Stories about: Program in Cellular and Molecular Medicine

Protein science 2.0: Amping up antibodies

Institute for Protein Innovation antibody libraries
The Institute for Protein Innovation, launching next week with $15 million in grants and philanthropy, aims to develop comprehensive, open-source libraries of antibodies targeting human proteins.

It began with the proteins. Before Watson and Crick unraveled DNA’s double helix in the 1950s, biochemists snipped, ground and pulverized animal tissues to extract and study proteins, the workhorses of the body.

Then, in 1990, the Human Genome Project launched. It promised to uncover the underpinnings of all human biology and the keys to treating disease. Funding for DNA and RNA tools and studies skyrocketed. Meanwhile, protein science fell behind.

While genomics unveiled a wealth of information, including the identity of genes that lead to disease when mutated, researchers still do not fully understand what all the genes really do and how mutations change their function and cause disease.

Now proteins are promising to provide the missing link.

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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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Genetic analysis backs a neuroimmune view of schizophrenia: Complement gone amok

schizophrenia C4
C4 (in green) located at the synapses of human neurons. (Courtesy Heather de Rivera, McCarroll lab)

A deep genetic analysis, involving nearly 65,000 people, finds a surprising risk factor for schizophrenia: variation in an immune molecule best known for its role in containing infection, known as complement component 4 or C4.

The findings, published this week in Nature, also support the emerging idea that schizophrenia is a disease of synaptic pruning, and could lead to much-needed new approaches to this elusive, devastating illness.

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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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