From the category archives:

Regenerative medicine

gene editing CRISPR T-cells stem cells HIV

The CRISPR system (red) at work.

CRISPR—a gene editing technology that lets researchers make precise mutations, deletions and even replacements in genomic DNA—is all the rage among genomic researchers right now. First discovered as a kind of genomic immune memory in bacteria, labs around the world are trying to leverage the technology for diseases ranging from malaria to sickle cell disease to Duchenne muscular dystrophy.

In a paper published yesterday in Cell Stem Cell, a team led by Derrick Rossi, PhD, of Boston Children’s Hospital, and Chad Cowan, PhD, of Massachusetts General Hospital, report a first for CRISPR: efficiently and precisely editing clinically relevant genes out of cells collected directly from people. Specifically, they applied CRISPR to human hematopoietic stem and progenitor cells (HSPCs) and T-cells.

“CRISPR has been used a lot for almost two years, and report after report note high efficacy in various cell lines. Nobody had yet reported on the efficacy or utility of CRISPR in primary blood stem cells,” says Rossi, whose lab is in the hospital’s Program in Cellular and Molecular Medicine. “But most researchers would agree that blood will be the first tissue targeted for gene editing-based therapies. You can take blood or stem cells out of a patient, edit them and transplant them back.”

The study also gave the team an opportunity to see just how accurate CRISPR’s cuts are. Their conclusion: It may be closer to being clinic-ready than we thought. Full story »

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Dolly sheep cloning somatic cell nuclear transfer epigenetics

Dolly the sheep, the first mammalian example of successful somatic cell nuclear transfer. (Toni Barros/Wikimedia Commons)

We all remember Dolly the sheep, the first mammal to be born through a cloning technique called somatic cell nuclear transfer (SCNT). As with the thousands of other SCNT-cloned animals ranging from mice to mules, researchers created Dolly by using the nucleus from a grown animal’s cell to replace the nucleus of an egg cell from the same species.

The idea behind SCNT is that the egg’s cellular environment kicks the transferred nucleus’s genome into an embryonic state, giving rise to an animal genetically identical to the nucleus donor. SCNT is also a technique for generating embryonic stem cells for research purposes.

While researchers have accomplished SCNT in many animal species, it could work better than it does now. It took the scientists who cloned Dolly 277 tries before they got it right. To this day, SCNT efficiency—that is, the percent of nuclear transfers it takes generate a living animal—still hovers around 1 to 2 percent for mice, 5 to 20 percent in cows and 1 to 5 percent in other species. By comparison, the success rate in mice of in vitro fertilization (IVF) is around 50 percent.

“The efficiency is very low,” says Yi Zhang, PhD, a stem cell biologist in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine. “This indicates that there are some barriers preventing successful cloning. Thus our first goal was to identify such barriers.” Full story »

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Hematopoietic hierarchy aging blood cell hematopoietic stem cell blood disorder Derrick Rossi

Blood-forming hematopoietic stem cells (top) give rise to all blood and immune cell types. In children with SCID, the steps leading to immune cells are broken.

In the world of fatal congenital immunodeficiency diseases, good news is always welcome, because most patients die before their first birthday if not treated. Babies with severe combined immunodeficiency disease, aka SCID or the “bubble boy disease,” now have more hope for survival thanks to two pieces of good news.

Transplants are looking up

First came a July paper in the New England Journal of Medicine (NEJM) by the Primary Immune Deficiency Treatment Consortium. This North American collaborative analyzed a decade’s worth of outcomes of hematopoietic stem cell transplant (HSCT), currently the only standard treatment option for SCID that has a chance of providing a permanent cure. Full story »

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cell fate map Boston subway

Credit: Samantha Morris, PhD, Boston Children's Hospital

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. Full story »

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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.

3)   Drugs discovered via zebrafish are in human clinical trials right now: A drug to enhance cord blood transplants for leukemia or lymphoma, and an anti-melanoma drug originally used to treat arthritis.

Zon, who co-founded the biopharm company Fate Therapeutics, will be part of a judging panel of clinicians and venture capitalists for the Innovation Tank at Boston Children’s Global Pediatric Innovation Summit + Awards (Oct. 30-31). Don’t miss it!

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A restored cornea grown from human ABCB5-positive limbal stem cells

A restored, clear cornea grown from ABCB5-positive limbal stem cells. (Image courtesy of the researchers)

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. Full story »

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Fat cells from mesenchymal stem cell transplant

The fat cells shown in yellow are descended from transplanted human mesenchymal stem cells (green) inside of a mouse after co-transplantation. The red stain shows native mouse fat cells.(Courtesy Juan Melero-Martin)

Joseph Caputo originally wrote this post for the Harvard Stem Cell Institute (HSCI). Vector editor Nancy Fliesler contributed.

Stem cell scientists had what first appeared to be an easy win for regenerative medicine when they discovered mesenchymal stem cells several decades ago. These cells, found in the bone marrow, can give rise to bone, fat and muscle tissue, and have been used in hundreds of clinical trials for tissue repair.

Uses range from tissue protection in heart attack and stroke to immune modification in multiple sclerosis and diabetes. Unfortunately, the results of these trials have been underwhelming. One challenge is that these stem cells don’t stick around in the body long enough to benefit the patient. Full story »

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spina bifida myelomeningocele

Prenatal cell therapy could avoid the need for invasive surgery to repair myelomeningocele.

The neural tube, which becomes the spinal cord and brain, is supposed to close during the first month of prenatal development. In children with spina bifida, it doesn’t close completely, leaving the nerves of the spinal cord exposed and subject to damage. The most common and serious form of spina bifida, myelomeningocele, sets a child up for lifelong disability, causing complications such as hydrocephalus, leg paralysis, and loss of bladder and bowel control.

New research from Boston Children’s Hospital, though still in animal models, suggests that standard amniocentesis, followed by one or more injections of cells into the womb, could be enough to at least partially repair spina bifida prenatally.

Currently, the standard procedure is to operate on infants soon after delivery. Full story »

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fountain of youth stem cellsThis post is condensed from a report from the Harvard Stem Cell Institute.

The liver has been a model of tissue regeneration for decades, and it’s well known that a person’s liver cells can duplicate in response to injury. Even if three-quarters of the liver is surgically removed, duplication alone can return the organ to its normal functioning mass. It’s why people are able to donate part of their liver to someone in need—like this mother to her son who was born with biliary atresia.

But what about people with more chronic liver damage? Researchers led by Fernando Camargo, PhD, of the Harvard Stem Cell Institute and Boston Children’s Hospital’s Stem Cell Program, have new evidence in mice that it may be possible to repair such liver disease by forcing mature liver cells to turn back the clock and revert to a stem cell-like state, able to generate functional liver progenitor cells to replace damaged tissue. Full story »

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Emir Seyrek Wiskott-Aldrich syndrome WAS gene therapy Dana-Farber/Boston Children's Cancer and Blood Disorders Center

Emir Seyrek was the first patient with Wiskott-Aldrich syndrome to be treated in the U.S. in an international gene therapy trial.

Seeing that his mother, Kadriye, wasn’t looking, Emir Seyrek got an impish grin on his face, the kind only a two-year-old can have. He quietly dumped his bowl of dry cereal out on his bed and, with another quick look towards his mother, proceeded to pulverize the flakes to dust with his toy truck. The rest of the room burst out laughing while his mother scolded him. Despite the scolding, though, the impish grin remained.

It was hard to believe that he arrived from Turkey six months earlier fighting a host of bacterial and viral infections. Emir was born with Wiskott-Aldrich syndrome (WAS), a genetic immunodeficiency that left him with a defective immune system. He was here because he was the first patient—of two so far—to take part in an international trial of a new gene therapy treatment for WAS at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. And that day he was having his final checkup at Boston Children’s Hospital’s Clinical and Translational Study Unit before going home. Full story »

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