Amyloids are abnormal proteins that aggregate into fibrils, causing dreadful human diseases. They are strongly implicated in Alzheimer’s disease, a leading cause of dementia in elderly people. Mad cow disease, a neurodegenerative disease, results from infection by prions, which are amyloids that can spread between cells and organisms.
Despite voluminous research on amyloids and prions, researchers still cannot explain how harmless, normal protein sequences go awry and assume the deadly amyloid shape.
“The initial amyloid ‘nucleation’ is extremely difficult to investigate in animal models,” says Yury Chernoff, a professor in the School of Biological Sciences. “To begin with, initial nucleation is extremely rare. We have no idea where the initial amyloid ‘nucleus’ comes from and what promotes its formation. And then accumulation of an amyloid to detectable levels takes a very long time.”
For these reasons, Chernoff’s Georgia Tech team and collaborators in Germany and Russia (St. Petersburg State University, where Chernoff also directs a research group) turned to yeast as a model to study the human amyloids. They published their findings in the Journal of Biological Chemistry in early January 2018.
According to Chernoff, yeast also form prions, and the initial nucleation of a yeast prion is also rare. “However,” he says, “it is easier to detect prion nucleation in yeast that in humans, because it is possible to analyze large numbers of yeast cells, and because yeast prions cause easily detectable traits.”
The researchers fused mammalian amyloid-forming proteins to the yeast prion-forming protein. They found that the resulting chimeric proteins nucleate an amyloid state in yeast much more frequently than yeast prion-forming protein does on its own. “Because the resulting amyloid nucleus further converts a normal yeast protein,” Chernoff says, “amyloid formation could be detected by the appearance of an easily observable trait, such as growth on specific medium.”
The researchers successfully applied the method to several proteins, including amyloid beta (associated with human Alzheimer’s disease), PrP (associated with mad cow disease), alpha synuclein (associated with Parkinson’s disease), and amylin (associated with type II diabetes).
“This assay opens a wide window to the early stages of dreadful human diseases caused by abnormal protein aggregation,” Chernoff says. “The more we understand how these diseases originate, the better we can develop treatments.”
Beyond revealing how human proteins undergo amyloid nucleation, Chernoff says, the assay will help researchers discover factors affecting amyloid nucleation in cells, find agents that favor the development of diseases, and identify treatments and conditions that can prevent the triggering cause of a disease.
Chernoff’s Georgia Tech team working on this project included current Ph.D. student Pavithra Chandramowlishwaran and former Ph.D. student Meng Sun, who are co-first authors on the paper, as well as undergraduate researcher Kristin Casey and research scientist Andrey Romanyuk.
Growth of the specially designed yeast strain on a specific medium enables researchers to detect nucleation of disease-related fibrils by human amyloid beta protein, associated with Alzheimer’s disease.
This work was supported by grants from the National Institute of Aging, NIH (through Emory University’s Alzheimer’s Disease Research Center) and the Creutzfeldt-Jakob Disease Foundation, as well as the Russian Science Foundation and the Russian Foundation for Basic Research (to the St. Petersburg group).
Dan Taylor, the Yellow Jackets' strength and conditioning coach for men basketball, takes advantage of the biomechanics lab on campus in order to collect data on and improve the performance of his players. Young-Hui Chang, the founder of the lab and a professor in the School of Biological Sciences, doesn't mind. Chang can use the data for his reserach into intuitive physics: the idea that people (and animals) have an innate ability to predict the physical actions of the world around them.
Dan Taylor, the Yellow Jackets' strength and conditioning coach for men basketball, takes advantage of the biomechanics lab on campus in order to collect data on and improve the performance of his players. Young-Hui Chang, the founder of the lab and a professor in the School of Biological Sciences, doesn't mind. Chang can use the data for his reserach into intuitive physics- the idea that people (and animals) have an innate ability to predict the physical actions of the world around them.
Named after the Amazons of Greek myth, the Molly is a small freshwater fish that is challenging the established belief that asexual vertebrates are not viable long term. Each daughter is essentially a clone of her mother. Yet the Molly is thriving, perhaps for 10,000 years. Pedram Samani, an evolutionary geneticist and postdoctoral researcher in the School of Biological Sciences, comments on the research in Nature Ecology & Evolution. His comments are echoed by Cosmos Magazine.
Jenny McGuire is one of several scientists featured in a documentary that WyomingPBS will air twice in February. The documentary is part of a series called “Main Street, Wyoming.” The episode, “Natural Trap Cave,” is about a pitfall cave in the Bighorn Mountains of northern Wyoming. The cave harbors fossils from 150,000 years ago, which scientists have been collecting for research.
“Inside the cave is like a refrigerator,” McGuire says. “The temperature is 40 degrees all year round, so everything preserves beautifully.” In the cave are layers of fossils dating back from 150,000 years to recent times, giving McGuire the opportunity to study how a community changes over long periods.
McGuire is an assistant professor with joint appointment in the Schools of Biological Sciences and of Earth and Atmospheric Sciences. She is using the fossils to understand what types of species fill ecological niches after extinction events and how long it takes populations to normalize after a major transition. Similar extinctions of large mammals are occurring today in Africa and South Asia, according to McGuire. She is using the data to determine what to expect not only from specific extinctions, but also from major ecological disruptions occurring worldwide.
In between field visits to Natural Trap Cave, McGuire outsources the fossil work through Fossil Wednesdays. On Wednesday afternoons, 3-5 PM, during the semester, McGuire’s lab is open to all who are interested in hunting for fossils in the rock samples she brought back from Natural Trap Cave.
“Folks come to Fossil Wednesdays to experience the excitement of making new discoveries, accompanied by dramatic soundtracks playing in the background,” McGuire says. “At the same time, it is a relaxed atmosphere for chatting and really getting your mind off the stresses of the week.”
Through Fossil Wednesdays, McGuire has brought the thrill of discovery-based biology to engineers, business majors, and staff members from across campus and beyond. She has also trained K-12 school teachers to bring the excitement of hypothesis-driven discovery to their students.
The WyomingPBS crew visited the cave in July 2017, according to McGuire. “They filmed us inside the cave and did individual interviews with several of us outside the cave.” In the preview provided by WyomingPBS, McGuire is on camera at the end, holding a fossil. In the documentary itself, McGuire first appears at around 5:15.
WyomingPBS will air the episode on Sunday, Feb. 18, at 9 PM and on Friday, Feb. 23, at 10 PM. It is at wyomingpbs.org and on WyomingPBS’s YouTube Channel after the broadcasts.
EDITOR'S NOTE: This item was revised on Feb. 20, 2018. The documentary was added from YouTube.
The Amazon molly, an all-female fish species, is thriving despite dismal views of the genetic health of asexual vertebrae. The story features a comment from the School of Biological Sciences Pedram Samani's editorial in Nature. Samani writes, "The main finding of the paper is that the species is in remarkably good genomic health."
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.