News Article | April 17, 2017
Scientists have uncovered how our ancestors may have wiped out an ancient retrovirus around 11 million years ago. Retroviruses, which include human immunodeficiency virus (HIV), are abundant in nature. Unlike other viruses, which do not usually leave a physical trace of their existence, retroviruses include a step in their life cycle where their genetic material is integrated into the genome of their host. This integration has created a genetic fossil record of extinct retroviruses that is preserved in the genomes of modern organisms. Writing in the journal eLife, researchers from the Rockefeller University and the Howard Hughes Medical Institute (HHMI), US, set out to discover how extinct viral lineages could have been eliminated. To do this, they analysed retroviral fossils left by human endogenous retrovirus T (HERV-T), which replicated in our primate ancestors for approximately 25 million years before it was eradicated about 11 million years ago. Working with Robert Gifford from the University of Glasgow, the team first compiled a near-complete catalog of HERV-T fossils in old-world monkey and ape genomes. They then reconstructed the HERV-T retrovirus' outer envelope protein - a type of protein that allows a virus particle to bind to cells and begin the viral replication cycle. "Our analyses first suggested that HERV-T likely used a cell-surface protein called MCT-1 to bind to cells and infect ancient old-world primates," says first author Daniel Blanco-Melo, who carried out the study at the Rockefeller University but is now a postdoctoral researcher at the Icahn School of Medicine at Mount Sinai, New York. "Next, we identified one particular fossilised HERV-T gene in the human genome that encodes an unexpectedly well-preserved envelope protein. This gene was absent in non-hominid primate genomes, but was integrated into an ancestral hominid genome around 13 to 19 million years ago. We believe its function may have been switched around this time so that it could block infection by causing MCT-1 depletion from cell surfaces." Taken together, these findings suggest a scenario in which HERV-T began to infiltrate primate germlines (series of cells that are seen as continuing through successive generations of an organism) using MCT-1 as a receptor. Ancestral hominids later evolved a defence mechanism whereby they switched a HERV-T gene to serve as an antiviral gene against itself. "Broadly speaking, this study shows how analysing viral fossils can provide a wealth of insight into events that occurred in the distant past," says senior author Paul Bieniasz, HHMI Investigator and Professor of Retrovirology at the Rockefeller University. "In particular, it represents an example of how viruses themselves can provide the genetic material that animals use to combat them, sometimes leading to their own extinction." The paper 'Co-option of an endogenous retrovirus envelope for host defense in hominid ancestors' can be freely accessed online at http://dx. . Contents, including text, figures and data, are free to reuse under a CC BY 4.0 license. eLife is a unique collaboration between the funders and practitioners of research to improve the way important research is selected, presented, and shared. eLife publishes outstanding works across the life sciences and biomedicine -- from basic biological research to applied, translational, and clinical studies. All papers are selected by active scientists in the research community. Decisions and responses are agreed by the reviewers and consolidated by the Reviewing Editor into a single, clear set of instructions for authors, removing the need for laborious cycles of revision and allowing authors to publish their findings quickly. eLife is supported by the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust. Learn more at elifesciences.org.
News Article | April 18, 2017
MIT researchers have developed a way to make extremely high-resolution images of tissue samples, at a fraction of the cost of other techniques that offer similar resolution. The new technique relies on expanding tissue before imaging it with a conventional light microscope. Two years ago, the MIT team showed that it was possible to expand tissue volumes 100-fold, resulting in an image resolution of about 60 nanometers. Now, the researchers have shown that expanding the tissue a second time before imaging can boost the resolution to about 25 nanometers. This level of resolution allows scientists to see, for example, the proteins that cluster together in complex patterns at brain synapses, helping neurons to communicate with each other. It could also help researchers to map neural circuits, says Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT. “We want to be able to trace the wiring of complete brain circuits,” said Boyden, the study’s senior author. “If you could reconstruct a complete brain circuit, maybe you could make a computational model of how it generates complex phenomena like decisions and emotions. Since you can map out the biomolecules that generate electrical pulses within cells and that exchange chemicals between cells, you could potentially model the dynamics of the brain.” This approach could also be used to image other phenomena such as the interactions between cancer cells and immune cells, to detect pathogens without expensive equipment, and to map the cell types of the body. Former MIT postdoc Jae-Byum Chang is the first author of the paper, which appears in the April 17 issue of Nature Methods. To expand tissue samples, the researchers embed them in a dense, evenly generated gel made of polyacrylate, a very absorbent material that’s also used in diapers. Before the gel is formed, the researchers label the cell proteins they want to image, using antibodies that bind to specific targets. These antibodies bear “barcodes” made of DNA, which in turn are attached to cross-linking molecules that bind to the polymers that make up the expandable gel. The researchers then break down the proteins that normally hold the tissue together, allowing the DNA barcodes to expand away from each other as the gel swells. These enlarged samples can then be labeled with fluorescent probes that bind the DNA barcodes, and imaged with commercially available confocal microscopes, whose resolution is usually limited to hundreds of nanometers. Using that approach, the researchers were previously able to achieve a resolution of about 60 nanometers. However, “individual biomolecules are much smaller than that, say 5 nanometers or even smaller,” Boyden said. “The original versions of expansion microscopy were useful for many scientific questions but couldn’t equal the performance of the highest-resolution imaging methods such as electron microscopy.” In their original expansion microscopy study, the researchers found that they could expand the tissue more than 100-fold in volume by reducing the number of cross-linking molecules that hold the polymer in an orderly pattern. However, this made the tissue unstable. “If you reduce the cross-linker density, the polymers no longer retain their organization during the expansion process,” said Boyden, who is a member of MIT’s Media Lab and McGovern Institute for Brain Research. “You lose the information.” Instead, in their latest study, the researchers modified their technique so that after the first tissue expansion, they can create a new gel that swells the tissue a second time — an approach they call “iterative expansion.” Using iterative expansion, the researchers were able to image tissues with a resolution of about 25 nanometers, which is similar to that achieved by high-resolution techniques such as stochastic optical reconstruction microscopy (STORM). However, expansion microscopy is much cheaper and simpler to perform because no specialized equipment or chemicals are required, Boyden says. The method is also much faster and thus compatible with large-scale, 3-D imaging. The resolution of expansion microscopy does not yet match that of scanning electron microscopy (about 5 nanometers) or transmission electron microscopy (about 1 nanometer). However, electron microscopes are very expensive and not widely available, and with those microscopes, it is difficult for researchers to label specific proteins. In the Nature Methods paper, the MIT team used iterative expansion to image synapses — the connections between neurons that allow them to communicate with each other. In their original expansion microscopy study, the researchers were able to image scaffolding proteins, which help to organize the hundreds of other proteins found in synapses. With the new, enhanced resolution, the researchers were also able to see finer-scale structures, such as the location of neurotransmitter receptors located on the surfaces of the “postsynaptic” cells on the receiving side of the synapse. “My hope is that we can, in the coming years, really start to map out the organization of these scaffolding and signaling proteins at the synapse,” Boyden said. Combining expansion microscopy with a new tool called temporal multiplexing should help to achieve that, he believes. Currently, only a limited number of colored probes can be used to image different molecules in a tissue sample. With temporal multiplexing, researchers can label one molecule with a fluorescent probe, take an image, and then wash the probe away. This can then be repeated many times, each time using the same colors to label different molecules. “By combining iterative expansion with temporal multiplexing, we could in principle have essentially infinite-color, nanoscale-resolution imaging over large 3-D volumes,” Boyden said. “Things are getting really exciting now that these different technologies may soon connect with each other.” The researchers also hope to achieve a third round of expansion, which they believe could, in principle, enable resolution of about 5 nanometers. However, right now the resolution is limited by the size of the antibodies used to label molecules in the cell. These antibodies are about 10 to 20 nanometers long, so to get resolution below that, researchers would need to create smaller tags or expand the proteins away from each other first and then deliver the antibodies after expansion. This study was funded by the National Institutes of Health Director’s Pioneer Award, the New York Stem Cell Foundation Robertson Award, the HHMI-Simons Faculty Scholars Award, and the Open Philanthropy Project.
News Article | April 20, 2017
VIDEO: In this video and the paper published in the April 20 issue of Cell , Andrew Goodman's group present a powerful system to modulate gene expression of a common member of... view more Gut microbes play wide-ranging roles in health and disease, but there has been a lack of tools to probe the relationship between microbial activity and host physiology. Two independent studies in mice published April 20 in the journal Cell have overcome this hurdle, making it possible to simultaneously visualize multiple bacterial strains in the gut by making them express unique combinations of fluorescent proteins. This approach allowed the researchers to pinpoint the location of the bacteria in the gut based on the rainbow of colors they emitted. Additionally, these tools also allowed precise control of the activity of bacterial genes in real time and in specific locations. "We found that tools from synthetic biology can allow us to ask new questions about the gut microbiota," says Andrew Goodman of Yale University School of Medicine, senior author of one of the studies. "We also imagine these strategies may provide a starting point for on-demand delivery of therapeutics or other molecules from the microbiota." Advances in sequencing technology have enabled in-depth characterization of bacterial species found in the gut, but tools to manipulate the gut microbiome have lagged far behind. Although tools have been developed for model organisms such as Escherichia coli, these systems do not work in Bacteroides, the most abundant genus within the guts of people in the United States. In one of the studies, Justin Sonnenburg of the Stanford University School of Medicine and his team developed a way to engineer Bacteroides, making it possible to simultaneously track multiple bacterial strains in the gut. These tools included a panel of synthetic promoters--DNA sequences that initiate transcription of particular genes. Using this panel of promoters, the researchers genetically engineered six different Bacteroides species to produce unique combinations of a red fluorescent protein (RFP) called mCherry and green fluorescent protein (GFP). They introduced the engineered species into mice that had been raised in a germ-free environment, and after two weeks, they analyzed sections of colon tissue using a fluorescence microscope to pinpoint the location of the bacteria in different parts of the gut. In a separate experiment, Sonnenburg and his team genetically engineered two Bacteroides strains to produce either GFP or RFP. They then introduced the RFP-expressing strain into the mouse gut, followed by the GFP-expressing strain one week later. It was clear that the RFP-expressing strain successfully colonized the colon and outcompeted the GFP-expressing strain, especially in tube-like glands called crypts. The findings demonstrate that colonization of these specific intestinal structures is a key step that allows longer-term gut residents to outcompete invading species. In future research, Sonnenburg and his team will continue to develop these tools to engineer bacteria to produce proteins at a precise time or location. "On the commercial side, the expression tools may allow us to deliver therapeutic proteins to the gut by producing them in the microbes that live inside of us," says Weston Whitaker, lead author of the Stanford study. "The use of bacterial cells for drug delivery opens the door to smart therapeutics that are produced at the right time and location." In the other study, Yale's Andrew Goodman and his team also developed a panel of synthetic promoters enabling the fine-tuned control of gene activity in diverse Bacteroides species. The researchers integrated these promoters into the Bacteroides genome and modulated gene activity using a tetracycline-regulated system, which allows transcription to reversibly turn on or off depending on the presence of a synthetic compound called anhydrotetracycline. In the OFF state, gene activity controlled by the synthetic promoters was completely shut off, but in the presence of anhydrotetracycline, gene activity rapidly increased by a factor of 9,000. The researchers next introduced the engineered bacteria into mice and confirmed that their tools allow gene activity in gut bacteria to be tightly controlled, simply by adding different amounts of anhydrotetracycline to the drinking water of mice. If extended to humans, this approach could potentially enable on-demand delivery of therapeutic compounds. Moreover, precise control of bacterial gene activity in specific locations in the gastrointestinal tract could be achieved by administering anhydrotetracycline through different routes, for example, via time- or pH-dependent delayed release capsules or surgically through catheterization. In future studies, Goodman and his team will apply their system to other microbes and other types of interactions between gut microbes and their hosts. "These tools open the door to new types of studies to better understand our microbiota and to define how gut commensal bacteria can be engineered for therapeutic purposes," Sonnenburg says. "However, before gut commensals can be engineered for therapeutics, it will be important to develop methods of safely and reliably colonizing the human gut, which will require more research." Cell, Whitaker et al.: "Tunable Expression Tools Enable Single-Cell Strain Distinction in the Gut Microbiome" http://www.cell.com/cell/fulltext/S0092-8674(17)30370-7 DOI: 10.1016/j.cell.2017.03.041 This work was funded by Stanford's Discovery Innovation Fund in Basic Biomedical Sciences, the National Institutes of Health NIDDK, the National Science Foundation, and the Crohn's and Colitis Foundation of America. Three co-authors are founders of Novome Biotechnologies and have filed a provisional patent based on the work. Cell, Lim et al.: "Engineered Regulatory Systems Modulate Gene Expression of Human Commensals in the Gut" http://www.cell.com/cell/fulltext/S0092-8674(17)30374-4 DOI: 10.1016/j.cell.2017.03.045 This study was funded by grants from the National Institutes of Health, the Burroughs Wellcome Fund, the DuPont Young Professors, Pew Scholars, and HHMI Faculty Scholars Programs. Cell (@CellCellPress), the flagship journal of Cell Press, is a bimonthly journal that publishes findings of unusual significance in any area of experimental biology, including but not limited to cell biology, molecular biology, neuroscience, immunology, virology and microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. Visit http://www. . To receive Cell Press media alerts, contact firstname.lastname@example.org.
News Article | April 26, 2017
The Howard Hughes Medical Institute's (HHMI) Medical Research Fellows Program has selected 79 talented medical and veterinary students to conduct in-depth, mentored biomedical research. Fifty-three percent of the awardees are female, the greatest representation of women in the program to date. Starting this summer, each fellow will spend a year pursuing basic, translational, or applied biomedical research at one of 32 academic or nonprofit research institutions across the United States. "The Med Fellows Program allows exceptional MD, DVM, and DDS students to effectively shift course and conduct rigorous research at top institutions throughout the country," says David Asai, senior director in science education at HHMI. "It's an extraordinary opportunity for future physicians, veterinarians, and dentists to explore the intersection of medicine and scientific discovery, and we hope that each student comes away further empowered to pursue a career as a physician-scientist." Now, 28 years after the Med Fellows Program was first launched, it has helped more than 1,700 medical, veterinary, and dental students establish a foothold in the research world. In this year's group, 18% of the fellows are from minority groups typically underrepresented in the biomedical sciences, and seven fellows will continue their research for another year. Tolu Rosanwo, a second-year fellow and medical student at Case Western Reserve University School of Medicine, says the program is a gift, but for Rosanwo, it was a gift that left her wanting more. "I couldn't leave just as my research was starting to show promise," she says. "I'm still intrigued by my initial question, and I want to see it through." That initial question dates back to Rosanwo's childhood, growing up with two siblings with sickle cell anemia. Her curiosity about what caused them to be sick turned into a committed desire to understand and contribute to a treatment for the disorder. Now, in the laboratory of George Daley, Dean of Harvard Medical School and an alumnus of the HHMI Investigator Program, she's trying to tackle that question. "An important and profound place to be is in between science and patients," she says. "I want to be a physician whose patient care is informed by research, and vice versa." Anna Cheng, a first-year fellow and current medical student at University of South Florida Morsani College of Medicine, started dabbling in the scientific method as a high school student. Science had always interested her, but when her best friend and her godmother found themselves in a fight against cancer, Cheng decided to narrow her scientific focus. "My best friend was diagnosed with leukemia and my godmother with ovarian cancer. I wanted to understand why - to figure it out," she says. "Yes, I was interested in cancer research, but I had personal factors that really drove me." During her undergraduate studies at Duke University, Cheng continued to make time for lab research, fitting it in over summers and in between coursework. And though she valued the experiences, the fleeting glimpses of bench time only whet her appetite for more. The Med Fellows Program, she says, provided her the opportunity for more sustained exposure to research. "I feel so fortunate, because now I get to pursue a project for an entire year," she says. After a thoughtful pause, she amends her statement. "But the program's experience isn't really just a year. It's something that will serve me well for the rest of my career." The Med Fellows Program takes a multilevel mentoring approach to help incoming fellows get off to a strong start, make new connections, and access a network of support throughout their fellowship year. Various meetings bring the fellows together to connect with newly minted Med Fellow alumni, early-career faculty, and senior investigators to participate in seminars and learn from physician-scientists at various career stages. The most direct form of support comes from each fellow's mentor. Cathy Wu, an alumna from the early days of the Med Fellows Program and associate professor at the Dana-Farber Cancer Institute, will be mentoring her third med fellow this fall. "The fellows are such a terrific bunch - they're brimming with enthusiasm, super smart, and eager to learn," Wu says. As someone who took great inspiration from her own mentors as a student in the program, Wu emphasizes that the mentor-mentee relationship is a crucial part in learning how to approach investigation. "Part of the Med Fellows Program is getting a sense of the opportunities and resources available - having the latitude to explore and learn about the investigative process. When I was a fellow, the program helped me cement research as part of my medical career," she says. "I'm eager for these students to have their year, too." In collaboration with HHMI, five partners - the American Society of Human Genetics, Burroughs Wellcome Fund, Citizens United for Research in Epilepsy, Foundation Fighting Blindness, and Parkinson's Foundation - will fund 8 of the 79 aspiring physician- and veterinarian- scientists, bringing the program's total investment to $3.4 million. The Howard Hughes Medical Institute plays an important role in advancing scientific research and education in the United States. Its scientists, located across the country and around the world, have made important discoveries that advance both human health and our fundamental understanding of biology. The Institute also aims to transform science education into a creative, interdisciplinary endeavor that reflects the excitement of real research. HHMI's headquarters are located in Chevy Chase, Maryland, just outside Washington, D.C.
News Article | May 25, 2017
In a paper published today in Nature, the team lays out its methodology for using Betzig's lattice light sheet microscope in combination with image-tracking technology developed in Drexel's Computational Image Sequence Analysis Lab, led by Andrew Cohen, PhD, to produce 3-D time lapse videos of organelle movement and generate quantitative data on their interactions. "The cell biology community has recognized for many years that the cytoplasm is full of many different types of organelles, and the field is recognizing more and more how significant cross-talk between these organelles is in the form of close contacts between these organelles," said Jennifer Lippincott-Schwartz, PhD, of HHMI's Janelia Research Campus, and senior author of the study. "When two organelles come close to each other they can transfer small molecules like lipids and calcium and communicate with each other through that transfer. But no one has been able to look at the whole set of these interactions at any particular time. This technology is providing a way to do that. But this paper is about a whole new technology, being able to tag six different objects with six different fluorophores, and unmixing the fluorophores so that you can observe the six different objects discretely." Betzig's microscopy technique uses layers of light grids that interact with fluorescent protein-tagged cells to build a 3D microscopic image. At Janelia Research Campus, Betzig and Lippincott-Schwartz have refined that technology to produce a detailed look inside the cell by tagging each organelle type with its own color. "The challenge is analyzing this data," Lippincott-Schwartz said. "It requires being able to simultaneously track these six different objects in 3D. What Andy Cohen and his group have done with the software system they have developed is enable us to really look at this in more quantitative ways than would be possible with conventional tools." Cohen's lab developed a tool called LEVER 3-D in 2015 to help researchers study 3-D images of neural stem cells. It applies an advanced image segmentation algorithm they developed that can identify boundaries of cells and track their movements. Prior to this technology being available to microbiologists, the processing of microscopic images and time-lapse footage would take massive amounts of time because they would have to create lineage trees by hand and attempt to follow cell changes by making their own observations when comparing images. This process is even more involved when multiple objects are being tracked in three dimensions. Lippincott-Schwartz's group used a battery of computer programs to filter out all the different pieces of light spectra emitted by the organelles, to begin to bring the 3-D images and video into focus. The process, called "linear unmixing," required more than 32 cores of a computer work station to sift through 7 billion sets of six-color images, pixel by pixel. Typically they would use expensive commercial software programs to stitch them into a 3-D volume to go about studying them. But these programs are expensive and time-consuming to use, and were not capable of the sophisticated analysis for tracking moving objects in order to make quantitative measurements of their behaviors and particularly how they interact. Cohen's algorithm automates the entire process, which saves researchers a lot of time and it also lets them ask – and answer – more questions about what the cells are doing. He further verified the data by working with Drexel colleague Uri Herschberg, PhD, an associate professor in the School of Biomedical Engineering, Science and Health Systems and College of Medicine, to check it against 2-D images of the cells. "It's some really impressive footage that gives biologists this ability to look deeper and deeper into live cells and see things they've never seen before—like six different organelles in a living cell in true 3-D," said Cohen, a professor in Drexel's College of Engineering. "But it's also a lot of work to begin quantifying what they're seeing—and that's where we can help, by using our program to automate big portions of that process and glean valuable data from it." Using the new technology to simultaneously look at six sets of organelles, Lippincott-Schwartz's teams at Janelia and at the National Institutes of Health are making exciting new observations. They are looking at how the organelles distribute themselves inside the cell, how often they interact with each other and where, when and how fast they move during various times in the cell's lifecycle. "One very interesting outcome is that we found the largest organelle in the cell, which is the ER [endoplasmic reticulum], at any particular time point will be occupying about 25 percent of the volume of the cytoplasm, excluding the nucleus. But if you track the way it disperses through the cytoplasm over a short period of time, like 15 minutes, you see that it explores 95 percent of the whole cytoplasm during that time period," Lippincott-Schwartz said. "We can do this for all of the other organelles at the same time to see how the cytoplasm is being sensed through the dynamic motions of dispersive activities of these organelles." Observing sub-cellular behavior is just the first application of this technology. Now that it has proven to generate usable data, the team will forge ahead to study what happens inside a cell when it is exposed to drug treatments and other common stresses on the system. The researchers suggest that it could be used to study many more than six types of microscopic objects. And it could help dig even deeper into the building blocks of life—into interactions of RNA particles and other proteins that play a role in a cell's function and the behavior of diseased cells. "As these tools continue to improve they will give researchers both a better look at cell behavior and many options for gathering and analyzing that data," Cohen said. "They will be able to ask and answer increasingly complicated questions and that's going to lead to some very exciting and important discoveries." Explore further: How plant cell compartments change with cell growth More information: Alex M. Valm et al. Applying systems-level spectral imaging and analysis to reveal the organelle interactome, Nature (2017). DOI: 10.1038/nature22369
News Article | May 11, 2017
How do T cells, the beat cops of the immune system, detect signs of disease without the benefit of eyes? Like most cells, they explore their surroundings through direct physical contact, but how T cells feel out intruders rapidly and reliably enough to nip infections and other threats in the bud has remained a mystery to researchers. In a new study, published online May 11, 2017 in Science, UC San Francisco researchers began to address this question by using cutting-edge techniques to capture videos of the surface of living T cells in more detail than ever before. Researchers had previously observed tentacle-like protrusions called microvilli covering the surface of T cells, but the new research revealed that these tentacles are in constant motion: they crawl across the cell surface, each independently searching for signs of danger or infection in a fractal-like pattern that allows T cells to spend the minimum time necessary feeling for a potential threat before moving on. "Previous techniques had allowed us to take snapshots of the surface of T cells, but that's like trying to understand a basketball game by studying a black-and-white photo," said Matthew Krummel, PhD, associate professor of pathology at UCSF and senior author of the new study. "Now we can watch these amazing little fingers of membrane move around in real-time - and it turns out they're incredibly efficient." Among other potential benefits, Krummel says, understanding how T cells efficiently sample their environment to search for invasive pathogens opens up new questions about what countermeasures infectious organisms or even cancer cells may have evolved as a way of avoiding detection, and could suggest new ways for researchers to help T cells see through such a ruse. Efficient search by T cells is key to an effective immune response As they make their rounds through the body, T cells make contact with a network of informants -- other immune cells that scour the body for potential signs of danger and display the protein fragments they find (called "antigens") on their surface for inspection by the T cells. If a T cell meets one of these so-called antigen-presenting cells and recognizes a protein fragment it carries as evidence of danger, the T cell sounds the alarm and triggers a more global immune response to fight off the invaders. Scientists estimate that you have only about 100 T cells in your body at any given moment that can recognize and responding to a specific antigen, such a protein from this year's flu virus, and these few cells each take days to patrol your entire body, Krummel said. "This means the immune system really needs to get ahead of whatever is attacking the body at the very first evidence that there's an intruder on board. If one T cell misses the signs of a virus, the next time a cell that can recognize the threat might come through that tissue, the virus has had hours to make tens of thousands of copies of itself." New imaging techniques reveal how immune cells "talk" using touch In the Science study, Krummel's team was able to study how T cells efficiently interrogate antigen-presenting cells in real time, thanks to a high-resolution cellular imaging technique called lattice light-sheet microscopy, which the team set up at UCSF in collaboration with its inventor, 2014 Nobel prize winner and study co-author Eric Betzig, PhD, of the Howard Hughes Medical Institute's Janelia Research Campus in Virginia. Using this technology, the team studied mouse T cells exploring simulated patches of antigen-presenting cell membrane in laboratory dishes, and found that the T cell microvilli move independently of one another in a fractal-like geometry, such as is often seen in nature as a way of optimizing efficient use of space, such as by plant roots or foraging animals. The researchers calculated that, thanks to this efficient search pattern, in an average minute-long encounter win an antigen-presenting cell, T cell microvilli can thoroughly explore 98 percent of the contact surface between the two cells -- called an "immunological synapse" after the neuronal synapses of the nervous system. This suggests that T cells are tuned to spend the minimum time necessary to get a clear read on the information available at each antigen-presenting cell before moving on, the authors say. To study the details of threat detection by microvilli, the authors devised a new approach that allowed them to simultaneously track microvilli as well as the T cell receptor (TCR) proteins T cells use to detect their target antigens. To do this, the team covered simulated patches of antigen-presenting cell membrane with tiny fluorescent particles called quantum dots, which questing T cell microvilli had to push out of the way to reach the membrane surface. This technique, dubbed synaptic contact mapping, allowed the researchers to visualize the microvilli as holes of negative space in the quantum dot fluorescence, while at the same time visualizing TCRs with a different-colored fluorescent marker. They found that normally, individual microvilli poke and prod at the antigen-presenting cell membrane for an average of about four seconds at a time. But when the microvilli found the antigen they were searching for, they stayed in contact with the antigen-presenting cell membrane for 20 seconds or more and accumulated large rafts of TCRs, suggesting that they were likely signaling the T cell to trigger its immune response. "These videos give me a much more visceral understanding of what's happening when T cells and antigen-presenting cells come into contact," Krummel said. "T cells have these anemone-like sensory organs, and when they want to get information from another cell, their only chance appears to be during this short period of intimate contact. If they don't detect a strong signal during that contact, they move on." Real-time imaging technology opens new opportunities to study immunity and disease Krummel's team also briefly studied the surfaces of other types of immune cells, such as dendritic cells and B cells, which play different roles in pathogen detection and immune response. They found that each cell type appears to use distinct patterns of surface protrusions -- such as tentacles, waves, or curtain-like ripples -- to probe and communicate with their environments, though more research is needed to understand these diverse patterns and how they interact with one another. (See video.) "Understanding how the immune system reliably detects and responds to the huge range of potential threats it has to deal with is one of the key questions we still face as immunologists," Krummel said. "Of course, the immune system also makes mistakes -- like when it attacks the body's own cells in autoimmune disease or fails to recognize cancerous cells as a threat. Understanding the mechanics and constraints of how the immune system recognizes threats in the first place could potentially help us correct those errors." En Cai, PhD, Kyle Marchuk, PhD, Peter Beemiller, PhD, and Casey Beppler, BS, of UCSF, were co-first authors of the new study. Other authors were Matthew G. Rubashkin, PhD, Valerie M. Weaver, PhD, and Audrey Gérard, PhD, of UCSF; Tsung-Li Liu, PhD, and Bi-Chang Chen, PhD, of Janelia; and Frederic Bartumeus, PhD, of the Center for Advanced Studies of Blanes in Girona, Spain and Institut Català de Recerca i Estudis Avançats (ICREA) in Barcelona. Funding for this research was provided by the National Institutes of Health (AI052116), National Cancer Institute (U01CA202241), a US Department of Defense National Defense Science and Engineering Graduate Fellowship, and a National Science Foundation Graduate Research Fellowship (1650113). Betzig is an inventor on patent application US 20130286181 A1, submitted by Howard Hughes Medical Institute (HHMI), which covers LLS imaging. The authors declare no competing financial interests. About UCSF: UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland - and other partner and affiliated hospitals and healthcare providers throughout the Bay Area. Please visit http://www. .
News Article | May 9, 2017
Thin air can reverse brain damage due to mitochondrial defects in mice. After a month of breathing air that contains about half the usual amount of oxygen, telltale lesions in the brains of these mice had disappeared, Howard Hughes Medical Institute (HHMI) Investigator Vamsi Mootha and colleagues report online May 8 in the Proceedings of the National Academy of Sciences. "We found, much to our surprise and delight, that we could actually reverse advanced disease," Mootha said. "I don't think anybody thought that these types of neurological diseases could be reversible." It's a remarkable turnaround -- though the result was seen in mice, not humans. More research is needed before a similar approach could be used to treat people, cautions Mootha, a mitochondrial biologist at Massachusetts General Hospital in Boston. Still, the findings hint at the promise of low oxygen therapy to prevent, or even reverse, mitochondrial disorders in people. One such disorder is Leigh syndrome, a rare disease that often appears in the first few years of life. The disorder is marked by progressive brain lesions, a loss of motor skills, developmental delays and a failure to grow. Most forms of the disease have no proven treatments. Yet Mootha and his team had what seems like a counterintuitive idea. In 2016, the researchers reported that hypoxia, or oxygen deficiency, actually improves the health of mice genetically engineered to have dysfunctional mitochondria, tiny power-producing organelles. Those results, published in Science, were tantalizing, and also raised a number of questions, such as how long these treated mice actually live, and whether hypoxia treatment needs to be continuous. The new findings answer some of these questions. "At a high level, this is exploring the remarkable potential and also the limitations of hypoxia," Mootha said. The mice in the study were genetically engineered to lack a gene called Ndufs4, which encodes a protein essential for a part of mitochondria called complex I. That same gene is mutated in some people with Leigh syndrome. When these mice were housed in chambers that contained normal air containing 21 percent oxygen, the equivalent of what a person would breathe at sea level, they developed brain lesions and had a median survival length of 58 days. But when these mice were kept in chambers that contained 11 percent oxygen, their median survival time stretched to 270 days, Mootha and colleagues found. What's more, MRI images revealed these mice had no signs of abnormally bright brain tissue, lesions that often signal degeneration. Eleven percent oxygen is close to what a person would encounter at high altitudes such as the base camp at Mount Everest. "Is it super comfortable? Certainly not," Mootha said, but a healthy person would be able to tolerate it. Based on his team's earlier work, Mootha wasn't surprised that the mice treated with hypoxia lived longer. But a different result was unexpected: A switch to hypoxic conditions seemed to actually reverse existing brain damage. After a month of breathing low oxygen air, lesions in the mices' brains disappeared, MRI images revealed. While the results in the mice are "profound and striking," Mootha emphasized that the research is still at an early stage. Much more work needs to be done before hypoxia can be used to treat people with mitochondria disorders. "We are not ready yet to go into the clinic," he said. Other results help illustrate remaining hurdles to developing a hypoxia therapy. Mootha and his team had hoped to find benefits for more moderate low-oxygen conditions, such as intermittent periods of hypoxia or slightly higher levels of oxygen. But so far, the results suggest that only continuous 11 percent oxygen does the trick. "The disappointing part was that we didn't come up with a more practical regimen, at least in this paper," Mootha said. Still, he and his team plan to keep looking for other ways to get the hypoxia benefits without the intense hypoxia conditions, perhaps with a small molecule. The researchers also plan to study how exactly the hypoxia response works -- how low-oxygen conditions kindle molecular efforts to protect and repair the brain. The results have implications that stretch beyond mitochondrial diseases. Neurodegenerative disorders that have been associated with aging, and even normal aging, have been linked to a diminished mitochondrial power. "As all of us age, our mitochondrial activity declines," Mootha said. Hypoxia, or a drug that mimics a key aspect of it, might one day be able to rejuvenate flagging mitochondria, and perhaps the aging body, too.
News Article | May 9, 2017
Forty-one scientists from 16 countries have been chosen as International Research Scholars, exceptional early-career scientists poised to advance biomedical research across the globe. The Howard Hughes Medical Institute (HHMI) has teamed up with the Bill & Melinda Gates Foundation, the Wellcome Trust, and the Calouste Gulbenkian Foundation to develop scientific talent around the world, and will award a total of nearly $26.7 million to this group of scholars. Each researcher will receive a total of $650,000 over five years. The award is a big boon for scientists early in their careers, and offers the freedom to pursue new research directions and creative projects that could develop into top-notch scientific programs. "This is an outstanding group of scientists who will push biomedical research forward worldwide, and we are thrilled to support them alongside our philanthropic partners," said David Clapham, HHMI's Vice President and Chief Scientific Officer. The scientists selected as International Research Scholars represent a diverse array of scientific disciplines and geographic locations. Scholars hail from research organizations and institutions from across the world, from Tanzania to Cambodia to Chile to Austria. Their research covers a broad variety of biological and medical research areas too, including neuroscience, genetics, biophysics, computational biology, and parasitology. "We are excited to join with our partners in supporting these superb scientists. We look to them to bring transformative innovation to priority global health problems," said Chris Karp, Director of Global Health Discovery & Translational Sciences at the Bill & Melinda Gates Foundation. These researchers' goals are innovative, wide-ranging, and forward-thinking. They seek to understand diverse topics, from how immune cells function to how pathogenic bacteria jump from the environment to humans, and are even investigating ways to watch genes switch on and off in living brains. "We are delighted to be a partner in supporting this outstanding community of international researchers. Their expertise and thirst for knowledge will enhance our understanding of how life works and the causes and consequences of disease, said Anne-Marie Coriat, Head of Research Careers at Wellcome Trust. A panel of distinguished scientists reviewed more than 1,400 applications, and evaluated both the impact of past work, including doctoral and postdoctoral achievements, and the promise of work to come. It's a researcher-focused approach that emphasizes the skills and talents of the individual, rather than solely the projects proposed. "We are proud to partner with HHMI, the Bill and Melinda Gates Foundation and the Wellcome Trust to support this truly exceptional group of young biomedical scientists. Biomedical research is increasingly at the core of the work of our research institute, the Instituto Gulbenkian de Ciência," said Gulbenkian Institute Director Jonathan Howard. HHMI, the Bill & Melinda Gates Foundation, the Wellcome Trust, and the Calouste Gulbenkian Foundation announced the 2017 International Research Scholar competition March 29, 2016. The competition was open to early-career scientists who held a full-time position at a research-oriented university, medical school, or nonprofit institution, and had been running their own labs for less than seven years. Candidates also had to work in an eligible country, and have received training in the United States or the United Kingdom for at least one year. Ido Amit wants to reveal how immune cells work, and what role they play in health and disease. His lab develops new single cell genomic technologies to study these cells in unprecedented resolution. Figuring out immune cells' actions will help advance the next generation of immunotherapy to fight cancer and other disorders. Melanie Blokesch studies Vibrio cholerae, a water-dwelling bacterium that wreaks havoc in the gut and causes the diarrheal disease cholera. Her team wants to map the molecular tools V. cholerae uses to jump from the environment to humans, which will help explain what triggers cholera outbreaks in endemic areas of the world. Carlos Blondel investigates the emergence of human pathogens by studying their molecular weaponry. He has worked with foodborne pathogens that cause gastrointestinal disease, such as Salmonella and Vibrio parahaemolyticus. Blondel recently used CRISPR/Cas 9 genome editing technology to uncover key interactions between V. parahaemolyticus and human cells. Yossi Buganim's goal is to bring therapeutic cells from the lab to the clinic. His team has invented and improved ways to reprogram adult cells into other cell types, including those able to generate nearly any kind of cell in the body. One day, such cells could be tapped for regenerative medicine replacing damaged tissues with those grown in the lab. Tineke Cantaert seeks to understand how the immune system responds to infection by flaviviruses such as Dengue and Zika. Currently, no treatment exists for infection by either virus. Identifying biomarkers for protective immunity might help scientists speed up the development of therapies and vaccines. Ling-Ling Chen is discovering new and unusual classes of RNA molecules called long noncoding RNAs. She's figuring out how these molecules form, what role they play in gene regulation, and how they may influence disease. She has found that some of these RNAs are conspicuously absent in people with the neurodevelopmental genetic disorder Prader-Willi syndrome. Mark Dawson is searching for ways to wipe out malignant stem cells without harming normal stem cells. He studies cancers such as acute myeloid leukemia, which are difficult to eradicate using traditional chemotherapies. Understanding how normal and malignant stem cells differ from each other could let researchers devise more effective, targeted treatments. Ana Domingos is investigating new molecular strategies to fight obesity. She has discovered a direct link between fat tissue and neurons of the sympathetic nervous system, which plays a role in burning fat. Stimulating these neurons could one day lead to a new treatment to cause fat loss. Idan Efroni is unraveling the mystery of plants' impressive regenerative abilities. He uses tomatoes to study how plants generate new stem cells and meristems to replace damaged or missing roots. Insight into this process might reveal clues about tissue regeneration in other organisms, and help scientists boost plant production for agriculture. Eran Elinav is fascinated by microbes that live around and in our body our microbiome. He has discovered important links between nutrition, gut microbes and the risk of developing common diseases, such as obesity and diabetes. Now, he wants to figure out how gut microbes impact human relapsing (or "yo-yo") obesity and its many complications. Qiaomei Fu is exploring the genetic roots of humankind. Her work has helped untangle the early history of modern humans and Neanderthals, and reveal how early agriculture affected European farmers. She wants to illuminate the human prehistory of Asia by investigating the ancient genomes of both humans and pathogens. Lena Ho is on the hunt for new peptides linked to human disease. She's looking for hidden gems among previously overlooked regions of our genome, and seeks to understand how the peptides work and how they can be used to combat common diseases of the cardiovascular and metabolic systems. Kathryn Holt uses genomic tools to study infectious disease-causing microbes important in global health, including Salmonella typhi, which causes typhoid fever, and Shigella sonnei, a bacterium responsible for dysentery. She wants to understand what makes pathogens emerge, and why some become resistant to antimicrobial drugs. In developing animal embryos, stem cell growth is tightly regulated so that the right kinds of cells emerge at the proper place and time. Catarina Homem is investigating how metabolism and nutrition influence this process, and how mistakes can lead to developmental defects and diseases such as cancer. Michael Hothorn is piecing together how plants sense essential nutrients in the soil and send signals from cell to cell. A molecular understanding of how plants detect and respond to changes in phosphorus levels, for example, could help researchers engineer crops that can survive when nutrients are scarce. Shalev Itzkovitz studies the design principles of mammalian tissues. He's taking a close-up look at individual cells to figure out how they work together in organs such as the intestine, liver, and pancreas. Advanced imaging techniques combined with single cell sequencing will help researchers determine the job description of cells in different organs. Martin Jinek is investigating how protein and RNA molecules team up to control gene expression and protect the genome. He has pioneered work on the powerful genome-editing system known as CRISPR-Cas9, and revealed key details of this system at the atomic level. His work could spur the development of new, cutting-edge technologies for editing genomes and genetic therapies. Luis Larrondo is unwinding the secrets of biological clocks, which help living organisms, including humans, plants and fungi, stay in sync with the Earth's daily rhythms. His research draws upon synthetic biology as well as optogenetics to probe the molecular components that keep biological clocks ticking. Human genomic DNA is packaged with histone proteins into tightly-wound bundles of fiber called chromatin. Guohong Li has used an imaging technique called cryo-electron microscopy to visualize these twisted fibers in 3D at a detail previously unseen. Now, he wants to view the fibers at atomic resolution, and figure out the role of the histones wrapped inside. A suite of chemical tags decorates the genomes of humans, plants, and other multicellular organisms. Ryan Lister is inventing new tools to edit these tags, a type of epigenetic modification, which can regulate gene expression, cell differentiation, and more. He also wants to explore their role in brain development, which could offer new insights into neurological disorders. Mitochondria, which generate energy for cells and regulate programmed cell death, are vulnerable to damage. Ying Liu is using worm genetics and biochemistry to investigate the cellular pathways that sense mitochondrial dysfunction and activate stress responses. Defects in these pathways may contribute to metabolic disorders, neurodegenerative diseases and cancer. Laura Mackay is working to identify pathways that guide the development of tissue-resident memory T cells, immune cells that reside in the body's peripheral tissues and protect against local infections. She wants to harness these cells to create new therapies for infectious disease, cancer, and autoimmune diseases. Judit Makara is investigating how neurons in the brain's hippocampus support creation of memories. She is interested in the synaptic and dendritic processing mechanisms that promote the recruitment of individual neurons into ensembles with coordinated activity to store information about places or events. Tomas Marques-Bonet is assessing genomic diversity among great apes. His work will help us understand the biological processes and features that make us human and has implications for conservation biology. He is also using comparative genomics to study changes in gene regulation and the genomic consequences of domestication. Seth Masters uses personalized medicine to identify genetic changes that cause severe inflammatory diseases early in life. These studies teach us about how the innate immune system works, and may also provide targets for the development of drugs to treat more common inflammatory conditions such as heart disease, inflammatory bowel disease, type 2 diabetes and neurological disorders. Ruben Moreno-Bote is interested in the idea that although the human brain can solve complex problems, it sometimes falls short on simple tasks. He is combining theoretical and experimental approaches to identify the factors that limit the amount of information stored in the brain. As stem cells develop into specialized cells, their cell fates are influenced by the biochemical pathways that process nutrients to synthesize cellular materials and convert food to energy. Shyh-Chang Ng is studying how these metabolic processes regulate muscle regeneration during aging. His work could deepen our understanding of the effects of nutrition and exercise, and suggest strategies for treating the aging-induced metabolic syndrome. Zaza Ndhlovu is investigating how the immune system is affected when patients with HIV begin combination antiretroviral therapy very early in the course of disease. His goal is to learn whether brief exposure to the virus is sufficient to prime a protective immune response that might one day be boosted by a vaccine. Fredros Okumu is developing species-specific methods of eliminating the malaria-transmitting mosquito Anopheles funestus, with the goal of stopping the disease's transmission in two districts in southeastern Tanzania. Although A. funestus is not the most populous mosquito species in the region, it is responsible for 82-95 percent of local malaria infections. Cellular perturbations, such as changes in nutrient or oxygen levels or accumulation of misfolded proteins, can be indicative of pathogen presence or disruption in normal physiology. Fabiola Osorio studies how the immune system recognizes and responds to signs of cellular stress for regulation of immunity. Biophysicist Hye Yoon Park is developing imaging technologies to visualize the cellular and molecular processes the brain uses to form, consolidate, and retrieve memories. She will use the new techniques to study how neuronal activity alters gene expression to rewire neural circuits during learning. Joseph Paton has discovered key signals in the brain involved in timing and decision-making. He is investigating the circuit mechanisms that generate these signals and transform them into actions. His work will help explain how animals free themselves from the immediacy of the current moment to learn and plan. Nicolas Plachta is using single-cell imaging technologies devised in his lab to study how developing embryos take shape. He wants to understand the molecular mechanisms that govern changes in cell fate, shape, and position and how these changes are coordinated across an entire embryo. Thomas Pucadyil is studying how biological membranes -- protective barriers that are highly resilient to rupture -- split apart to allow for the packaging and transport of cellular materials. He is searching for membrane fission catalysts that cells use to manage this energetically demanding process. Hai Qi is exploring how the immune system generates and maintains memory cells that remember past infections and stay poised to produce antibodies against returning pathogens. His research may open new avenues for vaccine development and suggest better ways to control autoimmune diseases. Asya Rolls wants to understand the connections between the brain and the immune system. She is particularly interested in how brain activity influences the immune system's ability to find and destroy tumors. Her research could reveal new ways to harness the body's inherent disease-fighting potential. Marvin Tanenbaum is developing an imaging approach that will allow researchers to observe individual messenger RNA molecules as they are translated into proteins in living cells. He will use the method to investigate how translation is regulated to control the fate and function of cells. Wai-Hong Tham is studying how malaria parasites interact with their human hosts. Specifically, she wants to understand how Plasmodium vivax, the dominant malaria parasite in countries outside of sub-Saharan Africa, recognizes and invades red blood cells inside the human body. Yanli Wang is studying mechanisms of two bacterial anti-virus defense systems. She is using structural biology to learn how the CRISPR-Cas and Argonaute systems use small molecules of RNA or DNA to find and cleave foreign genetic material. She is also looking for ways to modify their RNA/DNA-cleaving components to increase their efficiency as genome editing tools. Immediately after an egg is fertilized, DNA and its packaging proteins (histones) undergo drastic reorganization so that cells can acquire new identities in early embryos. However, how this is achieved remains poorly understood due to the extremely scarce experimental samples. By developing ultrasensitive tools for chromatin analysis, Wei Xie is working to decipher how such reprogramming occurs and whether chromatin associated "epigenetic" information can be passed on to the next generation. Manuel Zimmer is using the roundworm Caenorhabditis elegans to study the dynamics of neural networks. Using a whole-brain imaging approach developed in his lab, he aims to uncover the fundamental computations and their underlying mechanisms neural circuits use to interpret sensory information and generate appropriate behaviors. The Howard Hughes Medical Institute plays a powerful role in advancing scientific research and education. Its scientists, located across the country and around the world, have made important discoveries that advance both human health and our fundamental understanding of biology. The Institute also aims to transform science education into a creative, interdisciplinary endeavor that reflects the excitement of real research. HHMI is headquartered in Chevy Chase, Maryland. http://www. Guided by the belief that every life has equal value, the Bill & Melinda Gates Foundation works to help all people lead healthy, productive lives. In developing countries, it focuses on improving people's health and giving them the chance to lift themselves out of hunger and extreme poverty. In the United States, it seeks to ensure that all people - especially those with the fewest resources - have access to the opportunities they need to succeed in school and life. Based in Seattle, Washington, the foundation is led by CEO Sue Desmond-Hellmann and Co-chair William H. Gates Sr., under the direction of Bill and Melinda Gates and Warren Buffett. http://www. The Wellcome Trust is a global charitable foundation dedicated to improving health. We support bright minds in science, the humanities and the social sciences, as well as education, public engagement and the application of research to medicine. Our investment portfolio gives us the independence to support such transformative work as the sequencing and understanding of the human genome, research that established front-line drugs for malaria, and Wellcome Collection, our free venue for the incurably curious that explores medicine, life and art. http://www. The Calouste Gulbenkian Foundation is an international foundation that bears the name of businessman, art collector and philanthropist of Armenian origin, Calouste Sarkis Gulbenkian (1869-1955). For almost 60 years, the Foundation has been carrying out extensive activities both in Portugal and abroad through the development of in-house projects -- or in partnership with other institutions -- and by awarding scholarships and grants. Headquartered in Lisbon, where Calouste Gulbenkian spent his last years, the Foundation is also home to a scientific investigation centre in Oeiras, and runs delegations in Paris and London -- cities where Calouste Gulbenkian lived. http://www.
News Article | September 19, 2017
The Howard Hughes Medical Institute today announced the selection of 15 exceptional early career scientists as the first group of HHMI Hanna Gray Fellows. These recent PhD recipients will continue their training as postdoctoral fellows at 11 institutions in the U.S. Their research interests span a range of disciplines, including chemical biology, computational biology, genetics, immunology, microbiology, neuroscience, structural biology, and systems biology. Each fellow will receive up to $1.4 million in funding over eight years, with mentoring and active involvement within the HHMI community. In this two-phase program, fellows will be supported from early postdoctoral training through several years of a tenure-track faculty position. "Being a Hanna Gray Fellow is going to provide me support through what can be quite a hard transition. From postdoctoral researcher, which I am right now, towards starting my own lab and actually becoming a principal investigator," said new fellow Yvette Fisher, a postdoctoral researcher at Harvard Medical School. HHMI's Hanna H. Gray Fellows Program seeks to encourage talented early career scientists who have the potential to become leaders in academic research. In particular, this program aims to recruit and retain emerging scientists who are from gender, racial, ethnic, and other groups underrepresented in the life sciences, including those from disadvantaged backgrounds. "I'm excited about this program because I think it will have a positive impact on science," said HHMI President Erin O'Shea. "We have so many challenges in keeping the best people from diverse groups in the professoriate. But I think this program can drive real change in academia and have a catalytic effect on the next generation of students." The Hanna H. Gray Fellows Program represents HHMI's strong commitment to investing in early career scientists who are poised to make significant and important contributions to science in the years to come. This program will support these early career scientists at critical transitions in their academic careers. In keeping with HHMI's long-standing approach to support "people, not projects," fellows will have flexibility to change research focus and follow their curiosity during the duration of the award. A competition for the next group of Hanna Gray Fellows opens immediately. With continued commitment to support and promote diversity in the life sciences, the Institute will again select up to 15 fellows investing a total of up to $25 million for their support over eight years. This grant competition is open to all eligible applicants, and no nomination is required. Grants in support of fellows will be awarded only to institutions within the U.S (including Puerto Rico). The program is named for Hanna Holborn Gray, former chair of the HHMI Trustees and former president of the University of Chicago. Under Gray's leadership, HHMI developed initiatives that foster diversity in science education. HHMI continues to carry forward this work on college and university campuses across the U.S. "Hanna Gray is a remarkable person - a Renaissance historian and one of the first female presidents of a major research university," said O'Shea. "We thought it fitting to name this program after her because of her many years of service to HHMI and her prominence as a female leader in academia." Applicants may obtain more information and eligibility requirements at http://www. . The deadline for applications is January 10, 2018, at 3:00 PM (Eastern Time). The selection of fellows will be made by the end of June 2018 and grants can start as early as September 18, 2018, but no later than January 15, 2019. The Howard Hughes Medical Institute plays an important role in advancing scientific research and education in the United States. Its scientists, located across the country and around the world, have made important discoveries that advance both human health and our fundamental understanding of biology. The Institute also aims to transform science education into a creative, interdisciplinary endeavor that reflects the excitement of real research. HHMI's headquarters are located in Chevy Chase, Maryland, just outside Washington, D.C. With cutting-edge crystallography and microscopy techniques, Christopher Barnes aims to reveal -- in extreme detail -- how newly isolated antibodies neutralize HIV-1 by latching onto viral envelope proteins. Barnes also plans to uncover how the virus gains illicit entry into cells by examining the structural changes that help the virus lock into a cellular target. These insights may point out ways to devise even more powerful therapeutics, including rationally designed HIV-1 antibodies, which could help scientists stamp out the shifty virus for good. John Brooks is investigating how mammals' internal clocks affect microbes that live in the gut. The mix of microbial species in these communities oscillates throughout the day. Scientists have linked these swings to the circadian clock, the biochemical timekeeper that governs everything from appetite to sleep. Brooks plans to unravel how the circadian clock works with the innate immune system to regulate microbe metabolism. His results could expose how the clock/microbiota interplay shapes the health of the host. Lynne Chantranupong knows how to get cells to spill their secrets. She has characterized key regulators of a signaling pathway that tells cells to grow, a process that goes awry in cancer and diabetes. Now, she is setting her sights on the brain. Chantranupong plans to isolate intracellular packets that contain neurotransmitters, signaling molecules that carry messages between nerve cells. She wants to probe the contents of these packets using mass spectrometry. This high-resolution method promises to reveal a complex and dynamic atlas of neurotransmitters in the brain. Mitochondria provide the energy needed for nerve cells to function, but when aged or damaged, these organelles can potentially be harmful to the cell. Chantell Evans will explore the multiple ways neurons sequester and eliminate damaged mitochondria. This cleanup process, called mitophagy, can malfunction in people with Alzheimer's, Parkinson's, and other neurodegenerative diseases. By studying healthy nerve cells and cells from people with neurodegenerative diseases, Evans plans to find out how nerve cells perform this important quality control, and how the process might be corrected when something goes wrong. Yvette Fisher is investigating how nerve cells in the brain perform the myriad computations that underlie perception and behavior. She is particularly interested in the role of voltage-gated ion channels, which regulate the flow of ions in and out of a cell. Fisher is exploring the dynamic interactions between these channels in the fruit fly, by examining their activity in cells that may help the fly navigate using visual cues. Arif Hamid wants to understand how the brain uses a chemical messenger called dopamine to guide behavior. Using a microscopy technique that offers a window into living brain tissue, he will probe dopamine's actions in different groups of neurons, such as those that signal directly to blood vessels that supply the brain. Hamid's studies of the interactions between dopamine-producing neurons and blood vessels could deepen our understanding of how blood hormones influence decision-making and goal-directed behavior. With powerful new genetic tools, Silvana Konermann plans to untangle the complex web of genes that predispose a person to Alzheimer's disease. One of the strongest genetic risk factors for the neurodegenerative disease is a gene called APOE. Carrying the APOE4 version of the gene increases risk, while the APOE2 version is protective. Using a gene editing technology called CRISPR-Cas9, Konermann plans to systematically knock out parts of the genome as she hunts for other genes that interact with APOE. James Nuñez is developing new tools to allow researchers to manipulate the activity of multiple genes simultaneously. The CRISPR-based technology will help scientists unravel the tapestry of interactions within complex biological networks. Mammalian cells produce thousands of different RNA molecules that do not code for proteins, and their roles remain largely unexplored. Nuñez plans to identify and examine the function of mysterious molecules called long non-coding RNAs, which can promote the growth of cancer cells and stem cells. Just a few kinds of signals control the fates of cells that either maintain their stem cell state, divide or differentiate in a developing organism. Nicolás Peláez is investigating whether the timing and dynamics of these signals encode critical information. He plans to figure out how and if the sequence of developmental signals directs embryonic stem cells to transform into more specialized cell types. His findings could help researchers devise ways to repair or replace damaged tissues by directing cells into specific differentiation paths. Harold Pimentel is scoping out what happens when cells fail to prune RNA copies of genes. These copies contain interrupting sequences called introns that are usually spliced out before an RNA molecule serves as a template for protein production. Neglecting to trim away introns is sometimes associated with abnormal cellular behavior and disease. Pimentel plans to use computational methods he developed to analyze a vast set of RNAs in healthy and cancerous tissues to discover whether lingering introns play a part in cancer. Florentine Rutaganira wants to use chemical tools to decipher the roles of key signaling networks in choanoflagellates, single-celled organisms that are the closest living relatives of animals. Choanoflagellates produce a large number of tyrosine kinases, molecular signals essential for intercellular communication in animals. The presence of these molecules in choanoflagellates suggests that signaling components needed to communicate between cells is evolutionarily ancient. Tyrosine kinases may regulate choanoflagellate colony formation. Rutaganira expects her studies will spark new understanding of animal development, physiology, and disease. The p53 gene is the most commonly mutated gene in human cancers. Francisco J. Sánchez-Rivera plans to comb through human tumor data to systematically identify recurring -- but understudied -- p53 mutations, and figure out how they wreak havoc in the body. Many of these mutations are known to inactivate the p53 protein and eliminate its role as a tumor suppressor. But Sánchez-Rivera is particularly interested in mutations that create proteins with new abilities. His studies may kindle new therapeutic strategies relevant to a broad range of cancers. Biologists once thought that hybridization between species was rare and an evolutionary dead end. But recent advances in genomics have revealed that closely related species frequently exchange genes and pass them on to future generations. Molly Schumer wants to understand how these instances of hybridization shape the evolution of genomes and species. Combining work in the lab and field, she is building an understanding of factors that influence hybrid ancestry in the genome. Unchecked inflammation is the hidden culprit behind many diseases -- including inflammatory bowel disease, rheumatoid arthritis, and Alzheimer's. Autumn York is investigating how the immune system interacts with the body's metabolic pathways to control inflammation. She wants to expose how immune cells sense pathogen-triggered changes in fatty acid synthesis and then relay the message to limit inflammation. Her work may lead to new ways to prevent disease progression and suggest novel strategies to control infection. Debilitating migraine headaches, which afflict up to 15 percent of the world's population, are thought to be sparked by nerve cells called trigeminal ganglion neurons. Wendy Yue aims to find out what activates these pain-sensitive cells. By exciting, shutting down, or genetically altering these neurons in mice, Yue will explore their contribution to migraine pain. Her experiments will also clarify whether and how blood vessels participate in the generation of migraine headaches.
News Article | September 19, 2017
Each fellow will receive up to $1.4 million in funding over eight years, with mentoring and active involvement within the HHMI community. In this two-phase program, fellows will be supported from early postdoctoral training through several years of a tenure-track faculty position. "Being a Hanna Gray Fellow is going to provide me support through what can be quite a hard transition. From postdoctoral researcher, which I am right now, towards starting my own lab and actually becoming a principal investigator," said new fellow Yvette Fisher, a postdoctoral researcher at Harvard Medical School. HHMI's Hanna H. Gray Fellows Program seeks to encourage talented early career scientists who have the potential to become leaders in academic research. In particular, this program aims to recruit and retain emerging scientists who are from gender, racial, ethnic, and other groups underrepresented in the life sciences, including those from disadvantaged backgrounds. "I'm excited about this program because I think it will have a positive impact on science," said HHMI President Erin O'Shea. "We have so many challenges in keeping the best people from diverse groups in the professoriate. But I think this program can drive real change in academia and have a catalytic effect on the next generation of students." The Hanna H. Gray Fellows Program represents HHMI's strong commitment to investing in early career scientists who are poised to make significant and important contributions to science in the years to come. This program will support these early career scientists at critical transitions in their academic careers. In keeping with HHMI's long-standing approach to support "people, not projects," fellows will have flexibility to change research focus and follow their curiosity during the duration of the award. A competition for the next group of Hanna Gray Fellows opens immediately. With continued commitment to support and promote diversity in the life sciences, the Institute will again select up to 15 fellows investing a total of up to $25 million for their support over eight years. This grant competition is open to all eligible applicants, and no nomination is required. Grants in support of fellows will be awarded only to institutions within the U.S (including Puerto Rico). The program is named for Hanna Holborn Gray, former chair of the HHMI Trustees and former president of the University of Chicago. Under Gray's leadership, HHMI developed initiatives that foster diversity in science education. HHMI continues to carry forward this work on college and university campuses across the U.S. "Hanna Gray is a remarkable person – a Renaissance historian and one of the first female presidents of a major research university," said O'Shea. "We thought it fitting to name this program after her because of her many years of service to HHMI and her prominence as a female leader in academia." The Howard Hughes Medical Institute plays an important role in advancing scientific research and education in the United States. Its scientists, located across the country and around the world, have made important discoveries that advance both human health and our fundamental understanding of biology. The Institute also aims to transform science education into a creative, interdisciplinary endeavor that reflects the excitement of real research. HHMI's headquarters are located in Chevy Chase, Maryland, just outside Washington, D.C.