect heme production give rise to different clinical presentations of porphyria — including one form that may be responsible for vampire folklore. …
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.
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.” …
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. …
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. …
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.
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.”
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.
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.
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. …