Stories about: PCMM

Why evolution is the challenge — and the promise — in developing a vaccine against HIV

HIV surrounds and attacks a cell.
HIV surrounds and attacks a cell.

To fight HIV, the development of immunization strategies must keep up with how quickly the virus modifies itself. Now, Boston Children’s Hospital researchers are developing models to test HIV vaccines on a faster and broader scale than ever before with the support of the Bill & Melinda Gates Foundation.

“The field of HIV research has needed a better way to model the immune responses that happen in humans,” says Frederick Alt, PhD, director of the Boston Children’s Program in Cellular and Molecular Medicine, who is leading the HIV vaccine research supported by the Gates Foundation.

The researchers are racing against HIV’s sophisticated attack on the human immune system. HIV, the human immunodeficiency virus, mutates much faster than other pathogens. Within each infected patient, one virus can multiply by the billions.

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Microbial murder mystery solved

Bacteria, pictured in Petri dish culture here, can become resistant to antibiotics - but not killer cells. Why? New research from Boston Children's Hospital helps solve this microbial murder mystery.Immune cells called “killer cells” target bacteria invading the body’s cells, but how do they do this so effectively? Bacteria can quickly evolve resistance against antibiotics, yet it seems they have not so readily been able to evade killer cells. This has caused researchers to become interested in finding out the exact mechanism that killer cells use to destroy bacterial invaders.

Although one way that killer cells can trigger bacterial death is by inflicting oxidative damage, it has not yet been at all understood how killer cells destroy bacteria in environments without oxygen.

Now, for the first time, researchers have caught killer cells red-handed in the act of microbial murder

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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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Science seen: A “wheel of death” for bacteria

inflammasome innate immunity

The innate immune system acts like a border patrol for the body, picking up bacteria and other invading pathogens using molecular sensors. One key player is the inflammasome, a multi-protein complex depicted here through cryo-electron microscopy (cryo-EM). Using structural biology tools like cryo-EM and X-ray crystallography, the Wu lab in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine show how protein components come together in inflammasomes to form a “wheel of death” against bacterial infection.

Once they detect an invader, inflammasomes send out signals that trigger infected cells to die using an inflammatory death pathway called pyroptosis. They also call for backup from the adaptive immune system, in the form of inflammation. (Image: Wu laboratory/Liman Zhang)

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Microptosis: Programmed death for microbes?

trypanosoma parasites immune defense apoptosis microptosis
Trypanosoma parasites in a blood smear. (CDC)

Of the various ways for a cell to die — necrosis, autophagy, etc. — apoptosis is probably the most orderly and contained. Also called programmed cell death (or, colloquially, “cellular suicide”), apoptosis is an effective way for diseased or damaged cells to remove themselves from a population before they can cause problems such as tumor formation.

“Apoptosis has special features,” says Judy Lieberman, MD, PhD, an investigator in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine. “It’s not inflammatory, and it activates death pathways within the cell itself.”

Conventional wisdom holds that apoptosis is exclusive to multicellular organisms. Lieberman disagrees. She thinks that microbial cells — such as those of bacteria and parasites — can die in apoptotic fashion as well. In a recent Nature Medicine paper, she and her team make the case for the existence of what they’ve dubbed “microptosis.” And they think it could be harnessed to treat parasitic and other infections.

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Improved cell cloning technique makes the jump from mice to humans

cells somatic cell nuclear transfer cloning
(Lonely/Shutterstock)

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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Sun Hur, PhD: Overcoming barriers to reveal innate immunity’s secrets

Self-discovery is a theme that unites Sun Hur’s life and work. Growing up with a passion for physics, Hur pursued a scientific career in chemistry before launching her own research group in biology. Today, Hur, an investigator in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine (PCMM), uses her considerable intellectual gifts to uncover how the immune system distinguishes self from non-self.

In the video above, produced by the Vilcek Foundation (which honors and supports foreign-born scientists and artists who have made outstanding contributions to society in the United States), Hur talks about her personal and scientific journey since coming to the U.S. from her native South Korea in 2000. Overcoming cultural and language barriers, she has turned her childhood fascination with order and chaos toward exploring how the innate immune system recognizes invaders, in particular disease-causing viruses that generate a double-stranded RNA during replication.

These studies, which could open doors to new treatments for cancer and inflammatory diseases, recently garnered her the Vilcek’s 2015 Prize for Creative Promise in Biomedical Science.

Adapted from announcements originally published by the Vilcek Foundation and the PCMM.

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

HIV (green dots) budding from a white blood cell. (CDC)
HIV (green dots) budding from a white blood cell. (CDC)

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.

The reason: immune reconstitution inflammatory syndrome, or IRIS. Doctors think it represents a kind of immune rebound. As the antiretrovirals start to work, and the patient’s immune system begins to recover from HIV, it notices TB’s presence and overreacts.

“It’s as though the immune system was blanketed and then unleashed,” says Luke Jasenosky, PhD, a postdoctoral fellow with Anne Goldfeld, MD, of Boston Children’s Hospital’s Program in Cellular and Molecular Medicine. “It then says, ‘I can start to see things again, and there are a lot of bacteria in here.'”

Though potentially severe, even fatal, IRIS may actually be a good sign: there is evidence that patients who develop it tend to fare better in the long run. But why does it arise only in some patients?

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A simpler way to measure complex biochemical interactions

DNA nanoswitches electrophoresis Wesley Wong PCMM Wyss Institute
Do you really need complex high-end analytical equipment to study molecular interactions, or will an electrophoresis gel do the trick?

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.

“Determining which molecules interact, and measuring the strength of these interactions is fundamental for many areas of research, from drug discovery to understanding the mechanisms underlying disease,” says Wesley P. Wong, PhD, a biophysicist with Boston Children’s Hospital’s Program in Cellular and Molecular Medicine (PCMM), Harvard Medical School and the Wyss Institute for Biologically Inspired Engineering.

Technologies abound for studying molecular-level interactions quantitatively. But most are complex and expensive, requiring dedicated instruments and specific training on how to prep samples and run the experiments.

Wong and his team, including graduate student Mounir Koussa and postdoctoral fellows Ken Halvorsen, PhD (now at the RNA Institute) and Andrew Ward, PhD, have created an alternative method that democratizes the process. Using electrophoresis gels, found in just about any biomedical laboratory, they’ve developed what they call DNA nanoswitches. These switches let researchers make interaction measurements without complex instruments, at a cost of pennies per sample.

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Can breast cancer cells tell each other to metastasize?

Extracellular vesicles exosomes microRNA breast cancer metastasis
Breast cancer cells might be able to give each other the ability to metastasize using microRNAs packaged into extracellular vesicles similar to these exosomes. (Photo: Kourembanas Laboratory, Boston Children's Hospital)

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.

According to a study by Judy Lieberman, MD, PhD, of Boston Children’s Hospital’s Program in Cellular and Molecular Medicine, breast cancer cells that can metastasize can tell those that can’t to turn that ability on. That conversation takes place via small pieces of RNA called microRNAs, delivered in microscopic packages called extracellular vesicles.

According to Lieberman, not only do her team’s data give insight into the metastatic process, they might also reveal the first example of cancer cells teaching each other.

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