Research

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2015




December 14, 2015

Putting Structure Around the Genetic Basis of Some Immune Diseases

The saying in the design world is that form follows function. But in biology, and protein biology in particular, it would be more correct to say that form begets function. Shape and structure are the foundation for most protein-based interactions in cells, and are why basic functions like receptor binding, antibody neutralization and gene transcription work.

Two enzymes in the immune system’s B cells, called RAG1 and RAG2, are a perfect example. Together, they form a complex that splices antibody-producing genes together in unique combinations through a process called V(D)J recombination. They do a similar job in T cells to build antigen-binding T-cell receptors (TCRs). In either case, the enzymes are essential to a robust immune response.

In a recent Cell paper, a team led by Hao Wu, PhD, of the Program in Cellular and Molecular Medicine (PCMM) at Boston Children’s Hospital and Maofu Liao, PhD, at Harvard Medical School used electronic microscopy to reveal how RAG1 and 2 interact at a structural level, both with each other and with DNA. The structural biology images they’ve created show plainly what mutations in the genes for these proteins do to cause disease.

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Hao Wu, Ph.D. 

HaoWu1

 
 
 
November 12, 2015

Using passenger alleles to elucidate the targeting of AID in Immunity

By Paul Guttry

Researchers in the laboratory of Frederick Alt at the Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine (PCMM) at Children's Hospital Boston, led by Leng-Siew Yeap and Joyce K. Hwang, have fundamentally changed our understanding of how the crucial mutagenic activity of activation-induced cytidine deaminase (AID) is targeted during antibody maturation.

In an article published online in Cell on November 19, 2015, they demonstrate that the DNA sequence encoding the antigen-binding variable (V) region of B-cell antibodies lies in a genomic location privileged for mutational diversification by AID.  Their study further reveals that no specialized mechanism beyond sufficient exposure to AID is required to generate antibodies whose neutralizing function depends on high levels of variable-region mutations and deletions.


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Related Investigator

Fred Alt, Ph.D. 

   
 November 4, 2015

Improved cell cloning technique makes the jump from mice to humans

By Tom Ulrich

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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Related Investigator

Yi Zhang

 
   
 October 22, 2015

Genomic loops keep genes and enzymes on track and out of trouble

The looping organization of DNA may itself be a basic form of gene control

BOSTON, Oct. 22, 2015 /PRNewswire-USNewswire/ -- A study of where and how an enzyme cuts DNA may have inadvertently revealed a basic principle of gene regulation, say researchers in Boston Children's Hospital's Program in Cellular and Molecular Medicine (PCMM). The study, reported in the journal Cell, suggests that the cell can lock or "sandbox" genes and enzymes that act on them within loops of DNA and protein, confining their activity to minimize the risk of genetic disaster.

In our cells, DNA and its associated proteins—a combination called chromatin—are folded and wrapped in complex ways to form chromosomes. Researchers have long noted within a chromosome, the chromatin is organized into a series of loops. These loops can range in size from a few thousand to nearly 2.5 million base pairs, large enough to contain one or more complete genes.

The study team—led by co-first authors Jiazhi Hu, PhD, and Yu Zhang, PhD, and senior author Frederick Alt, PhD—believes these loops may form the backbone of a fundamental organizing principle for genomic processes.

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Related Investigator

Fred Alt, Ph.D. 

 
 
   

A bias towards efficiency in antibody class switching

By Paul Guttry

Researchers in the laboratory of Frederick Alt of the Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine (PCMM) at Children's Hospital Boston have made important strides towards resolving a long-standing question about how different classes of antibodies are made. Led by Junchao Dong, Rohit A. Panchakshari, and Tingting Zhang in collaboration with teams at several other major research centers, the Alt lab adapted a highly specific and sensitive genetic assay they originated in 2011 to propose the existence of a guiding principle behind the production of viable antibodies by lymphocytes called B cells.

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Related Investigator

Fred Alt, Ph.D. 

 
   

How our neutrophils might sabotage wound healing in diabetes

By Tom Ulrich

When you get a cut or a scrape, your body jumps into action, mobilizing a complicated array of cells and factors to stem bleeding, keep the wound bacteria-free and launch the healing process.

For most of us, that process is complete in a couple of weeks. But for many people with type 1 and type 2 diabetes, delayed wound healing can have permanent consequences. For example, between 15 and 25 percent of diabetes patients develop chronic foot ulcers. Those ulcers are the root cause of roughly two-thirds of lower limb amputations related to diabetes.

Why don’t these wounds close? Blame a perfect storm of diabetic complications, such as reduced blood flow, neuropathy and impaired signaling between cells. According to research by Denisa Wagner, PhD, of Boston Children’s Hospital’s Program in Cellular and Molecular Medicine, a poorly understood feature of our immune system’s neutrophils may be one more ingredient in the storm.

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Related Investigator

Denisa D. Wagner, Ph.D. 

   

The Art of Endocytosis

On April 15, 2015, The Boston Globe described a new sculpture by artist Rudolfo Quintas, named "Absorption". This 880-pound digital media sculpture is the result of discussions had with Dr. Tomas Kirchhausen regarding the essential cellular process of endocytosis. Quintas spent three weeks in Kirchhausen's lab, where they discussed ways in which this process could be translated into an installation artwork.


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Tomas Kirchhausen, Ph.D.


   

When HIV and TB coexist: Digging into the roots of IRIS 

By Tom Ulrich

Millions of people worldwide suffer from co-infection with tuberculosis (TB) and HIV. While prompt antibiotic and antiretroviral treatment can be a recipe for survival, over the years, physicians have noticed something: two or three weeks after starting antiretrovirals, about 30 percent of co-infected patients get worse.

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Related Investigator

Anne Goldfeld, M.D.


   

A simpler way to measure complex biochemical interactions

By: Tom Ulrich

Life teems with interactions. Proteins bind. Bonds form between atoms, and break. Enzymes cut. Drugs attach to cell receptors. DNA hybridizes. Those interactions make the processes of life work, and capturing them has led to many medical advances.

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Can breast cancer cells tell each other to metastasize?

By Tom Ulrich


Not all cancer cells are created equal. In fact, to call a cancer a cancer, in the singular, is something of a misnomer. Really, a patient could be said to have cancers, as every tumor is actually a mixture of cells with different mutations and capabilities. 

One of those capabilities is the ability to escape the main tumor and spread, or metastasize, to other sites in the body. Not every cancer cell has this ability. But just like bacteria can share the ability to resist antibiotics, at least some cancer cells may be able to share the ability to spread.

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Related Investigator

Judy Lieberman, 

M.D., Ph.D. 



   

Shedding light on AID off-targeting and lymphoma

By: Paul Guttry

Researchers in the laboratory of Frederick Alt at the Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine (PCMM) at Boston Children's Hospital, led by Feilong Meng and in collaboration with teams at several other major centers working on the genetics of immunology and cancer, have identified a relationship between sites of convergent gene transcription, the presence of intragenic super-enhancers, and the mis-targeting of the mutagenic activity of activation-induced cytidine deaminase (AID).

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On the hunt for gene editing's collateral damage

By: Tom Ulrich

Labs the world over are jumping on the gene editing bandwagon (and into the inevitable patent arguments). And it's hard to blame them. As these technologies have evolved over the last two decades starting with the zinc finger nucleases (ZFNs), followed by transcription activator-like effector nucleases (TALENs) and CRISPR—they've become ever more powerful and easier to use.

But one question keeps coming up: How precise are these systems? After all, a method that selectively mutates, deletes or swaps specific gene sequences (and now can even turn genes on) is only as good as its accuracy.

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A promising strategy against HIV

Harvard researchers genetically ‘edit’ human blood stem cells

By: B. D. Colen, Harvard Staff Writer

Harvard Stem Cell Institute (HSCI) researchers at Massachusetts General(MGH) and Boston Children’s hospitals (BCH) for the first time have used a relatively new gene-editing technique to create what could prove to be an effective technique for blocking HIV from invading and destroying patients’ immune system.

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Related Investigator

Derrick Rossi, Ph.D.


 


   

Removing roadblocks to therapeutic cloning to produce stem cells

By: Tom Ulrich

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.

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Related Investigator

Yi Zhang, Ph.D.

 


 


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