New study, published in Hepatology, shows the regenerative capacity of liver cells

Patients suffering from chronic liver disease often develop liver fibrosis (the accumulation of scar tissue), which frequently results in cirrhosis, which means a loss of liver function, which often comes with a choice between a liver transplant and certain death.

It’s a perfect storm of terrible things as sustained fibrosis dampens the regenerative capacity of hepatocytes, thwarting their ability to make a therapeutic response, resulting in a grim prognosis and high mortality. At its essence, this is a communication problem, based on a study by a team of researchers in the lab of Chong Hyun Shin at the Georgia Institute of Technology.

Their findings explain how signaling pathways and cell-cell communications direct the cellular response to fibrogenic stimuli. But they also identify some novel potential therapeutic strategies for chronic liver disease. Results of the study (funded by the National Institutes of Health, the Emory/Georgia Tech Regenerative Engineering and Medicine Center, and Georgia Tech’s School of Biology) were published recently in the journal Hepatology.

“We aim to understand the molecular and cellular mechanisms that mediate the effects of sustained fibrosis on hepatocyte regeneration, using the zebrafish as a model,” explains Shin, assistant professor in the School of Biology, with a lab in the Parker H. Petit Institute for Bioengineering and Bioscience. Her fellow authors are Frank Anania (Emory), Mianbo Huang, Angela Chang, Minna Choi and David Zhou.

In their fibrotic zebrafish model, they studied the effects that different levels of signaling have on the regeneration of liver cells (hepatocytes). Specifically, they took note of the relationship between ‘Wnt’ and ‘Notch’ (signaling pathways). They discovered that lower level Notch signaling promotes cell regeneration (the proliferation and differentiation of hepatic progenitor cells, or HPCs, into hepatocytes), while high levels suppressed it. And they discovered that antagonistic interaction between Wnt and Notch modulates regenerative capacity: Wnt signals can suppress Notch signals, or, in other words, when Wnt is up, Notch is down, and hepatocyte regeneration can happen.

The data, says Shin, “suggest an essential interplay between Wnt and Notch signaling during hepatocyte regeneration in the fibrotic liver, providing legitimate therapeutic strategies for chronic liver failure in vivo.”

Inducing tissue regeneration via stem or progenitor cells, while delaying fibrosis, has been on the rise as antifibrogenic strategies of great potential, according to Shin, whose studies offer a clue of how to guide the differentiation of HPCs into hepatocytes in patients suffering from chronic liver failure. “Overall,” she explains, “employing the in vivo-based hepatic regeneration strategy may allow us to complement fundamental drawbacks in stem cell therapy, opening up new avenues of endogenous cellular regeneration therapy.”

This research is supported by grant number K01DK081351 from the National Institutes of Health (NIH), the Regenerative Engineering and Medicine Research Center Pilot Award (GTEC 2731336), and the School of Biology, Georgia Institute of Technology.

Read Hepatology journal abstract here

Pacific corals and fish can both smell a bad neighborhood, and use that ability to avoid settling in damaged reefs.

Damaged coral reefs emit chemical cues that repulse young coral and fish, discouraging them from settling in the degraded habitat, according to new research. The study shows for the first time that coral larvae can smell the difference between healthy and damaged reefs when they decide where to settle.

Coral reefs are declining around the world. Overfishing is one cause of coral collapse, depleting the herbivorous fish that remove the seaweed that sprouts in damaged reefs. Once seaweed takes hold of a reef, a tipping point can occur where coral growth is choked and new corals rarely settle.

The new study shows how chemical signals from seaweed repel young coral from settling in a seaweed-dominated area. Young fish were also not attracted to the smell of water from damaged reefs. The findings suggest that designating overfished coral reefs as marine protected areas may not be enough to help these reefs recover because chemical signals continue to drive away new fish and coral long after overfishing has stopped.

“If you’re setting up a marine protected area to seed recruitment into a degraded habitat, that recruitment may not happen if young fish and coral are not recognizing the degraded area as habitat,” said Danielle Dixson, an assistant professor in the School of Biology at the Georgia Institute of Technology in Atlanta, and the study's first author.

The study will be published August 22 in the journal Science. The research was sponsored by the National Science Foundation (NSF), the National Institutes of Health (NIH), and the Teasley Endowment to Georgia Tech.

The new study examined three marine areas in Fiji that had adjacent fished areas. The country has established no-fishing areas to protect its healthy habitats and also to allow damaged reefs to recover over time.

Juveniles of both corals and fishes were repelled by chemical cues from overfished, seaweed-dominated reefs but attracted to cues from coral-dominated areas where fishing is prohibited. Both coral and fish larvae preferred certain chemical cues from species of coral that are indicators of a healthy habitat, and they both avoided certain seaweeds that are indicators of a degraded habitat.

The study for the first time tested coral larvae in a method that has been used previously to test fish, and found that young coral have strong preferences for odors from healthy reefs.

"Not only are coral smelling good areas versus bad areas, but they’re nuanced about it," said Mark Hay, a professor in the School of Biology at Georgia Tech and the study's senior author. "They’re making careful decisions and can say, 'settle or don’t settle.'"

The study showed that young fish have an overwhelming preference for water from healthy reefs. The researchers put water from healthy and degraded habitats into a flume that allowed fish to choose to swim in one stream of water or the other. The researchers tested the preferences of 20 fish each from 15 different species and found that regardless of species, family or trophic group, each of the 15 species showed up to an eight times greater preference for water from healthy areas.

The researchers then tested coral larvae from three different species and found that they preferred water from the healthy habitat five-to-one over water from the degraded habitat.

Chemical cues from corals also swayed the fishes' preferences, the study found. The researchers soaked different corals in water and studied the behavior of fish in that water, which had picked up chemical cues from the corals. Cues of the common coral Acropora nasuta enhanced attraction to water from the degraded habitat by up to three times more for all 15 fishes tested. A similar preference was found among coral larvae.

Acropora corals easily bleach, are strongly affected by algal competition, and are prone to other stresses. The data demonstrate that chemical cues from these corals are attractive to fish and corals because they are found primarily in healthy habitats. Chemical cues from hardy corals, which can grow even in overfished habitats, were less attractive to juvenile fishes or corals.

The researchers also soaked seaweed in water and tested fish and coral preferences in that water. Cues from the common seaweed Sargassum polycystum, which can bloom and take over a coral reef, reduced the attractiveness of water to fish by up to 86 percent compared to water without the seaweed chemical cues. Chemical cues from the seaweed decreased coral larval attraction by 81 percent.

"Corals avoided that smell more than even algae that's chemically toxic to coral but doesn't bloom," Dixson said.

Future work will involve removing plots of seaweed from damaged reefs and studying how that impacts reef recovery.

A minimum amount of intervention at the right time and the right place could jump start the recovery of overfished reefs, Hay said. That could bring fish back to the area so they settle and eat the seaweed around the corals. The corals would then get bigger because the seaweed is not overgrown. Bigger corals would then be more attractive to more fish.

"What this means is we probably need to manage these reefs in ways that help remove the most negative seaweeds and then help promote the most positive corals," Hay said.

This research is supported by the National Science Foundation (NSF), under award number OCE-0929119, and the National Institutes of Health, under award number U01-TW007401. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of the sponsoring agency.

CITATION: Dixson et al., "Chemically mediated behavior of recruiting corals and fishes: A tipping
point that may limit reef recovery." (August 2014, Science). http://www.sciencemag.org/content/345/6199/892 

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Media Relations Contacts: Brett Israel (@btiatl) (404-385-1933) (brett.israel@comm.gatech.edu) or John Toon (404-894-6986) (jtoon@gatech.edu)

Scientific Contacts:

Mark Hay
mark.hay@biology.gatech.edu
Fiji phone numbers: 679-833-3300 or 679-979-5991 (cell). 679-653-0093 (landline)
Skype: Markhaygt

Danielle Dixson
danielle.dixson@biology.gatech.edu
Belize phone: 011-501-532-2392
Skype: Danielle.Dixson

Writer: Brett Israel

Dr. Joel Kostka, a Professor jointly appointed in Biology and Earth & Atmospheric Sciences, was recently awarded $1.0 million in research grants by the U.S. Department of Energy (DOE) to study the microbially-mediated carbon cycle in boreal or northern peatlands. Peatlands sequester one-third of all soil carbon and currently act as major sinks of atmospheric CO₂.  The ability to predict or to simulate the fate of stored carbon in response to climatic disruption remains hampered by our limited understanding of the controls of C turnover and the composition and functioning of peatland microbial communities. Given their global extent and uncertain fate with climatic change, boreal or northern peatlands are considered a high priority for climate change research. The overall goal of this project is to investigate the rates, pathways, and controls of organic matter decomposition by microbes in response to warming and elevated carbon dioxide in peatlands. The project will be conducted at the Marcell Experimental Forest (MEF) in northern Minnesota where US Department of Energy’s (DOE) Oak Ridge National Laboratory (ORNL) and the USDA Forest Service are developing a climate manipulation field site known as Spruce and Peatland Response Under Climatic and Environmental Change (SPRUCE).  In the Minnesota peatland, DOE is building 10 open top enclosures (12 m in diameter and 8 m in height).  Inside these enclosures, the peat soil and air will be heated and carbon dioxide concentrations raised to simulate future climate change.  Kostka’s project will examine changes to the microbial communities during this large scale climate change experiment.  The project team includes collaborators at Florida State University and ORNL. 

Dr. Kostka was interviewed last week by BBC radio on microbial hydrocarbon degradation (http://www.thenakedscientists.com/HTML/podcasts/specials/show/20140809/)

It also went out on the 5 Live show on Saturday morning - http://www.bbc.co.uk/programmes/b04cf3q8

GT Biology 2012 PhD graduate Douglas Rasher won the George Mercer Award from the Ecological Society of America this year. This prestigious award recognizes the best paper published in Ecology over the past 2 years by an ecologist younger than 40 years old. Rasher, now a postdoctoral research associate at the University of Maine, provides rich new insights for the management and conservation of coral reefs in his 2013 “Consumer diversity interacts with prey defenses to drive ecosystem function,” in Ecology. The study, which he conducted as a graduate student at the Georgia Institute of Technology, shows that interactions between algal defenses and herbivore tolerances create an essential role for consumer diversity in the functioning and resilience of coral reefs.

In an article in the September issue of BioScience, Samantha Joye and colleagues describe Gulf of Mexico microbial communities in the aftermath of the 2010 Macondo blowout. The authors describe revealing population-level responses of hydrocarbon-degrading microbes to the unprecedented deepwater oil plume.

The spill provided a unique opportunity to study the responses of indigenous microbial communities to a substantial injection of hydrocarbons. Surveys of genetic identifiers within cells known as ribosomal RNA and analyses relying on modern techniques including metagenomics, metatranscriptomics, and other methods revealed quickly changing population sizes and community structures. The presence of oil-degrading microbes, which was determined through the use of ribosomal RNA signatures, was found even after the dissipation of the initial plume, which provides evidence that seed populations persist and may be maintained by natural oil seepage or small accidental leaks.

Perhaps one of the most striking features of the microbial response to the blowout was the rapid formation of large flocs of marine “snow.” The flocs were initially observed in the upper water column and constituted the precursors to a massive pulse of oil-derived sediment that settled near the wellhead in the weeks following the accident. The rapid movement of oil to the seafloor in the form of microbe-induced marine snow represents a previously unrecognized outcome for marine hydrocarbons that may have far-reaching implications. The authors performed laboratory simulations of marine oil snow formation and identified several possible microbial mechanisms for the formation of the snow, including the creation of mucus webs through the action of bacterial oil degraders. As a result of their findings, Joye and her colleagues call for the inclusion of marine snow in the federal oil budget, which is intended to describe the fate of discharged oil.

The authors close with a call for additional research. Further study is needed both to increase the understanding of oil-degrading microbes and to quantify the rates at which they may degrade spilled oil.

The ability to accurately repair DNA damaged by spontaneous errors, oxidation or mutagens is crucial to the survival of cells. This repair is normally accomplished by using an identical or homologous intact sequence of DNA, but scientists have now shown that RNA produced within cells of a common budding yeast can serve as a template for repairing the most devastating DNA damage – a break in both strands of a DNA helix.

Earlier research had shown that synthetic RNA oligonucleotides introduced into cells could help repair DNA breaks, but the new study is believed to be the first to show that a cell’s own RNA could be used for DNA recombination and repair. The finding provides a better understanding of how cells maintain genomic stability, and if the phenomenon extends to human cells, could potentially lead to new therapeutic or prevention strategies for genetic-based disease.

The research was supported by the National Science Foundation, the National Institutes of Health and the Georgia Research Alliance. The results were reported September 3, 2014, in the journal Nature.

“We have found that genetic information can flow from RNA to DNA in a homology-driven manner, from cellular RNA to a homologous DNA sequence,” said Francesca Storici, an associate professor in the School of Biology at the Georgia Institute of Technology and senior author of the paper. “This process is moving the genetic information in the opposite direction from which it normally flows. We have shown that when an endogenous RNA molecule can anneal to broken homologous DNA without being removed, the RNA can repair the damaged DNA. This finding reveals the existence of a novel mechanism of genetic recombination.”

Most newly-transcribed RNA is quickly exported from the nucleus to the cytoplasm of cells to perform its many essential roles in gene coding and expression, and in regulation of cell operations. Generally, RNA is kept away from – or removed from – nuclear DNA. In fact, it is known that annealing of RNA with complementary chromosomal DNA is dangerous for cells because it may impair transcription elongation and DNA replication, promoting genome instability.

This new study reveals that under conditions of genotoxic stress, such as a break in DNA, the role of RNA paired with complementary DNA may be different, and beneficial, for a cell. “We discovered a mechanism in which transcript RNA anneals with complementary broken DNA and serves as a template for recombination and DNA repair, and thus has a role in both modifying and stabilizing the genome,” Storici explained.

DNA damage can arise from a variety of causes both inside and outside the cell. Because the DNA consists of two complementary strands, one strand can normally be used to repair damage to the other. However, if the cell sustains breakage in both strands – known as a double-strand break – the repair options are more limited. Simply rejoining the broken ends carries a high risk of unwanted mutations or chromosome rearrangement, which can cause undesirable effects including cancer. Without successful repair, however, the cell may die or be unable to carry out important functions.

Beginning in 2007, Storici’s research team showed that synthetic RNA introduced into cells – including human cells – could repair DNA damage, but the process was inefficient and there were questions about whether the process could occur naturally.

To find out whether cells could use endogenous RNA transcripts to repair DNA damage, she and graduate students Havva Keskin and Ying Shen – who are first and second authors on the paper – devised experiments using the yeast Saccharomyces cerevisiae, which is widely used in the lab for genetics and genome engineering. The researchers developed a strategy for distinguishing repair by endogenous RNA from repair by the normal DNA-based mechanisms in the budding yeast cells, including using mutants that lacked the ability to convert the RNA into a DNA copy. They then induced a DNA double-strand break in the yeast genome and observed whether the organism could survive and grow by repairing the damage using only transcript RNA within the cells.

The DNA region that generates the transcript was constructed to contain a marker gene interrupted by an intron, which is a sequence that is removed only from the RNA during the process of transcription, explained Keskin. Following intron removal, the transcript RNA sequence has no intron, while the DNA region that generates the transcript retains the intron; thus they are distinguishable. Only the repair templated by the transcript devoid of the intron can restore the function of a homologous marker gene in which the DNA double-strand break is induced, she added.

The researchers measured success by counting the number of yeast colonies growing on a Petri dish, indicating that the repair had been made by endogenous RNA. Testing was done on two types of breaks, one in the DNA from which the RNA transcript had been made, and the other in a homologous sequence from a different location in the DNA.

The research team, which also included scientists from Drexel University, found that proximity of the RNA to the broken DNA increased the efficiency of the repair and that the repair occurred via a homologous recombination process. Storici believes that the repair mechanism may operate in cells beyond yeast, and that many types of RNA can be used.

“We are showing that the flow of genetic information from RNA to DNA is not restricted to retro-elements and telomeres, but occurs with a generic cellular transcript, making it more of a general phenomenon than had been anticipated,” she explained. “Potentially, any RNA in the cell could have this function.”

For the future, Storici hopes to learn more about the mechanism, including what regulates it. She also wants to learn whether it takes place in human cells. If so, that could have implications for treating or preventing diseases that are caused by genetic damage.

“Cells synthesize lots of RNA transcripts during their life spans; therefore, RNA may have an unanticipated impact on genomic stability and plasticity,” said Storici, who is also a Georgia Research Alliance Distinguished Cancer Scientist. “We need to understand in which situations cells would activate RNA-DNA recombination. Better understanding this molecular process could also help us manipulate mechanisms for therapy, allowing us to treat a disease or prevent it altogether.”

In addition to Storici, the paper’s authors include Alexander Mazin, a professor in the Department of Biochemistry and Molecular Biology at Drexel University; postdoctoral fellow Fei Huang and graduate student Mikir Patel, also from Drexel; Havva Keskin, a Georgia Tech graduate student; Ying Shen, a Ph.D. graduate from Georgia Tech who is now a postdoctoral fellow at Boston University School of Medicine; and graduate student Taehwan Yang and undergraduate student Katie Ashley from School of Biology at Georgia Tech.

This research is supported by the National Science Foundation under award number MCB-1021763, by the National Institutes of Health under award numbers CA100839 and P30CA056036, and by the Georgia Research Alliance under award number R9028. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of the sponsoring agencies.

CITATION: Havva Keskin, et al., “Transcript-RNA-templated DNA recombination and repair,” Nature 2014. http://dx.doi.org/10.1038/nature13682

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Dr. Marc Weissburg Professor of Biology, along with a team of multidisciplinary investigators have been awarded $2.5 million dollar grant to develop approaches for sustainable and resilient infrastructure. A key feature of the plan is to use, and compare, ecological and engineering approaches  and principles for  increasing cycling, reducing waste, and maintaining function in the face of perturbation. The team will examine complex interactions between infrastructure (e.g. water, transportation and energy systems) that traditionally have been ignored. Atlanta will provide both data and a possible test case for the principles developed. This proposal represents a unique and powerful interdisciplinary research and educational initiative, with graduate students from many fields being co-mentored by faculty from different disciplines. Along with Dr. Weissburg, the investigators consist of Dr. John Crittenden (PI, CEE), Dr. B. Ashuri (COA), Dr. J Clark (Ivan Allen) and Dr. R. Fujimoto (CS). Senior personnel come from many other units, including Mechanical Engineering, Industrial Systems Engineering and GTRI.

Researchers have sequenced the genomes and transcriptomes of five species of African cichlid fishes and uncovered a variety of features that enabled the fishes to thrive in new habitats and ecological niches within the Great Lakes of East Africa.

The study helps explain the genetic basis for the incredible diversity among cichlid fishes and provides new information about vertebrate evolution. The genomic information from the study will help answer questions about human biology and disease.

"Our study reveals a spectrum of methods that nature uses to allow organisms to adapt to different environments,” said co-senior author Kerstin Lindblad-Toh, scientific director of vertebrate genome biology at the Broad Institute of Harvard and MIT, a biomedical and genomic research center. “These mechanisms are likely also at work in humans and other vertebrates, and by focusing on the remarkably diverse cichlid fishes, we were able to study this process on a broad scale for the first time.”

The new study was published in the September 3 advance online edition of the journal Nature. The work was a collaboration between the Broad Institute of MIT and Harvard, the Georgia Institute of Technology, and the Eawag Swiss Federal Institute for Aquatic Sciences, in addition to more than 70 scientists from the international cichlid research community.

African cichlid fishes are some of the most diverse organisms on the planet, with over 2,000 known species. Some lakes are home to hundreds of distinct species that evolved from a common ancestral species in the Nile River. Like Darwin’s finches, the cichlids are a dramatic example of adaptive radiation, the process by which multiple species radiate from an ancestral species through adaptation.

In the new study, the researchers sequenced the genomes and transcriptomes – the protein-coding RNA - from ten tissues of five distinct lineages of African cichlids. The sequenced species include the Nile tilapia, representing the ancestral lineage, and four East African species: a species that inhabits a river near Lake Tanganyika; a species from Lake Tanganyika colonized 10-20 million years ago; a cichlid species from Lake Malawi colonized 5 million years ago; and species from Lake Victoria where the fish radiated only 15,000 to 100,000 years ago.

The researchers found a number of genomic changes at play in the adaptive radiation. Compared to the ancestral lineage, the East African cichlid genomes possess an excess of gene duplications, alterations in regulatory elements in the genome, accelerated evolution of protein-coding elements in genes for pigmentation, and other distinct features that affect gene expression.

“It’s not one big change in the genome of this fish, but lots of different molecular mechanisms used to achieve this amazing adaptation and speciation,” said Federica Di Palma, co-senior author of the Nature study and director of science in vertebrate and health genomics at The Genome Analysis Center in the UK.

Some changes in the genome appear to have accumulated before the species left the rivers to colonize lakes and radiated into hundreds of species. This suggests that the cichlids were once in a period of reduced constraint. During this time, the fishes accumulated diversity through genetic mutations, and the relaxed constraint – in which all individuals thrived, not just the fittest – allowed genetic variation to accumulate. As the fish later inhabited new environmental niches within the lakes, new species could form quickly through selection. In this way, a reservoir of mutations – and resultant phenotypes – represented a genomic toolkit that allowed quick adaptation.

More work remains to fully dissect the mutations that cause each of the varying phenotypes in cichlid fish, which could help explain how similar forms or traits evolved in parallel in different lakes.

"By learning how natural populations, such as fishes, adapt and evolve under selective pressures, we can learn how these pressures affect humans in terms of health and disease,” Di Palma said.

Todd Streelman, professor in the School of Biology at Georgia Tech and a co-author of the study, studies Lake Malawi cichlid species to address biological questions that are difficult to study in traditional model organisms.

"These fishes provide a great way to identify the genes that control traits in natural populations," Streelman said. “Now that we understand the genome sequences of some of these species, it’s a lot easier to interpret all of the new genetic and genomic data we collect in the lab.”

His lab studies natural mechanisms of lifelong tooth replacement and the genomics of complex social behavior using closely-related Malawi cichlids. The new genome sequence of the Lake Malawi cichlid will allow Streelman’s lab to investigate which genes are turned on or off during these processes.

Streelman's research group cultures roughly 25 different Malawi cichlid species in aquatic facilities at Georgia Tech, through research funded by the National Institute of Dental and Craniofacial Research (NIDCR) and the National Institute of General Medical Sciences (NIGMS).

This work was funded in part by the National Human Genome Research Institute (NHGRI), the Swiss National Science Foundation, the German Science Foundation, Biomedical Research Council of A*STAR, Singapore, the European Research Council, US National Institute of Dental and Craniofacial Research (NIDCR), and the Wellcome Trust.

 CITATION: David Brawand, et al."The genomic substrate for adaptive radiation in African cichlid fish." (Nature, September 2014) http://dx.doi.org/10.1038/nature13726   

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 Writer: Leah Eisenstadt, Broad Institute of Harvard and MIT

Each team to receive $100K for two years to kick-start new research.

Three interdisciplinary teams with wide-ranging goals at the Parker H. Petit Institute for Bioengineering and Bioscience have gotten off to a fast start on pioneering explorations in biotechnology, thanks to a homegrown program that supports innovative early-stage research.

The winning teams of the 2014 Petit Bioengineering and Bioscience Collaborative Seed Grant are working to improve the prediction of disease (Hang Lu and Patrick McGrath), design better drug delivery strategies to fight cancer (M.G. Finn and Susan Thomas), and unveil (and better understand) the processes through which cell receptor signaling is initiated (Robert Dickson and Cheng Zhu).

Each of these fledgling collaborative teams was awarded $100,000 for two years to kick-start new research en route to long-range aspirations.

“The seed grant program is fantastic, because it supports bold ideas that don’t have preliminary data,” says Lu, a professor in the School of Chemical and Biomolecular Engineering. “Patrick and I have been wanting to work on this particular idea of evolving model systems to study multigenic diseases. We are extremely happy to have the support to pursue it now. We’re hoping to garner preliminary data to seek NIH funding in the long run.”

The program, now in its third year, gets to the heart of the Petit Institute mission, as it encourages a multidisciplinary approach to cutting-edge research, with each team bringing together an engineer and a scientist in a collaborative research endeavor, addressing complex biotech challenges by combining the distinct strengths of each lab. For example, as Lu and McGrath (assistant professor in the School of Biology) explain in their proposal, “Technologically and conceptually, what we propose here has never been done before. This pilot is truly enabled by the genomics know-how of the McGrath lab and the technological advancement of the Lu lab, which is a unique combination not found elsewhere.”

By applying a directed evolutionary approach, they expect to eventually be able to identify interacting genes that can be used as biomarkers for lifespan and age-related diseases, “and also as synergistic drug targets that can be used to ameliorate side-effects by lowering dose-levels of pharmaceuticals.”

Zhu, professor in the Wallace H. Coulter Department of Biomedical Engineering, he and Dickson, professor in the School of Chemistry and Biochemistry), are “trying to develop methods that allow in situ measurements of protein-protein interactions in live cells,” says Zhu. “The lacking of such methods hinders the development of a broad field in biology.” Currently, no method allows this kind of crucial measurement, Zhu and Dickson say in their proposal.

Meanwhile, Finn (professor and chair in the School of Chemistry and Biochemistry) and Thomas (assistant professor in the George W. Woodruff School of Mechanical Engineering) are working on a project with what they say will ultimately “impact the drug delivery field by introducing a new chemical means to temporally control drug release,” according to their proposal.

“In some ways, this approach runs counter to the prevailing drive in the field toward ever more sophisticated ways to respond to environmental cues,” the researchers say, adding, “While such technologies are undoubtedly valuable, there is also value in a cleavage mechanism that one can use like an alarm clock.” Stretching the analogy a bit further, they describe an alarm clock in which the start and end times, and intensity (and composition of the alarm) are all programmable.

“Results from this study,” Finn and Thomas say in their proposal, “will form the basis of numerous collaborative grant applications and a long-term collaboration between two labs with distinct but synergistic expertise aimed towards the design and effective drug delivery strategies for cancer therapy.”

Funding for the seed grants comes mainly from the Petit Institute’s endowment as well as contributions from the College of Sciences and the College of Engineering. Each research team receives $50,000 a year for two years, with the second year of funding contingent on submission of an external collaborative grant proposal.

The increasing acidification of ocean waters caused by rising atmospheric carbon dioxide levels could rob sharks of their ability to sense the smell of food, a new study suggests.

Elevated carbon dioxide levels impaired the odor-tracking behavior of the smooth dogfish, a shark whose range includes the Atlantic Ocean off the eastern United States. Adult sharks significantly avoided squid odor after swimming in a pool of water treated with carbon dioxide. The carbon dioxide concentrations tested are consistent with climate forecasts for midcentury and 2100. The study suggests that predator-prey interactions in nature could be influenced by elevated carbon dioxide concentrations of ocean waters.

“The sharks’ tracking behavior and attacking behavior were significantly reduced,” said Danielle Dixson, an assistant professor in the School of Biology at the Georgia Institute of Technology in Atlanta. “Sharks are like swimming noses, so chemical cues are really important for them in terms of finding food.”

The study is the first time that sharks’ ability to sense the odor of their food has been tested under conditions that simulate the acidity levels expected in the oceans by the turn of the century. The work supports recent research from Dixson and other research groups showing that ocean acidification impairs sensory functions and alters the behavior of aquatic organisms.

The study was published August 11 the journal Global Change Biology and was sponsored by the National Science Foundation (NSF).

Carbon dioxide released into the atmosphere is absorbed into ocean waters, where it dissolves and lowers the pH of the water. Acidic waters affect fish behavior by disrupting a specific receptor in the nervous system, called GABA_A, which is present in most marine organisms with a nervous system. When GABA_A stops working, neurons stop firing properly.

Dixson’s previous research has shown that fish living on coral reefs where carbon dioxide seeps from the ocean floor were less able to detect predator odor than fish from normal coral reefs. Study co-author Philip Munday, from James Cook University in Australia, has shown in previous work that a tiny coral reef predator fish, the dottyback,also loses interest in food in waters that simulate ocean acidification conditions forecast for the future.

In the experimental part of the new study, conducted at Woods Hole Oceanographic Institute in Cape Cod, Massachusetts, 24 sharks from local waters were studied in a 10-meter-long flume. The flume resembled two lanes of a swimming pool. Odor from a squid was pumped down one lane of the flume, while normal seawater was pumped down the other side.

Sharks tend to prefer one side of a tank over the other, so researchers first assessed each sharks’ side preference. Then the research team ran control experiments under normal ocean conditions to ensure that the sharks were tracking the food cue. Under present-day water conditions, sharks adjusted their position in the flume to spend a greater amount of time on the side containing the squid odor plume, regardless of the individual shark’s natural side preference.

Next, sharks spent five days in holding pools of three different carbon dioxide concentrations: local water concentration today (405 ± 26microatmospheres (µatms) CO₂), projected midcentury concentration (741 ± 22 µatms CO₂),projected concentration for 2100 (1,064 ± 17 µatms CO₂). Sharks were not fed while in the holding pools to ensure they were motivated to track a food odor. The sharks were then released into the flume and their tracking behavior was observed.

Sharks from the normal seawater pool and mid-level carbon dioxide pool spent more than 60 percent of their time in the water stream containing the food stimulus. Sharks from the high carbon dioxide pool spent less than 15 percent of their time in the water stream containing the food stimulus. These sharks avoided the odor plume even when it was on the side of the flume that the sharks’ naturally prefer.

The food odor stream was pumped through bricks to make the plume flow better and to give the sharks a target to attack. Sharks treated under mid and high CO₂ conditions also reduced their attack behavior.

“They significantly reduced their bumps and bites on the bricks compared to the control group,” Dixson said. “It’s like they’re uninterested in their food.”

Exposure to carbon dioxide did not significantly affect the sharks’ overall activity levels. The gill rate of the sharks – an indicator of heart rate – held in different water conditions was not significantly different, suggesting that differences in stress to the sharks was not likely affecting the experimental results.

Dixson noted that the study was carried out under laboratory conditions and thus does not allow for the full evaluation of the potential effects of ocean acidification on predatory abilities of the smooth dogfish.

Live food was not used as the odor cue because sharks can detect prey with their other senses, such as hearing and their ability to detect electrical impulses. By using an odor cue, the researchers were focusing on only the chemical sensing of sharks. Dixson’s future work will explore how sharks’ other senses might be affected by ocean acidification.

Sharks are an ancient species, and in the past have adapted to ocean acidification conditions projected for the future. But they’ve never had to adapt to changes happening as quickly as they are today.

“It’s the rate of change that’s happening that’s concerning. Sharks have never had to deal with it this fast,” Dixson said.

This research is supported by the National Science Foundation (NSF) under award number NSF-IOS-0843440. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of the sponsoring agency.

CITATION: Danielle L. Dixson, et al., “Odor tracking in sharks is reduced under future ocean acidification conditions.” (Global Change Biology, August 2014) http://onlinelibrary.wiley.com/doi/10.1111/gcb.12678/full

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