Diamond Blackfan anemia (DBA) has long been a disease waiting for a cure. First described in 1938 by Louis K. Diamond, MD, of Boston Children’s Hospital and his mentor, Kenneth Blackfan, MD, the rare, severe blood disorder prevents the bone marrow from making enough red blood cells. It’s been linked to mutations affecting a variety of proteins in ribosomes, the cellular organelles that themselves build proteins. The first mutation was reported in 1999.
But scientists have been unable to connect the dots and turn that knowledge into new treatments for DBA. Steroids are still the mainstay of care, and they help only about half of patients. Some people eventually stop responding, and many are forced onto lifelong blood transfusions.
Researchers have tried for years to isolate and study patients’ blood stem cells, hoping to recapture the disease process and gather new therapeutic leads. Some blood stem cells have been isolated, but they’re very rare and can’t be replicated in enough numbers to be useful for research.
Induced pluripotent stem (iPS) cells, first created in 2006 from donor skin cells, seemed to raise new hope. They can theoretically generate virtually any specialized cell, allowing scientists model a patient’s disease in a dish and test potential drugs.
There’s been just one hitch. “People quickly ran into problems with blood,” says hematology researcher Sergei Doulatov, PhD. “iPS cells have been hard to instruct when it comes to making blood cells.” …
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. …
Your hospital just received a #1 ranking from U.S. News & World Report. What does this mean relative to your role there?
I’ve been at Boston Children’s Hospital for 25 years, and it’s really satisfying to be at the premier institution for clinical care. And we’re very lucky to have one of the premier stem cell programs in the world. I have a strong sense that my impact on society is as a physician-scientist, bringing basic discoveries to the clinic. We’re able to have a huge impact on finding new diagnoses and new therapies for our children.
What inspires you to do your job every day?
As a hematologist I take care of patients who have devastating diseases – a variety of blood diseases and cancer. When I see these children, I’m always wondering, could there be ways to treating them that haven’t been thought of before? Successfully treating a child gives them an entire lifetime of health. …
Scientists are now able to create cardiac heart muscle cells from patients with heart disease. But cells alone aren’t enough to fully study cardiac disorders — especially rhythm disorders that require the activity of multiple cells assembled into tissues.
Together with researchers at Harvard’s Wyss Institute, Pu’s lab recently modeled a rare rhythm disorder called catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT is a dangerous disease in which the heart’s rhythm can suddenly jolt abnormally without warning. Undetectable on a resting electrocardiogram (EKG), CPVT does not affect patients at rest. However, exercise or emotional upset trigger high levels of adrenaline, which can lead to life-threatening arrhythmia, cardiac arrest and possibly sudden death. …
Can you describe your work and its potential impact on patient care?
We modeled a form of heart-muscle disease in a dish. To do this, we converted skin cells from patients with a genetic heart muscle disease into stem cells, which we then instructed to turned into cardiomyocytes (heart-muscle cells) that have the genetic defect. We then worked closely with bioengineers to fashion the cells into contracting tissues, a “heart-on-a-chip.”
How was the idea that sparked this innovation born?
This innovation combined the fantastic, ground-breaking advances from many other scientists. It is always best to stand on the shoulders of giants. …
Since 2009, Boston Children’s Hospital has committed $6.2 million to support 58 hospital innovations ranging from therapeutics, diagnostics, medical devices and vaccines to regenerative medicine and healthcare IT projects. What a difference six years makes.
The Technology Development Fund (TDF) was proposed to Boston Children’s senior leadership in 2008 after months of research. As a catalyst fund, the TDF is designed to transform seed-stage academic technologies at the hospital into independently validated, later-stage, high-impact opportunities sought by licensees and investors. In addition to funds, investigators get access to mentors, product development experts and technical support through a network of contract research organizations and development partners. TDF also provides assistance with strategic planning, intellectual property protection, regulatory requirements and business models.
Seeking some “metrics of success” beyond licensing numbers and royalties (which can come a decade or so after a license), I asked recipients of past TDF awards to report back any successes that owed at least in part to data generated with TDF funds. While we expected some of the results, we would have never anticipated such a large impact. …
If you’ve lost your way on the Boston subway, you need only consult a map to find the best route to your destination. Now stem cell engineers have a similar map to guide the making of cells and tissues for disease modeling, drug testing and regenerative medicine. It’s a computer algorithm known as CellNet.
As in this map on the cover of Cell, a cell has many possible destinations or “fates,” and can arrive at them through three main stem cell engineering methods:
• reprogramming (dialing a specialized cell, such as a skin cell, back to a stem-like state with full tissue-making potential)
• differentiation (pushing a stem cell to become a particular cell type, such as a blood cell)
• direct conversion (changing one kind of specialized cell to another kind)
Freely available on the Internet, CellNet provides clues to which methods of cellular engineering are most effective—and acts as a much-needed quality control tool. …
At TEDx Longwood this spring, Leonard Zon, MD, founder and director of the Stem Cell Program at Boston Children’s Hospital, took the stage. In his enthusiastic yet humble style, he took the audience on a journey that included time-lapse video of zebrafish embryos developing, a riff by Jay Leno and a comparison of stem cell “engraftment” to a college kid coming home after finals: “You sleep for three days, and on day 4, you wake up and you’re in your own bed.” Three takeaways:
1) Stem cells made from our own skin cells can help find new therapeutics. With the right handling, they themselves can be therapeutics, producing healthy muscle, insulin-secreting cells, pretty much anything we need. (So far, this has just been done in mice.)
2) Zebrafish, especially when they’re see-through, can teach us how stem cells work and can be used for mass screening of potential drugs. The Zon Lab boasts 300,000 of these aquarium fish, and can mount robust “clinical trials” with 100 fish per group.
Severe burns, chemical injury and certain diseases can cause blindness by clouding the eyes’ corneas and killing off a precious population of stem cells that help maintain them. In the past, doctors have tried to regrow corneal tissue by transplanting cells from limbal tissue—found at the border between the cornea and the white of the eye. But they didn’t know whether the tissue contained enough of the active ingredient: limbal stem cells.
How cancer research led to a regenerative treatment for blindness.
Results have therefore been mixed. “Limbal stem cells are very rare, and successful transplants are dependent on these rare cells,” says Bruce Ksander, PhD, of the Massachusetts Eye and Ear/Schepens Eye Research Institute. “If you have a limbal stem cell deficiency and receive a transplant that does not contain stem cells, the cornea will become opaque again.”
Limbal stem cells have been sought for over a decade. That’s where a “tracer” molecule called ABCB5—first studied in the context of cancer—comes in. …