Dr. Joshua Weitz, Associate Professor of Biology, was named a Simons Foundation Investigator in Ocean Processes and Ecology and awarded a three-year grant from the Simons Foundation. Dr. Weitz will examine physical and ecological principles governing the interplay between viruses and zooplankton in the North Pacific Ocean. Dr. Weitz joins a new initiative, SCOPE -- the Simons Collaboration on Ocean Processes and Ecology -- co-directed by Edward DeLong and David Karl at the University of Hawai'i, Manoa. The purpose of the collaboration is to advance understanding of the biology, ecology, and biogeochemistry of microbial processes that dominate Earth's largest biome: the global ocean. The collaborative effort will measure, model and conduct experiments at a model ecosystem site located 100 km north of Oahu. The Simons Foundation's mission is to advance the frontiers of research in mathematics and the basic sciences. The Foundation sponsors a range of programs that aim to promote a deeper understanding of our world.
In the past year, more than 21,000 individuals have been infected with Ebola virus disease in West Africa and more than 8,000 are reported to have died. The outbreak response is one of the largest and most complex that the CDC and global health community have conducted. Although the outbreak seems to be turning around, there is an ongoing need for intervention and monitoring to reduce the new case count to zero.
This past week the Georgia Institute of Technology hosted a two-day workshop, "Modeling the Spread and Control of Ebola in West Africa," with more than 180 participants to discuss the use of dynamical models to support, interpret and enhance public health practices to help stop the spread of the disease.
"There is a growing coalition of modelers working at different scales - from how the disease is transmitted at the community level, to how the virus is evolving - who can contribute to support the response effort on the ground," said Joshua Weitz, chair of the organizing committee and associate professor in Georgia Tech's School of Biology.
The lectures and discussions focused on four major questions: How much confidence should we have in forecasts of the epidemic? How do we evaluate control strategies? What are the challenges in implementing these strategies? How do we communicate models to each other, public health scientists and to the broader community?
Participants in the workshop came from universities in the United States, Canada and England, as well as from the Centers for Disease Control and Prevention (CDC), the White House Office of Science Technology and Policy, the Biomedical Advanced Research and Development Authority, the Red Cross, Intel, IBM and the United States national laboratories. Speakers and panelists represented a wide array of professions and backgrounds.
Ebola is particularly tricky to model, said one speaker, because "this Ebola outbreak has not developed in the way that past outbreaks have evolved, that means we've not been able to rely on past experiences to map out our response this time around."
Epidemiological modeling, including forecasting and evaluating control strategies, is vital to the success of the response. Initially, models of Ebola spread had high degrees of uncertainty regarding the potential scope of the outbreak. This uncertainty stemmed, in part, from the lack of detailed case data and chains of transmission. Models were also poorly informed with respect to the relative importance of urban and rural transmission. Models did not have accurate estimates of the extent and speed at which safe burials would become widespread and Ebola treatment units would be built. Changes in behavior and widespread interventions are necessary to avert worst-case scenarios.
The challenge in linking models to case data are many. Much of the data needed is gathered by public health professionals and doctors, many of whom are responding to patients and working to slow the spread of the disease. Multiple panelists pointed out the need to identify data collection protocols that could serve to inform predictive models while balancing the need to respond to those they are sent to aid.
There were many other challenges to modeling the effectiveness of control efforts. Logistical challenges included traveling along roads in Africa, the transmission of Ebola from animals to humans, as well as the complications of dealing with a number of governments and scientists with different ideas of how to respond and what data to share. Communication was considered essential to move from model predictions to policies that could support an effective response.
The final panel addressed this issue by considering communication of models amongst three sectors: government, academia and the media. Experts in modeling are not usually trained to communicate with policy makers. This can lead to miscommunication, or a lack of communication. Translating scientists' results to the public and to policy makers is key. For example, communicating the need for safe burials helped to reduce the transmission of Ebola during burial ceremonies. Informing policy makers of the risks of inaction helped to galvanize support for a much larger response effort in Fall 2014.
Despite the challenges, there is some room for optimism. New cases of Ebola virus disease have dropped in the past month, particularly in Liberia. The reasons are many, including changes in behavior and the impact of interventions. Individuals with Ebola are not infectious until symptomatic, which facilitates contact tracing and leads many to believe that a successful public health response is possible. New Ebola vaccines have also been developed to be utilized in Phase II trials planned by the CDC for testing in West Africa in the coming months. Vaccine trial design was the topic of an extended breakout discussion and panel talk.
"The modeling community has work to do," remarked Weitz at the close of the meeting. "This workshop has helped to identify many scientific and engineering challenges necessary to understand how the virus spread to so many people (unlike past Ebola outbreaks), how to enact a more effective response to the ongoing epidemic and how to prevent future epidemics."
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Biology faculty member Dr. Danielle Dixson is among 126 scientists in North America who have been awarded a 2015 Sloan Research Fellowship, a two-year grant given to early career scholars to support their pursuit of scientific knowledge.
Dixson, an assistant professor in the School of Biology, investigates the influence sensory cues have on the behavior of coral reef organisms. Her recent work, featured on the cover of the journal Science, found that coral larvae and juvenile fishes can smell the difference between a reef that is unhealthy and one that is a suitable home. She has also published recent work showing that acidic oceans make sharks less interested in their food.
Dixson conducts research around the globe on coral reef ecology, and the Sloan Research Fellowship will allow her to continue conducting the fieldwork vital to her research.
“I am very honored and excited to have been selected as a Sloan Fellow,” Dixson said. “These funds will allow my lab to conduct research in Belize investigating how larval fishes and corals use chemical cues in settlement site selection and predator evasion.”
Dr. Frank Stewart was awarded $540,000 in March 2015 by the Simons Foundation to investigate the microbiomes of reef fish. The Simons Foundation has made ocean processes and ecology one of their priority areas for investigation. They have initiated a Collaboration on Ocean Processes and Ecology (SCOPE) that will measure, model and experimentally manipulate a complex system representative of a broad swath of the North Pacific Ocean. This collaboration aims to advance our understanding of the biology, ecology and biogeochemistry of microbial processes that dominate the global ocean. A central premise of SCOPE is that we must study the ocean ecosystem in situ, at a variety of levels of biological organization (e.g., genetic, biochemical, physiological, biogeochemical and ecological), and at highly resolved, nested scales of space and time in order to fully describe and model it.
By investigating fish microbiomes, Dr. Stewart hopes to better understand how bacteria interact with their hosts in the ocean. Symbiosis between microorganisms and higher eukaryotes is among the most pervasive evolutionary and ecological strategies in nature, impacting fundamental processes including speciation, ecosystem structuring, primary production, nutrient cycling, and disease. A surge of studies exploring the commensal microbiome of the human body has identified complex networks of factors shaping microbiome acquisition, composition, and function, as well as a range of host developmental and immunological outcomes affected by microbiome activity. For most animal lineages, excluding humans, the ecology and evolution of host-associated microbiomes are almost completely unexplored. This is true for the largest and most diverse of the vertebrate groups, the teleost fishes. In many ocean regions, notably in productive coastal zones and reefs, teleosts play vital roles in material and energy transport and ecosystem structuring. Teleosts on coral reefs represent over 2500 fish species and engage in a complex network of ecological interactions including nutrient recycling, herbivory, corallivory, and symbiosis. Fish also serve cryptic roles as habitats for microorganisms. Given the phylogenetic and ecological breadth of reef teleosts and the potential for host species-specificity in vertebrate microbiomes, reef fish microbiomes are hypothesized to harbor a wide diversity of uncharacterized bacterial lineages. Such lineages may play important roles as mediators of fish nutrition and disease prevention and as inocula for free-living or coral microbiome populations.
Dr. Stewart will execute an integrated research plan over three years to sample deeply across this spectrum, combining 1) 16S rRNA gene sequencing, multivariate, and indicator analyses to identify determinants of fish gut and mucus microbiome composition, 2) quantitative metagenomic and single-amplified genome (SAG) sequencing of indicator microbes to identify shared (core) and peripheral (host-specific) functional properties, and to enable comparisons to pathways in microbiomes of other major vertebrate groups, and 3) targeted experiments to quantify acquisition and transmission dynamics of fish microbiomes. The proposed work will help to quantify connectivity between host-associated and external microbial niches, as well as identify host benefits of microbial-association, potentially including unrecognized contributions to immunity, digestion, and chemical signaling between host individuals.
Dr. Joel Kostka’s research group has a paper soon to be published in the International Society for Microbial Ecology journal entitled “Metabolic potential of fatty acid oxidation and anaerobic respiration by abundant members of Thaumarchaeota and Thermoplasmata in deep anoxic peat”. It is an important contribution because archaea are thought to play a key role in the microbial carbon cycle of peatlands, which store close to one-third of all soil carbon. One reviewer commented, "The value of this communication is immense for the understanding of bioactive carbon sequestration as the representatives of both phyla account for the vast majority of the microbial community in peat bogs."
They studied archaea that are very abundant in global soils as well as those of peatlands. In spite of their abundance on a global scale, the metabolism of archaea is not understand nor is their role in the carbon cycle because none of these organisms has been cultivated. This paper uses a metagenomic approach to determine the metabolic potential of these archaea which could play a key role in the response of peat microbial communities to climate change. Samples were collected at the Marcell Experimental Forest in northern Minnesota, where the DOE is carrying out a large scale climate manipulation study. SPRUCE site.
Researchers have developed a new informatics technology that analyzes existing data repositories of protein modifications and 3D protein structures to help scientists identify and target research on “hotspots” most likely to be important for biological function.
Known as SAPH-ire (Structural Analysis of PTM Hotspots), the tool could accelerate the search for potential new drug targets on protein structures, and lead to a better understanding of how proteins communicate with one another inside cells. SAPH-ire has been tested on a well studied class of proteins involved in cellular communication, where it correctly predicted a previously-unknown regulatory element.
“SAPH-ire predicts positions on proteins that are likely to be important for biological function based on how many times those parts of the proteins have been found in a chemically-modified state when they are taken out of a cell,” explained Matthew Torres, an assistant professor in the School of Biology at the Georgia Institute of Technology. “SAPH-ire is a tool for discovery, and we think it will lead to a new understanding of how proteins are connected in cells.”
The tool and its proof-of-concept testing were reported June 12 in the journal Molecular and Cellular Proteomics. The research was supported by the National Institutes of Health’s National Institute of General Medical Sciences (NIGMS) and Georgia Tech.
Through modern mass spectrometry proteomics techniques, scientists have identified more than 300,000 post-translational modifications (PTMs) in different families of proteins across numerous species. These PTMs come in many forms, resulting from the action of different enzymes, and are often indicators of how and where proteins contact one another to bring about different cell behaviors. The number of PTMs detected by mass spectrometry has grown so rapidly that researchers experimentally investigating the function of the modifications have been unable to keep up.
“Mass spectrometry is so effective that it has created an exponential curve in the knowledge of how proteins are modified,” said Torres. “The rate at which we can detect new PTMs has now far surpassed the rate at which we can understand what they do, from a classical biochemical approach. You have so much information that you don’t know where to begin.”
But that’s exactly where SAPH-ire begins. Aimed at bridging the gap between PTM detection and analysis of function, SAPH-ire collects non-redundant and experimentally verified PTM data across all known members of a protein family. Since members of a protein family share the same or similar protein structures, PTMs found within the family can be related to one another in three-dimensional space to produce a set of observed PTM frequencies, termed “hotspots.”
The PTM hotspots are projected onto 3D protein structures available in the Protein Data Bank (PDB), which allows the entire set of family-specific PTMs to be visualized on any protein structure that is representative for the family. Once projected there, SAPH-ire integrates multiple quantitative features from each hotspot to create a PTM “Functional Potential Score.” Each PTM hotspot can then be ranked in order of highest to lowest potential for having significant biological function.
“We have gone through all of what might be considered the meta-data that exists in the public domain, collected all the PTMs and all the structures, then organized them into their specific protein families,” Torres explained. “We are looking at PTMs through time, in a sense, because we have information from organisms that are evolutionarily distant from each other, though their proteins are related as members of a protein family.”
To prioritize research with the most significant potential impact, scientists might examine PTM hotspots that SAPH-ire identifies as having high function potential, but no known function.
Torres’ lab has been investigating unique families of “G” proteins, some of which cooperate with cell surface receptors that control the binding of hormones and neurotransmitters, as well as a majority of pharmaceutical drugs. Because of their importance to therapeutics, these proteins have been extensively studied over a period of 50 years or so. Using SAPH-ire, the researchers discovered something surprising about this group of protein families.
“We discovered a new regulatory element within a specific G protein family that has been largely ignored because it’s pretty unimpressive from a purely structural viewpoint,” Torres said. “SAPH-ire predicted that this element was going to be important from a modification point of view, and we confirmed experimentally that it was.”
SAPH-ire was conceived by Torres and developed by him and graduate student Henry Dewhurst, while experimental validation of the tool was accomplished by graduate student Shilpa Choudhury. Their next step is to develop collaborations with scientists who will try it out on the protein families they study. The Georgia Tech researchers are also creating a database that other protein scientists can query to help them identify and prioritize PTM hotspots, and they expect to see their program become part of informatics systems used to analyze large volumes of proteomics data emerging from labs around the world.
“SAPH-ire will help bring meaning and context to all the data that is being produced about PTMs,” Torres said. “Connecting SAPH-ire to other programs that convert mass spec data into actual PTM data could provide immediate biological relevance and prioritization for biochemists and others. It is likely to expose many new and unsuspected relationships between protein modification, protein structure and function.”
This research was supported by the National Institutes of Health, National Institute of General Medical Sciences (NIGMS), under grant number 5R00 GM094533-05. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
CITATION: Henry M. Dewhurst, Shilpa Choudhury and Matthew P. Torres, “Structural Analysis of PTM Hotspots (SAPH-ire) – a Quantitative Informatics Method Enabling the Discovery of Novel Regulatory Elements in Protein Families,” (Molecular and Cellular Proteomics, 2015). http://dx.doi.org/10.1074/mcp.M115.051177
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The Gordon and Betty Moore Foundation and Research Corporation for Science Advancement awarded 5 grants totaling $731k to teams of researchers pursuing "ambitious, high-risk, highly impactful discovery research on untested ideas in physical cell biology."
One of the winning teams—composed of Brian Hammer (Georgia Tech), Raghuveer Parthasarathy (University of Oregon) and Joao Xavier (Memorial Sloan-Kettering Cancer Center)—proposed a long term project titled, “Rebooting the Gut Microbial Ecosystem using Bacterial Dueling”.
Studies abound linking particular diseases, such as Crohn’s, to the bacteria in our gut. Their project aims to demonstrate that bacterial dueling can be used to eliminate harmful bacteria in the gut and repopulate it with healthy bacteria.
To begin, the researchers will introduce vibrio cholerae into a sample of zebrafish. V. cholera is an aggressive bacterium that feeds on chitin, a complex carbohydrate and major component of exoskeletons. Zebrafish, a common sight in home aquariums, is an excellent model organism that also happens to have a taste for chitin-rich zooplankton.
When chitin is ingested, some of the sugars are released and sensed by V. cholera, which turns on its dueling machinery.
“What this means is that the response to chitin results in the production of a special protein factor (a transcription factor) in each Vibrio cholerae cell that can turn on the dueling machinery,” Dr. Hammer explained. “We can also genetically engineer Vibrio cholerae cells so that this special factor is always produced. These cells do not need chitin to activate dueling; it's on all the time.” Woe unto any microbe squatting alongside V. cholerae.
Interestingly, some strains of V. cholerae are especially bellicose, keeping their dueling machinery armed at all times, no chitin required.
Using fluorescent microscopy, the scientists will observe and subsequently model V. cholerae’s behavior under various conditions—by using different strains of V. cholerae (those that need chitin and those that are always battle-ready) and by manipulating the presence of chitin and other food sources.
For this research to ever have therapeutic applications, V. cholerae must be kept from running amok. Accordingly, the team plans to design a strain of V. cholerae with an off-switch. Hammer elaborated, “Basically, we engineer the cells so that they can only grow if provided an essential factor (a chemical we can add) for their cell wall. If we add that chemical to flasks of cells in the lab, and presumably into the water with the fish, the Vibrios grow normally. To make the cells self-destruct we simply remove that chemical from the water or move the fish into new water lacking that chemical.”
The last step in this study will be to repopulate the zebrafish’s gut with microbes found in healthy zebrafish.
If successful it “would suggest that we can develop dueling bacteria that could be used in humans to replace harmful bacteria in the gut with healthy ones… Finally, what I think is also really cool about our study is that [by manipulating chitin in the fish’s diet] it may also link the food we eat to how gut microbes interact,” beamed Hammer.
In August, Biology assistant professor Patrick McGrath was awarded a 5 year, $1.47 million grant by the National Institutes of Health to study the genetic architecture of aging. Most common diseases have a strong but complex genetic component. Understanding their genetic underpinnings will allow for their predictions and suggest targets for their amelioration. McGrath and colleagues will identify how age and epistasis affect traits in model organisms with the goal of identifying principles that can be applied to better predict the genetic variants responsible for human diseases.
A complex mixture of common and rare variants typically shape most biological traits – their exact effects mediated by extensive genetic interactions and organismal age. These observations are mainly correlative as little is known about the mechanisms that generate epistasis and age-dependence. Improved understanding of these processes could identify principles useful for predicting how causal factors act in novel genetic backgrounds and therapeutic techniques to take advantage of their non-linear effects to ameliorate disease. The broad objective of the proposed research is the identification of causative genetic variants affecting reproduction in the round worm C. elegans with age-dependent effect sizes and epistatic interactions. McGrath intends to mechanistically dissect their causes in the context of organ and multicellular circuit function. His team will study how life history changes in sperm number, a limited resource necessary for reproduction, creates age-dependent genetic architecture. Finally, they will study how epistasis and aging are shaped by the function of the underlying neural circuits responsible for the regulation of reproduction. These experiments will leverage C. elegans tractability to identify principles relevant to the study of human diseases.
In August, Biology Professor Yury Chernoff was awarded a 3 year NSF Molecular and Cellular Biology grant to investigate the control of heritable protein aggregation by ribosome-associated chaperones. The goal of this research is to investigate how physiological changes regulate protein-based inheritance in yeast. Protein-based heritable elements, in particular fungal prions, are novel kind of genetic elements; they produce heritable changes in their host cells without any change in the DNA of their genes. This occurs by switching between protein isoforms, one of which (prion isoform) is able to reproduce itself by inducing other molecules of the same protein to switch into the same isoform. This project examines how these transitions are aided by another class of proteins, molecular chaperones, whose normal function is to promote correct protein folding and prevent misfolding. Understanding the physiological control of protein-based inheritance may have an impact on the industrial use of yeast and other fungi. The research team includes graduate and undergraduate students and will strengthen the research infrastructure of Georgia Tech.
In August, Biology assistant professor Will Ratcliff and his collaborators received a three year, $562,000 NASA grant to investigate the origin and evolutionary consequences of multicellular life cycles. All multicellular organisms exhibit a characteristic life cycle that alternates between stages of reproduction, growth and development. This life cycle is critical for the evolution of multicellular complexity, playing a central role in transporting fitness from cells to multicellular individuals. Despite their importance, the evolutionary origins of multicellular life cycles are poorly understood. A key factor limiting progress has been the fact that evolutionary transitions to multicellularity on Earth have been both ancient and rare. Using a combination of synthetic biology and experimental evolution, we have created novel multicellular organisms in fungal and algal model systems. This gives us a unique opportunity to investigate the origin of multicellular life cycles, and assess their role in the evolution of complex life.