A new study of both computer-created and natural proteins suggests that the number of unique pockets – sites where small molecule pharmaceutical compounds can bind to proteins – is surprisingly small, meaning drug side effects may be impossible to avoid. The study also found that the fundamental biochemical processes needed for life could have been enabled by the simple physics of protein folding.
Studying a set of artificial proteins and comparing them to natural proteins, researchers at the Georgia Institute of Technology have concluded that there may be no more than about 500 unique protein pocket configurations that serve as binding sites for small molecule ligands. Therefore, the likelihood that a molecule intended for one protein target will also bind with an unintended target is significant, said Jeffrey Skolnick, a professor in the School of Biology at Georgia Tech.
“Our study provides a rationalization for why a lot of drugs have significant side effects – because that is intrinsic to the process,” said Skolnick. “There are only a relatively small number of different ligand binding pockets. The likelihood of having geometry in an amino acid composition that will bind the same ligand turns out to be much higher than anyone would have anticipated. This means that the idea that a small molecule could have just one protein target can’t be supported.”
Research on the binding pockets was published May 20 in the early edition of the journal Proceedings of the National Academy of Sciences. The research was supported by the National Institutes of Health (NIH).
Skolnick and collaborator Mu Gao have been studying the effects of physics on the activity of protein binding, and contrasting the original conditions created by the folding of amino acid residues against the role played by evolution in optimizing the process.
“The basic physics of the system provides the mechanism for molecules to bind to proteins,” said Skolnick, who is director of the Center for the Study of Systems Biology at Georgia Tech. “You don’t need evolution to have a system that works on at least a low level. In other words, proteins are inherently capable of engaging in biochemical function without evolution’s selection. Beyond unintended drug effects, this has a lot of implications for the biochemical component of the origins of life.”
Binding pockets on proteins are formed by the underlying secondary structure of the amino acids, which is directed by hydrogen bonding in the chemistry. That allows formation of similar pockets on many different proteins, even those that are not directly related to one another.
“You could have the same or very similar pockets on the same protein, the same pockets on similar proteins, and the same pockets on completely dissimilar proteins that have no evolutionary relationship. In proteins that are related evolutionarily or that have similar structures, you could have very dissimilar pockets,” said Skolnick, who is also a Georgia Research Alliance Eminent Scholar. “This helps explain why we see unintended effects of drugs, and opens up a new paradigm for how one has to think about discovering drugs.”
The implications of this “biochemical noise” for the drug discovery process could be significant. To counter the impact of unintended effects, drug developers will need to know more about the available pockets so they can avoid affecting binding locations that are also located on proteins critical to life processes. If the inevitable unintended binding takes place on less critical proteins, the side effects may be less severe.
In addition, drug development could also move to a higher level, examining the switches that modulate the activity of proteins beyond binding sites. That may require a different approach to drug development.
“The strategy for minimizing side effects and maximizing positive effects may have to operate at a higher level,” Skolnick said. “You are never going to be able to design unintended binding effects away. But you can minimize the undesirable effects to some extent.”
In their study, Skolnick and Gao used computer simulations to produce a series of artificial proteins that were folded according the laws of physics, but not optimized for function. Using an algorithm that compares pairs of pockets and assesses the statistical significance of their structural overlap, they analyzed the similarity between the binding pockets in the artificial proteins and the pockets on a series of native proteins. The artificial pockets all had corresponding pockets on the natural proteins, suggesting that the simple physics of folding has been a major factor in development of the pockets.
“This is how life, at least the biochemistry of life, could have gotten started,” said Skolnick. “Evolution would have optimized the functions, but you don’t need that to get started at a low level of efficiency. If you had a soup of our artificial proteins, even with no selection you could at least do low-level biochemistry.”
Though the basic biochemistry of life was made possible by simple physics, optimizing the binding process to allow the efficiencies seen in modern organisms would have required evolutionary selection.
“This is the first time that it has been shown that side effects of drugs are an inherent, fundamental property of proteins rather than a property that can be controlled for in the design,” Skolnick added. “The physics involved is more important than had been generally appreciated.
Research reported in this news release was supported by the Institute of General Medical Sciences of the National Institutes of Health (NIH) under award number GM48835. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
CITATION: Jeffrey Skolnick and Mu Gao, “Interplay of physics and evolution in the likely origin of protein biochemical function,” (Proceedings of the National Academy of Sciences, 2013).
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Eric Gaucher, associate professor in Georgia Tech's School of Biology, was named as one of 14 young faculty from seven nations to receive an early career grant by DuPont. The DuPont Young Professor program is designed to help promising young and untenured research faculty begin their research careers.The $75,000 award is unrestricted and not tied to a specific research project.
"It is a wonderful honor to receive this award because, in many regards, it is a validation that there is utility associated with our research," said Gaucher. "This is also validation for Georgia Tech because it demonstrates that the Institute has been successful in fostering the development of research and technology that reaches beyond the academic environment."
Gaucher came to Tech in 2008 with a Ph.D. in evolutionary and biomedical sciences from the University of Florida. His research is focused on understanding the origins and evolution of life on earth. Last year, Gaucher's lab resurrected a 500-million-year-old gene from a bacterium and inserted it into a modern bacterium, Escherichia coli (E. coli). As a result they've been able to watch how the gene evolves.
"Our research exploits a unique protein-engineering platform of interest to DuPont because recombinant proteins have become extremely prevalent throughout society yet we desperately need new ways to improve how such proteins are engineered and developed," said Gaucher. "We will use the money associated with this award to validate that our platform is useful to diverse sectors such as bioindustry, agriculture and biomedicine."
Since 1968, DuPont has provided nearly $50 million in grants to more than 680 young professors in more than 130 institutions in 14 countries. In addition to providing unrestricted funding to new faculty, this prestigious program enables DuPont to build future research partnerships with emerging, global academic leaders.
Research interests within the class of 2013 Young Professors represent key components of DuPont science and include promising research in the fields of: environmental remediation, genomic prediction, optics in nanoscience, pest management, phytochemicals for nutrition and medicine, plant breeding, protein engineering, studies of the human microbiome, sustainable energy and fuel production, and, water treatment and desalinization.
Professors are nominated by a member of the DuPont technical staff and the nominator serves as the liaison between the company and the faculty member. During the three-year award, each grant recipient is invited to present a seminar on his or her work to the DuPont research community.
The new Engineered Biosystems Building will be a giant leap forward in creating the infrastructure that inspires and sustains scientific discovery at Georgia Tech. EBB will enable us to expand our commitment to improving and saving lives by providing bringing new treatments, medical technologies, medications, and therapies to patients. The key to innovation lies in collaboration, and the EBB is designed to facilitate research across disciplinary and institutional boundaries. Partnerships are integral to the success of EBB, especially between faculty from the Colleges of Sciences, Engineering, Computing, and between Georgia Tech researchers and those from Emory University, Children’s Healthcare of Atlanta, and other institutions. The research conducted in EBB will help distinguish Georgia Tech as a national leader in biomedicine and biotechnology.
EBB will provide 200,000 square feet of technologically advanced laboratories for faculty, researchers, and students to pursue Georgia Tech’s growing research agenda in the biological sciences. The building will also strengthen the Georgia Tech’s ability to attract and retain the best faculty from around the world. It will allow the College of Sciences to increase the size of its faculty in Biology over the next decade. In turn, these exceptional teacher-scholars will draw the brightest, most talented graduate students to Tech. Moreover, EBB will significantly enhance Georgia Tech’s commercialization efforts, stimulate job growth in the state, and generate new startup companies.
Gross-chromosomal rearrangements are a hallmark of cancers and hereditary diseases. On the other hand, these events can trigger the generation of polymorphisms and lead to evolution. The driving force behind chromosomal rearrangements is DNA double strand breaks. A variety of factors can contribute to the generation of breaks in the genome. A paradoxical source of breaks is the sequence composition of the genomic DNA itself. Eukaryotic and prokaryotic genomes contain sequence motifs capable of adopting secondary structures often found to be potent inducers of double strand breaks culminating into rearrangements. These regions are therefore termed fragile sequence motifs.
A recently published study authored by Natalie Saini and colleagues in the lab of Kirill Lobachev (School of Biology), demonstrates that two particular types of fragile sequence motif, inverted repeats and triplex-forming repeats, increase mutation frequency in surrounding DNA regions. Interestingly, repeat-induced mutagenesis was found to spread large distances on either side flanking the break-point and requires the activity of an error-prone DNA polymerase. Remarkably, repair of the induced double-strand break via homologous recombination, a process previously thought to be error-free, also yields mutations and reconstitutes the repeats. This discovery is the first demonstration that inverted repeats and triplex-forming repeats provide a long-term source of DNA breakage and mutagenic repair. Consequently, secondary structure-forming repeats are a dual threat to genome stability due to their inherent potential to induce both rearrangements and mutations in the flanking DNA regions.
The study was published in Public Library of Science (PLoS) Genetics on 13 June 2013 and can be found at: http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1003551. Funding for this research was provided by grants from the NSF and NIH to Kirill Lobachev.
By studying rapidly evolving bacteria as they diversify and compete under varying environmental conditions, researchers have shown that temporal niches are important to maintaining biodiversity in natural systems. The research is believed to be the first experimental demonstration of temporal niche dynamics promoting biodiversity over evolutionary time scales.
The temporal niches – changes in environmental conditions that occur during specific periods of time – promoted frequency-dependent selection within the bacterial communities and positive growth of new mutants. They played a vital role in allowing diversity among bacterial phenotypes to persist.
The research provides new insights into the factors that promote species coexistence and diversity in natural systems. Understanding the mechanisms governing the origin and maintenance of biodiversity is important to scientists studying the roles of both ecology and evolution in natural systems.
“This study provides the first experimental evidence showing the impact of temporal niche dynamics on biodiversity evolution,” said Lin Jiang, co-author of the paper and an associate professor in the School of Biology at the Georgia Institute of Technology. “Our laboratory results in bacteria can potentially explain the diversity dynamics that have been observed for other organisms over evolutionary time.”
The research, which was supported by the National Science Foundation, was published July 9 in the journal Nature Communications.
In experimental manipulation of the bacterium Pseudomonas fluorescens, the researchers showed that alternating environmental conditions in 24-hour cycles strongly influences biodiversity dynamics by helping to maintain closely-related phenotypes that might otherwise be lost to competition with a dominant phenotype. The experiment followed the bacteria through more than 200 generations over a period of nearly two weeks.
In the laboratory, Jiang and graduate student Jiaqi Tan established communities of the bacterium in test tubes called microcosms. In designing the experiments, they collaborated with Colleen Kelly, a senior research associate in the Department of Zoology at the University of Oxford.
“You begin with one phenotype, and within two days, you might have two or three different phenotypes,” said Jiang. “The system can do this in a matter of days.”
Through a 12-day experimental period, the researchers subjected one group of cultures to 24-hour periods in which they were alternately allowed to grow undisturbed and shaken vigorously. To control for the impact of starting conditions, cultures within those two groups were chosen to begin with a period of static growth, while others began with a period of shaken growth. Finally, groups of control cultures were grown under continuous shaking or continuous static conditions.
During the study, the researchers periodically measured the population sizes of each phenotype present in each culture. Cultures subjected to alternating shaking and static conditions produced the highest level of diversity among the closely-related bacteria, which is often studied because it diversifies so rapidly.
“Static conditions promoted diversification,” Jiang explained. “But the shaking tended to maintain the diversity that had evolved. Both conditions were essential for high biodiversity.”
In experiments, the ancestral bacterial phenotype, which is known as “smooth morph,” quickly diversifies and generates two niche-specialists, known as “wrinkled spreader” and “fuzzy spreader.” Those, in turn, diversify into additional phenotypes. Competition for oxygen in the microcosms in which the bacteria grow is believed to drive the diversification; shaking the microcosms changes the levels of oxygen available to each phenotype. Because different phenotype groups inhabit different sections of the container, the shaking eliminated the preferred niches of some phenotypes.
The diversification in the microcosms experiencing constant shaking was much slower than in static microcosms. In microcosms experiencing temporal niche dynamics – the alternating shaking and non-shaking periods – the diversity increased rapidly and was maintained longer than in the other environments. The researchers found that the two different temporal niche dynamics environments – which differed only in their starting conditions – both produced richer biodiversity than those environments without it.
While the diversification occurred rapidly over a period of four days, the decline in the number of phenotypes due to natural competition took longer. Some of the phenotypes were ultimately excluded through the competitive processes.
“Diversity typically increases with time, then plateaus,” said Jiang. “Without temporal niche, diversity tends to decline. Temporal niche allows a greater diversity to be maintained over time than would be possible otherwise.”
Though the study focused on rapidly diversifying bacteria, the researchers believe it may have broader implications. The general theory of temporal niche dynamics was developed with more complex organisms, such as plants and corals, in mind.
“The mechanisms that promote biodiversity, which we call frequency-dependent selection, are very common in species,” said Tan. “As long as you have a strong intra-species competition within the populations, you are expected to see this frequency-dependent selection. Based on this most common mechanism that we find in this system, there are implications for other ecosystems.”
For the future, the researchers would like to study the effects of combining spatial and temporal niches in evolution.
“From this experiment, we know that temporal niche can maintain biodiversity,” said Tan. “Similarly, we want to manipulate spatial diversity to see if heterogeneity in the spatial scale can affect the maintenance of biodiversity.”
This research was supported by the National Science Foundation under grants DEB-1120281 and DEB-1257858. Any opinions expressed are those of the authors and do not necessarily represent the official views of the National Science Foundation.
CITATION: Jiaqi Tan, Colleen K. Kelly and Lin Jiang, “Temporal niche promotes biodiversity during adaptive radiation,” (Nature Communications, 2013). http://dx.doi.org/10.1038/ncomms3102
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The bacterium Vibrio cholerae annually causes millions of cases of the often fatal disease cholera, typically in regions where access to clean drinking water is limited. V. cholerae can be introduced into water by infected individuals who can sometimes be asymptomatic, however this microbe is also a natural inhabitant of aquatic waters. Since the summer following the tragic January 2010 earthquake in Haiti, an on-going cholera epidemic has resulted in more than 600,000 individual cases and 7,500 deaths. The emergence of this cholera epidemic has sparked questions as to whether the origin of the outbreak was imported or indigenous. Previous genome sequencing studies suggested that a strain of V. cholerae was inadvertently introduced into Haiti by United Nations security forces deployed from Nepal, where cholera outbreaks occurred weeks before the troops were deployed to the island. Subsequent studies, however, suggest that the strain may have acquired DNA through “horizontal gene transfer” from other Vibrio organisms in the local environmental – a phenomenon that may have contributed to the outbreak.
In a new study published in the journal mBio, the Centers for Disease Control and Prevention’s Cheryl Tarr and Lee Katz (School of Biology Ph.D. recipient) along with Georgia Tech’s School of Biology Professor Brian Hammer, his student Elena Antonova, and other colleagues, analyzed a set of isolates collected in Haiti at various times and locations since 2010. Genome sequencing of these isolates supports a model in which the outbreak was due to a single point-source introduction of V. cholerae to the island. Further analysis revealed that not only have the Haiti isolates not acquired new genes from the environment, but they are also severely impaired for the ability to undergo horizontal gene transfer, which typically allows bacteria to adapt quickly to new environments. On-going studies are underway to identify the mutation that prevents the Haiti strains from taking up environmental DNA.
The study was published on July 2, 2013 in mBio, the online open access journal from the American Society for Microbiology, and can be found at: http://mbio.asm.org/content/4/4/e00398-13. Funding for Hammer’s work in this study was provided by a grant from the National Science Foundation.
Patrick McGrath, an Assistant Professor in the School of Biology, has been chosen as an Ellison Medical Foundation New Scholar in Aging (http://www.ellisonfoundation.org/program/aging-new-scholar) to study how complex genetics can influence the aging process in the small nematode C. elegans. Dr. McGrath joined the School of Biology in 2012.
In humans, lifespan is a heritable trait, meaning that differences in our genes influence how fast we age. The McGrath lab plans to identify new signaling pathways controlling aging that are preferentially modified by combinations of natural polymorphisms segregating within a population.
The foundation’s New Scholar awards provide support for new investigators to help establish their labs. The award provides funding of $100,000 per year for a four-year period.
New Scholar applications are by invitation only. This is the first year that Georgia Tech has been invited to nominate a candidate to apply.
More information about McGrath lab research can be found at http://mcgrathlab.biology.gatech.edu.
For the majority of cancer patients, it’s not the primary tumor that is deadly, but the spread or “metastasis” of cancer cells from the primary tumor to secondary locations throughout the body that is the problem. That’s why a major focus of contemporary cancer research is how to stop or fight metastasis.
Previous lab studies suggest that metastasizing cancer cells undergo a major molecular change when they leave the primary tumor – a process called epithelial-to-mesenchymal transition (EMT). As the cells travel from one site to another, they pick up new characteristics. More importantly, they develop a resistance to chemotherapy that is effective on the primary tumor. But confirmation of the EMT process has only taken place in test tubes or in animals.
In a new study, published in the Journal of Ovarian Research, Georgia Tech scientists have direct evidence that EMT takes place in humans, at least in ovarian cancer patients. The findings suggest that doctors should treat patients with a combination of drugs: those that kill cancer cells in primary tumors and drugs that target the unique characteristics of cancer cells spreading through the body.
The researchers looked at matching ovarian and abdominal cancerous tissues in seven patients. Pathologically, the cells looked exactly the same, implying that they simply fell off the primary tumor and spread to the secondary site with no changes. But on the molecular level, the cells were very different. Those in the metastatic site displayed genetic signatures consistent with EMT. The scientists didn’t see the process take place, but they know it happened.
“It’s like noticing that a piece of cake has gone missing from your kitchen and you turn to see your daughter with chocolate on her face,” said John McDonald, director of Georgia Tech’s Integrated Cancer Research Center and lead investigator on the project. “You didn’t see her eat the cake, but the evidence is overwhelming. The gene expression patterns of the metastatic cancers displayed gene expression profiles that unambiguously identified them as having gone through EMT.”
The EMT process is an essential component of embryonic development and allows for reduced cell adhesiveness and increased cell movement.
According to Benedict Benigno, collaborating physician on the paper, CEO of the Ovarian Cancer Institute and director of gynecological oncology at Atlanta’s Northside Hospital, “These results clearly indicate that metastasizing ovarian cancer cells are very different from those comprising the primary tumor and will likely require new types of chemotherapy if we are going to improve the outcome of these patients.”
Ovarian cancer is the most malignant of all gynecological cancers and responsible for more than 14,000 deaths annually in the United States alone. It often reveals no early symptoms and isn’t typically diagnosed until after it spreads.
“Our team is hopeful that, because of the new findings, the substantial body of knowledge that has already been acquired on how to block EMT and reduce metastasis in experimental models may now begin to be applied to humans,” said Georgia Tech graduate student Loukia Lili, co-author of the study.
Welcome to a new year at Georgia Tech. Now that you’re back, it’s time to start thinking about studying abroad. Yes, you just got here, but since you’re at Georgia Tech, that means you think ahead and plan, so come to the open house at the Office of International Education this Wednesday from 11 am - 1 pm on the second floor of the Savant Building and start planning to see the world.
One student who’s seen the world is Bibiana “Bibi” Garcia. She’s starting her fifth year at Georgia Tech with a major in biology. She was born and raised in South America, but moved to Augusta, Ga when she began high school. Having lived in various countries, it was, perhaps, natural for her to want to study abroad. But she keeps doing it because she loves learning and says she learns something new in each place she visits.
“Traveling to a different country on your own is an excellent opportunity to do something outside of your comfort zone and challenge yourself so that you can grow as a person,” said Garcia.
Lorie Paulez, director of education abroad in Tech’s Office of International Education said that it’s not only about challenging yourself, but it’s about setting yourself up for a better career.
“We are finding more and more employers looking for graduates that have international experience these days,” said Paulez. “Because having gone abroad and having to learn to function in a culture that’s not your own gives you special skills and shows a certain amount of adaptability, flexibility and problem solving skills.”
Some students just go abroad once during their time at Tech, while others, like Garcia, go on multiple trips. Her first study abroad experience came in 2011 with the three-month Pacific Program where the group went to Wellington, New Zealand; Sydney, Australia and Brisbane, Australia. This past year, she returned to Sydney for a five-month exchange program with the University of New South Wales for a more in-depth experience.
“My philosophy is to look at my life and experience each day,” said Garcia. “I try to learn as much as I can from those around me and take advantage of every opportunity and experience available to me.”
Tech has a number of study abroad experiences available, said Paulez. There are the traditional summer study programs, but there are also exchange programs, like the one Garcia attended in Sydney, where students spend a semester or two abroad. Either of these programs may offer a research component, or service opportunities.
And knowing another language before you go isn’t necessary for all programs.
“We have options for everyone,” said Paulez. “Sometimes we have students who have already been studying a language, or a particular place or culture and they want to enhance that. But we also have students who have never been out of the United States and don’t speak another language.”
Interested in learning more? Then go to the Study Abroad Open House on Wednesday to get all your burning questions answered.
Elizabeth McMillan, working in the Kubanek Lab, was awarded the top presentation award at the Undergraduate Research Kaleidoscope event this week. Elizabeth studies chemically mediated competition specific to the red tide, Karenia brevis. Her presentation focused on examining the variation in the response of algal competitors from two different marine communities to chemicals released by K. brevis.