Stories about: Program in Cellular and Molecular Medicine

Transfusing engineered red blood cells to protect against autoimmune disease

Red blood cells, pictured here, could be engineered to protect against autoimmune disease
Transfusions of engineered red blood cells could help prevent and/or treat autoimmune disease.

Autoimmune disease is usually treated using general immunosuppressants. But this non-targeted therapy leaves the body more susceptible to infection and other life-threatening diseases.

Now, scientists at Boston Children’s Hospital, the Massachusetts Institute of Technology (MIT) and the Whitehead Institute for Biomedical Research think they may have found a targeted way to protect the body from autoimmune disease. Their approach, published in Proceedings of the National Academy of Sciences, uses transfusions of engineered red blood cells to re-train the immune system. Early experiments in mice have already shown that the approach can prevent — and even reverse — clinical signs of two autoimmune diseases: a multiple-sclerosis (MS)-like condition and Type 1 diabetes.

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Protecting immune cells from exhaustion

T cell exhaustion
Boosting a naturally occurring protein could prevent T-cells from burning out

Run the first half of a marathon as fast as you can and you’ll likely never finish the race. Run an engine at top speed for too long and you’ll burn it out.

The same principle seems to apply to our T cells, which power the immune system’s battle with chronic infections like HIV and hepatitis B, as well as cancer. Too often, they succumb to “T cell exhaustion” and lose their capacity to attack infected or malignant cells. But could T cells learn to pace themselves and run the full marathon?

That’s the thinking behind a research study published last week by The Journal of Experimental Medicine. “Our research provides a clear explanation for why T cells lose their fighting ability,” says Florian Winau, MD, “and describes the countervailing process that protects their effectiveness.”

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Bridging academia and industry: Q & A with scientist and entrepreneur Timothy Springer

Timothy Springer on entrepreneurship

Biological chemist and molecular pharmacologist Timothy A. Springer, PhD, is poised at the nexus of academia and industry. As an academic — currently at Harvard Medical School, the Program in Cellular and Molecular Medicine at Boston Children’s Hospital and the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center — he has used monoclonal antibodies as research tools to unravel key mysteries of the immune system. As an entrepreneur, his discoveries — and those of others he has backed — have successfully launched seven companies. Drawing from his own entrepreneurship experience, he now aims to create his own innovation center, focused on accelerating antibody science toward drug discovery while helping nurture and mentor young scientist entrepreneurs. Vector sat down with Springer for his insights.

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Timothy Springer: scientist, serial entrepreneur and social advocate

Tim Springer resized

At the dawn of his career, immunologist, biological chemist, molecular pharmacologist and seven-time biomedical entrepreneur Timothy Springer thought science was a bad idea. “I was suspect of the purposes that science had been put to,” he says, “making Agent Orange and napalm.”

It was 1966, and Springer was a Yale undergrad thinking, “What the hell good is this Ivy League education? The best and brightest, the Ivy League-educated people, totally screwed up in getting us into the Vietnam War.”

So he dropped out. For a year, he lived on a Native American reservation in Nevada for Volunteers in Service to America (VISTA). He helped the Tribal Council draft resolutions, launched a 4-H club and lobbied for paved roads so kids could go to school.

Finally, he returned to school at the University of California, Berkeley — trying anthropology, sociology and psychology. Switching to biochemistry his junior year, Springer asked his advisor, scientific visionary Daniel Koshland, Jr., former editor of Science, “Do you think I can do this — graduate with a degree in biochemistry?”

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When antibiotics fail: A potential new angle on severe bacterial infection and sepsis

bacterial infection sepsisBacterial infections that don’t respond to antibiotics are of rising concern. And so is sepsis — the immune system’s last-ditch, failed attack on infection that ends up being lethal itself. Sepsis is the largest killer of newborns and children worldwide and, in the U.S. alone, kills a quarter of a million people each year. Like antibiotic-resistant infections, it has no good treatment.

Reporting this week in Nature, scientists in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine (PCMM) describe new potential avenues for controlling both sepsis and the runaway bacterial infections that provoke it.

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‘Hotspots’ for DNA breakage in neurons may promote brain genetic diversity, disease

DNA breakage brain
DNA breaks in certain genes may help brains evolve, but also can cause disease (Constantin Ciprian/Shutterstock)

As organs go, the brain seems to harbor an abundance of somatic mutations — genetic variants that arise after conception and affect only some of our neurons. In a recent study in Science, researchers found about 1,500 variants in each of neurons they sampled.

New research revealing the propensity of DNA to break in certain spots backs up the idea of a genetically diverse brain. Reported in Cell last month, it also suggests a new avenue for thinking about brain development, brain tumors and neurodevelopmental/psychiatric diseases.

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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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How our neutrophils might sabotage wound healing in diabetes

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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Drawing a ring around antiviral immunity

Ubiquitin RIG-I innate antiviral immunity Sun Hur
Ubiquitin (pink ovals) doesn’t just tag proteins for recycling. It also may help keep our antiviral immune response in balance. (Image courtesy: Sun Hur)

If you follow cancer biology, then you’ve probably heard of ubiquitin before. Ubiquitin tags a cell’s damaged or used proteins and guides them to a cellular machine called the proteasome, which breaks them down and recycles their amino acids. Proteasome-blocking drugs like Velcade® that go after that recycling pathway in cancer cells have been very successful at treating two blood cancers—multiple myeloma and mantle cell lymphoma—and may hold promise for other cancers as well.

Less well known, however, is the fact that ubiquitin helps normal, healthy cells raise an alarm when viruses attack. Ubiquitin works with a protein called RIG-I, part of a complex signaling pathway that detects viral RNA and triggers an innate antiviral immune response.

Sun Hur, PhD, a structural biologist in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine, has been studying RIG-I and other members of the innate cellular antiviral response for some time. And in a recent paper in Nature, she provided a structural rationale for how ubiquitin helps RIG-I do its job, and how that might help keep our immune system from getting out of hand.

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Catching platelets with NETs: Neutrophils and deep vein thrombosis

Sea cucumbers drive off attackers by expelling their innards. Neutrophils do the same, forming NETs to fight bacteria. But that same capability might also help fuel dangerous blood clots. (Anders Poulsen/Wikimedia Commons)

Sea cucumbers have an unusual way of defending themselves. When threatened, they ensnare their foes with sticky threads. Some even expel their own internal organs to repel attackers.

Immune system cells called neutrophils sometimes do much the same: When confronted with bacteria, they unravel and shoot out their chromatin—the tightly wound mix of DNA and proteins that keeps genes packaged in cells. The resulting molecular mesh, known as a neutrophil extracellular trap, or NET, traps and kills bacteria, providing an additional line of defense against bloodstream infections.

But neutrophils and NETs can go awry. Since 2010, Denisa Wagner, PhD, of the Program in Cellular and Molecular Medicine at Boston Children’s Hospital, has been studying NETs’ role in deep vein thromboses (DVTs)—blood clots that form in veins deep in the body where blood clots shouldn’t, usually in the legs.

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