BONNIE BASSLER receives Shaw Prize in life science and medicine

PHOTO BY ALENA SOBOLEVA

PHOTO BY ALENA SOBOLEVA

Bonnie Bassler, the Squibb Professor in Molecular Biology and chair of the Department of Molecular Biology, was named a 2015 Shaw Laureate in life science and medicine on June 1, 2015. Awarded by the Hong Kong-based Shaw Foundation, the Shaw Prize honors recent breakthroughs by active researchers in the fields of mathematics, astronomy, and life and medical sciences.

Bassler was recognized for her well-known work in quorum sensing, a widespread process that bacteria use for cell-to-cell communication. Understanding quorum sensing “offers innovative ways to interfere with bacterial pathogens or to modulate the microbiome for health applications,” according to the prize citation. Bassler, a Howard Hughes Medical Institute investigator, shares the $1 million prize with E. Peter Greenberg, a University of Washington professor of microbiology. The 2015 prizes were awarded during a Sept. 24 ceremony in Hong Kong.

–By Morgan Kelly

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How to train your worm to explore the circuits involved in learning

Angelina Sylvain

Angelina Sylvain, a graduate student in the Princeton Neuroscience Institute, trains C. elegans roundworms to associate food with the smell of butterscotch for her studies of the neural circuits involved in learning and memory. (Photo by Molly Sharlach)

AS AN UNDERGRADUATE, Angelina Sylvain was fascinated to learn that devastating declines in cognition and muscle coordination could be caused by changes in a single gene — the cause of Huntington’s disease. She was intrigued by the fact that brain surgery on an epileptic patient cured him of seizures, but wiped out his ability to form short-term memories.

These remarkable discoveries first drew Sylvain to the field of neuroscience, though she never imagined that her own efforts to understand the human brain would involve training tiny worms.

A fourth-year graduate student in the Princeton Neuroscience Institute, Sylvain seeks to understand how the activities of neurons in the brain lead to particular behaviors and memories.

“The problem with studying the human brain is that we have 86 billion neurons,” she said. “But worms have only 302. And they’re transparent, so you can use imaging techniques to indirectly observe the activities of neurons.”

The millimeter-long roundworms, known by the scientific name Caenorhabditis elegans, can be found squirming underfoot in temperate environments. In the lab, they swim in petri dishes and feast on E. coli bacteria. Working with Coleen Murphy, an associate professor of molecular biology and the Lewis-Sigler Institute for Integrative Genomics, Sylvain teaches the worms to associate food with the scent of butanone, a chemical that smells like butterscotch.

During the training process, Sylvain tracks the activation of individual neurons as the worms learn to identify and move toward the alluring odor. She uses specially engineered worms in which specific neurons glow green in response to calcium ions, hallmarks of neuron activation. At first, only a sensory neuron lights up when the worms smell butanone. But after the worms learn to associate butanone with a meal, Sylvain can detect the activation of an entire neural circuit — a sensory neuron, an interneuron and a motor neuron. The motor neuron leads the worm to swim toward the scent.

By training the worms, Sylvain hopes to answer basic questions about how long-term memories are formed. She plans to examine the numbers and combinations of neurons required to establish memories, as well as the adaptability of memory-forming pathways. By eliminating specific neurons, she can test whether the worms can still form memories, and how the circuits change.

Sylvain relishes both the challenges and the rewards of academic research. “Academia offers a fantastic combination of the ability to teach and mentor, and also to ask awesome research questions,” she said. “It’s always a struggle when experiments fail. But when things finally work out, there’s a great sense of satisfaction that you’ve uncovered something nobody else knows.”

Coleen Murphy’s research group is funded by the National Institute on Aging of the National Institutes of Health.

–By Molly Sharlach

Captured on video: Virus-sized particle trying to enter cell

Virus video

Researchers captured video of a virus-like particle trying to enter a cell (Image courtesy of Kevin Welsher)

RESEARCHERS AT PRINCETON UNIVERSITY achieved an unprecedented look at a virus-like particle as it tries to break into and infect a cell. The video reveals the particle zipping around in a rapid, erratic manner until it encounters a cell, bounces and skids along the surface, and either lifts off again or, in much less time than it takes to blink an eye, slips into the cell’s interior. The work, conducted by Professor of Chemistry Haw Yang and postdoctoral researcher Kevin Welsher, was supported by the U.S. Department of Energy and published in the Feb. 23, 2014, issue of Nature Nanotechnology.

–By Catherine Zandonella

Small RNAs fight cancer’s spread

Tumor cells spread toward bone

Breast cancer cells (right) spread toward the hindlimb bone (left), using natural bone-destroying cells (osteoclasts) to continue their advance. (Image courtesy of Yibin Kang)

Cancer patients may benefit from a dual strategy for tackling their disease in a class of molecules called microRNAs. Molecular biology graduate student Brian Ell has revealed that microRNAs — small bits of genetic material capable of repressing the expression of certain genes — may serve as both therapeutic targets and predictors of metastasis, or a cancer’s spread from its initial site to other parts of the body.

MicroRNAs are specifically useful for tackling bone metastasis, which occurs in about 70 percent of late-stage cancer patients. During bone metastasis, tumors invade the tightly regulated bone environment and take over the osteoclasts, cells that break down bone material. These cells then go into overdrive and dissolve the bone far more quickly than they would during normal bone turnover, leading to bone lesions and ultimately pathological conditions such as fracture, nerve compression and extreme pain.

“The tumor uses the osteoclasts as forced labor,” explained cancer metastasis expert in the Department of Molecular Biology Yibin Kang, who is Ell’s adviser. Their research is supported by the National Institutes of Health, the Department of Defense, the Susan G. Komen for the Cure Foundation, the Brewster Foundation and the Champalimaud Foundation.

MicroRNAs can reduce that forced labor by inhibiting osteoclast proteins and thus limiting the number of osteoclasts present, as Kang’s lab observed when mice with bone metastasis injected with microRNAs developed significantly fewer bone lesions. Their findings suggest that microRNAs could be effective treatment targets for tackling bone metastasis. And that’s not all: microRNAs may also help doctors detect the cancer’s spread to the bone, with trials in human patients demonstrating a strong correlation between elevated levels of another group of microRNAs and the occurrence of bone metastasis.

Kang, the Warner-Lambert/Parke- Davis Professor of Molecular Biology, said he ultimately hopes to extend mice experimentation to clinical trials. “In the end, we want to help the patients,” he said.

–By Tara Thean

Princeton role in federal BRAIN initiative

Princeton neuroscientists are poised to play a leading role in revolutionizing our understanding of the human brain as outlined in President Barack Obama’s BRAIN Initiative, announced in April 2013. David Tank, co-director of the Princeton Neuroscience Institute (PNI) and the Henry L. Hillman Professor in Molecular Biology, was named a member of the steering committee appointed to lay out the scientific strategy for the project.

–By Catherine Zandonella

Princeton research takes asymmetry to heart

Rebecca Burdine

Rebecca Burdine (left), assistant professor of molecular biology, and graduate student Jessica Rowland use zebrafish to study why heart defects occur and what can be done to prevent them.

Ask most people to draw a heart and they will make a symmetrical drawing with two equal sides. But the human heart is far from symmetrical. The right side is slightly smaller, built for pumping blood into the nearby lungs, while the left side is larger and made for propelling blood throughout the body. When defects in this asymmetric development occur, the result is often fatal. Congenital heart defects are the most common types of birth defects, affecting nearly 40,000 infants born in the United States each year.

Jessica Rowland, a graduate student in Princeton’s Department of Molecular Biology, is studying the genes that orchestrate this development of the two very different sides of the heart. What Rowland and her adviser, Rebecca Burdine, assistant professor of molecular biology, learn could aid our understanding of why heart defects occur and what we can do to prevent them.

The researchers use zebrafish as a model organism because the fish reproduce quickly and it is easy to manipulate their genes — knocking out their activity, or, alternatively, turning up their expression — then observe the outcome. In a room reminiscent of a pet store, floor-to-ceiling aquariums provide homes for roughly 15,000 of the silver-colored, half-inch-long fish.

The heart starts out as two symmetric clumps of cells, one on each side of the body. During embryonic development, these cells come together in the middle of the embryo and fuse to create a structure called the cardiac cone. Cells on the left side of this cone are exposed to a set of events called the Nodal signaling pathway. In zebrafish, the Nodal gene is called southpaw, because it is expressed only on the left side of the heart. This gene orchestrates the process as the entire cone rotates, tilts and elongates into a tube that extends asymmetrically to the left to take shape as the heart.

Rowland is exploring how expression of southpaw, specifically on the left, sets off other gene pathways that act downstream to cause the cells to migrate and elongate into the asymmetrically positioned tube. Rowland has a National Science Foundation pre-doctoral fellowship and the research is funded by the National Institute of Child Health and Human Development.

In a recent study, Rowland compared heart cells in which expression of the southpaw gene was either turned up or turned off. The researchers found that turning up southpaw expression led to the turning on of a handful of specific gene pathways. “Several of these pathways have to do with cell migration, which makes sense because the heart cells are moving to new locations,” Rowland said. The team is now exploring exactly how these pathways control heart cell migration and development.

 

Crescent-shaped bacteria reveal their secrets

Caulobacter cells

Inside the Caulobacter cell (green), CTP Synthase (red) forms filaments that curve the normally straight cells. (Image courtesy of Michael Ingerson-Mahar)

Nature is nothing if not green. It reduces, reuses and recycles whenever possible. Now Princeton researchers have discovered that bacteria can repurpose proteins used for cell growth into structural supports that maintain cell shape.

“We’ve identified a bacterial species that appears to have stolen something that evolved for a regulatory purpose and started using it for a structural purpose,” said Zemer Gitai, an associate professor of molecular biology. “This discovery hints at a paradigm for how structures such as the cytoskeleton have evolved.”

Gitai and his team found that a protein called CTP synthase — known to be crucial for producing the nucleic acid RNA that is essential for cell growth and energy — also keeps the cells of the bacteria Caulobacter crescentus in their distinctive crescent-roll shape. The researchers were among the first to discover that many of the cells’ proteins are fixed in place rather than free-floating inside the cell. CTP synthase was one of the proteins they had expected to see located throughout the cell.

The researchers observed that CTP synthase instead links up to form wispy, spider silk-like strings that are stocks of premade enzymes. Gitai theorized that they are a cell’s way of storing the enzymes for times when the cell needs to make new RNA quickly. The researchers found that C. crescentus’ shape is due to shortened CTP synthase strings on one side of the cell, which force the normally straight bacterium to curl into a crescent. The research was published in the journal Nature Cell Biology in August 2010, and supported by the U.S. Department of Energy Office of Science, the Human Frontiers Science Program and the Arnold and Mabel Beckman Foundation.

Eventually, Gitai said, studies of how cells create their own shapes and structures could aid our understanding of self-assembly, a feat common in nature but very unlike how humans build things. “We humans can learn a lot from studying how the cell accomplishes this feat,” he said.

 

 

Senior thesis research leads to potential cancer therapies

Kristan Scott

Kristan Scott (right) prepares a sample of yeast cells with Alison Gammie, senior lecturer in molecular biology.

For his senior thesis, Princeton molecular biology major Kristan Scott studied a mutant gene linked to colorectal cancer and to the cancer’s ability to resist chemotherapy. Scott helped find the ideal combination of cancer treatments that restored sensitivity to the drugs. This result suggests a potential new chemotherapeutic approach for treating certain cancers.

Scott worked with thesis adviser Alison Gammie, a senior lecturer in the Department of Molecular Biology who oversees a lab with Professor of Molecular Biology Mark Rose. The Gammie lab focuses on the role of mismatchrepair protein mutations in the growth of cancer. These proteins act as a kind of biological spell-check to ensure that genes are free of errors.

Scott focused his work on MSH2, a gene associated with hereditary non-polyposis colorectal cancer, which accounts for roughly 5 percent of all colorectal cancer cases. Mismatchrepair genes can experience mutations that make the MSH2 gene itself a mutant and can lead to colorectal and other cancers with a strong resistance to chemotherapy, Scott said.

Scott examined how the mutations in MSH2 bestow that strong defense against chemotherapy. He worked with the chemotherapy drug cisplatin — frequently used to treat colorectal cancer — and a yeast strain developed by Tim Arlow, a doctoral student in Gammie’s lab. The yeast strain was sensitive to a spectrum of drugs, yet had the defective MSH2 gene. Thus, the researchers knew the yeast should be responding to the treatment and could then better understand why cells with mutant MSH2 genes were resistant to cisplatin.

Scott helped figure out that a combination of cisplatin and a cancer treatment called bortezomib restored the sensitivity of some defective yeast strains to chemotherapy, an important result that expanded on Arlow’s work, Gammie said. The work was funded by the New Jersey Commission on Cancer Research.

 

Princeton biologist Bonnie Bassler receives L’Oréal-UNESCO For Women in Science award

Bonnie Bassler

Bonnie Bassler

Bonnie Bassler, the Squibb
Professor in Molecular Biology and
a Howard Hughes Medical Institute
Investigator, was among five scientists
worldwide selected to receive
the 2012 For Women in Science
Award presented by UNESCO and
cosmetics company L’Oréal. The
award, now in its 14th year, recognizes
women whose work promotes
the advancement of science. Bassler
and her fellow honorees received
their awards and a prize of $100,000
during a ceremony at the UNESCO
headquarters in Paris.
Bassler is the second Princeton
recipient after President Shirley M.
Tilghman, a renowned molecular
biologist who received the award in
2002. Bassler has been a faculty
member at the University since
1994 and is best known for her
efforts to understand quorum
sensing, the process by which
bacteria communicate.