As the medical community continues to make positive strides in personalized cancer therapy, scientists know some dead ends are unavoidable. Drugs that target specific genes in cancerous cells are effective, but not all proteins are targetable. In fact, it has been estimated that as few as 10 to 15 percent of human proteins are potentially targetable by drugs. For this reason, Georgia Tech researchers are focusing on ways to fight cancer by attacking defective genes before they are able to make proteins.

Professor John McDonald is studying micro RNAs (miRNAs), a class of small RNAs that interact with messenger RNAs (mRNAs) that have been linked to a number of diseases, including cancer. McDonald’s lab placed two different miRNAs (MiR-7 and MiR-128) into ovarian cancer cells and watched how they affected the gene system. The findings are published in the current edition of the journal BMC Medical Genomics.

“Each inserted miRNA created hundreds of thousands of gene expression changes, but only about 20 percent of them were caused by direct interactions with mRNAs,” said McDonald. “The majority of the changes were indirect – they occurred downstream and were consequences of the initial reactions.”

McDonald initially wondered if those secondary interactions could be a setback for the potential use of miRNAs, because most of them changed the gene expressions of something other than the intended targets. However, McDonald noticed that most of what changed downstream was functionally coordinated.  

miR-7 transfection most significantly affected the pathways involved with cell adhesion, epithelial-mesenchymal transitions (EMT) and other processes linked with cancer metastasis. The pathways most often affected by miR-128 transfection were different. They were more related to cell cycle control and processes involved with cellular replication – another process that is overactive in cancer cells.

“miRNAs have evolved for millions of years in order to coordinately regulate hundreds to thousands of genes together on the cellular level,” said McDonald. “If we can understand which miRNAs affect which suites of genes and their coordinated functions, it could allow clinicians to attack cancer cells on a systems level, rather than going after genes individually.”

Clinical trials for miRNAs are just beginning to be explored, but definitive findings are likely still years away because there are hundreds of miRNAs whose cellular functions must be fully understood. Another challenge facing scientists is developing ways to effectively target therapeutic miRNAs to cancer cells, something McDonald and his Georgia Tech peers are also investigating.

McDonald is a professor in the School of Biology in Georgia Tech’s College of Sciences.

Ninety-six percent of a chimpanzee’s genome is the same as a human’s. It’s the other 4 percent, and the vast differences, that pique the interest of Georgia Tech’s Soojin Yi. For instance, why do humans have a high risk of cancer, even though chimps rarely develop the disease?

In research published in September’s American Journal of Human Genetics, Yi looked at brain samples of each species. She found that differences in certain DNA modifications, called methylation, may contribute to phenotypic changes. The results also hint that DNA methylation plays an important role for some disease-related phenotypes in humans, including cancer and autism.

“Our study indicates that certain human diseases may have evolutionary epigenetic origins,” says Yi, a faculty member in the School of Biology. “Such findings, in the long term, may help to develop better therapeutic targets or means for some human diseases. “

DNA methylation modifies gene expression but doesn’t change a cell’s genetic information. To understand how it differs between the two species, Yi and her research team generated genome-wide methylation maps of the prefrontal cortex of multiple humans and chimps. They found hundreds of genes that exhibit significantly lower levels of methylation in the human brain than in the chimpanzee brain. Most of them were promoters involved with protein binding and cellular metabolic processes.

“This list of genes includes disproportionately high numbers of those related to diseases,” said Yi. “They are linked to autism, neural-tube defects and alcohol and other chemical dependencies. This suggests that methylation differences between the species might have significant functional consequences. They also might be linked to the evolution of our vulnerability to certain diseases, including cancer.” 

Yi, graduate student Jia Zeng and postdoctoral researcher Brendan Hunt worked with a team of researchers from Emory University and UCLA. The Yerkes National Primate Research Center provided the animal samples used in the study. It was also funded by the Georgia Tech Fund for Innovation in Research and Education (GT-FIRE) and National Science Foundation grants (MCB-0950896 and BCS-0751481). The content is solely the responsibility of the principal investigators and does not necessarily represent the official views of the NSF.

At the 2012 annual meeting of the International Society of Chemical Ecology in Vilnius, Lithuania, Professor Julia Kubanek delivered an invited lecture sponsored by the society. This award is made each year to a chemical ecologist whose recent work is at the forefront of the field, and is named after the late Milt Silverstein and John Simeone, pioneers of this field and co-founders of the Journal of Chemical Ecology.  Professor Kubanek presented "War in the Plankton: Sublethal and reciprocal impacts of red tide algae on competing phytoplankton", co-authored by Georgia Tech current and former students Kelsey Poulson-Ellestad, Jessie Roy, Robert Drew Sieg, Christina Jones, Emily Prince, Tracey Myers, as well as former GT postdoctoral researcher Clare Redshaw, and collaborators Facundo Fernandez (GT), Brook Nunn (University of Washington), Jerome Naar (University of North Carolina at Wilmington), and Mark Viant and Jon Byrne (University of Birmingham UK).  

Dr. Kubanek is a Professor in the School of Biology at Georgia Tech. Her invited lecture is described below:

War in the Plankton: Sublethal and reciprocal impacts of red tide algae on competing phytoplankton

How individual species come to be dominant members of marine planktonic communities is not deeply understood; however, it is thought that chemistry plays a substantial role.  For example, some red tide-forming dinoflagellates produce toxic secondary metabolites that are hypothesized to enhance dinoflagellate fitness by acting as grazer deterrents, allelopathic agents, or antimicrobial defenses.  In field and lab experiments we have shown that the red tide dinoflagellate Karenia brevis is allelopathic, inhibiting the growth of several co-occurring phytoplankton species, but that K. brevis natural products other than well-known brevetoxins are responsible for suppressing most of these species.  At least one phytoplankton competitor, Skeletonema costatum, retaliates against K. brevis, reducing its allelopathic effects and degrading waterborne brevetoxins.  Several other phytoplankton species also metabolize brevetoxins, removing these toxins from the water column and mitigating the negative effects on invertebrates.  Death is a rare outcome of K. brevis allelopathy, with more subtle responses predominating, such as reduced photosynthetic output and increased cell permeability.  These changes in cellular metabolism and physiology may be more readily characterized and measured by a systems biology approach than by growth or cell lysis assays.  NMR metabolomics has provided preliminary evidence for sub-lethal impacts of exposure to K. brevis allelopathy on the metabolism of neighboring phytoplankton.  Future work will expand upon these initial results with mass spectrometry-based metabolomics and proteomics methods, as well as experiments with other vulnerable competing phytoplankton species, with the goal of identifying cellular targets and understanding the molecular mechanisms of red tide allelopathy.  Our results indicate that chemically-mediated interactions are reciprocal, and that ecosystem-level consequences of red tides (such as fish kills caused by waterborne toxins) may depend upon which other phytoplankton species are present.

Dr. Joshua Weitz (Associate Professor, School of Biology) has been awarded a grant from the Program in Biological Oceanography on "Understanding the Effects of Complex Phage-Bacteria Infection Networks on Ocean Ecosystems". The award provides over $470,000 over 4 years to study the interaction between viruses and bacteria in ocean ecosystems.

Bacteria and their viruses (phages) make up two of the most abundant and genetically diverse groups of organisms in the oceans. The extent of this diversity has become increasingly apparent with the advent of environmental sequencing. However, the ongoing discovery of new taxonomic diversity has, thus far, out-paced gains in quantifying the function of and interactions among phages and bacteria. In this proposal, Weitz will develop a theoretical framework for characterizing the effect of complex phage-bacteria interactions on microbial ecosystem structure and function.

As part of this grant, Weitz will also help train quantitative biologists interested in microbial systems.  The training will include the development of a new course, opportunities for undergraduate research, and opportunities for hands-on laboratory experience for modelers in collaboration with the viral ecology laboratories of Matt Sullivan (U of Arizona) and Steven Wilhelm (UT-Knoxville).

New Georgia Tech research shows that cell stiffness could be a valuable clue for doctors as they search for and treat cancerous cells before they’re able to spread. The findings, which are published in the journal PLoS One, found that highly metastatic ovarian cancer cells are several times softer than less metastatic ovarian cancer cells.

Assistant Professor Todd Sulchek and Ph.D. student Wenwei Xu used a process called atomic force microscopy (AFM) to study the mechanical properties of various ovarian cell lines. A soft mechanical probe “tapped” healthy, malignant and metastatic ovarian cells to measure their stiffness.

“In order to spread, metastatic cells must push themselves into the bloodstream. As a result, they must be highly deformable and softer,” said Sulchek, a faculty member in the George W. Woodruff School of Mechanical Engineering. “Our results indicate that cell stiffness may be a useful biomarker to evaluate the relative metastatic potential of ovarian and perhaps other types of cancer cells.”

Just as previous studies on other types of epithelial cancers have indicated, Sulchek also found that cancerous ovarian cells are generally softer and display lower intrinsic variability in cell stiffnesss than non-malignant cells.

Sulchek’s lab partnered with the molecular cancer lab of Biology Professor John McDonald, who is also director of Georgia Tech’s newly established Integrated Cancer Research Center.

“This is a good example of the kinds of discoveries that only come about by integrating skills and knowledge from traditionally diverse fields such as molecular biology and bioengineering,” said McDonald. “Although there are a number of developing methodologies to identify circulating cancer cells in the blood and other body fluids, this technology offers the added potential to rapidly determine if these cells are highly metastatic or relatively benign.”

Sulchek and McDonald believe that, when further developed, this technology could offer a huge advantage to clinicians in the design of optimal chemotherapies, not only for ovarian cancer patients but also for patients of other types of cancer.

This project was supported in part by the National Science Foundation (NSF) (Award Number CBET-0932510). The content is solely the responsibility of the principal investigators and does not necessarily represent the official views of the NSF.

New Georgia Tech research shows that cell stiffness could be a valuable clue for doctors as they search for and treat cancerous cells before they’re able to spread. The findings, which are published in the journal PLoS One, found that highly metastatic ovarian cancer cells are several times softer than less metastatic ovarian cancer cells.

Assistant Professor Todd Sulchek and Ph.D. student Wenwei Xu used a process called atomic force microscopy (AFM) to study the mechanical properties of various ovarian cell lines. A soft mechanical probe “tapped” healthy, malignant and metastatic ovarian cells to measure their stiffness.

“In order to spread, metastatic cells must push themselves into the bloodstream. As a result, they must be highly deformable and softer,” said Sulchek, a faculty member in the George W. Woodruff School of Mechanical Engineering. “Our results indicate that cell stiffness may be a useful biomarker to evaluate the relative metastatic potential of ovarian and perhaps other types of cancer cells.”

Just as previous studies on other types of epithelial cancers have indicated, Sulchek also found that cancerous ovarian cells are generally softer and display lower intrinsic variability in cell stiffnesss than non-malignant cells.

Sulchek’s lab partnered with the molecular cancer lab of Biology Professor John McDonald, who is also director of Georgia Tech’s newly established Integrated Cancer Research Center.

“This is a good example of the kinds of discoveries that only come about by integrating skills and knowledge from traditionally diverse fields such as molecular biology and bioengineering,” said McDonald. “Although there are a number of developing methodologies to identify circulating cancer cells in the blood and other body fluids, this technology offers the added potential to rapidly determine if these cells are highly metastatic or relatively benign.”

Sulchek and McDonald believe that, when further developed, this technology could offer a huge advantage to clinicians in the design of optimal chemotherapies, not only for ovarian cancer patients but also for patients of other types of cancer.

This project was supported in part by the National Science Foundation (NSF) (Award Number CBET-0932510). The content is solely the responsibility of the principal investigators and does not necessarily represent the official views of the NSF.

Earlier this month a team of undergraduates brought home a silver medal in the 2012 International Genetically Engineered Machine (iGEM) competition. iGEM is considered the premiere undergraduate synthetic biology competition where teams design, construct and analyze novel biological systems to perform new functions in living cells.

The competition, which featured 195 teams from around the globe, took place October 12-14 in Pittsburgh as part of iGEMs Americas East Regional Jamboree. Tech’s team consisted of five undergraduates: biology majors Natalie Chilcutt, Joseph Elsherbini and Jennifer Goff as well as Mitesh Agrawal and Jennifer Boothby from biomedical engineering.

The students began work on their project this past summer, engineering a synthetic biosensor system in bacteria, inspired by the cell-cell communication process called “quorum sensing” studied in the Hammer lab. The students used a technique called bimolecular fluorescence complementation (BiFC) to document a response to an extracellular chemical signal in the model bacterium E. coli. The bacteria were engineered to make two halves of a naturally green fluorescent protein (GFP) that are not fluorescent independently and only interact to form a complete fluorescent protein in the presence of a defined chemical signal. This novel system has the potential to be tailored to respond to different extracellular molecules, such as toxins, metabolites and pollutants,  and is designed to provide a more rapid response than traditional biosensor.

This year’s iGEM project (http://2012.igem.org/Team:Georgia_Tech) arose from a National Science Foundation-sponsored (NSF) collaborative synthetic biology project currently underway involving the Hammer lab and multiple engineering collaborators (http://www.ece.gatech.edu/research/labs/bwn/monaco/index.html). The team was supported by funding from the School of Biology, NSF as well as Georgia Tech’s President’s Undergraduate Research Awards and the Undergraduate Research Opportunities Program.

The team is advised by Brian Hammer, assistant professor in the School of Biology, and Mark Styczynski, assistant professor in the School of Chemical & Biomolecular Engineering. The team is mentored by postdoctoral fellow Patrick Bardill (biology) with assistance from Ph.D. students Samit Watve (biology) and Youssef Chahibi (electrical & computer engineering). The iGEM advisory board includes additional faculty, Joshua Weitz, Eric Gaucher and Harold Kim, who have served as past advisors.

Most of us gaze in wonder at how clouds of all different shapes and sizes form and vaporize across the beautiful October Atlanta sky. Few of us think about bacteria playing a role in this process. This is not the case for Natasha DeLeon-Rodriguez, a School of Biology graduate student in the lab of Kostas Konstantinidis (http://enve-omics.gatech.edu/).

Natasha aims to understand how bacteria affect cloud formation – a proposal that has earned her a NASA Earth and Space Science Fellowship (NASA-NESSF).  This competitive fellowship supports research at the intersection of microbiology, genomics and atmospheric science.

To accomplish her research, Natasha quantifies the number of bacterial cells collected from the mid-to-upper troposphere (five to six miles high in the atmosphere) onboard a NASA DC-3 aircraft. She is currently investigating the mechanism by which these bacterial cells serve as nuclei for cloud condensation and ice formation. The long-term goal of her project is to apply her discoveries to improve regional and global atmospheric models that are able to describe the cloud formation process.

This work is conducted in collaboration with the Nenes lab from the School of Earth and Atmospheric Sciences and Bruce Anderson of NASA Langley Research Center.

Yingying Zeng, a graduate student in the School of Biology, is the lead author on a new paper that describes the complete structure of satellite tobacco mosaic virus (STMV). This is the first model for the structure of any virus that specifies the position of every single atom. Zeng combined high-resolution data from x-ray crystallography, chemical data on the structure of the RNA genome, and knowledge-based molecular modeling methods to develop her model. STMV is a small virus that has served for many years as a model system for investigating the relationships between viral structure and function. The new model has implications for understanding the pathway of viral assembly. These methods can be extended to investigate the structures of human viral pathogens and, in the long run, to the design of novel drugs aimed at inhibiting viral assembly.

This was a collaborative effort headed by Steve Harvey (School of Biology), and it included contributions from Christine Heitsch (School of Mathematics) as well as Steven Larson and Alexander McPherson (University of California, Irvine). The paper appeared in the October issue of the Journal of Structural Biology.

Corals under attack by toxic seaweed do what anyone might do when threatened – they call for help. A study reported this week in the journal Science shows that threatened corals send signals to fish “bodyguards” that quickly respond to trim back the noxious alga – which can kill the coral if not promptly removed.

Scientists at the Georgia Institute of Technology have found evidence that these “mutualistic” fish respond to chemical signals from the coral like a 911 emergency call – in a matter of minutes. The inch-long fish – known as gobies – spend their entire lives in the crevices of specific corals, receiving protection from their own predators while removing threats to the corals.

This symbiotic relationship between the fish and the coral on which they live is the first known example of one species chemically signaling a consumer species to remove competitors. It is similar to the symbiotic relationship between Acacia trees and mutualist ants in which the ants receive food and shelter while protecting the trees from both competitors and consumers.

“This species of coral is recruiting inch-long bodyguards,” said Mark Hay, a professor in the School of Biology at Georgia Tech. “There is a careful and nuanced dance of the odors that makes all this happen. The fish have evolved to cue on the odor released into the water by the coral, and they very quickly take care of the problem.”

The research, supported the National Science Foundation, the National Institutes of Health and the Teasley Endowment at Georgia Tech, was reported November 8 in the journal Science. The research was done as part of a long-term study of chemical signaling on Fiji Island coral reefs aimed at understanding these threatened ecosystems and discovering chemicals that may be useful as pharmaceuticals.

Because they control the growth of seaweeds that damage coral, the importance of large herbivorous fish to maintaining the health of coral reefs has been known for some time. But Georgia Tech postdoctoral fellow Danielle Dixson suspected that the role of the gobies might be more complicated. To study that relationship, she and Hay set up a series of experiments to observe how the fish would respond when the coral that shelters them was threatened.

They studied Acropora nasuta, a species in a genus of coral important to reef ecosystems because it grows rapidly and provides much of the structure for reefs. To threaten the coral, the researchers moved filaments of Chlorodesmis fastigiata, a species of seaweed that is particularly chemically toxic to corals, into contact with the coral. Within a few minutes of the seaweed contacting the coral, two species of gobies – Gobidon histrio and Paragobidon enchinocephalus – moved toward the site of contact and began neatly trimming away the offending seaweed.

“These little fish would come out and mow the seaweed off so it didn’t touch the coral,” said Hay, who holds the Harry and Linda Teasley Chair in Environmental Biology at Georgia Tech. “This takes place very rapidly, which means it must be very important to both the coral and the fish. The coral releases a chemical and the fish respond right away.”

In corals occupied by the gobies, the amount of offending seaweed declined 30 percent over a three-day period, and the amount of damage to the coral declined by 70 to 80 percent. Control corals that had no gobies living with them had no change in the amount of toxic seaweed and were badly damaged by the seaweed.

To determine what was attracting the fish, Dixson and Hay collected samples of water from locations (1) near the seaweed by itself, (2) where the seaweed was contacting the coral, and (3) from coral that had been in contact with the seaweed – 20 minutes after the seaweed had been removed. They released the samples near other corals that hosted gobies, which were attracted to the samples taken from the seaweed-coral contact area and the damaged coral – but not the seaweed by itself.

“We demonstrated that the coral is emitting some signal or cue that attracts the fish to remove the encroaching seaweed,” Hay said. “The fish are not responding to the seaweed itself.”

Similar waters collected from a different species of coral placed in contact with the seaweed did not attract the fish, suggesting they were only interested in removing seaweed from their host coral.

Finally, the researchers obtained the chemical extract of the toxic seaweed and placed it onto nylon filaments designed to stimulate the mechanical effects of seaweed. They also created simulated seaweed samples without the toxic extract. When placed in contact with the coral, the fish were attracted to areas in which the chemical-containing mimic contacted the coral, but not to the area contacting the mimic without the chemical.  

By studying the contents of the fish digestive systems, the researchers learned that one species – Gobidon histrio – actually eats the noxious seaweed, while the other fish apparently bites it off without eating it. In the former, consuming the toxic seaweed makes the fish less attractive to predators.

The two species of fish also eat mucus from the coral, as well as algae from the coral base and zooplankton from the water column. By defending the corals, the gobies are thus defending the home in which they shelter and feed.

“The fish are getting protection in a safe place to live and food from the coral,” Hay noted. “The coral gets a bodyguard in exchange for a small amount of food. It’s kind of like paying taxes in exchange for police protection.”

As a next step, Hay and Dixson would like to determine if other species of coral and fish have similar symbiotic relationships. And they’d like to understand more about how the chemical signaling and symbiotic relationship came into being.

“These kinds of positive interactions needs to be better understood because they tell us something about the pressures that have gone on through time on these corals,” said Hay. “If they have evolved to signal these gobies when a competitor shows up, then competition has been important throughout evolutionary time.”

CITATION: Danielle L. Dixson and Mark E. Hay, Corals chemically signal mutualistic fishes to remove competing seaweeds, Science (2012).

This research has been supported by the National Science Foundation (NSF) under grant OCE-0929119 and by the National Institutes of Health under grant U01-TW007401. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NSF or the NIH.

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