Stories about: Program in Cellular and Molecular Medicine

To monitor health, simply trip the ‘nanoswitches’

WATCH: DNA nanoswitches change shape in the presence of biomarkers. The shape change is revealed in a process called gel electrophoresis. Credit: Wyss Institute at Harvard University

“Nanoswitches” — engineered, shape-changing strands of DNA — could shake up the way we monitor our health, according to new research. Faster, easier, cheaper and more sensitive tests based on these tools — used in the lab or at point of care — could indicate the presence of disease, infection and even genetic variabilities as subtle as a single-gene mutation.

“One critical application in both basic research and clinical practice is the detection of biomarkers in our bodies, which convey vital information about our current health,” says lead researcher Wesley Wong, PhD, of Boston Children’s Hospital Program in Cellular and Molecular Medicine (PCMM). “However, current methods tend to be either cheap and easy or highly sensitive, but generally not both.”

That’s why Wong and his team have adapted their DNA nanoswitch technology — previously demonstrated to aid drug discovery and the measure of biochemical interactions — into a new platform that they call the nanoswitch-linked immunosorbent assay (NLISA) for fast, sensitive and specific protein detection. It’s described this week in the Proceedings of the National Academy of Sciences.

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Finding what fuels the “runaway train” of autoimmune diseases

Competing B cells, pictured here, produce autoantibodies that contribute to autoimmune disease
Natural selection on a small scale: Immune cells called B cells battle each other to produce the best antibody. Here, green represents the B cells that are producing the “winning” antibody, which stamp out competing B cells (other colors). Credit: Carroll lab

A newly-unveiled discovery, four years in the making, could change the way we look at autoimmune diseases and our understanding of how and why immune cells begin to attack different tissues in the body.

“Once your body’s tolerance for its own tissues is lost, the chain reaction is like a runaway train,” says Michael Carroll, PhD, of Boston Children’s Hospital and Harvard Medical School (HMS). “The immune response against your own body’s proteins, or antigens, looks exactly like it’s responding to a foreign pathogen.”

A team led by Carroll has spent years investigating mouse models of lupus to better understand the ins and outs of autoimmune diseases. Its latest findings, published in Cell, reveal that rogue B cells — immune cells that produce antibodies and program the immune system to attack certain antigens — can trigger an “override” that launches the body into an autoimmune attack. Adding insult to injury, B cells’ immune targeting instructions can rapidly expand to order an attack on additional tissue types within the body.

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“Shapeshifter” that regulates blood clotting is visually captured for the first time

GIF of VWF, which regulates blood clotting, elongating and relaxing on loop
A single molecule of von Willebrand factor is visually captured, as it elongates and relaxes in response to blood flow conditions, for the very first time. Credit: Springer/Wong labs (Boston Children’s Hospital and Harvard Medical School)

We are normally born with a highly sophisticated array of molecules that act as “sentries,” constantly scanning our bodies for injuries such as cuts and bruises. One such molecular sentry, known as von Willebrand factor (VWF), plays a critical role in our body’s ability to stop bleeding.

To prevent hemorrhage or life-threatening blood clots, VWF must strike a delicate balance between clotting too little or too much. Researchers have long suspected that the mechanical forces and shear stress of blood flow could be closely-related to VWF’s function.

“In some ways, like in the movie Star Wars, VWF may be considered a Jedi knight in our body that can use ‘the force’ to guard the bloodstream,” says Timothy Springer, PhD, of Boston Children’s Hospital and Harvard Medical School (HMS).

It has not been possible to witness exactly how VWF senses and harnesses these mechanical forces — until now.

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Newly-discovered epigenetic mechanism switches off genes regulating embryonic and placental development

Artwork depicting DNA and the code of genes

A biological process known as genomic imprinting helps control early mammalian development by turning genes on and off as the embryo and placenta grow. Errors in genomic imprinting can cause severe disorders and profound developmental defects that lead to lifelong health problems, yet the mechanisms behind these critical gene-regulating processes — and the glitches that cause them to go awry — have not been well understood.

Now, scientists at Harvard Medical School (HMS) and Boston Children’s Hospital have identified a mechanism that regulates the imprinting of multiple genes, including some of those critical to placental growth during early embryonic development in mice. The results were reported yesterday in Nature.

“A gene that is turned off by epigenetic modifications can be turned on much more easily than a gene that is mutated or missing can be fixed,” said Yi Zhang, PhD, a senior investigator in the Boston Children’s Program in Molecular and Cellular Medicine, a professor of pediatrics at HMS and a Howard Hughes Medical Institute investigator. “Our discovery sheds new light on a fundamental biological mechanism and can lay the groundwork for therapeutic advances.”

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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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