Fall 2013 Issue by Carolina Scientific

Carolina

Carolina Scientific

sc覺ent覺fic Fall 2013 | Volume 6 | Issue 1

Understanding the mechanisms of blood vessel formation helps researchers develop cancer therapies. Full story on page 16.

Carolina

scÄąentific Executive Board

Mission Statement: Founded in Spring 2008, Carolina Scientific serves to educate undergraduates by focusing on the exciting innovations in science and current research that are taking place at UNC-Chapel Hill. Carolina Scientific strives to provide a way for students to discover and express their knowledge of new scientific advances, to encourage students to explore and report on the latest scientific research at UNCChapel Hill, and to educate and inform readers while promoting interest in science and research.

Editor-in-Chief Managing Editor Associate Editor Associate/Design Editor Copy Editor Publicity Chair Fundraising Chair

Letter from the Editor:

Kati Moore Sneha Rao Hannah Aichelman Erin Moore Matthew Leming Josh Sheetz Linran Zhou

Advisors

This semester we are pleased to present an issue of Carolina Scientific that covers research from a greater variety of fields than ever before. In this issue you can learn how an auditory implant allowed a boy to hear for the first time (page 20), how dinosaur bones found in North Carolina helped identify a new species (page 26), and how the way we perceive othersâ&#x20AC;&#x2122; minds affects how we judge right from wrong (page 44). We hope that through these stories we will communicate research in an engaging way, encourage undergraduates to pursue research, and foster a passion for discovery in the university community and beyond. - Kati Moore

on the cover

Image courtesy of iStock/Getty Images.

UNC researchers study the mechanisms of blood vessel formation and their association with tumor cell circulation. See page 16 for the full story.

Faculty Advisor Tom Linden, M.D. Graduate Advisor Courtni Kopietz Graduate Advisor Daniel Lane

Contributors Staff Writers

Copy Staff

Sainath Asokan Corey Buhay Glynis Coyne Brian Davis Catherine Dirks Sheryl Fuehrer Navaneet Galagali Tracie Hayes Kimberly Hii Karthika Kandala Hetali Lodaya Nathan Moore Dasean Nardone-White Sam Resnick Samantha Richards Mai Riquier Jenna Sawafta Emily Smith Christine Son Austin Sun Preethika Sundararaj Ashlyn Young Chris Zack Larry Zhou

Elizabeth Bartholf Corey Buhay Thalita Cortes Brian Davis Julia Filler Kimberly Hii Leah Johnson Cody Phen Christine Son Hope Thomson

Design Staff Sheryl Fuehrer Apoorva Gupta Tracie Hayes Jennifer Jackson Stephanie Liffland Matt Morrow Kelci Schilly Austin Sun Anna Youqi Tang Ying Zhou

Carolina Scientific

contents Biology

Computer Science

Turning Up the Heat

Choosing Wisely

Long Gene Protection

The Crowded Cytosol

The Viral Change-Up

Unlocking Natureâ&#x20AC;&#x2122;s Potential

Uncoiling the Mitotic Spring

Hybrid Photovoltaic Cells

Guiding Sea Turtles Home

A Leading Light

Branching Not Just for Trees

The Art of Chemical Synthesis

Chris Zack

Glynis Coyne

Dasean Nardone-White Nathan Moore Emily Smith

Sainath Asokan

From Factory to Fork

Lending an Ear to Innovation

Larry Zhou

Catherine Dirks Corey Buhay

Sheryl Fuehrer Mai Riquier

Information Science

Hetali Lodaya Christine Son

Navaneet Galagali

Chemistry

Sam Resnick

Health & Medicine

The Road Not Taken

Been There, Done That Kimberly Hii

Linguistics & Psychology

Biomedical Engineering

Speaker Normalization Samantha Richards

Donâ&#x20AC;&#x2122;t Judge a Tumor by Its Size

Morality 101

Microfluidics

The Subtle Side of Memory

Growing Pains

Jenna Sawafta

Ashlyn Young

Geology

A Ruling Reptile

You Are What You Eat

Tracie Hayes

Brian Davis Austin Sun

Preethika Sundararaj

Undergraduate Research

Karthika Kandala

Spotlight:

Tanner Fadero and Katie Weinel

carolina_scientific@unc.edu | carolinascientific.web.unc.edu | facebook.com/CarolinaScientific |@uncsci

biology

turning up the HEAT hybrid fitness under extreme temperatures

Dr. Christopher Willett’s laboratory studies the population dynamics and ecologial adaptive mechanisms of the copepod Tigriopus californicus, which inhabits rocky tidal pools on the California coast. Image courtesy of Dr. Willett.

long the shores of California lives a species of tiny crustacean called Tigriopus californicus, commonly known as the copepod (Figure 1).1,2 Copepods are ubiquitous in the world’s oceans and freshwater. This species of copepod lives in the intertidal zone of the California coast and spends much of its time in rocky tide pools.3 While copepods generally experience the mild weather conditions typical of California’s coasts, these copepods are occasionally subjected to dangerously hot conditions during extreme weather events.3 The copepods must be able to withstand these extreme conditions in order for individual populations to survive, and thus they have evolved to be able to tolerate these occasional

dangerous bursts of heat.3 Dr. Chris Willett of UNC-Chapel Hill’s department of biology studies Tigriopus californicus and its ability to tolerate heat.3 In a previous study, he found that among different populations of copepods along the west coast of the United States, populations from the south have a greater heat tolerance than those in the north, creating a northsouth gradient of heat tolerance.3 The study also found that populations of copepods from northern Californian shores exhibit greater fitness under normal temperature conditions than populations from southern California.1 These results indicate a tradeoff between fitness at normal temperatures and fitness under thermal stress, mean-

Figure 1. Tigriopus californicus. Image by H. Limen and H. MacIsaac, courtesy of NOAA. ing that if one copepod is better than another at surviving high temperature events, it will be outcompeted at normal temperatures.3 Copepods almost never migrate;

Carolina Scientific therefore, copepods rarely mate with in- the less heat-tolerant parental populadividuals from a different population, re- tion, and occasionally had higher fitsulting in very little exchange of genetic ness under thermal stress than the more material between populations.3 heat-tolerant parental population. The Dr. Willett says this lack of be- second generation of hybrids, however, tween-population mating “sets up the tended to have lower fitness than the opportunity for local adaption, whether first hybrid generation, even though the there might be slightly different salinity- second generation in this experiment type conditions, or temperature-type usually had greater fitness than the less conditions that occur at any particular fit parental population.1 rocky outcrop area … you have [the] This may be because each parenpotential for natural selection to cause tal population has genes with alleles the evolution of local adaptation there.”1 that were unique to that population. When two distinct populations do inter- Some of these alleles are recessive, and breed, their hybrid offspring are often they have a negative effect on a copeless able to survive (and reproduce) in pod’s fitness. When two different pareneither parental environment.3 This phe- tal copepod populations are interbred, nomenon is known as hybrid break- no individual in the first generation of down.1 offspring can possibly have two copies In an effort to better understand of these recessive alleles, therefore none this phenomenon, Dr. Willett tested hy- of these offspring will be affected. In the brid populations of second generation copepods for hybrid hybrid population, When two distinct breakdown under however, there can be populations do inter- a negative effect on thermal stress.1 “The general breed, their hybrid individual offspring with both copies of intellectual setup is just that we’re trying offspring are often less these alleles.3 In fact, to figure out when fit to survive in either by the second generayou’ve got hybridization, the hybrid popution, are environmen- parental environment. lations often have a tal factors really imThis phenomenon lower fitness than the portant or is it more parental population, is known as hybrid which is the result of just things going wrong in the genome hybrid breakdown.1 breakdown. itself and it doesn’t Hybrid breakreally matter what’s down may be expecthappening with the environment?”3 ed in copepod populations because the Dr. Willett interbred populations parental populations have each adapted of copepods from different latitudinal to their own specific environment, and regions of California to create hybrid hybrid populations may not be wellpopulations. In one experiment, hybrid adapted to any particular environment. offspring populations descended from Also, mixing two populations can mix two different southern parental popula- genes from different populations that tions and hybrid offspring populations don’t necessarily work well together.1 descended from a northern and a southThe interactions between genes ern parental population were constantly in the mitochondrial DNA (mtDNA) subjected to heat stress. and genes in the nucleus are particuIn another experiment designed larly susceptible to this form of hybrid to test fitness under acute heat stress, breakdown, as mtDNA evolves at a rate similar populations were subjected to of about 60–70 times that of the genetic various high temperatures for one hour. material in the nucleus in copepods.3 In both experiments, the survival rate of This means that the mtDNA from one each population was used as a measure population which has adapted to work of fitness.1 in relative harmony with the DNA from Dr. Willett found that the first the nucleus may be very different from generation of hybrids tended to have the mtDNA from another population, higher fitness under thermal stress than which implies that mtDNA from one

biology

Dr. Christopher Willett population may be in some ways incompatible with the nuclear DNA from another population. While the second generation of hybrids is expected to have a lower fitness under thermal stress than the first hybrid generation, the finding that the second hybrid generations was almost always fitter than the less fit parental population differs from the findings of several previous studies.1 Dr. Willett believes that this unexpected result could indicate that hybrid breakdown is lower under certain types of stress in some organisms.1 His results also show that the environment plays a significant role in hybridization.3 Dr. Willett is continuing his research on the study of how copepods evolve to adapt to heat stress in the short term, which will help scientists understand how the physiological mechanisms underlying heat tolerance might evolve under global climate change.3

References

1. Willett, C.S. “Hybrid Breakdown Weakens under Thermal Stress in Population Crosses of the Copepod Tigriopus californicus.” Journal of Heredity 103, 103–114. 2012. 2. Copepod. Retrieved from http:// dictionary.reference.com/browse/ copepod?s=t&ld=1172. 3. Interview with Christopher Willett, Ph.D. 9/20/2013.

biology

CHOOSING WISELY: What mathematical models can tell us about mate choice

By Glynis Coyne

der to understand the many factors that can affect how a new species evolves. However, evolution is so slow that studying an experimental population can take far too long to be practical. Therefore, a method has emerged which uses modern technological capabilities to gain insights into the long-studied questions of evolution. Dr. Maria Servedio of Dr. Maria Servedio UNC-Chapel Hill’s biology department uses computer-based mathematical models to examine the ways in which learning experiences can affect how organisms choose their mates. Also known as mate choice, this process can have a major impact on speciation.1 Choosing the right mate can be vitally important for the survival of a species. For example, cross-breeding between mallards and native wild ducks in Florida is putting the native species in danger of extinction.2,3 Dr. Servedio used her models to examine what would happen to a theoretical species in different learning scenarios. For example, if the males of a species learned only to avoid females of a different species, how would that affect the species as a whole? What if, instead, the species learned to prefer their own females — how would the species be affected then?2 With these “proof of concept” models — built on the rules of genetics and her collaborator Dr. Reuven Dukas’ observations of Drosophila — Dr. Servedio was able to see how each kind of learning produced a different effect on the whole population.1,2 Researchers have only recently begun to realize that Figure 1. A fruit fly, Drosophila. Researchers are finding that mate choice behavior might have a learned component; for even fruit flies can learn to choose mates. Image by Sanfruit flies in particular, it was long assumed that learning was ja565658 [CC-BY-SA-3.0]. n the course of Charles Darwin’s famous study in the Galapagos Islands, he noticed that, although the species of finches he found had very distinctive beaks, they shared many basic similarities. This led him to postulate that these different varieties of finches had in fact descended from a single species of finch. This single species had later evolved into many different species, each adapting to a different island environment. The process by which a single species develops into two or more different species is called speciation. Biologists have been studying this process ever since Darwin saw its effects in the birds of the Galapagos. Traditionally, researchers study model species, such as the fruit fly, Drosophila, in or-

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conspecific encounter

MATING 101

Meeting a male of the same species increases a female’s preference for her own species. Concept by Dr. Servedio, image by Erin Moore.

not a factor at all. “Drosophila are notorious for courting anything,” says Dr. Servedio. “Male Drosophila will court other dead males at the bottom of the vial … anything that remotely resembles a Drosophila!”2 But, she explains, Dr. Dukas found that if a male fruit fly of one species tried to mate with a female of a different species, she would reject him, and that male would learn to prefer females of his own species.2 It was in graduate school that Dr. Servedio first started using models as a research tool. Not only did she like the mathematical, logicbased quality of this method, she also had more practical concerns. “I have to say, a lot of the appeal in working with the computers instead of actual organisms,” Dr. Servedio said, “[was] because a lot of my friends were trying to start up these new systems, and [had to deal with] all those practical things that, with a model, you didn’t have to worry about at all. It just doesn’t happen with your simulations! They don’t die!”2 These models don’t just make Dr. Servedio’s research less frustrating — these results have provided basic insights into the effects of learning on the level of populations and even species,1,2 which could not have been understood nearly as efficiently by studying living organisms. Researchers studying speciation have been using a fish called the three-spined stickleback as a model species for decades, yet only recently have they realized that these fish can learn from experience which mates to choose.2 Live animal studies have mostly ignored how this kind of behavioral learning could affect a species’ evolution. “A lot of times you’re trying to control [experiences that would influence learning] away,” Dr. Servedio explains. “You’re trying to make sure that all your flies are virgins … and you’re not testing to see how these experiences

would change things.”2 These models are a tool for studying learning effects such as these on a scale impractical for human reasoning or live organisms.1,2 These insights have more than just theoretical applications. A better understanding of how populations merge and separate from their species is invaluable in the field of conservation, where the merging of species can be a very real problem. The wild ducks of Florida, already declining in population, are in danger of merging entirely into the Mallard population and becoming extinct.2,3 In deep, isolated rift lakes formed by cracks in the Earth’s crust, fish called cichlids exist in an amazing number of different species. As the lake water becomes cloudy and polluted, however, many of these species disappear entirely, as it becomes impossible for fish to be selective about their mates.2 Dr. Servedio’s work has not only given important insights into the mechanisms of learning and speciation, it has also shown how these methods can be used as an effective tool for studying species as a whole.

For fruit flies in particular, it was long assumed that learning was not a factor at all. “Drosophila are notorious for courting anything,” says Dr. Servedio.

References

1. Servedio, M.R., Dukas, R. “Effects on Population Divergence of Within-Generational Learning About Prospective Mates.” Evolution 67(8), 2363–2375. 2013. 2. Interview with Maria R. Servedio, Ph.D. 9/13/2013. 3. Bowers, F. Environmental Assessment for Control of Free-Ranging Resident Mallards in Florida. (2002, May). Retrieved from http://www.fws.gov/southeast/news/2002/ Mallards/.

biology

Long gene protection prevents autism Researchers recently found that inhibitors of the protein topoisomerase reduce expression of genes linked to autism spectrum disorders.

BY SAM RESNICK

utism spectrum disorder (ASD) is a developmental disorder of the brain that varies in severity. Children diagnosed with ASD often have difficulty with social interaction, intellectual development and development of motor coordination.1 Symptoms vary across a wide spectrum, and those who are diagnosed can excel in music, math or art. ASD is not an uncommon disease in children; approximately one in 90 children are diagnosed. Vaccinations have been thought to cause ASD, however many scientists dispute these claims. Instead, they argue that ASD results from a combination of multiple things gone wrong.1 Members of the Zylka and Philpot labs in the UNC-Chapel Hill School of Medicine, and the Chamberlain lab in the University of Washington department of neurobiology, have made advances in understanding exactly what causes ASD. Dr. Ian King, a member of Dr. Mark Zylkaâ&#x20AC;&#x2122;s lab, headed this team of researchers. They have described a mechanism by which topotecan, a drug that inhibits an enzyme called a topoisomerase can lead to misregulation of multiple genes. Investigation into how topoisomerases normally function revealed a molecular mechanism that could be a cause of ASD. Their recent publication in Nature bolsters the idea that ASD can result from defects in the expression of multiple genes, and, in particular, genes that are exceptionally long. Topoisomerases are responsible for relaxing the strands of DNA.4 Imagine a rubber band twisted along itself: when the middle of the rubber band coil is pulled apart, the coils on the ends of the rubber band get tighter (Figure 1). This is similar to what happens when DNA is unwound for transcription to RNA. Topoisomerases are natureâ&#x20AC;&#x2122;s remedy for this supercoil-

Dr. Mark Zylka and Dr. Ian King.

Figure 1. A rubber band is a useful analogy for DNA supercoiling. Image courtesy of bioinfo.org.

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Figure 2. (Left) Genes with a longer length are expressed less when treated with topoisomerase. (Right) A model of brain development in a child without ASD and in a child with ASD. Left image reprinted by permission from MacmillanPublishers Ltd: Nature. King et al. copyright 2013. Right image courtesy of Human Brain Mapping. ing upstream and downstream of where DNA is being tran- that were affected by the loss of topoisomerase were linked scribed into RNA. These proteins allow DNA to unwind and to ASD. They concluded that factors that inhibit the function of topoisomerases in development likely contribute to the ease the stresses from coiling. When topoisomerases are inhibited, as is the case when change of being diagnosed with ASD. Dr. King thinks that this group has uncovered the tip treated with topotecan, this unwinding does not seem to hapof a potentially huge iceberg pen. concerning brain develop“We wanted to identify what kinds of genes were af“It seems as if the inability of DNA ment. The researchers are already considering future imfected when topoisomerases to uncoil properly prevents long plications of this finding and were treated with a drug that ways to delve further into the inhibited their function,” says genes from being expressed.” issue. Dr. King, the postdoc who was - Dr. Ian King “We are currently looklead author of the study.3 ing at how environmental To do this, Dr. King and conditions affect topoisomercollaborators looked at the relative levels of expression of RNA in cells that were treated with ases in development,” says Dr. King, looking to examine how topotecan and cells that were untreated through a technique the environment could possibly affect the severity of ASD.3 called RNA sequencing (RNA-seq). Dr. King describes this techIt has been previously noted that topoisomerases are nique as “a method that allows us to see changes in levels of sensitive to environmental conditions. There seems to be a transcription across all genes at once.”3 high probability that other mental illnesses, such as schizoStatistical analysis of the data recovered in the RNA se- phrenia, develop in a similar fashion to ASD because long quencing experiment showed that genes with a longer physi- genes are essential to proper brain development. Future recal length were not expressed as much as genes of shorter search on this topic could potentially lead to explanations for length (Figure 2). “It seems as if the inability of DNA to uncoil familial cases of mental illness. properly prevents long genes from being expressed,” says Dr. King.3 This finding gave the members of these labs insight into the Philpot lab’s previous discovery. They found that this drug References was able to activate expression of a gene that is normally si- 1. Autism Spectrum Disorder. Retrieved from http://www. lenced by a separate gene that is very long. nimh.nih.gov/health/topics/autism-spectrum-disorders It was when the researchers were looking through pervasive-developmental-disorders/index.shtml. the list of genes that were affected by the loss of topoisom- 2. King, I.F., Yandava, C.N., Mabb, A.N., Hsiao, J.S., Huang, erase that they made the connection to ASD. It turns out that H., Pearson, B.L., Calabrese, J.M., Starmer, J., Parker, J.S., in human development, many of the genes that determine Magnuson, T. “Topoisomerases Facilitate Transcription of proper brain maturation are long genes. A comparison be- Long Genes Linked to Autism.” Nature 501, 58–62. 2013. tween genes in which the expression of RNA went down and 3. Interview with Ian King, Ph.D., 9/20/2013. a list of genes considered as having an effect in ASD led to a 4. Plasschaert, R.N., Bartolomei M.S. “Autism: A Long Gesurprising discovery. They saw that a high number of genes netic Explanation.” Nature 501, 36–37. 2013.

biology

Research in Dr. Christina Burch’s laboratory investigates the evolution of bacterial viruses to investigate the genetics of adaptation.

gaining the advantage when competition is fierce

THE VIRAL CHANGE-UP By Dasean Nardone-White

n recent years, there has been a lot of talk and speculation about Earth’s inevitable depletion of resources. While many are not sure what to think of this, the fact remains that population size is increasing steadily.1 With around seven billion people and counting currently living in the world, it is by no means a stretch of the imagination to envision a fight for resources in the future. It is precisely this fight for resources that the lab of Dr. Christina L. Burch studies at the University of North Carolina

Figure 1. United Nations estimate of the growth of the human population through 2100. Image by Tga.D [CC BY-SA 3.0].

at Chapel Hill. However, instead of people, Dr. Burch and her team study viruses and the effects that the struggle for resources, specifically the struggle for access to hosts, have on their evolution. Ever since Charles Darwin wrote about the “struggle for existence” in On the Origin of Species, it has been thought that limited resources leads some individuals to begin to Dr. Christina Burch use new, untapped resources to escape the struggle. In the case of viruses, this means that when they are deadlocked in a fierce battle for a particular host, some of them will look to new hosts for survival. In natural populations it is generally not possible or not ethical to experimentally manipulate the presence or absence of competitors. As a result, very few experiments have been done to directly test the theory that, when competition is fierce, viruses can obtain a mutation to infect new hosts. Dr. Burch’s work gets around this limitation of natural population by monitoring the evolution of virus populations in the lab. Using a type of virus that infects bacteria, called phi-6 bacteriophages,3 Dr. Burch and her team designed an experiment to test the theory that as competition for access to hosts increases, the viruses gain mutations that allow them to infect new hosts. In their experiment, Dr. Burch and her colleagues (including Lisa Bono, the graduate student at the head of this project) created two different environments. In both environments, some viruses were present, along with a number

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Figure 2. (Left) test tubes illustrate the different environments created in the experiment. The clearer test tubes contained more viruses than the more turbid, cloudy ones. (Right) Plate that was initially filled with both standard and novel hosts. The dark circles (plaques) illustrate where the viruses infected both hosts. Images courtesy of Dr. Burch. of hosts that the viruses normally infected (called standard hosts). Hosts that the viruses needed a mutation to infect (called novel hosts) were also included.2,3 In the first environment, there was an unlimited supply of hosts, so the viruses did not have to fight as hard to infect the standard hosts. In the second environment, there was a severely limited supply of hosts, so the viruses had to struggle for a chance to infect the standard hosts. Dr. Burch and her team continued to supply uninfected hosts to the viruses, ultimately repeating this experiment 60 times.3 They did this with the expectation that some of the viruses would develop a mutation allowing them to branch out and infect some of the novel hosts because there were not enough standard hosts to go around. In the final step of the experiment, Dr. Burch coated petri dishes with both standard and novel hosts. She then introduced the viruses into the petri dishes. This experiment tested the hypothesis that the environment with a limited supply of hosts would be more likely to promote a mutation in the virus that would allow it to jump to the novel hosts (in addition to the standard hosts that they normally infected). The viruses in the environment with an unlimited amount of hosts would be less likely to accumulate a mutation that would allow them to infect the novel hosts because they were under no pressure to infect new hosts when they were already adapted to infecting the standard hosts. Dr. Burch’s hypotheses were supported by her findings. When she introduced the viruses onto the petri dishes, two types of circular plaques appeared. One plaque was clear and the other was more turbid (cloudy).2 The first plaque was clear because the viruses infected both the novel hosts and the standard hosts. These clear plaques correlated to the groups of viruses that had fewer hosts per virus. These viruses are classified as generalists because they did indeed generate a mutation that allowed them to not only infect their standard hosts, but also the novel hosts.3 The second plaque was turbid because the group of vi-

ruses that were in an environment with a comfortable amount of hosts infected their normal standard hosts, but did not infect the novel hosts because they were under no pressure to gain the mutation to do so. These viruses were then classified as specialists.3 Dr. Burch’s findings supported the theory that as the struggle for resources increases in a population, individuals within that population will begin to search out new resources. Originally, Dr. Burch was not interested in the idea of evolutionary biology. More intrigued by microbiology as an undergraduate, she recalled how learning about topics such as the Hardy–Weinberg equilibrium were “at that time, pretty obvious, and therefore not that interesting.”2 However, Dr. Burch soon found that she had an interest in evolutionary biology because she was able to combine her love of biology with her passion for math. Dr. Burch says she hopes that her team’s research will be helpful in understanding host jumps in viruses. The phi-6 bacteriophage that she used in the experiment contains RNA instead of DNA, and therefore is a model of other RNA viruses such as HIV and the Flu, both of which are famous for adapting to infect humans.2 Ultimately, a better understanding of why viruses acquire mutations to infect new hosts (and under what conditions this happens) will be key in combating the dangerous viruses that have mutated to infect humans, as well as those viruses that may pose a threat to humans in the future.

References

1. World Population. Retrieved from http://en.wikipedia. org/wiki/World_population. 2. Interview with Christina L. Burch, Ph.D. 9/25/2013. 3. Bono, L.M., Gensel, C.L., Pfenning, D.W., Burch, C.L. “Competition and the origins of novelty: experimental evolution of nich-width expansion in a virus.” Biology Letters 9(1). 2012.

biology Dr. Kerry Bloom studies cell division dynamics to investigate how cells can break the covalent backbone of the DNA double helix. Image by Hrz2 [CC-BY-SA-3.0S].

uncoiling the

MITOTIC SPRING Re-examining the Mechanisms of Cell Division BY NATHAN MOORE

hen you shrink down to the size of a cell, the rules change. An entirely different set of assumptions is used to understand a cell-sized world. In destroying these assumptions, Dr. Kerry Bloom hopes to uncover the mechanistic forces at play in mitotic division.1 On a cellular level, both inertia and gravity are negligible. Brownian motion, the random motion of particles suspended in a fluid, is the major force at play within the cell. Due to this motion, our understanding of processes like the separation of sister chromatids in metaphase cannot be conceptualized with traditional projections of Newtonian physics, and the spring force involved must be reconsidered as well.1 As Bloom’s research indicates, a linear spring model does not

correctly predict microtubule spindle length and chromatin dynamics.2 Dr. Bloom utilizes yeast to study the dynamics of mitotic division. Several features of budding yeast make it a particularly viable test group, including a “streamlined and stereotypic” mitotic spindle.2 Yeast enables researchers to observe the cell cycle without all of the “bells and whistles”

Dr. Kerry Bloom

Figure 1. Model of chromatin loops in mitosis in budding yeast. Chromatin, the DNA and protein structure, is subject to extensive compaction and coiling. Part of Bloom’s research examines how these coils behave in mitosis.The model shows DNA loops in yellow, microtubules in green, spindle pole body in red, and cohesin and condensin as blue and purple rings, respectively. Image courtesy of Dr. Bloom.

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that complicate mammalian cell division. “The remarkable thing about nature is how conserved the basic processes are,” Bloom explains. “The engines that actually run the cell cycle are the same genes from yeast to mammals, and you can take a mammalian gene and put it into a yeast cell whose ‘engine’ you’ve removed, and the mammalian gene will work and run the cell cycle.”1

“No one thinks about the dynamics of chromatin in terms of motion, and how important—or not—it is on how things are passed on in a hereditary sense.” - Dr. Kerry Bloom Dr. Bloom’s research group tags parts of the cell with fluorescent proteins that allow them to directly observe many mitotic forces at play and then compare these findings with constructed mathematical models. In the lab, Dr. Bloom tests these models through manipulations of microtubule dynamics and by examining the role and movement of chromosomes at the pericentromere, the region of DNA surrounding the point where microtubules connect to induce separation. In conjunction with these physical tests, Bloom and his team generate mathematical models to explain what they see.1,2,3 “The math model is our solution to gaining intuition,” Dr. Bloom says. With the vast number of proteins and other variables at play in mitosis, it would be nearly impossible to derive an equation that describes all the forces at work within a cell. However, by starting with a set of assumptions and constructing a relatively simple understanding of what is at work, Dr. Bloom can mold his original intuition to the new set of circumstances that come with the alien physics of the cell’s interior. He adds that invariably the results differ, but that allows him to exploit what he sees as the heart of scientific discovery: something goes wrong, and one must figure out why.1 Dr. Bloom’s work fits into a larger understanding of how the cell manages to preserve fidelity in its genetic code from generation to generation. Dr. Bloom also studies epigentics, looking at how the protein structure that contains DNA contributes to heritability. “No one thinks about the dynamics of chromatin in terms of motion, and how important — or not — it is on how things are passed on in a hereditary sense.” Unraveling the human genome is only a fraction of what heritability entails.1 Dr. Bloom’s lab is working towards the answers on one of the cell’s greatest existing mysteries: how the cell is able to quickly and competently correct a break in the covalent backbone of the double helix. They argue that understanding the motion of the chromosomes will have vast implications for how the cell is able to correct the information. Dr. Bloom calls it the live cell analysis on DNA repair because of its focus on observing the actual events inside the cell, rather than analyzing the enzymes involved in the process.

Figure 2. (A) A classic view of chromatin dynamics. (B) An updated model; with images of stained chromatin supporting this in (C). Reprinted from Biochimie, 92, Larson, M.E.; Harrison, B.D.; & Bloom, K., “Uncovering chromatin’s contribution to the mitotic spindle: Applications of computational and polymer models.” 1741–1748, Copyright (2010), with permission from Elsevier. The lab’s current hypothesis arose from the aforementioned collaboration with mathematicians. The chromosomes function like a spring with two tethered ends, the telomeres at the ends and the centromere in the middle with a mobile interior. “It’s a slinky,” he explains. His theory is that the mechanism is that simple: the telomere lets go, allowing the chromosome to remain stationary, but the spring-like characteristics of the chromosome work to its advantage.1 With this hypothesis, Bloom and his collaborators are challenging classic assumptions of cell function.

References 1. Interview with Kerry Bloom, Ph.D. 9/23/2013. 2. Stephens, A.D., Haggerty, R.A., Vasquez, P.A., Vicci, L., Snider, C.E., Shi, F., Quammen, C., Mullins, C., Haase, J., Taylor, R.M., et al.. “Pericentric chromatin loops function as a nonlinear spring in mitotic force balance.” Journal of Cell Biology. 200, 757–772. 2013. 3. Verdaasdonk, J.S., Gardner, R., Stephens, A.S., Yeh, E., Bloom, K. “Tension-dependent nucleosome remodeling at the pericentromere in yeast.” Molecular Biology of the Cell 23, 2560–2570. 2012.

biology

Guiding Sea Turtles By Emily Smith

Home The earth’s magnetic fields seem to give sea turtles an internal GPS, allowing them to return to familiar places year after year.

magine waking up in the middle of nowhere, 1000 miles away from home, with no technology or people to help you get back. While this may sound like a nightmare, many species have internal mechanisms to handle this situation that allow them to not only know where they are, but also tell them how to return home. Researchers are beginning to delve into this phenomenon which guides the migration of birds, sea turtles and salmon. Dr. Catherine Lohmann of the UNC-Chapel Hill department of biology has been researching this mystery in salmon and sea turtles. In a vast ocean, with no distinguishable landmarks, sea turtles must have some sort of internal GPS mechanism to guide themselves. Dr. Lohmann hypothesized that sea turtles accomplish this by sensing the Earth’s magnetic field.1 The Earth’s magnetic field varies in inclination across the Earth. The magnetic equator has an inclination of zero,

Figure 1. Lohmann lab with the setup for the sea turtle magnetic navigation experiment. The large blue tub is what the turtles swam in, and the box below it is the magnetic coil. Image courtesy of Dr. Catherine Lohmann.

and the inclination increases toward the Northern and Southern magnetic poles. The magnetic poles currently reside near the geographic North and South Poles, but tilted to the side, which is the same relationship the geographic and magnetic equators share. Isolines, which represent an equal amount of magnetic force, are drawn vertically across the Earth to represent Dr. Catherine the locations of inclines (Figure 1). The Lohmann Earth’s magnetic field also varies in intensity, with horizontal lines of varying intensity bisecting lines of inclination. UNC-Chapel Hill is located at an incline of approximately 65 percent. The combination of varying intensity and inclination across the Earth creates a distinct “magnetic map,” similar to the system of polar coordinates that we use. Dr. Lohmann hypothesized that sea turtles were able to utilize this map2 but realized that the ability to sense directions using the magnetic field was not enough. “Knowing which way north is doesn’t tell you [that] you should go north. And so you need to know something about where you are and where you want to be and how those two things are related,” Dr. Lohmann said.1,2 Dr. Lohmann knew that, in order for sea turtles to return years later to where they were born in order to breed, they must imprint their magnetic birthplace to memory. Then, using their innate magnetic mapping ability, they should be able to determine their current location in relation to their birthplace and return. In order to test this hypothesis, Dr. Lohmann created an experiment which used a magnetic coil to alter the magnetic field surrounding the turtle, such that the magnetic location would match that of a location many miles either south or north of the turtle’s true location (Figure 1). She stated, “We had a young turtle, but not a baby, but a young turtle swimming in this and it was old enough that it has a home and it

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Image courtesy of Brocken Inaglory [CC-BY-SA-2.5,2.0,1.0].

wants to stay near that home. So if you take it away from the home, it will try to swim back to it.â&#x20AC;? The turtle was then placed in a large tub filled with water and tethered to the center of the tub, so that it could continuously swim in a direction without reaching the edge (Figure 2). The location and direction in which the turtle swam was then observed.2 Dr. Lohmann found that all turtles placed in a magnetic field matching a northern site swam to the south, and most turtles placed in a magnetic field matching a southern location swam to the north (Figure 3).2 Thus, the turtles that were tricked into thinking they were in northern waters (by applying a magnetic field matching a northern site), tended to swim south, presumably to return to the previous. These results supported Dr. Lohmannâ&#x20AC;&#x2122;s hypothesis that turtles were able to detect the magnetic map of the Earth and use magnetic imprinting to return to where they have been before. There are two main theories of how animals are able to sense magnetic fields. The first is that animals have tiny pieces of magnetite in their nervous systems that respond to the push and pull of magnetic fields, which allows them to detect their locations. The second theory involves a chemical reaction occurring in the eyes of animals, which allows them to actually see the magnetic field. Some scientists believe that both theories may be occurring simultaneously. Dr. Lohmann plans to do future research on how sea turtles sense magnetic fields.1 Dr. Lohmannâ&#x20AC;&#x2122;s lab hopes to answer two questions: How do animals guide themselves in an indistinctive landscape, and how can animals remember where they have been and return there? While this experiment has shed light on how animals can navigate without landmarks, there is still uncertainty involved with imprinting. The magnetic field of the Earth slowly changes over time. If an animal were to live long enough, the magnetic location which they once imprinted on

Figure 2 (left). Isolines of magnetic inclination surrounding the southeastern U.S. Figure 3 (right). When turtles believed they were at a northern site, they swam south, whereas those that believed they were in a southern site swam north. Images courtesy of Dr. Lohmann. could move away from the physical location they were born in. In this case, it is hypothesized that turtles may just need to get into the vicinity of their birthplace in order to breed.1 However, further research is required to see how turtles would react to changing magnetic landscapes.

References

1. Lohmann, C. Orientation and Navigation of Sea Turtles. (2010, September 24). Retrieved from http://www.unc.edu/ depts/oceanweb/turtles/. 2. Interview with Catherine Lohmann, Ph.D. 9/12/2013.

biology

growing branches isnâ&#x20AC;&#x2122;t just for trees

BLOOD VESSEL FORMATION BY SAINATH ASOKAN

that must function properly and in unison with other processes in order for us to lead healthy lives. An imbalance of angiogenesis can easily cause the body to lose control if the process occurs excessively or insufficiently; excessive angiogenesis can cause blood vessels to feed diseased tissues and allow tumor cells to escape into circulation.5 Insufficient angiogenesis can cause heart diseases such as coronary artery disease and stroke due to lack of blood vessel growth and circulation.1 Since blood vessels sometimes nourish small tumors that can eventually metastasize (Figure 1), understanding the basic mechanisms of blood vessel formation can potentially help develop cancer therapies that prevent such growth. Dr. Victoria Bautch in the department of biology, her post-doctoral researcher, Dr. John Chappell, and Dr. Kevin P. Mouillesseaux Figure 1. Illustration of angiogenesis: blood vessels feed- of the Lineberger ing metastasizing tumors in the human body. Reprinted Comprehensive Canfrom Bergers et. al. Nat Rev Cancer 2003, 3, 401-410. cer Center have embarked on several

ver imagine how difficult it would be to navigate places without a GPS? Ever think about the possible struggles of writing that class paper late at night not being given any guidelines or expectations to follow? Interestingly, blood vessels seek this same guidance and direction when forming in our bodies. Angiogenesis, the physiological process through which blood vessels form from preexisting vessels, is a pivotal biological mechanism in our body

Dr. Victoria L. Bautch

Dr. John Chappell

approaches to study the blood vessel formation process and further learn about the unique signaling pathways involved. Through this work, they made a recent breakthrough in the relationship between expression of vascular endothelial growth factors (VEGF) and the signaling feedback loop that directs angiogenesis. Their study was featured in the June issue of Arteriosclerosis, Thrombosis, and Vascular Biology sponsored by the Journal of the American Heart Association. Angiogenic sprouting from preexisting vessels is initiated by several growth factors that are released from nutrient-deprived tissues.2 The endothelial cells that emerge as a result of these growth factors use local guidance cues to direct their extension and connection to neighboring target vessels. The two particular molecular mechanisms that regulate this vascular network for-

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biology

Figure 2. Left: Release of blood vessel growth factor, VEGF, by cancers to encourage blood vessels to grow and provide nutrients to tumors, courtesy of Journal of Experimental Medicine. Right: A-C) Wild-Type vessels with and without the Notch pathway inhibited. D-F) Vessels genetically lacking the Flt-1 receptor with and without the Notch pathway inhibited. Image courtesy of Arteriosclerosis, Thrombosis, and Vascular Biology. mation process are the vascular endo- the group hypothesized that genetic thelial growth factor (VEGF) and Notch loss of Flt-1 would cause an elevation of pathways.3 While the VEGF pathway the VEGF pathway, eventually activating mainly induces and directs the sprout- Notch signaling and leading to defects ing of endothelial cells (Figure 2, left), in vessel branching and dysmorphogenthe Notch pathway is significant in facili- esis.4 tating communication between cells as As expected, the Notch signaling well as determining which cells succeed pathway did simultaneously increase in in the competition expression when “By learning more about the VEGF pathway for tip cell position (i.e., lead the way elevated due the effectiveness of Notch was for other cells to to loss of Flt-1; inhibitors in a tumorfollow). A key difhowever, contrary ference between their initial hyfilled environment, we are to the two pathways pothesis, even is that the Notch going to be able to design though the overall pathway must be commore effective therapies.” cell-to-cell suppressed to promunication and -Dr. John Chappell mote cell prolifdecision making eration and vessel process was disexpansion since it is also used to restrict rupted and vessel branching decreased, neighboring cells from following along it actually caused cells to decide to and forming new branches. In addition, sprout more, leading to increased tip receptors for VEGF-A molecules bind to cell numbers (Figure 2, right).4 To further Flt-1 or Flk-1 proteins to help modulate investigate Flt-1 interactions with the the proliferation of endothelial cells and Notch pathway, a Notch inhibitor was guide vessel branching.3 added to the cells, making them more For this study, Dr. Chappell and sensitive to relative cells around them others decided to focus in on the Flt-1 having more or less Notch. This expectreceptor due to its ability to decrease edly caused a sudden revival of vessel the amount of VEGF-A that has access branching and endothelial proliferation to the cell surface; in particular, they in the vessels lacking the Flt-1 recepbelieved that understanding the effect tor, revealing many details about the of this receptor on the two pathways relationship between the two signaling would provide a clearer picture regard- pathways and its most important receping their relationship with each other. tor.3 Since the VEGF-Notch pathway feedDr. Chappell pointed out an imback loop controls angiogenesis and Flt- portant diagnostic implication of this 1 negatively modulates VEGF signaling, research: “By learning more about the

effectiveness of Notch inhibitors in a tumor-filled environment, we are going to be able to design more effective therapies for not only tumors but also various other diseases where blood vessel formation is important and move them towards clinical relevance.”3 With further understanding of the basic mechanisms cells use to make decisions, Dr. Chappell, Dr. Bautch and Dr. Mouillesseaux agree that the possible development of drugs targeted towards controlling vascular networks and their growth would be more feasible.

References

1. Li, W., Hutnik, M., Smith, R., Li, V. Understanding Angiogenesis. (2012, April 27). Retrieved from http://www. angio.org/ua.php. 2. Leading causes of death. (2013, January 11). Retrieved from http:// www.cdc.gov/nchs/fastats/lcod.htm. 3. Angiogenesis Inhibitors. (2011, October 7). Retrieved from http://www. cancer.gov/cancertopics/factsheet/ Therapy/angiogenesis-inhibitors. 4. Interview with John Chappell, Ph.D. 9/27/2013. 5. Chappell, J.C., Mouillesseaux, K.P., Bautch, V.L. “Flt-1 (Vascular Endothelial Growth Factor Receptor-1) Is Essential for the Vascular Endothelial Growth Factor–Notch Feedback Loop During Angiogenesis.” Arteriosclerosis, Thrombosis, and Vascular Biology 33, 1952–9. 2013.

nutrition

from FACTORY to FORK understanding the effects of processed foods on obesity by Hetali Lodaya

t’s hard to dispute the fact that Americans are gaining weight; as it stands, over one-third of American adults are now overweight.1 Some of this gain has been attributed to the increasing amounts of processed food consumed in the United States. In his new book “Salt, Sugar, Fat,” journalist Micheal Moss asserts that the processed food industry has “hooked consumers … the same way the cigarette industry hooked smokers on nicotine.”2 But what are Americans actually buying, and how does that translate to calories consumed and weight gained? The Popkin research group in the Carolina Population Center at UNC-Cha-

pel Hill was given the chance to tackle this question in 2010. A number of processed food companies and CEOs collaborated to create the Healthy Weight Commitment Foundation and pledged to “reduce calories by 1.5 trillion by 2015.”3 Principle investigator Dr. Barry Popkin, a professor in the Gillings School of Global Public Health and author of “The World is Fat,” was recruited to conduct an independent evaluation to see whether companies met this goal. An initial report on their evaluation methods was published in Obesity Reviews this year.4 An analysis at this level of detail had never been conducted before, and

Figure 1. Manufacturers of processed foods such as those shown here committed to decreasing calories in their food products by 1.5 trillion by the year 2015. Image courtesy of Matt MacGillivray/Flickr.

Dr. Shu Wen Ng

Dr. Barry Popkin

study co-author Dr. Shu Wen Ng said that the researchers “spent the first year of that grant figuring out if we could do the evaluation. There was no existing way to measure what was in the food supply and what Americans were buying.”5 The researchers decided to use sales data, right down to individual bar codes, or UPC codes, on food items to determine exactly what Americans were buying. This data was then overlaid with data about the nutrient content for any given item. Although the industry commitment was only to reduce calories, Ng said that the researchers also wanted a nuanced look at the demographics of which populations were buying what foods, and how their health outcomes might be subsequently affected. “We really care about who did they impact … specifically,” said Ng. “A lot of minority groups might be more vulnerable, or people from lower income households might be more vulnerable, in terms of gaining access to more nutritious foods.” In order to get this buyer-level view of what exactly Americans are eating, Ng and colleagues started with the National Health and Nutrition Examination Survey, or NHANES. The largest data

Carolina Scientific set available on food consumption, participants in NHANES report exactly what they ate for the past 24 hours.1 These data are collected in two-year waves. Foods a survey participant reports eating — a cup of yogurt, for example — are matched back to food composition tables that assign that yogurt a standard nutrient value. This, says Ng, is where the analysis loses precision. Nutrient values listed in food composition tables are general, representing an average of whatever is in the market at a given time, so they cannot get into the specifics of different brands or versions of a food item. A processed food from 1990 might be very different than one being sold today. The researchers decided to link UPCs from sales data to appropriate items in food composition tables. Because the sales data shows how much of any given UPC, or any given brand, was purchased, this gives a more detailed look at what exact products Americans are buying. “In the case of plain unsweetened yogurt, there might be 100 different kinds of plain unsweetened yogurt out there in the marketplace. So we’ll link every one of those UPCs to that one … food code,” said Ng. “Then we can basically create our own nutrient profile

Researchers wanted a nuanced look at the demographics of which populations were buying what foods, and how their health outcomes might be subsequently affected. measurement for plain unsweetened yogurt that is a weighted average of those 100 UPCs, weighted by the volume of sales. We derive what we think is a more reflective nutrient profile for plain unsweetened yogurt.” Having published preliminary findings showing the research method, Ng and colleagues are now working through years of NHANES data sets to evaluate the 1.5 trillion calorie commitment.

nutrition

High fertility/ mortality

High prevalence infectious disease

Reduced mortality, changing age structure

Receding pestilence, poor environmental conditions

Focus on family planning, infectious disease control Reduced fertility, aging

Receding famine

Focus on famine alleviation/prevention

Chronic diseases predominate

Focus on healthy aging spatial redistribution

High prevalence undernutrition

Nutrition-related noncommunicable diseases predominate

Focus on medical intervention, policy initiatives, behavioral change

Figure 2. The nutrition transition theory links patterns of food consumption and activity with health outcomes in a given population. The United States, according to Ng, is “probably somewhere in the last two categories,” given its shifts away from agrarian production into more consumption of processed foods. Figure concept: Popkin (2002), revised 2006. One of the most interesting parts of this work, Ng says, is that it allows researchers to break down what different subpopulations are consuming, instead of reporting “average” figures that are essentially driven by consumption amounts. “We can say that Hispanics tend to buy more colas of a particular brand and then weigh those more heavily than other brands for Hispanics. But then … whites weigh it more appropriately for how whites purchase soda and then [are] able to create nutrient profiles for subpopulations,” said Ng. Given that obesity trends are different among demographic subpopulations, these findings may have policy implications for addressing the obesity epidemic in America. They could also provide interesting insight related to the “nutrition transition,” a theory outlining how societies move through different patterns of food consumption as they advance technologically and socially. First developed by Dr. Popkin in the early 90s, this theory is now used by health researchers across the world. “Already, in some of the newer data, we’re seeing in some areas obesity trends seem to be plateauing,” said

Ng. “The question is, is this a permanent thing … or is this just temporary?”

References

1. National Health and Nutrition Examination Survey. (2013, September 30). Retrieved from http://www.cdc. gov/nchs/nhanes.htm. 2. Boeschenstein, N. How The Food Industry Manipulates Taste Buds With ‘Salt Sugar Fat’. (2013, February 26). Retrieved from http://www.npr.org/ blogs/thesalt/2013/02/26/172969363/ how-the-food-industry-manipulatestaste-buds-with-salt-sugar-fat. 3. Daniells, S. Healthy Weight Commitment Foundation: We’ve delivered on promise to cut calories in the marketplace. (2013, June 3). Retrieved from http://www.foodnavigator-usa. com/Manufacturers/Healthy-WeightCommitment-Foundation-We-vedelivered-on-promise-to-cut-caloriesin-the-marketplace. 4. Ng, S.W., Dunford, E. “Complexities and Opportunities in Monitoring and Evaluating US and Global Changes by the Food Industry.” Obesity Reviews. 2013. 5. Interview with Shu Wen Ng, Ph.D., 9/20/2013.

medicine

Three-year old Grayson Clamp wears a device that collects sound and converts it to radio waves that stimulate an auditory brainstem implant device, allowing him to hear. Image by Sara Davis.

Lending an ear to

INNOVATION

First auditory brainstem implant trial performed at UNC Hospitals

BY CHRISTINE SON

20 20

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medicine

“Daddy loves you.”

Grayson Clamp was three years old when he heard these words for the first time. Grayson was born with CHARGE syndrome, a genetic condition that is accompanied with hearing loss sometimes resulting from the absence of nerves connecting the inner ear to the brain. Due to his condition, Grayson’s communication was very limited; he could not hear or speak. Sign language was his only means of communication until Grayson underwent a procedure that forever changed his life. CHARGE is an acronym for a set of abnormal congenital Dr. Matthew Ewend (left) and Dr. Craig Buchman (right) characteristics found in newborn children. Each letter stands performed Grayson’s surgery. for a characteristic finding: coloboma, or a hole in one of the structures of the eye; heart defects; atresia, or absence of the was chosen from numerous other children enlisted in a reposterior nasal opening; retardation of growth or develop- search trial at the UNC School of Medicine because of his high ment; genital or urinary abnormalities; and ear abnormalities cognitive abilities, his competence in using cued speech, a viand deafness.2 sual system based on phonetics, the alignment of his anatomy The auditory brainstem implant (ABI) device was first and his supportive parents. developed in the 1970s in Los Angeles for patients who lacked “Motivation that we have seen for the children who get cochlear or auditory nerves. Right around the 21st century, Dr. cochlear implants was how transformative it is for them and Vittorio Colletti of the University their family,” said Dr. Ewend. “Once of Verona Hospital in Verona, Italy, we became comfortable with usBecause Grayson does not have ing technology that goes directly applied the device to children for the first time.1 This set a precedent into the brain [on adults], we the nerves to transmit inforfor future cases of such auditory wondered and wanted to study mation, the ABI will mimic the in a meaningful way whether we conditions. After hearing about the connecting nerves that directly could have the same impact on potential uses of the ABI device, stimulate the cochlear nucleus. kids who won’t benefit from coDr. Matthew Ewend, chair of the chlear implants.” department of neurosurgery, The surgery begins by Dr. Holly Teagle, Dr. John Grose and Dr. Shuman He, all fac- making an incision behind the ear, then removing a small ulty members in the UNC School of Medicine, joined Dr. Craig window of bone. After confirming that no nerves are present, Buchman, the principal investigator, in the study. The group an electrode is placed right down to the hearing part of the received approval from the United States Food and Drug Ad- brain stem. The brain normally localizes auditory information ministration (FDA) to perform surgery on Grayson in early at the cochlear nucleus, which is located on the floor of the April 2013. In the United States, the use of ABIs is currently fluid space inside the brain known as the ventricle (Figure 1). approved for adults 12 or older and those with neurofibroma- Because Grayson does not have the nerves to transmit infortosis type 2, a debilitating brain tumor disorder that results in mation, the ABI will mimic the connecting nerves that directly growth on the cranial nerve VIII that disrupts conveyance of stimulate the cochlear nucleus. The main benefit of this syssensory information from the inner ear to the brain.1 Grayson tem is that it utilizes the natural pathway in the brain, rather

Figure 1. (Left) An auditory brainstem implant device. (Right) Schematic of the auditory brainstem implant (ABI) surgery. An electrode is placed on the part of the brain stem that controls hearing, directly stimulating the cochlear nucleus. Images courtesy of Dr. Buchman.

medicine

Figure 2. Grayson Clamp was chosen for the clinical trial because of his lack of cochlear nerves, high cognitive abilities, and his parents’ commitment to the pursuit of spoken language for him. After three years of no hearing, Grayson heard his father’s voice for the first time after receiving the auditory brainstem implant. Image by Stephanie Mahin. than intruding through the brain.1.5 After recovering from the surgery, Grayson wears an external device that looks similar to a hearing aid. The device has a magnetically aligned antenna to transmit information to the internal stimulator. For people with normal hearing, when they hear a sound, it goes through the eardrum, the inner ear, the hearing nerve and then to the brain stem. For Grayson, his external device converts the sound he is hearing to a code that is delivered by radio waves across the skin to the internal, stimulating device. This bypasses the damaged part of Grayson’s hearing.1,5 “Hearing loss in children is very common — about 3–4 children out of every 1000 births has hearing loss,” said Dr. Buchman. “Early detection and early intervention in children is really key, allowing them to develop spoken language and ultimately go on to greater heights, and that is why it is so critical that we are in tuned to being involved in evaluating kids early on.” Dr. Buchman and his team recommend that Grayson avoid contact sports and anything that would put him at risk for head trauma. Grayson will also have frequent hospital visits to continually change and optimize the way the device is stimulating his brain. Based on Grayson’s feedback, his reaction to the stimulation and development of speech, appropriate adjustment will be made to the implanted system.1

“We don’t know exactly how good Grayson will be able to hear over time, but he is already responding to sound,” Dr. Buchman said. “Only time will tell.” The success of this device in children will largely depend on both the safety of the surgery and the effectiveness at providing sound awareness and improved communication abilities for the children.1 Dr. Buchman is currently working with nearly 20 other children who are on the same clinical trial as Grayson, and he hopes that these children have the same success.

References

1. Interview with Craig A. Buchman, M.D. 9/16/2013. 2. CHARGE syndrome. (2013, September 23). Retrieved from http://ghr.nlm.nih.gov/condition/charge-syndrome. 3. Brain stem implant changes young boy’s life. (2013, June 20). Retrieved from http://research.unc.edu/2013/07/02/ brain-stem-implant-changes-young-boys-life/ 4. Castillo, M. Deaf boy with auditory brain stem implant stunned after hearing dad for first time. (2013, June 20). Retrieved from http://www.cbsnews.com/8301-204_16257590253/deaf-boy-with-auditory-brain-stem-implantstunned-after-hearing-dad-for-first-time/ 5. Interview with Matthew G. Ewend, M.D. 9/18/2013.

Carolina Scientific

Size

don’t judge a

TUMOR by its

by Jenna Sawafta

he use of ultrasound enables clinicians to not only examine babies in the womb but also evaluate the effectiveness of cancer treatments by monitoring tumor size. Recent research in the Biomedical Engineering department, a joint department of UNC-Chapel Hill and NC State, has developed innovative techniques to improve not only the diagnosis of cancer, but also the way in which doctors evaluate cancer treatments.1 Dr. Paul Dayton and his Ph.D. student Sunny Kasoji are working on developing a new method to better observe the progression of cancer. The Dayton lab focuses on different applications of ultrasound contrast imaging using microbubble contrast agents.1,2 These types of imaging help diagnose cancer and assess effectiveness of treatment. Contrast ultrasound permits the separation between vasculature and soft tissue within an ultrasound image, which is difficult to accomplish using traditional ultrasound.3 “With the advantages of being low cost, safe, and highly portable, contrast-enhanced ultrasound imaging will

likely play an increasingly important role in the future of diagnostic medicine,” Dr. Dayton said. Molecular imaging describes any type of imaging that enables clear observation of the molecular changes in tissues. The Dayton lab uses ultrasound contrast to detect molecular changes within the body.1,3 Microbubbles are used as the contrast agent for ultrasound imaging. These microbubbles are lipid-shelled bubbles of extremely small size, between one and ten micrometers.2 Proteins are attached to the microbubbles before they are injected into the body, enabling them to bind to endothelial cells near tumors that express specific biomarkers.3 The microbubbles that do not bind to the cells are naturally filtered out by the liver and the spleen, providing a clear image of just the tumor.1 Microbubbles have many applications in the diagnosis of cancer and the evaluation of treatments.1 After a patient has been diagnosed with cancer, a physically taxing treatment system evaluated mainly on tumor size typically follows. Although studies show that size and vessel growth

biomedical engineering of the tumor are related, some tumors can stay the same size while the blood vessels inside them degenerate, indicating that the treatment is working.4 The Dayton lab looks inside the Dr. Paul Dayton tumor to evaluate its physiological response to treatment.1 This kind of imaging, called perfusion imaging, works by injecting microbubbles into the body and allowing them to flow through the entire vasculature and soft tissue around it. Measurements such as blood flow and volume allow doctors to evaluate the physiological response of the tumor.4 The innovation behind perfusion and molecular imaging can help limit the number of severe treatments a patient undergoes by enhancing the doctors’ ability to evaluate cancer treatment.1 With cutting edge biomedical technologies such as ultrasound contrast imaging, doctors will be better able to view tumors, evaluate treatment progress, and localize the side effects of treatment to specific areas of the body using small contrast agents.3,4 In the future clinicians will likely move away from using invasive diagnostic techniques such as tissue biopsies and radiation imaging and move toward more noninvasive methods such as contrast enhanced ultrasound and molecular imaging.

References

Figure 1. (Left) Compares contrast enhanced ultrasound image to traditional b-mode image of a rabbit kidney. (Right) Acoustic angiography produces high resolution images of the vasculature while almost eliminating noise from background soft tissue. Images by the Dayton lab.

1. Ultrasound in Pregnancy. Retrieved from http://sogc.org/publications/ ultrasound-in-pregnancy/. 2. Interview with Sunny Kasoji, M.A. 9/19/2013. 3. Dayton, P.A., Streeter, J.A. “An In Vivo Evaluation of the Effect of Repeated Administration and Clearance of Targeted Contrast Agents on Molecular Imaging Signal Enhancement.” Theranostics 3(2), 93–98. 2013. 4. Gessner, R., Dayton, P.A. “Advances in Molecular Imaging with Ultrasound.” Molecular Imaging 9(3), 117–127. 2009.

biomedical engineering

Microfluidics the pocket sized diagnostic device By Ashlyn Young

magine a future where patients can provide a drop of blood and receive a diagnosis. This future may not be so far out of reach. Dr. Steve Soper, of the UNC-Chapel Hill and NC State joint department of biomedical engineering, and his group are investigating a novel alternative to replace and downsize the current tools used for cancer diagnosis, which are often expensive and inconvenient for use in developing countries that lack the funds and the expertise to use them. A cancer diagnosis is often made by biopsy and imaging of tumor cells, either with expensive imaging equipment or invasive surgical procedures. Rather than relying on these inconvenient analytical methods, Dr. Soper’s project works “to develop hardware and

software for analyzing circulatory tumor cells in peripheral blood.”2 By focusing on circulating tumor cells, diagnosis can be achieved with a simple noninvasive blood analysis. Circulating tumor cells are the preliminary signs that indicate the spread of cancer. After a tumor forms, tumor vessels undergo angiogenesis, which allows the cancer cells to enter the blood stream and infiltrate various systems,3 a process known as metastasis. Before these tumor cells migrate through the endothelial cells of the blood vessels, they circulate through the blood stream, and are appropriately deemed circulating tumor cells (CTCs). Tumors release CTCs fairly early in development, making them a key marker in cancer screening.3

Figure 1 (below). Device channels are fabricated to be mere micrometers wide to allow cell sorting and differentiation. Image courtesy of Dr. Soper.

Figure 2 (above). The magnified SEM image of a CTC isolating microsystem channel. Image courtesy of Dr. Soper.

Dr. Soper’s team utilizes microfluidics to extract tumor cells from circulation and identify them for use in a diagnosis. The device used is a small PlexiDr. Steven Soper glas chip engraved with micrometer-sized channels. This hardware is designed to pull tumor cells out of circulation, a daunting task since only 1 to 100 CTCs can be found in 1 mL of blood. What used to require a high-precision experiment that may take hours for an experienced scientist to run now can be achieved with a credit-card sized polymer square and a blood sample. This means that cancer cells can be separated and identified by any physician, regardless of experience and equipment availability. These devices are built in plastics with the same injection molding method used to create CDs, and can be inexpensively massproduced for industry.2 Dr. Soper’s devices are also extremely versatile. The same design can be used to identify and diagnose numerous types of cancers, and even identify other infectious diseases. This device could even potentially be utilized to test water supplies for bacterial infiltration, all in less than an hour. Dr. Soper’s team recently published a study expanding on the use of microfluidics as a non-invasive method for pancreatic cancer screening.4 Pancreatic cancer is considered one of the most fatal forms of cancer due to the an-

Carolina Scientific atomic position of the pancreas, resulting in difficult biopsy and late diagnosis. Through the use of a thermoplastic modular microsystem, analysis of pancreatic CTCs was achieved directly from whole blood. With a turnaround time of less than 1.5 hours, CTCs were selected from the blood samples with high yields and great ease. Microfluidic devices are also being utilized in Dr. Soper’s lab as an avenue for personalized medicine. There are often numerous strains of one disease, each requiring a different treatment. It is sometimes difficult for physicians to pinpoint the exact strain of the disease an individual has contracted, resulting in inappropriate treatment and ultimate progression of the illness. Dr. Soper’s group approached this issue by fabricating a thermoplastic microfluidic system that detects strain-specific bacterial pathogens.5 Their microfluidic system, referred to as a “lab-on-a-chip,” can extract DNA from a target cell and undergo molecular testing to identify mutations in the target genome area. These mutations indicate the presence and specific strain of the disease. Similar methods are also being explored for early diagnosis in stroke victims2 as well as specific strain identification of tuberculosis.1

biomedical engineering

Figure 4. The process of cancer metatesis. Reprinted from Cancer Letters 253, Paterlini-Brechot, P., Benali, N.L., “Circulating tumor cells (CTC) directions.” 180204., Copyright 2007, with permission from Elsevier. Dr. Soper said of his devices, “You can put these in doctors’ offices in isolated parts of our country, rural areas or you can put them in countries that don’t have access to major cancer cen-

ters to help them diagnose these diseases, which is very interesting to say the least.”2

References

1. Chen, Y., et al. “Identification of methicillin-resistant Staphylococcus aureus using an integrated and modular microfluidic system.” Analyst 138, 1075–1083. 2012. 2. Interview with Steven A. Soper, Ph.D. 9/20/2013. 3. Paterlini-Brechot, P., Benali, N.L. “Circulating tumor cells (CTC) detection: clinical impact and future directions.” Cancer Letters 253, 180–204. 2007. 4. Kamande, J.W, et al. “Modular Microsystem for the Isolation, Enumeration, and Phenotyping of Circulating Tumor Cells in Patients with Pancreatic Cancer.” Analytical Chemistry 85(19), 9092–9100. 2013. 5. Chen, Y., et al. “Modular microfluidic system fabricated in thermoplastics for the strain-specific detection of bacterial pathogens.” Lab Chip 12, 3348–3355. 2012.

geology

A RULING REPTILE from the Late Triassic BY TRACIE HAYES

auisuchians include a group of archosaurs (meaning “ruling reptile”) from the Triassic Period that were around right before an extinction that preceded dinosaurs taking over.1,2 “When dinosaurs were just getting going, these guys were the top predators,” said Dr. Joseph G. Carter, professor of paleontology at UNC-Chapel Hill’s department of geological sciences, about rauisuchians.1 A particularly special one was found close to home, in the Durham sub-basin of North Carolina.3 In 1994, two UNC geology majors, Brian Coffey and Marco Brewer, found the first evidence of Postosuchus alisonae, a member of the rauisuchians, in a brick quarry.2 Only her left ankle was visible, until the next day when Dr. Carter and a team of UNC undergraduate and graduate students came back to the quarry to begin uncovering the skeleton (Figure 2).2 Dr. Carter explained that as the excavation began, they “found that the animal was much bigger than [they] thought.”1 Consequently, it was necessary to take larger chunks out of the ground to understand the size of what they were excavating.1 As the process continued, Dr. Carter and the students

Figure 1. Postosuchus alisonae’s gastralia, or belly armor. Image courtesy of Dr. Carter.

found many other organisms near and within Postosuchus alisonae.1 She had a full stomach with the remains of her prey, including an armored reptile (called an aetosaur), and a mammal-like reptile (called Plinthogomphodon herpetairus, or “brick molar toothed, in reptile company”)2 that is a comparatively close relative to humans.1 Given the extensive evidence of prey in Postosuchus alisonae’s stomach, Dr. Carter determined that Dr. Joseph Carter she did not die of starvation.1 Rather, she died in pursuit of more food. She was chasing after Dromicosuchus grallator, a crocodylomorph, whose skeleton was found below her own at the excavation site. Most likely, she was hunting in the mud of a lake, and after attacking her prey, got stuck.1,3 Then, as she fell, she pushed the Dromicosuchus into the ground beneath her, resulting in him becoming an almost perfectly preserved fossil. Dromicosuchus is also a completely new genus and species, making this find even more impressive.1 “It turned out we had not only one big animal to put together, but two big animals to put together, and then all the pieces in the stomach. So it’s like having a three dimensional jigsaw puzzle with two different pictures, [and] you don’t know what the puzzle is supposed to look like,” said Dr. Carter about the process of identifying and arranging the organisms.1 Cleaning up the skeleton and preparing the reconstruction was an extensive time commitment on the part of the researchers. “I would spend a whole afternoon on one single knuckle,” Dr. Carter explained about removing the bones from the rock.1 Over 200 students helped with the project, including Dr. Carter’s graduate student Karin Peyer. Postosuchus alisonae’s skeleton was originally flat in the ground, but due to erosion at a sloping angle, much of her

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Postosuchus alisonae’s skeleton, with bones found at the excavation site shown in black. Image by Dr. Karin Peyer. spine and tail were missing.1 Her head was sticking up, probably gasping for air as she was sinking into the mud, and so her skull was lost to erosion as well.1 Still, Postosuchus alisonae is possibly the most perfectly preserved rauisuchian found to date.1 “There were some bones as big as a pencil head, we had those too,” Dr. Carter added.1 Because of her completeness, it was even hard to compare her with others of her kind.1 There are many notable features of rauisuchians. The gastralia, or belly armor, is “soda straw” bone made by the skin that protects the stomach (Figure 1).1 Rauisuchians also had large heel bones, indicating that they walked by putting their heel on the ground in a manner similar to humans. In contrast to rauisuchians, most dinosaurs had smaller heel bones that were raised off the ground, making them more suited for running. A downward-facing hip socket (compared to sidewaysfacing) also distinguishes rauisuchians from dinosaurs.2 The perfectly complete, tiny hands of Postosuchus alisonae were key in identifying her as a new species.1 She was compared to one species of Postosuchus found in Texas and being studied at Texas Tech University, which has giant hands.1 Originally, this made it seem like Postosuchus alisonae was actually an entirely different genus.1 Dr. Carter even mentioned the possibility of naming this new genus “Tarheelosuchus.”1 But, later, another species of Postosuchus found in New Mexico was discovered to have tiny hands as well.1 The paleontologist at Texas Tech had mistakenly identified the large hand as part of his specimen.1 The hands of Postosuchus alisonae are still unique.2 Specifically, she has a claw on her thumb that is larger than her other claws.2 This likely enabled her to rip open armored reptiles better than other members of her genus.1 The reconstructed Postosuchus alisonae will be on display soon at the North Carolina Museum of Natural Sciences in Raleigh.1 Her discovery has been important in better understanding the rauisuchians in general, and, in turn, better understanding the incredible diversity of the world when these creatures walked over what is now UNC’s campus.3

Figure 2. Students working at the excavation site. Image courtesy of Dr. Carter.

References

1. Interview with Joseph G. Carter, Ph.D. 9/16/2013 2. Peyer, K. “All about Alison.” 3. Peyer, K., Carter, J.G. Sues, H., Novak, S.E., Olsen, P.E. “A new suchian archosaur from the Upper Triassic of North Carolina.” Journal of Vertebrate Paleontology 28(2), 363–381. 2008.

geology residence. Together, the dentin and enamel function as an ancient GPS; they can be used as a method for pinpointing the origins of humans and animals. According to the data collected through the mass spectrometer, which was used to analyze the strontium isotopes, the individuals found in the foundations of the By Karthika Kandala courthouse who were 25 years and younger had dentin and enamel r. Drew Coleman, a distinguished professor in the de- that could both be traced to New Dr. Drew Coleman partment of geological sciences at UNC-Chapel Hill, be- York, but the individuals who were lieves that the key to finding one’s ancestors lies not in older than 25 had enamel which could be traced to the West popular ancestry websites, but in your teeth. Instead of fam- Coast of Africa, and dentin which indicated that they were loily records and old government documents, Dr. Coleman uses cal to New York.2 Although the project was completed with isotope geochemistry. the conclusion that some of the individuals were from AmeriIn collaboration with a team of geologists and archae- ca and some of them were from Africa, Dr. Coleman’s work did ologists, Dr. Coleman traces the migration routes of various not end there. Currently, Dr. Coleman serves as a geochemical ancient groups of individuals. It was in the early ’90s that Dr. specialist in research endeavors that focus on migration and Coleman was first intrigued by human migrations; a colleague trade patterns. It was through this role that Kelsey Rogers, a in Massachusetts introduced him to a topic that would then recent graduate of UNC, was able to pinpoint the location of go on to be recognized by scholars across the world. “They deer that existed in North Carolina hundreds of years ago and were digging a foundation for a courthouse [in New York], and consequently mapped the hunting patterns of local North during the excavation of the foundation, they started turn- Carolinians. ing up the remains of African AmeriDuring her senior year at UNC, cans,” said Dr. Coleman. His colleague Together, the dentin and Kelsey Rogers became involved discovered that the site for the new with undergraduate research in the enamel function as an foundation was a burial ground for Afgeology department. Rogers’ work ancient GPS; they can be focused on tracing the original locarican Americans. This discovery posed a serious research question: “Were the used as a method for pin- tion of deer found in ancient human individuals first-generation migrants camps. The archaeological material pointing the origins of from Africa, or were they secondshe found was in our very own Hamhumans and animals. generation American migrants?” This ilton Hall. She applied the same techquestion was investigated through nique used by Dr. Coleman’s team: various modes, one of which was archaeological data, but the the strontium ratio analysis. Through her research, Rogers was most significant evidence was found through teeth. able to discover that the deer found in camps in the western Your teeth are a reflection of your body’s chemistry. part of the state were originally from the eastern part of North As Dr. Coleman said, “You are what you eat, and at that time Carolina, which indicated that individuals during that time pewhat you ate reflected your local geology.” The research team riod were willing to travel much farther than expected to get in New York used the compound strontium which is still used their food. Rogers is now a Masters student in Oceanography. The work of Dr. Coleman, his peers and students have by Dr. Coleman in other research ventures regarding migration patterns. Specifically, the ratio of strontium-87 relative to contributed greatly to the study of geochemistry and archaestrontium-86 in rocks is used to determine the age and chem- ology. Teeth have gained a new significance due to such reistry of rock. This is directly reflected in the strontium isotopes search endeavors, and it can be said that the answer to one’s of soil and water that is drained in an area. Since water makes origin lies in his or her teeth! up a majority of a human’s chemical composition, the strontium isotope can be used as a determinant in radiometric dating process. References The human tooth is divided into different layers. The 1. Interview with Drew Coleman, Ph.D. 9/20/2013. two layers used in the research by Dr. Coleman and his team included the enamel, which is the top most layer, and dentin, 2. Goodman, A., Jones, J., Reid, J., Mack, M. Blakey, M., Amarasiriwardena, D., Burton. P., Coleman, D. “Isotopic which is located directly below the enamel. Teeth, like one’s and elemental chemistry of teeth: Implications for places body, have an isotopic composition. The isotopic composition of enamel is determined at birth, and the composition of den- of birth, forced migration patterns, nutritional status and pollution.” New York African Burial Ground Skeletal Bioltin changes according to the body composition and surroundings. Therefore, the enamel can be used to determine people’s ogy Report 1, 217–268. 2004. 3. Interview with Kelsey Rogers. 9/23/2013. roots, and dentin can be used to determine people’s present

YOU ARE WHAT YOU EAT

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THE ROAD NOT TAKEN a more efficient approach to computer design

omputer design has traditionally been centered around the use of synchronous circuits, which can be thought of as a game of musical chairs, with the “chairs” being stages in the circuit and the people moving from one chair to the next as data moving from one stage to the next. Synchronous circuits are driven by an internal clock that tells data to move from one stage to the next with each clock cycle. The speed of a synchronous circuit cannot be greater than the speed of the slowest piece of data, making the speed of the circuit based on the worst-case performance of the slowest component. This is akin to forcing everyone to wait until the slowest person finishes moving to the next chair to keep the players from colliding, which is an inefficient way of playing musical chairs. The advent of multi-core processors with multiple subordinate clocks synchronized to a global clock has exacerbated the problem to an extent as to make pure synchronous design practically impossible. As a result, recent attention has turned towards the possibility of incorporating the asynchronous circuit, a clockless design that is both versatile and efficient. In other words, this would let everyone in the game of musical chairs move independently of the slowest member and make sure there are no collisions by ensuring proper communication between members. This is called a handshaking protocol, a fancy term for electronic communication that typically consists of a sequence of request and acknowledge signals.3 The elimination of an overbearing clock allows each stage of the circuit to progress independently, unhampered by a particularly dense piece of logic further down the line.4 As Dr. Montek Singh of the UNC department of computer science put it, “clocking creates discrete time intervals, whereas asynchronous design is based on a continuous time spectrum.”1 Pipelining is a method of engaging the previous stage while the next stage receives the input. So in the game of musical chairs, the previous chair becomes available as soon as the previous occupant has left it. In a synchronous circuit, the presence of a clock forces idle stages to process garbage values (when there is no more input), consuming power that is essentially wasted.1 Over millions of processing events, the cumulative effect of these power inefficiencies can be significant. In an asynchronous design, the lack of a clock allows stages of a circuit to act on demand and rest when they finish processing, allowing them to consume just enough power to keep the registers active. This amount of power is negligible in comparison to the power consumed for processing.1 Dr. Singh used pipelines to devise a novel handshaking protocol that builds on the successes of asynchronous circuits, improving throughput of data, minimizing power consumption, and reducing chip area. At the heart of Dr. Singh’s asynchronous pipelines is a

computer science

highly efficient handshaking protocol that allows neighboring stages to communicate their current statuses to one another and decide on the next course of action. Generally speaking, a pipeline consists of three parts: a function block, a completion generator, and a stage controller. The function block consists of gates that act upon the given input. Just as cells form the building blocks of living organisms, Dr. Montek Singh logic gates form the building blocks of digital circuits. Gates typically exist in one of two states: “evaluate” (take in new input) and “precharge” (reset). The signals that indicate a change in the state of a gate come from the stage controller, which uses information from the completion generator to determine whether the current stage and next stage are complete (hence the term). Based on this information, the stage controller sends out signals to precharge or evaluate a stage. The novelty in Dr. Singh’s design is the presence of an “isolate” phase, which makes it “effectively isolated from the gate inputs.”3 This is implemented immediately following evaluation, thus preventing garbage values from being generated in case the previous stage has not completed its data processing. Through this system, the previous stage can continue processing input while the current stage is in its isolate phase, leading to faster execution times and lower power consumption. The trend towards asynchronous design has become increasingly evident in recent years. In 2005, contactless smartcards incorporating embedded asynchronous processors (called MIFARE) were deployed on a mass scale in European countries and on a moderate scale in the United States.5 When a smartcard is moved in front of a scanner, it is akin to “moving a coil of wire through a magnetic field, which generates an electric current that can then be used to power the embedded processor.”1 It remains to be seen what other applications may be optimized through asynchronous technology and how it will extend our computing capabilities in the coming years.

References

1. Interview with Montek Singh, Ph.D. 9/18/2013. 2. Davis, A., Nowick, S.M. “An introduction to asynchronous circuit design.” The Encyclopedia of Computer Science and Technology 38. 1997. 3. Singh, M., Nowick, S.M. “The design of high-performance dynamic asynchronous pipelines: high-capacity style.” Very Large Scale Integration (VLSI) Systems, IEEE Transactions on 15(11), 1270–1283. 2007. 4. Tristram, C. It’s Time for Clockless Chips. (2001, October). Retrieved from http://www.cs.columbia.edu/async/ misc/technologyreview_oct_01_2001.html. 5. MIFARE Milestones. Retrieved from http://www.mifare. net/en/aboutmifare/history/.

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chemistry

The cytosol of a cell is often crowded with macromolecules such as proteins. The Pielak group at UNC investigates how this crowding affects protein stability. Image public domain.

the CROWDED CYTOSOL 30

Modeling macromolecular behavior in cells By Larry Zhou

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chemistry

he proteins in your cells are (CI2) (Figure 1) was suspended in solupacked into the cytosol without a tions of bovine serum albumin and hen lot of room to “stretch.” Gary Pielak, egg-white lysozyme to determine how Ph.D., and his group in UNC-Chapel Hill’s crowding by other proteins affected its chemistry department study this intra- stability.1 Nuclear Magnetic Resonance cellular crowding. Specifically, they aim (NMR) spectroscopy was used to deterto determine how this restriction of mine the stability of CI2 under these protein movement affects the stability conditions. of proteins when they are in crowded The results from this experiintracellular conditions. ment contradicted the previous model Proteins are long chains of amino based solely on hard-core repulsions.3 acids which have interacting forces that Protein crowding actually destabilized twist and mold CI2, showing that them into a 3-D while hard-core structure called repulsions staWhile hard-core the native state. bilize proteins, repulsions stabilize In the naweak non-covative state, enlent intermolecuproteins, weak zymes function lar forces like elecnon-covalent correctly, which trostatic, Van der is not the case Waals and hydrointermolecular forces when the 3-D phobic bonding destabilize proteins. structure is disfrom crowding turbed in the proteins destabidenatured state. lize proteins.3 In the context of the Pielak group’s reLooking ahead, the Pielak group search, protein stability is defined as the intends to improve their model of propreference between the native versus tein behavior inside cells. For example, the denatured state. crowding is being tested using cell lyA protein suspended in a relative- sate (cytosol) instead of pure protein. ly empty solution of buffer would have Since cytosol contains a variety a lot more room to “stretch” and move of macromolecules such as other prothan when in cytosol, the solution of dif- teins, metabolites, nucleic acids and ferent proteins and biological molecules respiration byproducts, all chemical interactions are considered.3 Initial experiin cells. Previous research on protein ments have shown that cell lysates have crowding has focused solely on “hard- a destabilizing effect like pure proteins, core repulsions,” defined as the repulsive but less so than most of the pure protein forces caused by compressing a struc- crowders.1 This research addresses a funture so tightly that the incompressible damental question of protein research. atoms are virtually next to each other. In these studies, inert synthetic There are many labs not just at UNC polymers were dissolved in solution and but all over the world that work with used to stimulate only hard-core repul- proteins, with vast amounts of research sions, meaning they had no chemical funding at play. Understanding how proteins interactions with the protein but still occupied space that a protein could have different stability in a simple buffer not physically access. Such experiments solution compared to in cells is necesfound this increased the stability of pro- sary because cytosolic interactions may teins.5 Because cytosolic molecules in- contribute to protein processes which teract chemically with proteins in addi- would not be accurately observed in a tion to excluding volume, this research simple buffer solution. provided an incomplete picture. In addition, the results of Dr. The current goal of the Pielak Pielak’s research address a paradox of group is to better understand protein protein stability. If proteins are always stability in cytosolic crowded condi- stabilized, they will never be able to be tions. To improve the previous model, recycled or degraded.2 the protein chymotrypsin inhibitor 2 For example, hemoglobin is

Dr. Gary Pielak

Figure 1. Chymotrypsin inhibitor 2 structure. Image public domain. an oxygen-transferring protein in red blood cells. When red blood cells naturally degrade, the body recycles the hemoglobin. Therefore, if a protein such as hemoglobin always remains in its stable state, it can never be degraded and recycled. A cell needs to be dynamic, so some destabilization is necessary for life.

References

1. Interview with Mohona Sarkar. 9/20/2013. 2. Interview with Gary Pielak, Ph.D. 10/10/2013. 3. Wang, Y., Sarkar, M., Smith, A.E., Krois, A.S., Pielak, G.J. “Macromolecular Crowding and Protein Stability.” Journal of the American Chemical Society 134, 16614–16618. 2012. 4. Freitas, R.A. Nanomedicine. (1998). Retrieved from http://www.foresight. org/Nanomedicine/Ch03_1.html. 5. Zhou, H., Rivas, G., Minton, A.P. “Macromolecular crowding and confinement: biochemical, biophysical, and potential physiological consequences.” Annual Review of Biophysics 37, 375–397. 2008.

chemistry

Unlocking Nature’s Talents Dr. Eric Brustad of UNC’s chemistry department transforms bacterial cells into synthetically useful chemical “factories.” Photo courtesy of NIAD/NIH.

By Catherine Dirks

unlocking nature’s POTENTIAL Exploring non-natural enzyme catalysis to augment cell capabilities BY CATHERINE DIRKS

odifying bacterial cells to produce useful chemicals may seem more like science fiction than science fact, but that’s exactly the direction in which the research of Dr. Eric Brustad is headed. His laboratory in UNC’s department of chemistry has engineered a new enzyme that functions in bacterial cells. This enzyme, named P411, catalyzes a reaction these cells have never achieved before. Cyclopropanation reactions produce cyclopropanes, which are triangleshaped molecules with three carbons. The carbon–carbon bonds are strained due to unfavorable angles, but cyclopropanes are commonly found in nature. They are formed via a complex series of reactions involving olefins (molecules with a carbon–carbon double bond) and cations (positively charged molecules), using enzymes. When chemists produce cyclopropanes in the lab, they use a different approach involving an olefin and a metal-bound carbene (a neutral carbon atom with two bonds and two unshared electrons).1 This reaction proceeds via

a similar mechanism used by the natural enzyme cytochrome P450 to insert oxygen into molecules with either a carbon–carbon double bond or a carbon– hydrogen single bond.2 The Brustad group previously showed that it was possible to mutate this enzyme to catalyze a cyclopropanation reaction which delivers a high yield of cyclopropane with a high degree of selectivity.3 This reaction could be carried out in water, but had only occurred in the laboratory (in vitro) and not within a cell (in vivo). For an in vivo reaction to be achieved, researchers had to assemble a biocompatible and cell-permeable catalyst, a difficult task when using synthetic reagents. However, the team’s newly designed P411 enzyme overcame these challenges and could even be produced directly by the cell itself.4 A key modification of the enzyme switched the amino acid cysteine for serine, enabling oxygen to coordinate to the iron active site. To activate the enzyme, the researchers used endogenous NADH as a reductant that is already

Dr. Eric Brustad’s research was featured on the August 2013 cover of Nature Chemical Biology. present in the cell.2 These enzyme alterations improved the reaction’s activity without compromising the selectivity of cyclopropane formation. The key to manufacturing whole cell catalysts, according to Dr. Brustad, is unlocking nature’s talents. “It is easy to do; after all, the cell

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chemistry

Nature’s biocatalysis O

enzymes for chemical synthesis

C C

Non-‐natural biocatalysis (cyclopropana4on)

does all the hard work for you,” Dr. Brustad said.5 These manufactured cells are also energy efficient and “green by nature.”5 These cells could one day be used to produce many different chemicals including hormones, pesticides and pharmaceuticals. Dr. Brustad recalls his early days as an undergraduate at Purdue University, where he first gained an interest in chemical biology when it was still an emerging field. While biochemistry is about studying the chemistry that goes on within living systems, Brustad describes his work as “applying chemical principles to biological systems.” As a postdoctoral fellow, he worked with Dr. Frances Arnold at the California Institute of Technology researching enzyme engineering and

evolution. It was this experience that inspired him to study new cellular chemistry. They have since collaborated together on this and other projects.

Figure 2. The Brustad group is primarily interested in “applying chemical principles to expand biological systems beyond nature’s design.” Cyclopropanation, shown here, proceeds via a complex series of reactions involving olefins (molecules with a carbon-carbon double bond) and cations (positiviely charged molecules), using enzymes. Image by Dr. Brustad.

requires interacting and engaging with those around you by having stimulating discussions and seeking out the answers to things you want to know. “Ask as many questions as you can,” Dr. Brustad said. The question now is just where the work of the Brustad group will lead. One thing is for sure — the work of the Brustad group is just the start of harvesting the power of nature and our quest to advance it for our own benefit.

The key to manufacturing whole cell catalsysts is unlocking nature’s talents. Today, Dr. Brustad heads a team of four graduate students and five undergraduate students. He enjoys working with his team of students because of their innovative and creative solutions to problems. Based on his undergraduate research experience, Dr. Brustad advises any aspiring chemical biologists to participate in undergraduate research. He has learned that successful research

Chemistry in a ﬂask

Chemistry in a cell

enzyme muta3on sulfur (S)  oxygen (O)

Figure 1. Engineering cells to improve in vivo reactivity is central to the Brustad group’s research. Image by Dr. Brustad.

References

1. Yetson, J. Editor’s Choice. (2013, July 12). Retrieved from http://www. sciencemag.org/content/341/6142/ twil.full. 2. Fesenmaier, K. Unlocking Natures New Talents. (2012, December 20). Retrieved from http://www.caltech. edu/content/unlocking-new-talentsnature. 3. Coelho, P.S., Brustad E.M., S.A., Kannan, A., Arnold, F.A. “Olefin Cyclopropanation via Carbene Transfer Catalyzed by Engineered Cytochrome P450 Enzymes.” Science 339, 307–310. 2013. 4. Coelho, P.S., Wang, J., Ener, M.E., Baril, S.A., Kannan, A., Arnold, F. H., Brustad, E.M. “A serine-substituted P450 catalyzes highly efficient carbene transfer to olefins in vivo.” Natural Chemical Biology 9, 485–487. 2013. 5. Interview with Eric M. Brustad, Ph.D. 9/24/2013.

chemistry

the future of solar power could be found in

HYBRID PHOTOVOLTAIC CELLS BY COREY BUHAY

he future of solar power could be “dirt cheap” polymers, say Dr. Liang Yan and Dr. Wei You of UNC-Chapel Hill’s chemistry department.1,2 Conventional photovoltaic cells are composed of expensive, inorganic materials, and Dr. Yan and Dr. You saw organic polymers as a possible inexpensive solution. However, polymers are not exempt from the constant tug-of-war between cost and efficiency.1 A solar cell, like nearly any other voltage-producing electronic device, relies on a positive-negative junction or “p–n junction,” an interface between two semiconducting materials in which the electron activity takes place. Gaps in the blanket of electrons that wrap the nuclei of the semiconducting atoms are called electron “holes.” Electrons diffuse from the n-doped region to the p-doped region, from the electronrich negative side to the positive, electron-poor side that is full of holes (Figure 1). The negative electrons chase the positive holes, and this establishes electron flow and therefore the flow of electricity.3 The efficiency of this electron flow is a major determinant of the material composing photovoltaics. Silicon (Figure 2, left) is currently the semiconductor most often used to produce solar power. Gallium arsenide (Figure 2, right) is an ef-

conduction band

Dr. Liang Yan

Dr. Wei You

fective alternative that is more efficient than silicon because it has a direct band gap, meaning an electron requires less energy to move from a normal energy level to an excited one after being struck by a photon of light (Figure 1). Silicon has an indirect band gap, or a higher energy barrier, so that the electron loses more energy in jumping the chasm between its relaxed energy state and excited state. Thus, even though silicon can absorb more light, it is less efficient in turning that light energy into electrons that can be used to produce voltage.4 The problem with gallium arsenide is its cost. To use Dr.

light

Figure 1: Electron hole transport

HOW DOES IT WORK? forbidden band

A photon of light must have a certain energy to impart to an electron for it to overcome its energy barrier to enter its excited state.

valence band electron

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chemistry

Figure 2. Silicon (left) is the semiconductor most often used to produce solar power. Dr. Yan and Dr. You used gallium arsenide (right) as an alternative to silicon in their research of photovoltaic cells. Left image public domain. Right image by W. Oelen [CC-BY-SA-3.0]. You’s analogy, a disc of silicon the size of a large pizza costs $10 while a disc of gallium arsenide the size of a small personal pizza can cost up to $100.1 Dr. You and Dr. Yan tried to balance the higher cost of the more efficient gallium arsenide by using a cheap polymer as their other material. The gallium arsenide became the ntype and the polymer became the p-type in their p-n junction. This experiment aimed to determine just how electrons moved through the polymer, and from there, how to make this movement more efficient.1 They expected to see a Type II heterojunction, a particular type of alignment between two dissimilar, semiconducting crystalline structures. What they found, though, was that the polymer was acting as a Schottky Barrier, a special case of a p–n junction that typically occurs between a metal and a semiconductor. Schottky barrier diodes can be useful in some applications because they can efficiently and quickly switch the direction of the electric current, but in the case of a solar cell, they are less efficient than the desired Type II heterojunction. Schottky barriers lose energy when the direction of the current is switched, and the higher the temperature, the more energy they lose.5 This means that they might not do as well in the hot sun. Dr. You remains positive about the knowledge gained from the experiment. He says the results actually provide useful information to pass on in order to save other scientists and researchers the trouble of trying to make polymers more efficient. “So the research is not a failure,” Dr. You said.1 The pair is now working on using silicon in addition to polymers in a tandem structure. A tandem structure forms a series of energy levels, like a set of stairs down which excited electrons can hop. Each small stair step down is a more effi-

cient use of energy than the one giant step they would have to make from completely excited to completely relaxed states. If all of these stair steps of energy are created using inorganic materials, the efficiency can be greatly increased, but at an unaffordable cost. Replacing a few of these expensive inorganic materials with organic materials such as polymers can lead to a much lower cost, though at lower efficiency.1 Dr. Yan and Dr. You hope to lessen this gap between low cost and high efficiency. With concerns of climate change and fossil fuel shortage on the rise, solar power is under ever-increasing pressure to become more affordable. The use of organic polymer parts certainly has the ability to make photovoltaics cheaper. For that reason, hybrid solar cells are still on the horizon, said Dr. You. “I personally believe, and we all believe, that the future will be the hybrid solar cell.”1

With concern of climate change and fossil fuel shortage on the rise, solar power is under everincreasing pressure to become more affordable. The use of organic polymer parts has the ability to make photovoltaics cheaper.

References

1. Interview with Liang Yan, Ph.D. and Wei You, Ph.D. 9/16/2013. 2. Current Group Members. Retrieved from http://www. chem.unc.edu/people/faculty/you/group/members.html. 3. Nave, C.R.. The Doping of Semiconductors. Retrieved from http://hyperphysics.phy-astr.gsu.edu/hbase/solids/ dope.html. 4. Direct and Indirect Band Gap Semiconductors. Retrieved from http://www.doitpoms.ac.uk/tlplib/semiconductors/direct.php. 5. Walters, K., Werner, B. Introduction to Schottky Rectifiers. Retrieved from http://www.microsemi.com/sites/ default/files/micnotes/401.pdf.

chemistry

a leading LIGHT controlling protein activity with light

laus Hahn, Ph.D., of the UNCChapel Hill Eshelman School of Pharmacy, compares cells to Transformers. “They’re continuously changing,” the Thurman Professor of Pharmacology says.1 Just as a Transformer changes its conformation according to the task at hand, the parts of the cell constantly rearrange to accommodate various

Dr. Hahn’s lab studies a protein domain which plays a key role in plants’ ability to control growth toward sunlight.

By Sheryl Fuehrer

functions. These cell parts are carefully controlled in their position, composition and timing in order to regulate cell behavior and cell communication. It is therefore important to study living cells to understand the mechanism of these behaviors. Understanding cellular growth and movement is important for developing new treatments of cancer and other disorders that result from dysfunctional cell behavior. Dr. Hahn and his lab study cellsignaling pathways, the complex system of chemical communication that governs and coordinates basic cellular activities. The ability of cells to perceive and correctly respond to their microenvironment forms the basis of development, tissue repair, immunity, and normal tissue homeostasis. The Hahn lab studies these cellular pathways by developing new techniques and engineering molecules to understand the behaviors within living cells. “A big part of this work is understanding the structures of proteins and literally engineering them by combining what nature has given us and making them do wild things that they don’t normally do,” Dr. Hahn said. Because of the multitude of reactions occurring simultaneously, it is difficult to see the reactions a protein is actually involved

in without forcing that protein to perform a different function. Dr. Hahn and his colleagues improved the study of cell behavior by making proteins visDr. Klaus Hahn ible in real time with fluorescent biosensors. When injected into a cell, a fluorescent protein biosensor will target the protein of interest. Upon binding, a dye attached to the biosensor protein will fluoresce, showing the target protein’s location and activity. Dr. Hahn’s lab, including research assistant professor Christopher MacNevin, Ph.D., has improved the use of biosensors by increasing their brightness and therefore their visibility in living organisms. The researchers also synthesized a small, membrane-permeable molecule to replace the protein in the biosensor. The molecule’s ability to freely enter the cell eliminates issues of cell rupture that resulted from previous methods such as injection.2 In the cell, this small molecule will bind and fluoresce to an active state of calmodulin — a protein that is important to understand since it

Figure 1. On left, darkness keeps Jα helix coiled and Rac1 is blocked. Addition of light uncoils Jα helix and Rac1 binds to effector. Image courtesy of Dr. Hahn.

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chemistry Figure 3. Photoactivation of the Rac1. Red circle (left cell) indicates a small laser light. Right cell shows Rac1 activated, causing the cell to protrude. This protrusion near the edge causes the cell to move and follow the light. Image courtesy of Dr. Hahn.

mediates crucial cellular processes such as apoptosis, intracellular movement and the immune response. This research has allowed scientists to observe protein activity by harmlessly injecting the biosensor into a live animal to study these various processes in real time. “This technology has the potential to reveal pathway dynamics in humans and genetically intractable cells,” Dr. Hahn said. Dr. Hahn’s lab has taken control of protein activity even further by manipulating light. Yi Wu, Ph.D., in collaboration with Brian Kuhlman, Ph.D., conducted research with photoreceptor proteins in the oat plant Avena sativa. A versatile lightresponsive protein domain called lightoxygen-voltage (LOV) from A. sativa plays a key role in plants’ ability to sense light and, more specifically, to control plants’ growth toward the sunlight.3 The LOV domain consists of a structure called the Jα helix, which is wound up in the dark. Hahn’s lab fused this plant helix to a protein called Rac1,

which is found in human cells (Figure 1). Rac1 regulates many different cellular processes including the cell cycle, cell–cell adhesion, and cell protrusion. It therefore regulates the cell’s motility, or its ability to move. Once fused, the LOV domain inhibits the activity of the Rac1 protein in the cell. However, when light is shined upon the LOV domain, the Jα helix is unwound, releasing the LOV domain from inhibiting Rac1 and therefore activating the protein by giving it freedom to bind to its effectors.5 This allows Rac1 to proceed with its original cellular processes. When the light is turned off, the Jα helix recoils, and Rac1 activity is once again shut off (Figure 2).4 To make sense of this phenomenon, Dr. Hahn’s lab took this light-activated version of Rac1 inside a living cell. When a small laser light was shined upon the cell, it protruded in that spot. When the light was shined upon the cell edges, the protrusions along the side

“This technology has the potential to reveal pathway dynamics in humans and genetically intractable cells,” -Dr. Klaus Hahn

Figure 2. An image of a cell when biosensors bind to their target protein and fluoresce. The turquoise indicates protein activity. Image courtesy of Dr. Hahn.

caused the cell to follow the light “like a horse following a carrot,” said Hahn (Figure 3). This technique offers a new tool to study some of the unsolved problems of cell behavior such as embryonic development, nerve regeneration, and cancer.5 Ongoing research uses the LOV domain to control nuclear import, which ultimately leads to the ability to control gene expression with light. Moreover, this research is versatile in its applications. For instance, scientists will have the capacity to use light to create a cancerous tumor and analyze cancer cell processes such as metastasis. Dr. Hahn and his lab will continue to develop tools that provide further insight into the complexity of the living cell. References 1. Interview with Klaus Hahn, Ph.D. 9/17/2013. 2. MacNevin, C.J., Gremyachinskiy, D., Hsu, C. W., Li, L., Rougie, M., Davis, T.T., Hahn, K.M. “Environment-sensing merocyanine dyes for live cell imaging applications.” Bioconjugate Chemistry 24(2), 215–23. 2013. 3. Lungu, O. I. “Sensing the light: Design of photoactivatable proteinprotein interactions using the lov2 domain.” (Doctoral dissertation), Available from ProQuest. (3509332) Retrieved from http://gradworks.umi. com/35/09/3509332.html. 2012. 4. Wu, Y., Frey, D., Lungu, O. I., Jaehrig, A., Schlichting, I., Kuhlman, B., Hahn, K.M. “A genetically encoded photoactivatable Rac controls the motility of living cells.” Nature 461, 104–110. 2009. 5. Graffenreid, E. Breakthrough Uses Light to Manipulate Cell Movement. (2009, August 9). Retrieved from http://www.med.unc.edu/www/newsarchive/2009/august/breakthrough-uses-light-to-manipulate-cell-movement.

chemistry

The Crimmins group at UNC investigates new methods to synthesize molecules found in nature, such as Brevetoxin A (shown here), a neurotoxin released by red algal blooms. Image public domain.

the art of

CHEMICAL SYNTHESIS By Mai Riquier

ach year, a phenomenon called red tide, caused by blooms of toxic algae, covers many square miles of ocean. The algae release a toxin known as Brevetoxin A. The toxin can become airborne, causing illness in some people who inhale it.1 When shellfish come into contact with Brevetoxin A, they take up the toxin and accumulate it in their tissues. People who eat this contaminated shellfish can then become sick with an illness known as neurotoxic shellfish poisoning. Dr. Michael Crimmins of UNC-Chapel Hill’s chemistry department has been on the quest to synthesize Brevetoxin A in the lab in order to create antidotes against neurotoxic shellfish poisoning. The toxin’s complex structure can be isolated from the pigmented algae that cause red tide, but Brevetoxin A is found in such small quantities in nature that the researchers needed to synthesize it to have enough to study.2

Constructing a natural molecule is often the gateway to finding a similar molecule that can be used as an antidote. In the case of Brevetoxin A, Dr. Crimmins’ goal is to create an analog, which is a simpler molecule than the original. Analogs are formed by changing one or more functional groups on the original molecule in order to simplify the molecular structure while still maintaining its properties and possibly creating more beneficial properties.2 The Crimmins laboratory attempts to create molecules found in nature through a series of chemical reactions. His team synthesizes these molecules in the lab from “organic compounds that can be bought and stitched together.” 2 The challenge, however, is creating the compound in a controlled way that only results in a specific structure with the desired biological activity. Many organic molecules have different forms called

Carolina Scientific enantiomers, which can be described as non-superimposable mirror images of each other. Our right and left hands, for example, are mirror images that will not match up when placed on top of each other. In organic molecules, this property is called chirality. The challenge of obtaining a single structure is being able to synthesize only one of these enantiomers, because only one of them has the biological activity that is useful for the laboratory. This is because these isolated molecules interact with enzymes, and while one enantiomer may fit into the shape of the enzyme, its mirror image will not.2 To synthesize the desired enantiomer, Dr. Crimmins develops chemical reactions that control how the molecule is synthesized in a specific 3-D structure. 2 “The molecule itself inspired us to create new chemistry,” Dr. Crimmins said. To test if these molecules are synthesized correctly, researchers conduct a structural analysis of the product using spectroscopic methods. Dr. Crimmins uses a method analogous to an MRI called nuclear magnetic resonance, which places a molecule in a magnetic field and pulses it with electromagnetic radiation. This electromagnetic radiation detects the hydrogen atoms in the molecule. By knowing where the hydrogen atoms are, Dr. Crimmins is able to visualize the structure of the molecule.2 In addition to Brevetoxin A, Dr. Crimmins has synthesized Ginkgolide B, a molecule from the Ginko Tree indigenous to China. This molecule is structurally complex and has been shown to reduce dementia. His laboratory also synthesized a rare compound called Spongistatin, which is found in marine sponges and, as Dr. Crimmins recalls, is the “most potent anti-tumor compound that anyone has even encountered.” Dr.

chemistry

“Making more and more complicated chemical structures defines where the frontier of [organic] chemistry is.” - Dr. Michael Crimmins Crimmins has since sent the isolated Spongistatin to the National Institute of Health for testing and clinical studies.2 Synthesizing these molecules was neither a quick nor easy feat. Creating Brevetoxin A took about eight years, Ginkgolide B took 13 years, and Spongistatin took five years. 2Despite the length of the process, Dr. Crimmins emphasizes the importance of organic synthesis research. “Making more and more complicated chemical structures defines where the frontier of that chemistry is,” he said. “Organic chemists have been doing this for a long time. [It is] an evolutionary process to show [chemists] constantly trying to push the envelope of the state of the art of chemical synthesis.”2

References

1. American Chemical Society Pressroom. Prized Science Episode 4: Taming the Red Tides. (2010, December 2). Retrieved from http://vimeo.com/17406316. 2. Interview with Michael T. Crimmins, Ph.D. 10/02/2013.

Figure 1. (Left) Ginkgolide B, a compound isolated from the Ginkgo tree, has been shown to reduce dementia. (Right) The Crimmins laboratory also synthesized the compound Spongistatin, a potent anti-tumor compound that can be found in marine sponges. Images courtesy of Dr. Crimmins.

information science

BEEN THERE, DONE THAT Preserving Researchers’ Working Notes with Linked Open Data BY KIMBERLY HII

fter researchers complete projects, the notes they make during the research process are often discarded. To preserve the research value in these working notes, as well as enable researchers to collaborate across related projects, researchers developed an open-source system for organizing and storing these notes called Editors’ Notes. Dr. Ryan Shaw, a professor at the School of Information and Library Science at UNC-Chapel Hill who helped develop Editors’ Notes, describes the system as a “web-based research environment in which researchers Dr. Ryan Shaw are able to track their own work and share research between projects.”1 Researchers in the humanities deal extensively with primary sources such as personal documentation, diaries, speeches and letters. Information from these sources is collected, annotated and organized in working notes, which are written and consulted extensively at every step of the research process. “The majority of the research produced by [documentary] editors and their assistants is represented by the working notes they develop to answer questions raised by their documents,”2 writes the development team of Editors’ Notes. “But it is very likely that the working note contains a variety of useful information that will not appear in the published footnote due to either lack of space or unresolved issues with the information.”2 The extensive documentation and substantial research work which comprise working notes also may not survive past

the completion of the publication for which the working notes were made. The development team writes that “[t]he majority of the research produced by editorial projects is not included in the published volumes, is not shared with other researchers, and is discarded when grants for publication expire.”2 The Editors’ Notes development team recognized the value of preserving these working notes for future access, as well as the potential for collaboration across related projects through sharing these working notes between researchers. Created as a tool to support documentary editing, Editors’ Notes also enables editors to sort, filter and visualize data, as well as cross-reference between sources and notes (Figure

Figure 1. Part of the Editors’ Notes data model. Illustrates conceptual links between the research topic, historical documents used in research, and working notes made during research. Image courtesy of Dr. Shaw.

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information science

Figure 2. Part of a working note on an event. Contains links to related topics and keeps track of relevant source documents as well as researchers’ comments. Image adapted by Kimberly Hii from Shaw et al. 2013. 2). Links between Editors’ Notes and external systems such as library databases and archives enables Editors’ Notes to pull data from these sources, while also enabling research data stored in Editors’ Notes to be more easily accessible. Editors’ Notes has primarily been used by documentary editing projects such as the Margaret Sanger Papers and the Emma Goldman Papers Project. Margaret Sanger and Emma Goldman were early twentieth-century radicals and advocates for women’s rights. As Sanger and Goldman’s lives overlapped significantly in terms of their social networks and the organizations to which they belonged, the historical researchers working on these papers recognized that the contextual work which had been completed in one project would be highly relevant to the other and vice versa. Working research notes are shared between the projects primarily by way of the Editors’ Notes system. Although Editors’ Notes is designed to foster collaboration between researchers and research projects as well as enable representation of many specific and different points of view, it remains primarily a tool for academic scholarship. Researchers using the system have autonomy over the access controls of their collaborators, which enables them to solicit additions without running the risk of having their notes compromised by vandals (as may happen on sites like Wikipedia, where anyone can edit articles). Dr. Shaw says that Editors’ Notes will be opened to the public this fall, when access to the system will be extended beyond its partner projects to all humanities researchers. Architecturally, Editors’ Notes will move away from a single central

server. It is hoped that notes can be maintained on individual editors’ computers or in the cloud, and shared and synced regularly. Further avenues of development may include improvement of interfaces for authoring linked data content and semantic content. The significance of linked open data is not limited to research in the humanities. Historically, the natural sciences — specifically biology — rank among the biggest and most significant users of linked data. Genetics and species databases are maintained using linked open data, which supports a collaborative research environment as well as enables updated information to be made quickly available to others. The linked data research community, which has traditionally focused on the technical dimension of linked data systems, is also developing an awareness of the linked data user base. “The linked data research community [is conducting] outreach to library and cataloguing communities,” Dr. Shaw says. “They are starting to recognize that they need to understand users.”1

Linked data is not limited to research in the humanities. Hisorically, the natural sciences rank among the biggest and most significant users of linked data.

References

1. Interview with Ryan Shaw, Ph.D. 9/19/2013. 2. Shaw, R., Golden, P., Buckland, M. “Using Linked Library Data in Working Research Notes.” IFLA Satellite Meeting on Information Technology Section: User Interaction Built On Library Linked Data. 2013.

linguistics

forging the tools of linguistic discovery

SPEAKER

NORMALIZATION by Samantha Richards

here is no doubt that the tinny jazzy tunes that have their origins in the recording studios of the twenties carry something of an inexplicable oddness to modern ears. This impression of peculiarity can be in part explained by the fact that people just don’t sound the way they did ninety odd years ago, a phenomenon that is not generally questioned by the casual listener. Mary Kohn, who just completed her Ph.D. in Linguistics at UNC-Chapel Hill, has made this curiosity the focus of her research. In doing so she has brought the field to the cusp of developments in our understanding of the way that spoken language evolves over time in its social and cultural context. Her ongoing investigation centers on pronunciation changes during adolescence, which has been previously targeted as

Fibber McGee and Molly, starring Marian and Jim Jordan (left to right), enjoyed huge success as a radio comedy series from 1939–1959. Linguists hope to one day understand why contemporary generations don’t speak the same way as those from this era. Image public domain.

the primary driving force behind the generational differences in ways of speaking. That is, it may soon be possible to identify predictable patterns in the ways that adolescents respond to their environment in manners of pronunciation — how influences of peer groups, parents, and other linguistic presences combine to produce generations that are linguistically distinct from previous Dr. Mary Kohn ones.2 Until recently, linguists were underequipped to deal with the technological challenges and confounding variables that proved to be roadblocks in the analysis of the shifts in pronunciation during adolescence. Providing the field with better tools to meet these challenges has been the subject of Dr. Kohn’s recent research. Dr. Kohn is interested in the ways in which children and adolescents respond in manners of speech to the social and cultural factors operating in their environments. However, understanding these responses is complicated by the fact that during this stage of life the body undergoes rapid physical changes that have a significant impact on the production of speech sounds. In order be able to analyze changes in language from sociocultural factors alone, the variable of physical change — the “physiological noise” — must be eliminated.1 To tackle this problem, linguists typically employ a body of algorithms based on detailed understanding of the physical growth of the organs used for speech. These algorithms, when applied to the data taken from recorded sound waves, effectively tease out the impact of environment from the concurrent impact of physiology, a process called normalization. The problem thus far has been the dearth of studies that have properly evaluated the effectiveness of these normalization techniques consistently from childhood through adolescence. Dr. Kohn’s specific contribution has been a rigorous comparative assessment of various normalization techniques that have provided the field with crucial and thoroughly defensible technological tools that are needed to address the question of adolescent speech change. The concept of “pronunciation” is a tricky one to pin down without using fairly rigorous standards — after all, our own experiences of sound are subjective enough that two

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linguistics

Sociocultural factors will shape the accents of these children differently than those of their parents. Image public domain. speakers with vastly different accents can sound more or less the same depending on our exposure to that accent. Linguistics approaches this topic mathematically by measuring sound waves from speech in terms of their relative amplification or depression, which reflects differences in the shape of the mouth and speech organs as the sound is produced.1 More specifically, these sound waves are broken up into identifiable units called “formants.” As Dr. Kohn explains, “[formants] are an acoustical correlate to pronunciation.”1 Because formants are largely based upon physical size, they also respond to physical changes. A smaller person, for example, would -Dr. produce higher-pitched formants, while a larger person would produce lower-pitched formants. In order to reduce the effects of size, two types of formant-based normalizations can be employed: one involving observation of a single isolated formant, and a second that involves observation of multiple formants at once.1 Like the other normalization techniques, these had never been analyzed comparatively in terms of their effectiveness at tackling the rapid and complex physical changes that occur between childhood and adulthood. Dr. Kohn found that single-formant normalization, called formant-intrinsic by linguists, is actually much more reliable when dealing with data from children, and for a simple reason. As children mature through their adolescent years, their vocal tract morphology

does not progress uniformly. Instead, the pharynx actually grows faster than the oral track. There are also significant gender differences in growth rates.1 For this reason, the various formants will be affected differently at a given point in a child’s development, which makes the observation of multiple formants at once less precise as a means of observing changes. The formant-intrinsic method avoids this issue of non-uniform change and is able to more directly reduce specific and predictable changes. This information will allow future researchers delving into the area of adolescent sound change to minimize extraneous information and extraneMary Kohn ous tests. Dr. Kohn underscores the bearing that her recent work will have on future research: “My small contribution … is all about coming up with strong scientific techniques to make sure that the analysis is being done in a rigorous way.”1 The grander question of our jazzy gramophone still stands, but Dr. Kohn and linguists who share her interests have done their part towards knocking down the barriers to discovery.

“My small contribution ... is all about coming up with strong scientific techniques to make sure that the analysis is being done in a rigorous way.”

References

1. Interview with Mary Elizabeth Kohn, Ph.D. 9/23/2013. 2. Kohn, M.E., Farrington, C. “Speaker normalization: Evidence from longitudinal child data.” Journal of Acoustical Society of America. 131(3), 2237–2248. 2012.

psychology

MORALITY 101 with Dr. Kurt Gray

BY BRIAN DAVIS

ince the beginning of civilized society, humans have attempted to define right and wrong in order to promote good deeds and punish bad ones. Recent research has found that the most important factor in making these calls is our perception of the minds of other beings.1 Dr. Kurt Gray, professor of psychology and principle investigator of the Mind Perception and Morality Lab at UNC-Chapel Hill, leads research that attempts to explain the essence of morality. He wanted to find out how people determine what is morally acceptable or unacceptable. Through his research, Dr. Gray discovered that people decide whether an action is moral or not based on their perception of agency and expe-

Moral Agent

rience of the recipient of the action. Dr. Gray calls this perceived agency or experience mind perception because you cannot be sure that other people actually have minds. This subjective feeling of “somebody being home”2 is based on our perception (e.g. human in vegetative state vs. conscious human). Mind perception is two-dimensional and includes agency, the capacity to do and act (e.g. self-control, judgment, ability to communicate), and experience - the capacity to feel and sense (e.g. hunger, fear, pain, pleasure).1

MORAL TYPECASTING Those cast as moral agents are seen to have agency, whereas those cast as moral patients are seen to have experience. Concept by Dr. Gray, image by Erin Moore. Moral Patient

either/or

Agency

Experience

These two dimensions are essential when people are confronted with a moral dilemma. Dr. Gray calls these two dimensions the “Moral Dyad.” All moral Dr. Kurt Gray dilemmas involve a moral agent and moral patient (the moral dyad).2 In the case of the moral agent, there are two factors that lead us to judge harshly or timidly, and they are represented by the Latin phrases actus reus and mens rea. Actus reus, which means “the guilty act,” must also be combined with mens rea — “the guilty mind” — in order for us to judge harshly.1 The punishment depends on the ability of the moral agent to understand the distinction between good and evil. This is why there is some ambivalence when it comes to scolding animals for soiling the carpet. Some people may perceive a guilty mind in their pet and judge them harshly, while others think their pet is innocent and will not punish the animal. In the case of the moral patient, the most important aspect we consider when making moral judgments is perceived experience (specifically, harm).2 If someone shoots a bullet through a wooden door, and then another bullet through a dog, we only think of one act as unethical. In this case,

psychology

Carolina Scientific DYADIC COMPLETION A dyadic template compels people to blame the agent for unjust suffering and to see immoral acts as inducing harm. Concept by Dr. Gray, image by Erin Moore.

Moral Dyad Agent Intention (Blame)

Patient Suffering

Harmless Wrongs

Injustice Agent Intention

Agent Intention

Patient Suffering

• suing corporations for disease • seeing God behind disasters • blaming the government for social ills

there are two moral patients — the door and the dog. However, only the dog is perceived to have a mind that can experience, so we define only the second act as immoral. The moral dyad is the framework we naturally use to work through moral problems as it lies in the foundation of our attribution of moral rights and responsibilities. We give more responsibilities to beings we perceive to have agency (e.g. infant human being vs. adult human being), and more rights to beings that we perceive to have the capacity to experience (e.g. door vs. dog).2 Dr. Gray became interested in morality in graduate school while investigating free will. Free will is something that, like morality, has been debated for millennia, but Dr. Gray says free will “is most interesting because of its implications on morality. If we don’t have free will, is there really such a thing as moral responsibility?”1 It was these broader questions of free will and their implications on our lives that motivated Dr. Gray to build a unifying framework to help explain the phenomenon of morality.1 As a result of his research, Dr. Gray has concluded that morality is a matter of perception and that “morality lies within each of our hearts.”1 Also astonishing is the fact that minds are a matter of perception, since “we can’t even be sure if other people have minds.”1 If morality is truly a matter of perception, then the question beckons: what is the evolutionary purpose

• flag-burning seems to harm veterans • personal drug use seems to harm families • homosexuality seems to harm children

for our brains to handle moral problems using the moral dyad? Psychologists widely agree that morality serves to subjugate our selfishness for the betterment of group living.1 “So with a sense of morality we can all get along and achieve better things than we could do if I murdered everyone I came across, right?”1 The moral dyad, from an evolutionary perspective,

“If we don’t have free will, is there really such a thing as moral responsibility?” - Dr. Kurt Gray

seems to serve as a general emotional guideline that we use to understand a diverse range of moral problems we may face in our lifetime.1 We are most likely going to face problems that evolution has not yet coded for, but having the moral dyad as a template will help our brains function as a general purpose problem solver.1 Similar to the human’s natural response to danger, which is to run away, using the moral dyad is a natural response when human beings are faced with moral problems. This mechanism leads people to develop moral principles that can result in safer and longer lives.1 On the contrary, the moral dyad can also make it difficult for people to

Patient Suffering

have constructive dialogue pertaining to morality. Because mind and harm in others are both perceived, there is no certainty that either actually exist. Therefore one person may be okay with killing and eating animals because he thinks they are just “silly robots with no mind,”1 while another person is against killing and eating animals because he perceives the animal to have a mind that experiences pain.1 Once people become aware of the moral dyad, however, it can lead to a better understanding of other people’s viewpoints. Once we know that morality is a matter of perception, we can discuss the factors that lead to those perceptions rather than arguing over which is right and which is wrong.

References

1. Interview with Kurt Gray, Ph.D. 9/16/2013. 2. Gray, K., Young, L., Waytz, A. “Mind Perception Is the Essence of Morality.” Psychological Inquiry 23, 101-124. 2012. 3. Gray, K., Waytz, A., Young, L. “The moral dyad: A fundamental template unifying moral judgment.” Psychological Inquiry 23, 206-215. 2012. 4. Gray, K., Schein, C. “Two minds vs. two philosophies: Mind perception defines morality and dissolves the debate between deontology and utilitarianism.” Review of Philosophy and Psychology 3, 405-423. 2012.

the subtle side of

MEMORY BY AUSTIN SUN

Image public domain.

hy are amnesiacs unable to recall what they had for breakfast in the morning but still know how to tie their shoes? The answer lies in the fact that memory is split into two components: explicit and implicit. Explicit memory, which is used when recalling what you had for breakfast, involves the conscious recollection of a past experience. Implicit memory, which is used to remember how to tie your shoes, involves the unconscious memory of past events and experiences. Amnesiacs experience difficulty with explicit memory but have normal functioning implicit memory.1 Implicit and explicit PRIMING: memory studies are branchincreased sensitivity es of cognitive psychology to stimuli due to that have been intense subjects of research within the prior experience field since the 1980s. During that time, scientists determined that memory could be split into perceptual and conceptual memory. Perceptual memory involves auditory or visual characteristics to recall something. For example, if someone were to say the fragment “inter-,” the first thing that may come to mind is “internet.” This has to do with the letters that make up the word “internet.” Conceptual memory involves associated characteristics or meanings. For example, if someone were to say the word “time,” the words “day” or “hour” may come to mind. This has to do with the actual meaning of the word “time.” Dr. Neil Mulligan, Ph.D., psychology professor and director of UNC-Chapel Hill’s cognitive psychology department, has spent the past two decades with colleagues researching implicit and explicit memory. In some of his most recent work, Dr. Mulligan studied differences between conceptual implicit memory and conceptual explicit memory. Prior to Dr. Mulligan’s work, no research had shown a strong difference between conceptual implicit and explicit memory.3 Dr. Mulligan’s study was oriented around category size as a variable. In this study, the participants were split into

two groups. One group was given a conceptual implicit memory test and the other group was given an conceptual explicit memory test. The participants were given study lists to read over. These study lists had twelve categories of words with varying numbers of associated words for each category, which was the variable for the study. For example, a category might be “a Dr. Neil Mulligan relative,” and the examples from the category would be “uncle” or “grandmother.” The participants were then tested; the explicit testing group was told to recall specific words from the study list given a category name, and the implicit testing group was given categories that may or may not have been from the study list and told to name words associated with each category. The proportion of words retrieved for each category size was measured. The two testing groups had opposite results.4 The

MARKETING AND MEMORY When a cup of coffee is mentioned, what brand comes to mind first? Brand recognition is a form of conceptual implicit memory; advertisers want their brand to come to mind first when you see a product.

Carolina Scientific STORAGE LONG TERM MEMORY

psychology

Dr. Mulligan’s research investigates the differences between conceptual implicit and explicit memory formation.

Explicit • Remembering a formula • Writing a research paper • Recalling last night’s dinner

Implicit • Riding a bicycle • Tying your shoes • Typing on a computer nonconscious

conscious nonverbal verbal emotional holistic/contextual procedural

implicit testing group had a higher proportion of words retrieved for categories of a larger size, and the explicit testing group had a higher proportion recollected for smaller-sized categories.4 With these results, Dr. Mulligan concluded a strong, qualitative difference between conceptual implicit and explicit memory.4 The implications of this revelation are predominantly theoretical in nature. “Conceptual implicit memory plays a role in many forms of human reasoning, problem solving for instance,” Dr. Mulligan said. “We may find ourselves influenced by past experiences in a way we aren’t necessarily aware of,” he added.2 The determination of the difference between conceptual implicit and explicit memory opens up more opportunity for research on conceptual implicit memory. Following his discovery on the difference between con-

ceptual implicit and conceptual explicit memory, Dr. Mulligan and one of his graduate students undertook a research project focused on the effects of conceptual implicit memory on advertising. The two looked into brand recognition based off of a category.5 For instance, when the category “soda” is mentioned, what brand names of soda comes to mind? Research on brand recognition is of particular interest to advertisers because advertisers want their brand to come to mind first. The research on advertising is a direct application of Dr. Mulligan’s recent study, in which each category is a type of product (soda, coffee, pizza delivery) and each associated word is a brand (Coca-Cola, Starbucks, Dominos, etc.).5 More opportunity for application of this subtle side of memory will arise as Dr. Mulligan continues to delve into the intricacies of conceptual implicit memory.

“We may find ourselves influenced by past experiences in a way we aren’t necessarily aware of.” - Dr. Neil Mulligan

References

Figure 1. Amnesiacs with damaged hippocampi, which control explicit memory formation, still have normal functioning implicit memory. Image public domain.

1. Graf, P., Schacter, D.L. “Implicit and Explicit Memory for New Associations in Normal and Amnesic Subjects.” Journal of Experimental Psychology: Learning, Memory, and Cognition 11, 501–518. 1985. 2. Interview with Neil Mulligan, Ph.D. 9/20/2013. 3. Mulligan, N.W., Besken, M. Implicit Memory. In The Oxford Handbook of Cognitive Psychology; Reisberg, Daniel; Oxford University Press: Oxford, 2013. 4. Mulligan, N.W. “Differentiating Between Conceptual Implicit and Explicit Memory: A Crossed Double Dissociation Between Category-Exemplar Production and Category-Cued Recall.” Psychological Science 23, 404–406. 2012.

psychology

growing pains BY PREETHIKA SUNDARARAJ

here’s no denying the fact that the adolescent years are tough for everyone. Although stress seems to be part and parcel of our teenage years, the psychological effects during these years are more confusing and more complex when considering the added anxiety brought about by experiencing racial discrimination, something commonly experienced by black adolescents during their lifetimes..2 Racial discrimination is defined as dominant group members’ actions that have a differential and negative effect on subordinate racial or ethnic groups.1 Prior research suggests that the effects of racial discrimination, pervasively experienced among black youth across the United States, significantly affect their mental health and psychological wellbeing.2 The effects of racial discrimination negatively affect one’s self-esteem, overall satisfaction with life, frustration, anxiety and depressive symptoms.3 As experiences of racial discrimination have been shown to increase with age,3 researchers are led to investigate the conditions under which depressive symptoms are shown and try to explain the indirect relationship between racial discrimination and depressive symptoms. It should be noted that adolescents and adults do not respond in the same way to perceived discrimination. Dr. Eleanor Seaton of UNC-Chapel Hill’s psychology department states that “most of the field, myself included, assumed that the way black adolescents thought about racial discrimination was the way black adults thought about it — and I found that to be not true. It prompted me to start to think that this is a different phenomenon in the adolescent period.”4 Insight into the experiences of discrimination from adolescents’ perspectives can prove to be quite valuable so that helpful mechanisms of intervention can be properly identified to lead to an overall better quality of life.

A group of researchers led by Dr. Seaton investigated the relationship between depressive symptoms and perceived racial discrimination, with coping strategies serving as mediators and racial identity dimensions as moderators of the relationship. Researchers have defined the condition under which a certain variable is present as the moderator, and the indirect relationship or the intermediate variable between the two variables as the mediator.4 Mediators address why certain effects occur while moderators describe when certain effects occur. This study polled black adolescents from high schools in the continen-

“Adolescents are unique. It can be a stressful and confusing time in general, and when you add another layer of race, it becomes even more confusing.”

-Dr. Eleanor Seaton tal United States about their experiences with racial discrimination, utilization of coping strategies, frequency of depressive symptoms and how they perceive their black identities. The mediators between perceived racial discrimination and depressive symptoms were operationalized coping strategies, or efforts one utilizes to respond to stressful events. Distraction is an example of a coping strategy. The moderators were conceptualized as racial identity dimensions, or the significance that adolescents attribute to being part of a particular racial or ethnic group. The results of Dr. Seaton’s research indicated that use of avoidant coping strategies was associated with greater depressive symptoms for those participants that endorsed the minority or oppressive ideology. The avoidant strategy is the unwillingness to think about or engage in the problem altogether, and

the minority or oppressive ideology includes emphasis on the commonality of oppression among all racial and ethnic groups. Avo i d a n t Dr. Eleanor Seaton coping strategies mediated the relationship between perceived racial discrimination and depressive symptoms in the context of minority or oppressive ideology as a moderator. Dr. Seaton noted that avoidant coping strategies are a significant mediator because black adolescents resort to avoidant coping mechanisms when they feel that the perceived racial discrimination is out of their control.3 Black adolescents might also feel that perceived racial discrimination is out of their control since it is experienced by all minority groups and not exclusively by African Americans.3 “Adolescents are unique,” says Dr. Seaton. “It can be a stressful and confusing time in general, and when you add another layer of race, it becomes even more confusing.”4 Dr. Seaton’s findings have given further insight into the compounding effects of racial discrimination, effects that are negative and that can lead to a lower quality of life. Most importantly, it has shown how truly complex the relationship between perceived racial discrimination, racial identity, coping mechanisms and mental health is, giving a new meaning to the term “growing pains.”

References

1. Racial Experiences of Youth Laboratory. Retrieved from http://www.reylab. com/About. 2. Seaton, E.K., Caldwell, C.H., Sellers, R. M., Jackson, J.S. “The prevalence of perceived discrimination among African American and Caribbean Black youth.” Developmental Psychology 44 (5), 12881297. 2008. 3. Seaton, E. K., Upton, R., Gilbert, A.,Volpe, V. (In press) “A moderated mediation model: racial discrimination, coping strategies, and racial identity among black adolescents.” Child Development. 4. Interview with Eleanor K. Seaton, Ph.D. 9/19/2013.

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Undergraduate Research TANNER FADERO

Biology | 2015 Tanner Fadero, a junior biology major in Dr. Kevin Slep’s cytoskeletal dynamics lab in the UNC biology department, conducts research concerning a structure/function analysis of the Drosophila homologue of the TACC family protein, otherwise known as DTACC. Tanner started working in the lab as a work-study student his first year at UNC, making Luria Broth, autoclaving glassware and washing dishes. He quickly became interested in cytoskeleton research being conducted by Jaime Campbell, a graduate student in the Slep lab who is now his mentor.

In his own words (edited for length and clarity): I was motivated to begin getting involved in research because of my own personal drive to learn about biology not only through classes and textbooks, but also by first-hand discovery. For me, there’s a difference in book knowledge gained from classes and the knowledge a researcher gains from experiments. Research in biology is not easy, nor does it often provide fruitful results. However, that’s not to say that it’s not rewarding. In fact, I find it even more rewarding to have finally carried out an experiment to completion after having failed several times to make it work. I learn more about the methods this way, and it has really taught me to be patient—not just in science, but in other aspects of my academic career as well. In addition, even if one of my experiments does go to completion, but I see a result that negates my hypothesis, it forces me to go back and really look over why the data does not match my original prediction. Doing this research over the past year has made me a more critical thinker, as well as someone who is not afraid to challenge his own thoughts and preconceptions. Simply talking to members of my own lab and other labs has opened up a whole world of research opportunities, both within and outside of UNC-Chapel Hill. For example, I am currently in the process of applying for a summer internship that was presented to me as a recommendation from a peer in my lab. What I like most about doing research is the sense of being at the forefront of knowledge. There’s just something about being one of the first people to learn something that is incredibly intellectually stimulating. As for what I dislike about research, that’s a tough one. I’d probably have to say the disappointment that comes when I realize that one of my experiments failed, even after putting in several days’ worth of effort. However, my disappointment is always short-lived, as I make sure to thoroughly take note of what failed and how I can prevent a similar problem from arising again as I begin to set up another trial.

Research has really taught me to be patient—not just in science, but in other aspects of my academic career as well.

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KATIE WEINEL

Biology, Psychology | 2013

Katie Weinel is a first year medical student in the UNC School of Medicine who conducted undergraduate research under the mentorship of Dr. Stephanie Zerwas, assistant professor in the UNC Department of Psychiatry’s Center of Excellence for Eating Disorders. Her honors thesis project examined the effect of anorexia nervosa on one’s response to the “rubber hand illusion,” in which a person is tricked into believing a fake hand is his or her own. In her own words (edited for length and clarity): I worked as an undergraduate trainee for the UNC Center of Excellence in Eating Disorders lab at the start of the second semester of my sophomore year. After taking abnormal psychology, my professor recommended that I get involved in undergraduate research. I went to the Office of Undergraduate Research database and looked for research positions that fit my interests. I wanted to gain more knowledge about clinical psychology compared to psychiatry, and the UNC Center of Excellence in Eating Disorders seemed like a great way to be able to talk to clinicians in both fields. I also wanted to learn more about eating disorders research and treatment. I had a friend that had suffered from an eating disorder, and I wanted to learn more about the various illnesses. I was fascinated by a research study examining the responses of patients with schizophrenia to the rubber hand illusion and wanted to see how women with eating disorders would respond to the illusion. Previous research has suggested that women with anorexia nervosa may be more susceptible to the illusion than healthy women. I wondered why that might be and wanted to find out more. It could possibly be because women with anorexia nervosa are less attuned to their own bodies, are highly affected by environmental cues regarding body image, and have abnormal processing of spatial and visual information about their own bodies. To understand this more thoroughly, I designed my honors thesis project to look at susceptibility to the rubber hand illusion in women with and without anorexia nervosa. Research is the opportunity to ask a question, find an answer, and then ask more questions. More concretely, research is the opportunity to learn something completely new and contribute to the body of knowledge regarding a certain subject or issue. I learned so much from working in my lab — I learned how to be self-sufficient, independent and goal-oriented. I learned how to conduct my own study from start to finish, how to interpret data and research results, how to talk about and discuss my own findings and their impact on the field. I think I learned more from my undergraduate research experience than I did in the classroom. It is my goal for my honors thesis project to be the start of a life-long mission to discover more effective treatments for individuals with eating disorders. As a psychiatrist, I plan to treat adolescents with anorexia nervosa or bulimia nervosa and collaborate with other researchers to find a cure using pharmacological- and psychotherapy-based interventions. I hope that my future research will inform and enhance the treatment of my patients as well as make a substantial impact on the field. I loved being able to independently lead my own project and enjoyed my interactions with patients in the inpatient and partial hospitalization units. I hardly knew anything about statistics before starting my thesis. It was frustrating struggling to understand the statistical analysis portion of the project. In the future, I hope to learn even more about statistics. Having background knowledge of statistics is a fantastic skill to have in a field like medicine where I will be reading many clinical trials and research studies to figure out the best treatments for my patients.

Research is the opportunity to ask a question, find an answer, and then ask more questions.

“The best scientist is open to experience and begins with romance— the idea that anything is possible.” - Ray Bradbury

Image by Ildar Sagdejev, [CC-BY-SA-3.0].

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scıentıfic Fall 2013 | Volume 6 | Issue 1

This publication was funded at least in part by Student Fees which were appropriated and dispersed by the Student Government at UNC-Chapel Hill.