Chemical biologists at Georgia Tech and peer institutions in the Greater Atlanta area are poised for a grand debut on April 21, 2018 – at the First Annual Greater Atlanta Chemical Biology Symposium, to be held at Emory University.
It is show time for the Southeast’s talent in chemical biology – the interdisciplinary field that uses chemistry tools and methods to understand and manipulate biological systems.
“Atlanta institutions are becoming a hotbed for research in chemical biology and related fields,” says Matthew Torres, an associate professor in the Georgia Tech School of Biological Sciences. “Institutional commitments and federal funding in the past five years,” he says, “have enhanced infrastructure to support world-class chemical biology research programs,” not only at Georgia Tech, but also at the symposium’s other host institutions: Emory University, Georgia State University, and the University of Georgia.
Faculty hiring has expanded the breadth of chemical biology research in the host institutions. “New hires, myself included, have been attracted to the community that is developing here,” says William Wuest, who joined Emory University in 2017 and chairs the symposium’s organizing committee.
“A lot is going on,” says M.G. Finn, professor and chair of the School Chemistry and Biochemistry and a member of the symposium’s organizing committee. “Chemical biology underpins vast activity in Atlanta on immunology, drug development, diagnostics, and many other applications. The symposium’s host institutions boast an impressive number and quality of chemical biology investigators.”
“Atlanta institutions are becoming a hotbed for research in chemical biology and related fields.”
In Georgia Tech alone, Finn notes, chemical biology research spans at least seven schools in the Colleges of Sciences and Engineering: Biological Sciences, Biomedical Engineering, Chemical and Biomolecular Engineering, Chemistry and Biochemistry, Electrical and Computer Engineering, and Physics. Chemical biology is also one of the main research areas supported by the Parker H. Petit Institute of Bioengineering and Bioscience (IBB), where the labs and offices of many Georgia Tech faculty doing chemical biology research are located.
In planning the April 21 symposium, Wuest drew upon his experience at his previous institution. Temple University regularly participates in an annual symposium on the chemistry-biology interface that highlights local talent in the Mid-Atlantic region, focusing on early-career faculty and students and featuring some keynote speaker, Wuest says. “It was wildly successful. I believe the time is right to start one in Atlanta.”
“The idea,” Finn says, “is to give chemical biologists in Atlanta – including undergraduate and graduate students, postdoctoral researchers, and faculty scientists – a venue to exchange results and ideas.”
“Chemical biology underpins vast activity in Atlanta on immunology, drug development, diagnostics, and many other applications."
The organizers have invited a diverse and interdisciplinary slate of nine keynote speakers, five of whom are from outside Georgia. Among the speakers from host institutions is Torres, who is also a member of IBB.
“My lab’s mission,” Torres says, “is to understand how post-translational modifications regulate the signaling of G proteins.” G proteins comprise a family of proteins mediating the transmission of myriad signals from outside the cell into the cell interior. They are major targets in the search for drugs to treat a variety of diseases. At the symposium, Torres will describe his lab’s work on the use of machine learning and neural networks to identify protein modifications involved in pharmacology and disease.
The symposium offers a way to liberate “chemical biology perspectives that are often maintained in isolation and rarely cross institutional boundaries,” Torres says. “A great deal can be gained by breaking these boundaries to create a more fluid and open community that is bigger and better than any one lab or any one institution alone.”
The symposium is free to all attendees, thanks to the generosity of the host institutions, the Georgia Research Alliance, and five journals: Journal of Medicinal Chemistry, ChemBioChem, ACS Medicinal Chemistry Letters, ACS Infectious Diseases, and ACS Combinatorial Science, whose editor-in-chief is Finn.
Researchers have found previously known skin itch receptors in the airways of mice. The receptors appear to contribute to bronchoconstriction and airway hypersensitivity, which are hallmarks of asthma and other respiratory disorders. The experiments in mice suggest that the receptors’ activation directly aggravates airway constriction. If the same process is active in people, the receptors may be a promising new target for development of drug therapies for asthma and related disorders.
In a report on the study in Nature Neuroscience, researchers say the receptors – called MrgprC11 – are present on nerve cells in the lower respiratory tracts of lab mice.
“The findings give us a fuller picture of what airway reactivity looks like,” says Xinzhong Dong, Ph.D., professor of neuroscience at the Johns Hopkins University School of Medicine Institute for Basic Biomedical Sciences.
Working closely with Dong was Liang Han, the paper’s first author and an assistant professor in the Georgia Tech School of Biological Sciences, where she conducted some of the reported work.
Asthma patients report an itchy sensation in their lungs just prior to a full-blown asthma symptom such as wheezing. This observation inspired the research team to study “itchiness” in the airway.
“Current investigations of the pathogenesis of asthma have largely focused on immune responses,” Han says. “However, anti-inflammatory treatment only partially controls asthma symptoms. We need to understand the involvement of non-immune systems in the disease, such as the potential role of MrgprC11.”
Using fluorescent antibodies that light up MrgprC11 in mice, the investigators observed MrgprC11 on vagus nerves, which serve as a main biochemical connection between airway cells and the brain.
To explore the effects of MrgprC11 on the airway, the researchers used an itch activator that specifically targets MrgprC11 to induce a reaction. They found that mice with MrgprC11 breathed more quickly and with more effort after exposure to the itch activator than did the mice lacking it.
“This result led us to the hypothesis that activation of MrgprC11 induces bronchoconstriction,” Han says. Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle. It leads to consequent coughing, wheezing, and shortness of breath.
Next, the researchers examined bronchoconstriction by measuring the airway resistance of mice with and without MrgprC11. The team saw increased airway resistance in mice with MrgprC11.
“These findings highlight the critical role of vagal sensory neurons in asthma,” Han says. “They reveal a neural mechanism underlying asthma and a potential therapeutic target for treatment.” Han says.
Other Georgia Tech coauthors of the study are Haley Steele, Yuyan Zhu, and Julie Wilson, who are, respectively, a Ph.D. student, a postdoctoral researcher, and a laboratory technician in Han’s lab.
This research was supported by the National Institutes of Health (NS054791 & NS087088), the National Heart, Lung and Blood Instiute (112919 &122228), and by the American Asthma Foundation.
School of Biological Sciences Professor Joshua Weitz wrote an opinion piece for the myAJC blog supporting the high school students who may choose to walk out on March 14 "to honor the students and staff killed in the Parkland, Fl., school shooting three weeks ago." He implores Georgia Tech to reassure students who engage in peaceful protest that their admission status will not be jeopardized.
If you could rewind time and let evolution happen all over again, would the end result resemble life as we know it? This is no longer a theoretical question. While he was at Georgia Tech, School of Biological Sciences' Eric Gaucher worked with Betul Kacar on a NASA-funded project to replay evolution again and again with the bacterium E. coli, rewinding the evolution of a specific key protein that the bacteria needed to survive.
Biological Sciences doctoral student Jennifer Pentz was selected for the 2018 O'Hara Fellowship.This fellowship is presented to top doctoral students in the College of Sciences following a nomination from each of the Schools in the College. The O'Hara Fellowship includes a financial award for each semester in 2018. Jennifer’s research focuses on how early developmental programs (clonal, aggregative) affect the evolution of multicellularity. Her research advisor is Professor Will Ratcliff.
Georgia Tech has selected Troy Hilley as the recipient of the 2018 Outstanding Achievement in Research Enterprise Enhancement Award. Hilley is the Academic and Research IT Support Engineer Lead for the School of Biological Sciences (SoBiosci). The award recognizes staff members who consistently improve Georgia Tech’s research programs but are not traditional researchers themselves.
Hilley is responsible for the day-to-day operations and maintenance of faculty, research group, and administrative computing infrastructure in SoBiosci. He also acts as a critical liaison between SoBiosci, the College of Sciences, and Georgia Tech computing teams. Yet in practice, Hilley does much more. As SoBiosci grows, he has established himself as a leader in thinking creatively and acting proactively to prepare SoBiosci for the rapidly changing environment for integrative computing.
“Troy is the reason we’ve managed to scale up so seamlessly,” a colleague says.
According to colleagues, Hilley has been instrumental in advancing SoBiosci’s research. Relentlessly pursuing institutional effectiveness, he has gone beyond his scope of duties to help faculty build infrastructure for effective research, assist with strategic planning of computational needs, and provide timely and expert assistance to advance computation-based discoveries in the life sciences.
Hilley’s advice and collaboration has enabled critical research publications, catalyzed translation of discoveries form lab to industry, and helped secure extramural funding for sustained work in SoBiosci.
“I love being able to assist people. I listen to the needs of faculty. My goal is for them to leave the office knowing that their needs will be met,” Hilley says. “It is an honor to be recognized by such an esteemed group and to be a small part of their research.”
Researchers experimenting with live zebrafish witnessed a 200% increase in the strength of intestinal contractions soon after the organisms were exposed to the cholera-causing bacterium Vibrio cholerae. The strong contractions led to expulsion of native gut bacteria.
The discovery, detailed in the Proceedings of the National Academy of Sciences, “was remarkable and unexpected,” the authors write.
The researchers – from the University of Oregon, Georgia Institute of Technology, and Memorial-Sloan Kettering Cancer Center – used genetic manipulation and cutting-edge three-dimensional microscopy to monitor what happens when the disease-causing microbe is initially introduced into the larvae of zebrafish, an organism commonly studied as a model for understanding health and disease in vertebrates, including humans.
The multidisciplinary team of physicists, molecular biologists, and microbiologists focused on the harpoon-like injection capabilities of the type VI secretion system. This appendage, found in many bacteria including Vibrio cholerae, transfers toxic proteins into competing healthy cells.
The scientists engineered Vibrio cholerae mutants with variations in that secretion system and then observed the behavior of the microbes as they invaded zebrafish colonized with Aeromonas veronii, a native species in that animal’s gut.
Instead of simply killing native Aeromonas gut bacteria upon contact, as expected, when Vibrio cholerae entered the gut the native bacteria were swiftly flushed out.
“The secretion system induced dramatic increases in the strength of the peristalsis process, the contractions that move gut contents down the gastrointestinal tract much like squeezing a tube of toothpaste from the end to the top,” says coauthor Brian K. Hammer, a microbiologist and associate professor in the School of Biological Sciences at Georgia Tech.
The researchers hypothesized that the unexpected bacterial manipulation in the digestive system might be driven by a particular piece of the type VI machinery known to bind to actin, a cellular scaffolding protein. When the scientists deleted the actin-binding domain from the bacterial gene, they saw that Vibrio cholerae lost its ability to enhance peristalsis and its ability to expel native Aeromonas.
The findings shed new light on how the waterborne Vibrio cholerae functions. According to the Centers for Disease Control and Prevention, Vibrio cholerae triggers more than 3 million cases of acute diarrheal illness and 100,000 deaths in people worldwide each year.
“Knowing the strategies by which the bacterium is able to invade the intestine can open doors to therapies that might disrupt these paths,” says corresponding author Raghuveer Parthasarathy, a professor of physics at the University of Oregon, whose imaging and analysis techniques were used in the study.
Because the type VI secretion system is also found in native gut bacteria, including those in the human gut microbiome, it could be harnessed for therapies, including specially designed probiotics, to promote beneficial species or to defend against disease invasion, Hammer says.
“We suspect that other gut microbes, both pathogenic and beneficial, might similarly make use of this secretion system to reshape their environment,” Parthasarathy says.
Most previous research on this secretion system has relied on studying bacteria outside of animals – on a Petri dish for example, or by examining fecal samples – to infer what is happening in the gut during infection.
While the research team captured the impact of invasion by Vibrio cholerae, understanding just how it takes root in the host, such as what specific cells in the animal are targeted, is an open question, Parthasarathy says.
“We still have no idea how the action of his secretion system’s harpoon is causing the changes in the muscle contractions,” Hammer says. “We suspect that what we are observing may be an immune response to irritation in the gut lining. But what cells in the gut are being poked?”
How the findings may reflect the colonization of Vibrio cholerae in humans is not known, but the role of the secretion system makes a similar result plausible, the researchers wrote in their conclusion.
BIRTH OF COLLABORATION
The findings emerged from a collaboration born in 2015 when Hammer, Parthasarathy, and coauthor Joao Xavier, a researcher at the Memorial Sloan-Kettering Cancer Center, discussed joint research possibilities during a conference, Scialog: Molecules Come to Life, in Tucson, Arizona.
The Scialog (Science and Dialog) was organized by the Research Corporation for Science Advancement and sponsored jointly with the Gordon and Betty Moore Foundation, with additional support from the Simons Foundation. The goal of Scialog is to rapidly catalyze new interdisciplinary collaborative teams, such as the one formed by Hammer, Parthasarathy, and Xavier, to work on high-risk, high-reward projects.
As a result, their three labs received an award from the Gordon and Betty Moore Foundation and the Simons Foundation to pursue their Scialog idea. The National Science Foundation, National Institutes of Health, M.J. Murdock Charitable Trust, and Kavli Microbiome Ideas Challenge also supported the research.
Trajectories of Vibrio cholerae bacteria (blue) swimming inside the gut of a larval zebrafish. The gut is visible as a gray background. The total duration of the movie that was “squashed” into this image is 3.5 seconds, and the total image width is about 0.3 mm. (Courtesy of Raghuveer Parthasarathy)
Joseph Rabinoff and Matthew Torres are two of Georgia Tech’s 2018 CTL/BP Junior Faculty Teaching Excellence Award winners. Jointly supported by the Center for Teaching and Learning and BP America, the award recognizes the excellent teaching and educational innovation that junior faculty bring to campus.
JOSEPH RABINOFF: Helping both students and faculty
Joseph Rabinoff was recently promoted to associate professor in the School of Mathematics. Because many undergraduates take the fundamental mathematics courses he teaches, Rabinoff has had a broad impact on Georgia Tech undergraduates.
Students say Rabinoff makes mathematics relevant and engaging, especially the introductory classes he teaches. For his part, Rabinoff seeks to ensure that all students, whatever their majors, understand and even appreciate the material.
Rabinoff was heavily involved in developing the curriculum and course materials for Math 1553, Introduction to Linear Algebra. This is an engineering core course that is taken by thousands of Georgia Tech students every year. He created lecture slides, interactive demonstrations, and online homework problems. With colleague Dan Margalit, Rabinoff wrote a free online textbook for the course, “Interactive Linear Algebra.”
Beyond the classroom, Rabinoff spearheaded the creation of the School of Mathematics’ course repository and has been the main contributor to its infrastructure and content. The repository contains up-to-date curated materials that a new teacher can just pick up and use.
The students are the most exciting part about being at Georgia Tech, Rabinoff said in a 2016 Q&A. “Some students are extremely hard-working and talented. I derive a lot of pleasure from interactions in class and office hours,” he said.
In turn, students praise Rabinoff for his enthusiasm, engaging lectures, friendliness, accessibility, and, yes, his “super” “Rabinoffice” hours, which one students says “are fantastic during exam weeks.”
“It is an honor to be recognized with this award,” Rabinoff says. “The students I see every week in class and in office hours are great kids, and all of the effort is for them. Pedagogy is special in this way: The reward is not abstract; it is visible every time I see in a student's face that a light went on in their head. I’m very fortunate to have the opportunity to teach in a place like Georgia Tech.”
MATTHEW TORRES: Teaching life skills
Matthew Torres also was recently promoted to associate professor, in the School of Biological Sciences. Although he always knew he would be a scientists, he never thought about being a teacher. At Georgia Tech he has recognized that, “first and foremost,” he is a teacher.
Having embraced the role of an educator, his dedication is obvious to students and colleagues. Students regard him not only as an excellent teacher, but also as someone who believes in them and sees their potential. Students say Torres’s mentorship goes beyond biology: Torres helps them develop critical skills that will serve them throughout their lives – such as written and spoken scientific communication, self-reflection, and how to confront failure productively.
Colleagues say Torres is a natural teacher, taking every opportunity to teach and mentor students in Georgia Tech and beyond. He gives students personal attention and invests time and resources to ensure student learning. A colleague describes Torres as “dedicated, caring, thoughtful, and highly successful in both teaching and research.”
Torres regularly invites undergraduates to do research in his lab, participating in work to address chemical biology questions that Torres’s research seeks to answer. These undergraduates are listed as coauthors on publications. In running his lab and in his teaching, Torres instills open communications and mutual respect as values that advance everyone’s progress.
Community engagement is important to Torres. He has volunteered to mentor high school students from the Gwinnett School of Mathematics, Science, and Technology. He routinely gives laboratory tours to local high schools focusing on science, technology, engineering, and mathematics (STEM).
“Winning this award is fantastic, but I’m also very lucky,” Torres says. “Lucky enough to have had wonderful students – undergraduate, graduate, and beyond – willing to join me on a journey in pursuit of greater understanding and scientific progress. Such a journey can’t happen because of a teacher alone – it takes bright, receptive, and brave students to help guide the way.”
Georgia Tech has named Jeffrey Skolnick the recipient of the 2018 Sigma Xi Sustained Research Award. The award recognizes Skolnick’s exceptional sustained imagination and productivity in the fields of systems biology, computational biology, bioinformatics, cancer metabolomics, protein structure prediction and evolution, drug design, and simulations of cellular processes.
Skolnick is the Mary and Maisie Gibson Chair, the Georgia Tech Alliance Eminent Scholar in Computational Systems Biology, and a professor in the School of Biological Sciences. He is also the director of the Center for the Study of Systems Biology.
In his research, Skolnick has developed algorithms to predict protein structure and function and ligand-protein interactions. Applications include drug discovery and prediction of off-target uses of already approved drugs.
Skolnick pioneered the field of ligand homology modeling, using the modeling algorithm FINDSITEcomb to infer protein function, predict a protein’s binding site, and screen virtual ligands. The insights from this work has enabled use of even low-resolution protein structures in virtual ligand screening. Skolnick is applying this knowledge to find other diseases that approved drugs could treat.
Drugs of interest include granisetron (Kytril), an antinausea and antiemetic agent; progesterone, a female hormone; acetaminophen, a pain reliever; and naproxen an anti-inflammatory and analgesic agent. Among diseases that existing drugs might help treat are cancer, pain, cardiovascular diseases, neurological diseases, cystic fibrosis, and diseases caused by genetic variations.
“The biochemical seeds of life could be prevalent.”
Using another algorithm, Skolnick has found a way to boost the odds that disease organisms will not quickly develop resistance to an antibiotic. The algorithm identifies compounds that target two or more receptor sites on proteins that inhibit a key cellular function. To develop resistance to such drugs, microbes would have to simultaneously develop mutations in all the target receptor pockets. Simultaneous mutations would be more challenging to the bugs than developing resistance in only one receptor site. The technique has been validated for a drug-resistant Escherichia coli.
Skolnick’s adventures with protein structures and functions have profound implications for the origins of life. For example, Skolnick and coworkers have shown that the ability to catalyze biochemical reactions is an intrinsic property of protein molecules, defined only by their structure and the principles of chemistry and physics. Accordingly, evolution is not necessary for the existence of proteins’ biochemical functions, although evolutionary selection may have optimized proteins for specific roles.
“The biochemical seeds of life could be prevalent,” Skolnick said about the work in 2016. “If you rain meteorites containing amino acids and somehow these polymerize to form small proteins, then a subset of these would fold to stable structure and a small subset of these could engage in rudimentary metabolism, all without any selection for biochemical function. Thus, the background probability for function is much larger than had been previously appreciated.”
By extension, extraterrestrial life could be ubiquitous.
The ability to do out-of-the-box research has been a hallmark of Skolnick’s career. “I am most grateful,” Skolnick says, “to the environment provided by Georgia Tech and to my collaborators who have enabled these ideas to come to fruition.”