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.
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? …
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.
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. …
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. …
Labs the world over are jumping onto 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.
Algorithms can predict the likely “off-target” edits based on the target’s DNA sequence, but they’re based on limited data. “The algorithms are getting better,” says Richard Frock, PhD, a fellow in the laboratory of Frederick Alt, PhD, at Boston Children’s Hospital. “But you still worry about the one rare off-target effect that’s not predicted but falls in a coding region and totally debilitates a gene.”
Frock, Alt (who leads Boston Children’s Program in Cellular and Molecular Medicine, or PCMM), fellow Jiazhi Hu, PhD, and their collaborators recently turned a method first developed in Alt’s lab for studying broken chromosomes into a quality assurance tool for genome editing. As a bonus, the method—called high-throughput genome translocation sequencing (HTGTS)—also reveals the “collateral damage” gene editing methods might create in a cell’s genome, information that could help researchers make better choices when designing gene editing experiments. …
CRISPR—a gene editing technology that lets researchers make precise mutations, deletions and even replacements in genomic DNA—is all the rage among genomic researchers right now. First discovered as a kind of genomic immune memory in bacteria, labs around the world are trying to leverage the technology for diseases ranging from malaria to sickle cell disease to Duchenne muscular dystrophy.
In a paper published yesterday in Cell Stem Cell, a team led by Derrick Rossi, PhD, of Boston Children’s Hospital, and Chad Cowan, PhD, of Massachusetts General Hospital, report a first for CRISPR: efficiently and precisely editing clinically relevant genes out of cells collected directly from people. Specifically, they applied CRISPR to human hematopoietic stem and progenitor cells (HSPCs) and T-cells.
“CRISPR has been used a lot for almost two years, and report after report note high efficacy in various cell lines. Nobody had yet reported on the efficacy or utility of CRISPR in primary blood stem cells,” says Rossi, whose lab is in the hospital’s Program in Cellular and Molecular Medicine. “But most researchers would agree that blood will be the first tissue targeted for gene editing-based therapies. You can take blood or stem cells out of a patient, edit them and transplant them back.”
The study also gave the team an opportunity to see just how accurate CRISPR’s cuts are. Their conclusion: It may be closer to being clinic-ready than we thought. …
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.
The idea behind SCNT is that the egg’s cellular environment kicks the transferred nucleus’s genome into an embryonic state, giving rise to an animal genetically identical to the nucleus donor. SCNT is also a technique for generating embryonic stem cells for research purposes.
While researchers have accomplished SCNT in many animal species, it could work better than it does now. It took the scientists who cloned Dolly 277 tries before they got it right. To this day, SCNT efficiency—that is, the percent of nuclear transfers it takes generate a living animal—still hovers around 1 to 2 percent for mice, 5 to 20 percent in cows and 1 to 5 percent in other species. By comparison, the success rate in mice of in vitro fertilization (IVF) is around 50 percent.
My first car was my grandfather’s 1980 Chevrolet Malibu. For about two years before my family gave it to me, it sat unused in Grandpa’s garage—just enough time for all of the belts and hoses to rot and the battery to trickle down to nothing.
Why am I telling this story? Because it’s much like what happens to the DNA in our blood-forming stem cells as we age.
Hematopoietic stem cells (HSCs) spend very little of their lives in an active, cycling state. Much of the time they’re quiescent or dormant, keeping their molecular and metabolic processes dialed down. These quiet periods allow the cells to conserve resources, but also give time an opportunity to wear away at their genes.
“DNA damage doesn’t just arise from mistakes during replication,” explains Derrick Rossi, PhD, a stem cell biology researcher with Boston Children’s Hospital’s Program in Cellular and Molecular Medicine. “There are many ways for damage to occur during periods of inactivity, such as reactions with byproducts of our oxidative metabolism.”
The canonical view has been that HSCs always keep one eye open for DNA damage and repair it, even when dormant. But in a study recently published in Cell Stem Cell, Rossi and his team found evidence to the contrary—which might tell us something about age-related blood cancers and blood disorders. …
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.
Your immune system’s B cells can produce antibodies against an amazing number of pathogens—viruses, bacteria, etc.—without ever having encountered them. That’s because, as they develop, your B cells reshuffle their antibody-producing genes into an amazing number of possible combinations—more than 100 million—to produce what’s called your primary pre-immune B cell repertoire.
It’s long been thought that in people and in mice this reshuffling process—called V(D)J recombination, after the B cells’ antibody-coding V, D and J gene segments—takes place in two places: the bone marrow and the spleen. But new research from a team led by Frederick Alt, PhD, and Duane Wesemann, MD, PhD, suggests that there may be one more place B cells go to undergo recombination: the gut. What’s more, that reshuffling in the gut may be influenced by the microbes that live there.