We Accelerate Discovery

Program Highlights

Genetic Diversity Protects Against Disease

Joseph Bondy-Denomy, a 2015 Early Independence awardee, published a paper examining the benefits of host diversity on the spread of disease using experiments on bacteria and viruses. Bacteria defend themselves against viruses using the CRISPR-Cas immune system, which captures random DNA fragments from the virus and uses that “memory” to protect itself from future infections. CRISPR-Cas generates lots of diversity because each bacterial cell can capture a different piece of viral DNA. When isolated individual bacteria grew up in a monoculture, the virus spread rapidly and killed the bacteria. When bacteria grew up in diverse populations, the virus went extinct rapidly. Viruses overpowered bacteria monocultures by rapidly evolving to overcome the CRISPR-Cas immunity, while in diverse bacterial populations, the virus was unable to overcome the large amount of genetic diversity and went extinct. These results demonstrate that mixed populations can increase the immunity level of the entire population.

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Hunting for RNA Binding Sites

Mitchell Guttman, a 2012 Early Independence awardee, published a paper detailing enhancements made to a method used to identify binding sites of RNA-binding proteins by UV crosslinking and immunoprecipitation (CLIP). The new method (termed eCLIP) decreases the amount of material needed and increases clarity while maintaining single-nucleotide binding resolution. eCLIP will save sequencing costs and improve reproducibility for identifying binding sites of RNA-binding proteins.

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Host-Bacteria Interaction Benefits Both

Gregory Sonnenberg, 2012 Early Independence awardee, published a paper revealing a unique host-bacteria interaction where selective subsets of commensal bacteria interact with host dendritic cells to facilitate tissue-specific responses that are mutually beneficial for the host and the microbe. It is currently thought that physical separation of the mammalian immune system and commensal bacteria is necessary to limit chronic inflammation. However, some species of bacteria can reside within intestinal lymphoid tissues of healthy mammals. Using mice, Sonnenberg demonstrates lymphoid-tissue-resident commensal bacteria colonized mice dendritic cells and modulated their cytokine production to protect mice from lethal intestinal damage, showing the host immune system and commensal bacteria can interact in ways that benefit both.

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Tracking Antibody Diversity

Gabriel Victora, a 2012 Early Independence awardee, used multicolor tags on individual B cells and their progeny to assess antibody diversity in germinal centers of lymphoid organs and to track the level of diversity over time. Victora found that germinal centers initially have a high rate of diversity which decreases at varying rates over time due to competition between the antibody clones. The decline in diversity happens even in the absence of an infection, which selects for the most efficient pathogen-fighting antibodies. These findings have implications for how to generate vaccines with broadly protective antibodies for highly variable pathogens such as influenza and HIV.

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Arsenic Stress Causes a Reduction in Ribosomes

John Hanna, a 2014 Early Independence awardee, recently published a paper showing that a reduction in ribosome abundance is a rapid, effective, and reversible stress response against misfolded proteins. Cells have adaptive responses to identify and mitigate potentially dangerous threats to stress, such as misfolded proteins. Using tandem mass tag-based mass spectrometry, Hanna found trivalent arsenic causes widespread reorganization of the cell and protein degradation. Ribosomes were down-regulated at the protein level, and suggests the major source of toxicity of trivalent arsenic derives from misfolding of newly synthesized proteins and identifies ribosome reduction as a rapid and effective proteotoxic stress response.

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Successful Vaccine Drops Meningitis A Deaths to Zero

Nicole Basta, a 2011 Early Independence awardee, was featured in The Economist for her work on the meningitis A vaccine MenAfriVac. Since the vaccine’s introduction to Africa in 2010, cases of meningitis A have plummeted to zero in 16 countries that used MenAfriVac in mass vaccination campaigns. Basta showed the MenAfriVac, which uses tetanus toxoid as the immunity-generating antigen, also boosts tetanus immunity and increased the number of people in Mali with long-term tetanus immunity from 20% to 59%, making the meningitis A vaccine an effective tetanus booster as well.

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Using Deep Brain Stimulation to Rescue Memory in Rett Syndrome

Rodney Samaco, a 2011 Early Independence awardee, tested deep brain stimulation in a Rett syndrome mouse model. Rett syndrome is a leading cause of intellectual disability in human females, and the mouse model reproduce the broad phenotype of the disorder, including impairment in cognitive, motor, social skills, and neurological disorders. Deep brain stimulation in the Rett syndrome mice corrected contextual fear memory, spatial learning, and memory and may be a useful tool in mitigating cognitive dysfunction in Rett syndrome.

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A Reference for Worldwide Human Genetic Variation

Jeffrey Kidd, a 2011 Early Independence awardee, and Pardis Sabeti, a 2009 New Innovator, are part of the 1000 Genomes Project Consortium which released the findings from their project to whole-genome sequence a diverse set of individuals from multiple populations. In all, they sequenced the genomes of 2,604 individuals from 26 populations, discovering 88 million variants. Their resource includes >99% of SNP variants with a >1% frequency for a variety of ancestries. They discuss the distribution of genetic variation across the globe and discuss implications for common disease studies.

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Spatial Recognition in Receptors

The tyrosine kinase AXL receptor plays an important role in blood clotting and immune regulation and is implicated in the drug resistance and spread of tumors. Despite the significant role of the AXL receptor, it is unknown how its ligand and other factors influence AXL activation. Meyer, a 2014 awardee, and colleagues sought to understand how the receptor senses interaction of its ligand, Gas6, with the lipid phosphatidylserine. Using quantitative experiments and mathematical modeling, Meyer and others show that AXL does not respond solely to concentrations of Gas6 but also to the spatial presentation of Gas6. This insight helps resolve AXL receptor function and will aid the design of future therapies to a wide range of cancers.

The AXL Receptor Is a Sensor of Ligand Spatial Heterogeneity. Meyer AS et al. Cell Systems. 2015 July 29; doi: 10.1016/j.cels.2015.06.002.

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Silencing the X Chromosome

In addition to protein coding genes, the human genome also encodes thousands of functional long non-coding RNA (lncRNA) genes. How these lncRNAs control gene regulation is unknown, largely because of technical limitations in defining lncRNAs complexes in the cell. Scientists at Caltech developed a new approach allowing them to look at lncRNA complexes in cells. Using this approach, the researchers studied Xist, an lncRNA that is required for silencing an entire X chromosome during normal female development. They were able to identify the proteins that directly interact with the Xist RNA and, ultimately, are necessary to silence transcription of the X-chromosome. One of these interacting proteins, called SHARP, is required for excluding RNA Polymerase from genes across the X chromosome. The protein does this by recruiting a key chromatin regulatory protein called HDAC3, which acts to modify the structure of chromatin to silence transcription. These results provide the first detailed view of how a lncRNA controls gene regulation.

The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3. McHugh CA et al. Nature. 2015 April 27; doi:10.1038/nature14443.

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Are Gut Bacteria the Key to Treating Low Serotonin Levels?

There is an increasing appreciation that mammals have co-evolved with trillions of microorganisms, collectively called the “microbiota,” which regulate a variety of biological processes, including the development and function of the nervous system. New research explores fundamental interactions between gut microbiota and the mammalian host in regulating levels of neurotransmitters. In a study from the laboratory of 2013 Early Independence Awardee Elaine Y. Hsiao at the California Institute of Technology, they find a striking ~60% of peripheral serotonin is regulated by microbiota and identify bacteria from mice and humans that can regulate host serotonin production in the gut. When microbe-free mice are colonized with serotonin-promoting microbes, serotonin levels rise and can correct enteric and hemostatic abnormalities related to low levels of serotonin. The researchers further reveal particular microbial metabolites involved in serotonin regulation. These findings reveal a fundamental host-microbial interaction and raise the question of whether microbe-based treatments for symptoms and diseases caused by low levels of serotonin are possible.

Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Yano JM et al. Cell. 2015 April 9; 161:264-276.

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2013 Early Independence Awardee Demonstrates Neurological Dysfunction in Mouse Model of Kabuki Syndrome is Potentially Reversible and Linked to Adult Neurogenesis

Dr. Hans Tomas Bjornsson, MD, PhD, an assistant professor at the McKusick Nathans Institute of Genetic Medicine and the department of pediatrics at the Johns Hopkins University School of Medicine, has published a paper in the journal Science Translational Medicine, describing that a deficiency of dentate gyrus neurogenesis may underlie some of the neurological dysfunction seen in a mouse model of Kabuki syndrome, a rare Mendelian cause of intellectual disability. Using a drug known to target the epigenetic machinery, Bjornsson and his team demonstrated recovery of the neurogenesis defect in association with normalization of hippocampal memory defects in the treated mice. These findings suggest that Kabuki syndrome may be a treatable cause of intellectual disability even in postnatal life and raises the possibility whether deficiency of neurogenesis may underlie additional causes of intellectual disability.

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2012 Early Independence Awardee Receives Young Investigator Award For Schizophrenia Research

Dr. Alan Anticevic, Ph.D., was selected as one of the Young Investigator Awardees at the 14th International Congress on Schizophrenia Research (ICOSR). The ISCOR meeting is held biennially and is intended to encourage the gathering and exchange of data, techniques, and ideas from the schizophrenia research community. The Young Investigator Awards are given to bright young scientists producing high quality research related to the field of schizophrenia. Dr. Anticevic is a 2012 NIH Director’s Early Independence Awardee (EIA) whose EIA funded research is focused on understanding the underlying mechanisms of cognitive and affective disturbances in neuropsychiatric conditions, including schizophrenia, though an approach which combines neuroimaging, pharmacology, and computational modeling. The ultimate goal of his research is to be able to facilitate rationally-guided cognitive treatments for this devastating illness.

Learn more about ISCOR 
Yale Press Release 

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Adam de la Zerda, Mitchell Guttman, Gregory Sonnenberg, Daniela Witten

Forbes Magazine Names 4 NIH Stars among the 2012 “30 under 30" in Science and Innovation

The NIH Director's Early Independence Award is a relatively new funding mechanism that provides an opportunity for exceptional junior scientists to "skip the post-doc," and start an independent research career at a supportive Institution directly following the completion of their graduate degree or clinical residency. For the second year in a row, Forbes Magazine has selected several NIH Director’s Early Independence Awardees for the honor of "30 under 30" in Science and Healthcare for 2012.

NIH Director's Blog
Forbes Magazine 

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Forbes Magazine Names 5 NIH Director's EIA Awardees
among Top Science and Innovation "30 under 30" for 2011John Calarco, Ph.D.James S. Fraser, Ph.D.Jeffrey M. Kidd, Ph.D.Harris H. Wang, Ph.DDaniela Witten, Ph.D

The NIH Director's Early Independence Award is a new funding mechanism that provides an opportunity for exceptional junior scientists to "skip the post-doc," and start an independent research career at a supportive Institution directly following the completion of their graduate degree or clinical residency. Five of the top honored "30 under 30" in Science and Innovation by Forbes Magazine are NIH Early Independence Awardees for 2011.

Press Release 

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