Stories about: Regenerative medicine

Improved cell cloning technique makes the jump from mice to humans

cells somatic cell nuclear transfer cloning

Roughly a year ago we told you about Yi Zhang, PhD — a stem cell biologist in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine — and his efforts to make a cloning technique called somatic cell nuclear transfer (SCNT) more efficient.

With SCNT, researchers take an egg cell and replace its nucleus with that of an adult cell (such as a skin cell) from another individual. The donated nucleus basically reboots an embryonic state, creating a clone of the original cell.

It’s a hot topic in both agriculture and regenerative medicine. SCNT-generated cells can be used to clone an animal (remember Dolly the sheep?) or produce embryonic stem (ES) cell lines for research. But it’s an inefficient process, producing very few animal clones or ES lines for the effort and material it takes.

Zhang’s team reported last year that they could boost SCNT’s efficiency significantly by removing an epigenetic roadblock that kept embryonic genes in the donated nucleus from activating in cloned cells. Now, in a new paper in Cell Stem Cell, Zhang and his collaborators report that they’ve extended their work to improve the efficiency of SCNT in human cells.

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Gene sifting for gene snipping: GWAS as a source of gene editing targets

Magnifying glass people GWAS gene editing
(Digital Storm/Shutterstock)

When genome-wide association studies (GWAS) first started appearing 10 years ago, they were heralded as the answer to connecting human genetic variation to human disease. These kinds of studies—which sift population-level genetic data—have revealed thousands of genetic variations associated with diseases, from age-related macular degeneration to obesity to diabetes.

However, thus far GWAS have largely come up short when it comes to finding new therapies. Few significant drug targets have come to light based on GWAS data (though some studies suggest that these studies could help drug makers find new uses for existing molecules).

Part of the problem may be that, until now, the right tools haven’t been available to exploit GWAS data. But a few recent studies—including two out of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center—have used GWAS data to identify therapeutically promising targets, and then manipulated those targets using the growing arsenal of gene editing methods.

Does this mean that GWAS’ day has finally come?

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Rescuing intestinal stem cells from attack in diabetes

diabetic enteropathy and colonic stem cells
Blood levels of the hormone IGFBP3 (enterostaminine), shown here in green, are markedly elevated in people with longstanding type 1 diabetes and launch a lethal attack on intestinal stem cells. Adding a protein that soaks up the excess hormone restores normal stem cell function and could help prevent or treat diabetic enteropathy. (All images by Riseon)

Up to 80 percent of people with long-standing type 1 diabetes develop gastrointestinal symptoms—abdominal pain, bloating, nausea, vomiting, diarrhea, constipation and fecal incontinence—that severely diminish quality of life. Recent evidence suggests that this condition, known as diabetic enteropathy, results from damage to the intestinal lining, but the details beyond that have been unclear.

A study in this week’s Cell Stem Cell, led by Paolo Fiorina, MD, PhD, now provides some answers. It demonstrates how diabetes can lead to destruction of the stem cells that maintain the intestinal lining, and identifies a potential drug that could protect these stem cells and prevent or treat diabetic enteropathy.

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Stress-induced stem cells debunked: The final word on STAP

In early 2014, controversy erupted when two papers in Nature indicated that exposing ordinary cells to stress—an acid bath or mechanical stress—could quickly and efficiently turn them into pluripotent stem cells, capable of developing into virtually all the tissues in the body.

The technique, called “stimulus-triggered acquisition of pluripotency,” or STAP, was lauded for its simplicity compared to other methods like nuclear transfer into egg cells or cellular reprogramming with a set of transcription factors.

Not so fast.

Six months later, the papers were retracted. And this week in Nature, a team led by George Q. Daley, MD, PhD, director of the Stem Cell Transplantation Program at Boston Children’s Hospital, and Peter Park, PhD, head of the Computational Genomics Group at Harvard Medical School (HMS) details what went wrong. In a companion paper, the Daley Lab provides a roadmap for verifying a cell’s pluripotent status.

Read the full story on the HMS website.

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So far, so good for gene therapy patient Emir Seyrek

Emir Seyrek gene therapy Wiskott-Aldrich ThrivingRemember Emir Seyrek, the Turkish boy who last year was the first patient in gene therapy trial for a genetic immunodeficiency called Wiskott-Aldrich Syndrome? Emir traveled back to the U.S. earlier this month for an annual follow-up visit with his care team at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. The news was quite good.

“Emir is the star of the trial,” Sung-Yun Pai, MD—a Dana-Farber/Boston Children’s gene therapy and immunodeficiency transplant specialist and lead (along with David Williams, MD, and Luigi Notarangelo, MD) of the U.S. arm of the trial—tells our sister blog, Thriving. “He has the highest platelet count of all of the children who have gone through gene therapy with this vector so far. His immune function is excellent, and we have no worries whatsoever from a bleeding standpoint. He’s perfectly safe to play like a normal child.”

Learn more about Emir’s progress on Thriving.


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Supercharged marrow transplant: Zebrafish reveal drugs that aid engraftment

Zebrafish stem cell engraftment bone marrow
(Jonathan Henninger and Vera Binder)

Bone marrow transplantation, a.k.a. stem cell transplantation, can offer a cure for certain cancers, blood disorders, immune deficiencies and even metabolic disorders. But it’s a highly toxic procedure, especially when a closely matched marrow donor can’t be found. Using stem cells from umbilical cord blood banked after childbirth could open up many more matching possibilities, making transplantation safer.

Except for one problem. “Ninety percent of cord blood units can’t be used because they’re too small,” says Leonard Zon, MD, who directs the Stem Cell Research Program at Boston Children’s.

But what if the blood stem cells in those units could be supercharged to engraft more efficiently in the bone marrow and grow their numbers faster? That’s been the quest of the Zon lab for the past seven years, in partnership with a see-through zebrafish called Casper.

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Gene therapy to germline editing: Promises, challenges, ethics

A report this April rocked the scientific world: scientists in China reported editing the genomes of human embryos using CRISPR/Cas9 technology. It was a limited success: of 86 embryos injected with CRISPR/Cas9, only 71 survived and only 4 had their target gene successfully edited. The edits didn’t take in every cell, creating a mosaic pattern, and worse, unwanted DNA mutations were introduced.

“Their study should give pause to any practitioner who thinks the technology is ready for testing to eradicate disease genes during [in vitro fertilization],” George Q. Daley, MD, PhD, director of the Stem Cell Transplantation Program at Boston Children’s Hospital, told The New York Times. “This is an unsafe procedure and should not be practiced at this time, and perhaps never.”

As Daley detailed last week in his excellent presentation at Harvard Medical School’s Talks@12 series, the report reignited an ethical debate around tampering with life that’s hummed around genetic and stem cell research for decades. What the Chinese report adds is the theoretical capability of not just changing your genetic makeup, but changing the DNA you pass on to your children.

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Transplant surgeon seeks to avoid transplants

First in a two-part series on metabolic liver disease. Read part 2.

Khashayar Vakili, MDIn the clinical world, Boston Children’s Hospital surgeon Khashayar Vakili, MD, specializes in liver, kidney and intestinal transplant surgeries, while in the lab he is doing work which, for some patients, could eliminate the need for a transplant surgeon altogether.

Vakili has been working at Boston Children’s for six years. During his transplant surgery fellowship, he spent several months learning about pediatric liver transplantation from Heung Bae Kim, MD, director of the Boston Children’s Pediatric Transplant Center, which prompted his interest in the field.

“When the opportunity to join the transplant team presented itself, I did not hesitate to accept,” he says.

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Souped-up fish facility boosts drug discovery and testing

closeup of zebrafish-20150526_ZebraFishCeremony-60The care and feeding of more than 250,000 zebrafish just got better, thanks to a $4 million grant from the Massachusetts Life Sciences Center to upgrade Boston Children’s Hospital’s Karp Aquatics Facility. Aside from the fish, patients with cancer, blood diseases and more stand to benefit.

From a new crop of Boston-Children’s-patented spawning tanks to a robotic feeding system, the upgrade will help raise the large numbers of the striped tropical fish needed to rapidly identify and screen potential new therapeutics. It’s all part of the Children’s Center for Cell Therapy, established in 2013. We put on shoe covers and took a look behind the scenes. (Photos: Katherine Cohen)

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Fast-regenerating mice offer clues for stroke, spinal cord and optic nerve injury

axon regeneration CNS
The CAST mouse from Thailand–genetically distinct from most lab mice–may have the right ingredients for nerve regeneration. (Courtesy Jackson Laboratory)

Second in a two-part series on nerve regeneration. Read part 1.

The search for therapies to spur regeneration after spinal cord injury, stroke and other central nervous system injuries hasn’t been all that successful to date. Getting nerve fibers (axons) to regenerate in mammals, typically lab mice, has often involved manipulating oncogenes or tumor suppressor genes to encourage growth, a move that could greatly increase a person’s risk of cancer.

A study published online last week by Neuron, led by the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, took a completely different tactic.

Seeing little success at first, the researchers wondered whether they were working with the wrong mice.

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