Fall 2015 -- Sorting Through the Weeds by Carolina Scientific

Carolina

Carolina Scientific

scıentıfic Fall 2015 | Volume 8 | Issue 1

SORTING THROUGH THE WEEDS one scientist’s lifelong relationship with the world of plants full story on page 14 1

Carolina

sc覺entific 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 UNC-Chapel Hill, and to educate and inform readers while promoting interest in science and research.

Letter from the Editors: For seven years, Carolina Scientific has chronicled research at UNC-Chapel Hill with a focus on making science accessible and relatable to all. Throughout that time, the format, style, and voice of the magazine have all evolved to become what they are today. This semester, we continue to expand our horizons and investigate subjects we never have. In this issue we delve deeper into the mind than ever before, learning about novel techniques to stimulate our brains (page 22) as well as the secrets behind addiction (page 26). We also inch closer to what may have once sounded like science fiction when we explore the fields of virtual reality (page 8), 3D printing in relation to medical procedures (page 32), and artificial organs on microchips (page 34). We hope you leaf through these pages and are filled with the same wonder and excitement we were. Enjoy! -Parth Majmudar

on the cover

Executive Board Editor-in-Chief Parth Majmudar Managing & Design Editor Tracie Hayes Associate & Copy Editor Ben Penley Associate Editors Kimberly Hii Seth Bollenbecker Treasurer Karthika Kandala Publicity Chair Jonathan Smith Fundraising Chair Sahana Raghunathan Online Content Managers Tirthna Badhiwala William Howland Digital Media Coordinator Nathan Lunsford Faculty Advisor Gidi Shemer, Ph.D. Contributors Staff Writers Andrew Bauer Sage Bauer Chloe Brown Maddie Fletcher Kate Foray Grace Guo Forrest Hayward Elizabeth Henry Shuyan Huang Hannah Jaggers Rebecca Landon Aakash Mehta Carrington Merritt Ashleigh Miller Allie Piselli Nicholas Rewkowski Ami Shiddapur Christine Son Alexandra Tribo Lynde Wangler Jeffrey Young Design Staff Gideon Kapange Jui Naik Rachel Quindlen Ben Sagmoe Nirja Sutaria

Dr. Alan Weakley, an ecologist and plant systematist at the UNC Herbarium, spends his life in nature attempting to create a definitive local plant database. Full story on page 14. Photograph of a spring crocus in bloom by Andrew Bauer.

Copy Staff Jesse Barnes Aly Helms Shuyan Huang Akil Gurupuran Aakash Mehta Carrington Merritt Sarah Miller Nicolas Rewkowski Ami Shiddapur Yujin Smith Brook Teffera Patrick Truesdell Illustrators Andrew Bauer Maddie Fletcher Laura Hamon Maura Hartzman Seeun Jung Kristen Lospinoso Ivy Somocurcio Smrithi Valsaraj Carley West Kelsey Winchester David Wright Julianne Yuziuk

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contents Special Topics

Questions Wikipedia Can’t Answer

Not Your Typical Science Major

A Future for Hermits

Kate Foray

Ashleigh Miller

Nicholas Rewkowski

Breaking Free from Addiction

Visualizing the Brain

Grace Guo

Jeffrey Young

Medicine

Plant Biology

Taming Tantrums with Technology

Hannah Jaggers

Plants Have Feelings Too Forrest Hayward

UNC’s Medicinal Garden Chloe Brown

There’s No Monotony in Botany

Plant Homicides

Alexandra Tribo

Andrew Bauer

Cystic Fibrosis Treatment

Print and Practice

Humans on Microchips

Targeting Tumors from Within

Source Code of Complex Disease

Maddie Fletcher Allie Piselli

Ami Shiddapur Christine Son Sage Bauer

Health

Psychology and Neuroscience

Raised Right

Lung in a Box

Predicting Pathology

Nature is the Best Guide

Transcranial Stimulation

Pickles and Peanut Butter

Elizabeth Henry Lynde Wangler

Carrington Merritt

Shuyan Huang

Rebecca Landon Aakash Mehta

carolina_scientific@unc.edu carolinascientific.org facebook.com/CarolinaScientific @uncsci

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Illustration by Kristen Lospinoso

The Questions Wikipedia Can’t Answer information on relinquishing a child for adoption By Kate Foray

iving in a world where the entirety of human knowledge is at our disposal at any moment allows us to use information to facilitate global communication, write last minute research papers and make decisions. Doctoral candidate Rachael Clemens studies Human Information Behavior, a branch of information and library science that looks into how people interact with information in a variety of different situations. She is interested in the study of information coping, where “information often plays a significant role in the coping and decision making strategies of one trying to resolve a crisis”.1 For her thesis, Clemens decided on a topic not many have experienced: relinquishing a child for adoption. “It [adoption] has an unusual element, so people don’t have everyday access to this specific type of information. But it also has a certain shame and stigma attached to it,” Clem-

ens said.2 This stigma makes birthmothers vulnerable in their decision making process. This vulnerability can lead to a rash decision that will impact both the mother and her child for the rest of their lives. It is important to have all the necessary information to make a good choice, especially when the life of another is on the line. Often, there is a compulsion to keep adoption situations secret to avoid social judgment, which can negatively affect the information seeking process by limiting the availability of information. In her study, Clemens hopes to provide information professionals, such as practitioners and social workers, with the knowledge they need to provide assistance to birth mothers considering giving their children up for adoption. By establishing where former birth mothers received their information and how it influenced their decisions, professionals can

Carolina Scientific better determine how to reach these women in their time of need. For a more in-depth analysis, Clemens is in the process of interviewing ten mothers who have given their children up for adoption within the last fifteen years. Starting with the pre-decision process, Clemens is slowly uncovering what information is hard to find and what the women Rachael Clemens are expecting to find. Additionally, she is investigating what options the mothers were aware of and how they trust the information they are receiving. “An interesting thing,” Clemens noted, “is the specialized vocabulary involved in adoption.”1 While it is vital to understand uncommon terms such as ‘open or closed adoption’ during the legal process, it is usually the first time the birth mothers encounter such jargon. These terms are simply not used in everyday life, which can make the situation even more stressful and

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al connection provided by support groups. However, Clemens sees hope in the age of technology. “There has been a change in the last twenty to thirty years. More adoption agencies are encouraging people to have some level of openness. Social media has helped birth parents keep up with their children,” Clemens said.1 Of the birth mothers interviewed in the study, most have noted that they take comfort in the connection they have to their children through social media. Information on how their children are doing and the constant assurance that they made the right decision is often only a click away. According to another study, about one million children in the United States live with an adoptive family.3 This means that a lot of mothers have made the decision to give up their children and have dealt with the consequences. Clemens pointed out that this is the concern of her study, “There is a lot of research on people who are adopted and a lot of research on adoptive parents, but the birth mother is the least studied. There is a need for more research in this area.”1 By investigating this life-long after-period of relinquishing a child for adoption, Clemens hopes to discover what information is needed to handle the pre- and post- adoption process, which will hopefully ease the decision-making process for birth mothers. Giving a child up for adoption is a decision that demands a solid understanding of the informational and emotional processes involved. Years of prejudice against this subject have restricted access to information that could positively benefit both birth mothers and their children. With so many children ending up with adopted families, one can only imagine the amount of birth mothers coping with the aftermath of their life-altering decision. Information may be the answer to this coping process, and perhaps contribute largely to the decision itself.

The knowledge that others are going through the same events brings a certain level of comfort to those going through a crisis, but fear of being judged can prevent many birth mothers from gaining access to the emotional connection provided by support groups.

References

1. Interview with Rachael Clemens, Ph.D. Candidate. 09/18/15. 2. Clemens, R. Human Information Behavior, Coping and Decision-Making in the Context of a Personal Crisis: An Interpretative Phenomenological Analysis of the Voices of Birthmothers on Relinquishing a Child for Adoption (Unpublished doctoral dissertation). UNC-Chapel Hill, NC. 2015. 3. Stolley, K. The Future of Children. 2015 3, 26-26.

overwhelming. Finding out how to best make this information available to birth mothers is the key to helping them make the best choice possible for themselves and for their children. Extending to the period after adoption, the study looks into informational coping, which is how birth mothers use information to deal with relinquishing their children. “Some people, when dealing with a crisis or certain stressful situations, find out every little thing, while others just try to ignore the information that stresses them out – though most people fall in between that spectrum,” Clemens said.1 Coping with relinquishing one’s child to a better life is not easy. “As with any personal loss, a grieving process is instrumental in coping with and adapting to a crisis. However, unlike the loss of a child through death, loss through adoption may be socially stigmatized.”2 This stigma could explain why there are so many support groups for parents who have experienced the death of a child but far fewer for birth mothers who have relinquished a child. The information provided through the sharing of experiences is what makes support groups so effective in the grieving process. The knowledge that others are going through the same events brings a certain level of comfort to those going through a crisis, but fear of being judged can prevent many birth mothers from gaining access to the emotion-

Figure 1. Birth mothers are often overlooked in the adoption process. Image by Tatiana Vdb, CC-BY-2.0.

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Not your typical UNC-Chapel Hill has a diverse population of students involved in many different majors – with a large group interested in studying science. Many of these students go on to study core sciences like biology, chemistry or physics, but do not know that there are other science majors offered here at UNC that can appeal to just about any personality. The Department of Allied Health Sciences and the UNC Gillings School of Public Health have opportunities in store for any undergraduate interested in a more unique, specialized field of science.

UNC Gillings School of Public Health Public Health is a field at the intersection of social science, natural science and health science.1 The goal is to prevent health problems before medical intervention is necessary and focuses on the community as a patient rather than the individual.1 The UNC Gillings School of Public Health (SPH) is ranked as the second best public health school in the nation and has four undergraduate majors, including Biostatistics, Health Policy and Management, Environmental Health and Engineering and Nutrition. All of the undergraduate majors have an application process as well as specific classes that must be taken prior to entry into the program. After acceptance, students must take four general Public Health courses – one in each of epidemiology, biostatistics, health policy and management and health behavior.

Biostatistics is a major for students who are interested in applying quantitative reasoning skills to public health issues. Many graduates go on to receive higher education in biostatistics or in other medical professions. Approximately 20% attend medical school after graduation.2 Those who go into the work force after graduation work in pharmaceutical industries, contract research organizations, medical or academic settings or governmental agencies that deal with health care.3 Nutrition is a division in the SPH that links nutrition science to health and looks for ways to improve overall human health.4 The nutrition major is very rigorous and competitive. Students are required to do research in biochemistry, nutrition epidemiology or nutrition intervention. The research requirement is unique to the nutrition major, and counts for class credit. This major is advertised as a pre-medical and pre-dental program. Approximately 60% of graduates with a Bachelor of Science in Public Health in Nutrition have been admitted to graduate schools.4 Starting Fall 2016, Nutrition is allowing for a dual degree to receive a master’s degree after adding one year of school.4

Health Policy and Management (HPM) is designed to develop professionals to work in the business side of public health and healthcare. HPM provides a cohort model of learning to prepare students to work in this field. There are many group projects and activities associated with this program. Graduates work in many different areas of public health such as hospital consulting, research institutes and local or governmental nonprofit groups.1 Many HPM students also continue their education by going to graduate, medical, dentistry or law school. Students learn how to tackle and manage problems that arise in public health and to solve them independently and as part of a group. Environmental Health and Engineering is a major that focuses on teaching students how environmental factors impact human health.5 Students have flexibility in their education and many have the opportunity to expand their education by concentrating in biology, chemistry or physics. Specialization is not a requirement, but rather a student’s personal choice. This major is especially tailored for problem solvers. There is also a possibility for students to complete an extra year to get their master’s degree. Most graduates go on to receive higher education in public health or other graduate work.6

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SCIENCE MAJOR

By Ashleigh Miller

Department of Allied Health Sciences Clinical Lab Science (CLS) is a degree program that allows students to combine science and healthcare. The major prepares students for positions in hospital laboratories.7 CLS provides a generalist education to train students to run and interpret tests in hematology (the study of blood), chemistry, microbiology and transfusion medicine (medicine concerned with transfusion of blood and its components).7 Like Radiologic Science, CLS is a twoyear degree within the Department of Allied Health Sciences. There is an application process as well as an online, written interview. Before applying to the program, students are highly encouraged to participate in “open lab” sessions to meet students and see the student laboratory, to take a tour with a current student or to sit in on a CLS lecture. This hands-on science education provides analytical and applied science in a healthcare setting where students are able to connect with individuals already working in the CLS field. After graduating, a national examination must be passed in order to work in a hospital, but the CLS department at UNC has 100% pass rate due to the work experience acquired through clinical rotations.7 All CLS graduates from UNC were hired within their field, usually thanks to references and connections made during the program, or pursue higher education such as a Master’s of CLS, Medical School or PA school.7

Radiologic Science is a division within the Department of Allied Health Sciences associated with the UNC School of Medicine. The Radiologic Science major provides students with access to healthcare through imaging techniques in preparation for certification to become a radiologic technologist. This two-year program is heavy in anatomy, physiology, imaging physics and pathophysiology in order for students to recognize different diseases and injuries. There are required pre-requisite classes, an application process, as well as oral and written interviews. Shadowing and exploration of the field is highly encouraged before completing the application. Once accepted into the program, students take classes as well as have clinical opportunities at UNC, Duke and Alamance Regional Medical Center. Students have the opportunity to specialize in a form of imaging that best suits them. After graduating with a Bachelor of Science in Medical Imaging, graduates can go on and take the national certification examination. If students choose to specialize, they may also go on to take the specialized certification examination. The Radiologic Science program is for students who are interested in self-directed, life long learning in a “high touch, high tech” field.11

Speech and Hearing Sciences (SHS), through the Department of Allied Health Science, has developed an undergraduate minor for students on the path to becoming Speech-Language Pathologists or Audiologists. A SpeechLanguage Pathologist diagnoses and treats language, communication and swallowing disorders.8 Audiologists diagnose and treat hearing and balance problems.8 A student interested in the SHS minor can major in any subject and can apply any year here at UNC. The minor requires five courses in different areas (biology and neurology, acoustics, psychological and developmental, linguistics and cultural) and recommends four courses (biology, physical science, statistics and social/behavioral sciences) for later certification by the national board.9 These courses are required by any master’s program and allow students to be involved in the field as undergraduates. UNC students interested in this minor have created their own undergraduate branch of National Student Speech Language and Hearing Association (NSSLHA). NSSLHA exposes students to the minor as well as the career.10

1. Interview with Karl Umble, Ph.D. 09/14/15. 2. Email with Jane Monaco, DrPH. 09/20/15. 3. UNC Gillings School of Public Health (May 2015). Biostatistics Bachelor of Science in Public Health. [Brochure]. Chapel Hill, NC. 4. Interview with Mirek Styblo, 09/18/15. 5. Message from Mike Aitken, Chair of Environmental Sciences and Engineering. http://sph.unc.edu/envr/message-from-the-ese-chair/ (accessed September 23rd, 2015). 6. Interview with Jack Whaley, 09/23/15. 7. Interview with Susan Beck, Ph.D. 09/14/15. 8. Interview with Brenda Mitchell, Ph.D. 09/15/15. 9. Preparatory Program of Study Required by the American Speech-Language- Hearing Association (ASHA) Leading to Speech-Language Pathology Certification. www. med.unc.edu. 10. National Student Speech Language & Hearing Association (NSSLHA) Undergraduates. http://nsslha.web.unc. edu (Accessed September 15th, 2015). 11. Interview with Joy Renner, M.A. 09/21/15.

References

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Title The Old Well created in a virtual environment. Image by Nicholas Rewkowski with Blender.

A future for

By Firstname Lastname

HERMITS By Nicholas Rewkowski

n this fast-paced modern world, we rely heavily on social media to maintain our interpersonal relationships. No means of communication is easier than grabbing a smartphone to make a phone call or send a quick text. However, an even more convenient solution could be just around the corner, one that may give us no reason to even touch our phones. Dr. Ming Lin, a virtual reality (VR) researcher in the computer science department at UNC-Chapel Hill, has been working to attain that very ability. Dr. Lin and her research team, the Geometric Algorithm for Modeling, Motion and Animation (GAMMA) Research Group are currently working on ways to create a multimodal social environment in a virtual setting.1 If this idea comes to fruition, it may spell the end of online interactions. “I don’t think that Mark Zuckerberg was naïve when Facebook acquired Oculus VR, because he sees virtual reality as a platform of sharing experiences, which it is, and that’s what Facebook is about; it’s about sharing those social experiences,” Dr. Lin said.1 If there is a way to compress all of the time spent responding to friends’ posts or complimenting their pets, it may become more convenient to be there with them ‘virtually.’ VR is currently used for many other applications that are not so obvious to the average consumer, such as flight simulation, medical training, video gaming and therapy. It is plausible, then, for VR to be used as a replacement for social media, which is not as specialized and is more accessible than its other uses. While some believe that these uses are not nearly as effective as hands-on training, “hands-on” is being redefined on a daily basis. The VR field has made massive strides towards efficiency, and in most applications such as flight

and medical training, it is much safer and cheaper to train through synthetic or man-made environments than to have the trainees start out in the real world. “It’s used in so many different applications; it’s just that not many people are aware of the potential of VR Dr. Ming Lin technology because it is used for very specialized training and applications,” Dr. Lin stated.1 The computer science and engineering communities have barely scratched the surface of its potential and continue to expand rapidly. It is not commonly known that the VR field has been expanding for over 30 years, so the sudden exploitation of VR for applications such as social media might seem quite surprising. The recent purchase of the Oculus VR company (the creators of the Oculus Rift) by Facebook has attracted many experimentalists and big businesses to the VR field. Only relatively recently has VR been thought of as a consumer product. Due to this ‘Big Bang’ of VR, it is now a reality for researchers and well-known companies like Facebook and Google to strive for the affordability of this booming product. “By feeling truly present, you can share unbounded spaces and experiences with the people in your life. Imagine sharing not just moments with your friends online, but entire experiences and adventures,” Mark Zuckerberg, the creator of Facebook, said when

Carolina Scientific he bought Oculus.2 While investing in VR certainly seems to be a risk, money from important figures like Zuckerberg is needed for any new product to expand. “This is an area that has been unfunded, primarily because there was just so much hype for VR in the 90s, and people expected so much so quickly. Computing power was very limited and there were some government agencies putting a little bit of investment in VR and they got impatient; they didn’t get enough of the results that they wanted quickly enough, so there is practically, in the US at least, no dedicated funding for VR at this moment,” Dr. Lin explained.1 She continued, “For $300 you can buy a headset which used to cost $20,000-$30,000, so I think a lot of it has already been done by companies interested in using VR as a platform to drive down the price tag, and I believe that’s going to happen, just like how computing used to be very expensive, but now computers are very affordable, and in fact, everyone wears one, one

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Figure 2. Virtual instruments being used by researchers. Image courtesy of the GAMMA Research Group. behind research tends to be the group at which it is focused “All three groups [policy-makers, providers and users of these converging technologies] need to work together to ensure that people retain control over the development of technologies that ought to serve us rather than determine how we interact,” Dr. Fiachra O’Brolcháin said.3 Innovation tends to be a multi-fold process, so the time that it will take for massive improvements to occur can be very difficult to predict. Ultimately, the success of virtual reality will be determined on how important the trading of experience is to the consumers, and with big businesses competing for the consumers’ attention, VR is certain to expand dramatically in the next few years. Social media might become irrelevant when we can finally see through the eyes of others and exchange these experiences directly. Researchers such as Dr. Lin are striving to create a world where everyone can be truly understood, which may potentially solve even more complex issues.

”It’s used in so many different applications; it’s just that not many people are aware of the potential of VR technology...” Dr. Ming Lin way or the other.”1 Now that companies like Facebook, Microsoft, Google, HTC and so many others are working hard to create a superior product, it is very likely that in the near future, social interactions will be redefined and entire lives could be shared. As promising as the field sounds, researchers such as Dr. Lin and her colleagues, like Dr. Fuchs, Dr. Manocha and the UNC GAMMA Research and Telepresence Groups, continue to struggle with the same issues that most other research fields do – time and money. One of the most important parts of expanding the virtual reality field is testing the synthetic environments from different viewpoints. This is even more important in the area of Dr. Lin’s focus – multimodal interaction. The rapid improvement of the VR field will likely not occur without the demand for improvement, especially since the true power

References

1. Interview with Ming Lin, Ph.D. 09/11/15. 2. Zuckerberg, M. (2014). I’m excited to announce that we’ve agreed to acquire Oculus VR, the leader in VR technology. Facebook.com. Retrieved September 19, 2015 from https://www.facebook.com/zuck/posts/10101319050523971. 3. O’Brolcháin, F.; Jacquemard, T.; Monaghan, D.; O’Connor, N.; Novitzky, P.; Gordijn, B. Sci eng ethics. 2015, 1-29.

Figure 1. Virtual painting, a specialized use of virtual reality. Image courtesy of the GAMMA Research Group.

plant biology

By Forrest Hayward

n forests where trees are close together, they grow tall and narrow rather than fat and bushy like a tree that is growing alone in the middle of a field. The factors that dictate this growth pattern and many other plant characteristics are not yet fully understood. Through his research on a family of plant genes shown to control plant development, Dr. Jason Reed in the UNCChapel Hill department of biology has

been working towards filling in these knowledge gaps. We know that the environment influences plant development, but what many people do not appreciate is how plants recognize and react to their environment. It turns out that, like humans, plants have senses. Plants cannot hear, smell or see things, but they do have mechanisms that pick up on signals like light, temperature and soil

...what many people do not appreciate is how plants recognize and react to their environment. It turns out that, like humans, plants have senses. 10

Photo by Alberto Salguero, CC BY-SA 3.0 moisture. Once a plant senses these external conditions, it begins producing hormones that can turn on genes which control growth in the parts of the plant that Dr. Jason Reed need to react to these stimuli.1 Dr. Reed expanded upon an example of this â&#x20AC;&#x201C; â&#x20AC;&#x153;A plant will bend towards the light. It does this because hormones in the plant are asymmetrically distributed, [with] more being on the shaded side of the stem, causing it to grow more.â&#x20AC;?1

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Figure 1. A side by side comparison of manipulated Arabidopsis and wild type. Photo by Forrest Hayward. The plant used for this research is Arabidopsis thaliana, a small plant with white flowers. The advantage this plant has over others is its very short life cycle. The plant’s quick development allows for conclusions to be drawn quickly rather than having to wait years for the plant to grow.1 Another advantage of using Arabidopsis is that it has been used in a great deal other research, creating a base of prior knowledge.1 There are a variety of methods used to test which genes produce the various growth promoting proteins, some of which include growing plants in different conditions, manipulating plant hormone levels and silencing or promoting a particular suspected growth gene and observing how doing so affects the plant’s development.1,2,3 A fairly stark contrast has been observed between wild type Arabidopsis and those that have been manipulated to express a particular gene of interest. Many of the manipulations cause plants to grow taller and increase the size of the flower’s reproductive parts. Other results have shown that increasing certain gene expressions can majorly stunt the growth of the plant. All of these conclusions demonstrate just how much plant development can potentially be manipulated. Another major aspect of Dr. Reed’s research is figuring out how the proteins that are ultimately made as a result of growth genes can interact with the plant’s plasma membrane and cell

wall, and how they cause the plant to develop and grow. Many of the proteins that have been observed increase membrane transport, which stretches the cell wall and leads to growth.1 Plant development manipulation will undoubtedly play a key role in the future of agriculture, especially in light of climate change and potential food crises. Modified crops suited for dry, windy, hot or cold environments may be needed. For example, if a plant was needed to grow in a windy environment in order to take advantage of otherwise unused arable land, it may be advantageous to stunt the growth of its stem so that it is less likely to blow over. Many plants have genes that cause them to grow tall as a means of competing with other plants for sunlight exposure.1 Though this may be to a plant’s advantage when it is growing in the wild, growing taller actually puts it at a disadvantage when growing amongst its own species. This is because it no longer has competition with different plants, yet it still uses extra energy and resources for unneeded growth that will ultimately increase its chances of becoming damaged in high winds. Unfortunately, without knowing which genes control the different aspects of growth, and why they get turned on, there is no informed or easy way to manipulate a plant’s

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Plant development manipulation will undoubtedly play a key role in future agriculture, especially in light of climate change and the potential food crisis. physical characteristics.1 This is where research can and will be applied to real world challenges. The importance of this research goes far beyond filling in the gaps of knowledge in regards to the way plants develop; this research could help feed the world.

References

1. Interview with Jason Reed, Ph.D. 09/03/15. 2. Chae, K.; Isaacs, C.; Reeves, P.; Maloney, G.; Muday, G.; Nagpal, P.; Reed, J. Plant J. 2012, 71(4), 684-97. 3. Reeves, P. et al. PloS Genetics. 2012, 8(2).

Figure 2. Arabidopsis in early stages, already showing a size difference due to manipulations. Photo by Forrest Hayward.

plant biology

Revitalizing UNC’s Medicinal Garden

BY CHLOE BROWN

ucked away on UNC-Chapel Hill’s campus between the Health Science Library and Koury Oral Science building lies a secret garden. Largely overlooked by the public, the Sam W. Hitt Medicinal Garden has been a campus fixture since 2005. Those who frequent this area of campus more than likely walk through the garden without realizing its significance. However, some have taken notice and are looking to bring more visitors to the location. Under the guidance of Dr. Alan M. Jones, a Kenan Distinguished Professor, the inaugural class of “The Physician’s Garden” is moving forward with the challenge of renewing the site. With assistance from outside sources, the Medicinal Garden will finally blossom into an on-campus destination. Ten years ago, when the Health Science Library (HSL) underwent major renovations, the family of late library director Sam W. Hitt donated money to help establish the garden.1 The garden is divided into five sections, two of which are lo-

cated at the front and another two are located behind the HSL. There is also a section between the HSL and Koury Oral Science. Despite its location near one of the busiest bus stops on campus, interest in the garden has withered. It is crowded – space is limited and plants, like people, love to move. In some sections, plants are overgrown and encroach on the walkway. Weeds stake their claim in the garden as well. They are veiled in the undergrowth, hidden among the desired varieties. Signage is sparse and, unless there is knowledge of species before entering the garden, it is difficult to identify the garden’s plants. As it is now, it is no surprise that some remain completely oblivious as they pass through. Nevertheless, the garden still preserves a purpose. The Medicinal Garden is more than a collection of plants; it is the representation of a past where the fine line between medicine and poison was often distorted. Before the onset of modern medicine, practitioners looked to nature for

Photograph by Andrew Bauer

Carolina Scientific healing. Even with good intentions, the effects of some plants regularly brought harm. For instance, White Snakeroot, which was once located in the garden, was believed by settlers to cure snakebites. This plant, however, poisoned early American farmers with an illness known as milk sickness.2 The garden contains many plants recognizable by name, like rosemary and ginger, and others that are more obscure, like yarrow and boneset.3 Ginger is used as a digestive aid and to treat poor circulation, while rosemary is thought to improve memory, relieve muscle pains and spasms and stimulate hair growth.4 Yarrow is a bitter plant and acts as an astringent.4 The garden also demonstrates how practices evolve over time. A tea made from the boneset plant is now commonly used to treat colds and fevers, but historically was placed inside casts to heal broken bones.4 “I see it as an illustration of tying together the past and the present, and that when you think of medicine it’s not just the pills you pick up from CVS or Target,” said Dawne Lucas, the Special Collections Librarian at the Health Sciences Library.1 “[Medicinal gardens] draw from past practices and some current practices as well,” Lucas said.1 The Special Collections at HSL oversees the garden. Laughing, Lucas clarified that “the librarians are not getting into the dirt and doing the gardening.”1 Instead, it is UNC Facilities Services that maintain the garden. Even with the ongoing maintenance of the garden, there is opportunity for UNC students to help in the garden’s beautification. “The Physician’s Garden” is a unique course offered for the first time this fall. It is composed entirely of transfer students and aims to provide knowledge of human and plant interactions in a variety of ways. Students in “The Physician’s Garden” are working with staff at HSL and the North Carolina Botanical Garden to bring change to the Medicinal Garden. Some of these changes include updating the list of plants, revamping the website and using new signage to provide visitors with an interactive and educational experience. It is expected that the class will be offered again and future students will carry on the project, with each subsequent class assisting in the growth of the garden. There is no doubt that there is work to be done, in and out of the garden. The hope is that as time goes on, those who repeatedly visit will be able to track the progress made. Likewise, newcomers to the garden will leave enriched with a sense of history and understanding of medicinal plant life. In the meantime, the garden will still be there, inviting visitors to get close and smell the rosemary.

plant biology

The Sam W. Hitt Medicinal Garden, photos taken by Chloe Brown (above). An assassin bug and honey bee found in the Medicinal Garden. Photos taken by Andrew Bauer (below).

References

1. Interview with Dawne Lucas. 09/18/2015. 2. Stewart, A. White Snakeroot. In Wicked Plants; Algonquin Books of Chapel Hill.; Chapel Hill, NC; Vol. 1, pp 213–215. 3. Plants A-Z. http://hsl.lib.unc.edu/medicinalgarden/atoz. (Accessed September 18th, 2015). 4. Herb Chart (Boneset, Ginger, Rosemary, Yarrow). http:// www.anniesremedy.com/chart.php. (Accessed October 12th, 2015).

plant biology

h, the outdoors: a source of terror and delight throughout millennia. Saunter through the woods for a while and you’re sure to come across some innocuous looking berries. They look eerily similar to edible fruits, but they’d kill you if you ingested them. The understanding of botanicals has been a gradual process over millions of years, to the detriment of some unfortunate primates via trial and error. However, Dr. Alan S. Weakley, a plant systematist and plant community ecolDr. Alan Weakley ogist, can navigate the outdoors without much fear. Contracted a rash from poison ivy? Crush up some leaves from Impatiens capensis (Jewelweed) and the mucilaginous substance will soothe it. Looking for something to munch on during your hike? Pick a few fruits from Vaccinium pallidum (Lowbush Blueberry) or Asimina triloba (Paw-Paw) and you’ll be fueled. As a plant systematist, Dr. Weakley can identify and differentiate between thousands of plants in the wild and hopes to pass along that knowledge to students at UNC-Chapel Hill. Dr. Weakley has been at UNC since 2002, working as an adjunct professor, mentor and as the director of the UNC Herbarium, which is currently the largest herbarium in the Southeastern United States. He attended UNC for his undergraduate degrees in botany and comparative literature and considers teaching at his alma mater a special privilege. He is the professor of a class called Local Flora, where he educates students about taxonomic significance in the world of flora and how to identify different species by rubbing, chewing, licking, crushing and smelling plants. Dr. Weakley considers this his dream job. He loves being a mentor to students who are interested in his field of work. “I find it satisfying to teach a new generation and educate people about the importance of plants and biodiversity in people’s lives.”1 When not in the classroom, Dr. Weakley can be found in the UNC Herbarium. The herbarium is essentially a museum of pressed and dried plant specimens from all over the globe. The specimens document the taxonomy, distribution, native species habitats and introduced naturalized species in the region. “These specimens form the basis for a variety of research – medicinal, conservational, classification, taxonomical, biogeographical for the area and beyond.”1 Dr. Weakley explains. The herbarium is currently undertaking the enormous task of digitizing all of these specimens, along with about a hundred other herbaria in the Southeast, in order to make the information more available to researchers and the public through the same data portals. To date, Dr. Weakley has collected over 400 specimens and has annotated over 3,500 for the herbarium.2 “The herbarium represents a kind of long term investment where I get to take advantage of information that has been gathered since the 1820s. I get to use resources that were generated in the past and I am generating resources that will be utilized in the future.”1 Indeed, some of the oldest specimens are nearly two hundred years old, yet still they maintain most of their form and color. Gathering, assorting and preserving them are an advantage to scientists who wish to obtain DNA samples, measure features, deduce phylogenetic significance and generate predictions about evolutionary patterns.

Carolina Scientific

plant biology

thereâ&#x20AC;&#x2122;s no monotony in botany

BY ALEXANDRA TRIBO ILLUSTRATION BY LAURA HAMON

plant biology

The phylogenetic patterns that plant systematists discover through their studies have predictive value and allow for hypotheses about the history of life. Virginia’s diverse and unique botanical heritage.3 Gardeners, botanists, and students alike can employ the material which include descriptions on morphology, habitat, fruiting times and status.3 The Digital Age demands alternative means of sharing information, and Dr. Weakley has complied through his development of an application for smartphones called FloraQuest. “It was developed because traditional manuals are so extensive and cover so many species. This makes for a rather large and unwieldy book that cannot readily be taken into the field,” said Dr. Weakley. The digital version offers some advantages to a manual because it utilizes visual key-to-keys, interactive dichotomous keys and geography to filter results. “You’re not going to find a fir tree in the piedmont of North Carolina, so it won’t show up in your results,” said Dr. Weakley. The app can also link to digital photos and line drawings that are not feasible to put in a printed book. There is also a social media aspect of FloraQuest, where users can post and share observations, report new findings and upload photographs to a database, which can be shared via Facebook or Twitter. The app excellently represents a modernization of the plant identification process and is a citizen science and crowdsourcing modality to building an information base of plants in the region. All of this is possible because of a scientist’s herculean willingness to tread through the often-merciless outdoors. The publication of digital and printed resources is the outcome of countless excursions. Plant systematics is tedious and dirty work, but it is necessary in order to identify and document Earth’s biodiversity and organize that information into

Figure 1. (Top) The undersurface of Thelypteris kunthii (Southern Shield Fern) exhibit geometrically arranged sori that contain spores that will eventually be dispersed. (Bottom) The leaves of Impatiens capensis (Jewelweed) can “deflect” water droplets and are virtually un-wettable. Photographs by Alexandra Tribo. The product of such extensive research is a colossal amount of information. Much of this has been partitioned into various texts, one of which Dr. Weakley has recently published alongside a team of collaborators. Flora of Virginia is a comprehensive manual of plants endemic to Virginia and the surrounding states comprising the Southeastern region. His work includes ongoing taxonomic research to ensure that the Flora reflects the most current nomenclature and phylogenetic relationships, development of keys for families, genera and species, and inclusion of phenology, habitat and identification information for taxa.3 The goal of this manual is to provide a tool for plant identification and study, to incorporate the latest genetics-based information on evolutionary relationships, and to increase appreciation of and interest in conservation of

Photograph by Andrew Bauer.

Carolina Scientific

plant biology

Figure 2. Many flora manuals contain botanically accurate illustrations as a reference. This one in particular depicts a species of passionflower, Passiflora miniata. an accessible catalogue. The phylogenetic patterns that plant systematists discover through their studies have predictive value and allow for hypotheses about the history of life.4 Every new discovery and subsequent classification help to expose the grand portrait of organismal life by uncovering the lineages of species and the previously unknown relationships amongst them. Dr. Weakley is one of the scientists dedicated to this purpose, even if it means trekking through foreign terrain during adverse weather conditions or figuring out how to bypass what botanists colloquially refer to as “rhodo-hells” – dense thickets of rhododendrons that often form an impasse in the field. “The relationship between humans and plants is a long one,” Dr. Weakley said, “We are completely dependent on plants for our lives, but the increase in the population and increase in urbanization has made the relationship more complicated and problematic.” This sentiment resounds with many within the field, who believe that humans ought to recognize their basic connection to the planet, despite the increasing

modernization of society. Dr. Weakley considered thoughtfully, “Maybe we have to work harder nowadays to stay cognizant of an understanding of the importance of plants and the natural world of our own existence.”

References

1. Interview with Alan S. Weakley, Ph.D. 09/04/2015. 2. Collectors of the UNC Herbarium: Alan Stuart Weakley. http://www.herbarium.unc.edu/Collectors/Weakley_Alan. htm. (Accessed September 4th, 2015). 3. The Flora, Conservation, and Education: Toward the Future. http://floraofvirginia.org. (Accessed September 21st, 2015). 4. What is Systematics and Why is it Important? http:// www.biosci.ohio-state.edu/~jfreuden/JVF/System.html. (Accessed September 7th, 2015).

plant biology

PLANT HOMICIDES By Andrew Bauer

Image by Scot Nelson, CC-BY-2.0.

he University of North Carolina is full of plant murderers. In an effort to make plants more resistant to bacterial infection, a UNC-Chapel Hill professor purposely infects sacrificial plants. Ultimately, the goal is to fully understand how plants are infected so that infection-resistant plants can be created. Every year, farmers ward off disease from their fields. In an attempt to curb the inevitable, farmers rely on the use of pesticides to maintain a healthy crop. While the use of pesticides contributes to higher yield percentages, pesticides have a multitude of negative impacts on the environment. Creating plants resistant to bacterial infection would greatly reduce pesticide use, which would have a significant and positive impact on the environment. Dr. Sarah R. Grant, a Research Associate Professor at UNC, has been diligently working over the last decade towards understanding the interactions between plants and their bacterial attackers. She has studied the effects of Pseudomonas syringae (P. syringae), plant bacteria that cause leaf spot disease, on the Arabidopsis plant. Dr. Grant selected Arabidopsis as her test subject because it is one of the few plants that has a fully sequenced genome. This allows a more in-depth understanding of how the plant is infected by P. syringae. To be successful in its infectious mission, P. syringae secretes an enzyme that interferes with Arabidopsis’s immune system. “Much like how a parasite wants to infect its host while keeping it alive, P. syringae’s goal is to infect the plant without triggering a defensive response,” Dr. Grant explained.1 From there, the bacteria consume the plant’s store of sugar

Figure 1. Spots forming on a leaf in order to prevent the spread of a bacterial infection. Image by Scot Nelson, CCBY-2.0.

to fuel its own reproduction. The bacteria are spread by the splashing of raindrops and cause yellow lesions on the plant’s leaves.1 Dr. Grant is particularly interested in the instances at which a plant “realizes” it is under attack. Plants cells are able to detect the presence of a bacterial infection Dr. Sarah Grant in two different ways. First, plant cells are sensitive to the presence of the flagella that many plant pathogens are equipped with. This part of the bacterium is what triggers a response from the plant. Secondly, plant cells possess effector-trigger immunity (ETI) receptors.1 It is the job of these receptors to notice the presence of effector proteins released by the attacking bacteria.2 These effector proteins are able to shut down the immune response of the plant. Once bacteria are detected, the plant initiates one of two possible responses. In the first scenario, when plant cells realize that the plant is under attack, they swiftly self-destruct around the infection, forming leaf spots that encapsulate the bacteria (Figure 1).2 While the plant does not have any means of getting rid of P. syringae, encapsulating it stops the spread of infection. This reaction is more of a Band-Aid – not a longterm solution to the problem. In the second scenario, if the plant possesses genes resistant to P. syringae, it is in a better immune state. From the beginning, the resistant plants are able to shut down the effector proteins in the bacteria.2 This is a more effective solution than forming spots, as it actively prevents a bacterial infection from occurring. While both encapsulating the infection and shutting down the bacteria’s effector proteins help plants survive, the latter mechanism is of particular interest to scientists. This is because Arabidopsis’s effector resistance genes allow it to maintain healthy, non-spotted foliage.1 The eventual production of plants resistant to bacterial infection will reduce pesticide use greatly. Thanks to the continuous hard work of Dr. Grant and other scientists, food crops are now being used in bacterial-resistant studies. After several years of investment, promising results are finally beginning to show.

References

1. Interview with Sarah Grant, B.S. 09/09/15. 2. Dodds, P. N.; Rathjen, J. P. Nat. Rev. Genet. 2010, 11, 539548.

Carolina Scientific

RAISED RIGHT

factors influencing a successful upbringing

By Elizabeth Henry

Illustration by Kristen Lospinoso

raumatic experiences – whether it was a car accident, a childhood bully or the death of a family member, we have all experienced some sort of trauma in our lives. While some people believe we can get past these events with few long-term effects, this is not always true. It is these experiences that shape who we are as people, and we can see these effects in studies of child development. Dr. Martha Cox is a professor in the psychology department at UNC-Chapel Hill. She is best known for her longitudinal research of families and the development of children. A longitudinal study is one which involves studying the same subjects over a long period of time, usually several years. The benefit of longitudinal research is that “it allows sequences of events to be observed and pieced together,” instead of ‘snapshots’ of one-time observations.1 Dr. Cox’s most recent research, called the Family Life Project, involves the study of 1200 children and is intended to help these children transition successfully from childhood to adolescence. Families were chosen from three counties in North Carolina and three counties in Pennsylvania with high poverty rates. Over a number of years, Dr. Cox and her fellow researchers conducted in-home visits with families to facilitate and observe the interactions between parents and children over a period of several hours. Experiments were done in the home to create a familiar and naturalistic environment for families. By observing how parents raise their children, researchers can intervene appropriately to best help both parents and children in their development. Early experiences in our lives can greatly impact our development, but one may not realize just how many environmental factors can affect the developmental process. Some of the more obvious factors include family relationships and schooling (referred to by psychologists as the ‘microsystem’), but one should also think of what is called the ‘exosystem.’2 This includes things that do not directly involve children but still affect them. For instance, if a mother has a stressful day at work, she may take that stress out on her husband and child, which in turn causes family tension and stress on the child. Even though the child had nothing to do with its mother’s bad

day at work, the child still experiences the negative effects of that stress. Some things Dr. Cox and her fellow researchers look for in their home visits include simple interaction between the parents and their child. “[We] set up certain situations and observe recorded videos of how the parent interacts with the child,” Dr. Dr. Martha Cox Cox said.1 For infants, it is very important to Dr. Cox that she sees the “signals” infants express when they are bored, agitated or showing any other emotions. “You can see how sensitive parents are to those kinds of signals, and how they help the infant stay regulated, which allows [the infant] to eventually regulate its own emotions and behavior,” Dr. Cox said.1 The self-regulation of a young child’s emotions is crucial going into the preschool years because children do not always get their way, and they must self-regulate their emotions in order to accept and move past difficult situations. This research has important implications in the everyday lives of children. “[This research] is very important for how well kids are going to do in school,” Dr. Cox said.1 If children do not have the support they need at home, it is almost impossible that they will do well in school. “It all starts in the home,” she said.1 The children Dr. Cox began studying as infants are now around 12 years old and transitioning into adolescence. While the Family Life Project is only funded long enough to see the children until the end of their middle school years, Dr. Cox hopes to be able to renew the funding and observe the children as they transition into late adolescence and early adulthood. She believes it will be both interesting and rewarding to see how the children in her study mature and live as adults.

References

1. Interview with Martha J. Cox, Ph.D. 09/15/15. 2. Santrock, J. W.; Child Development; McGraw-Hill Education: New York, 2014.

neuroscience

PREDICTING PATHOLOGY uncovering secrets of the mind Illustration by Seeun Jung

By Lynde Wangler

t’s a fact: as we age, our memory fades. Forgetting where you parked the car, what you did with your jacket or the name of that one acquaintance are all common instances in which we may realize our memory is not what it used to be. Even though we recognize the aforementioned occurrences as indicative of typical age-related decline, several, more nuanced signs exist that may be the key to distinguishing normal from pathological aging. Dr. Kelly Giovanello and her research team in the Cognitive Memory of Neuroscience Laboratory (CMN lab) at UNC-Chapel Hill are working to interpret these signals in order to create a predictive model for identifying people who are at an elevated risk of developing Alzheimer’s disease. The CMN lab investigates the neural associations involved in memory using a “multimodal method,” in which information from several distinct imaging techniques is integrated to provide a detailed visual of the brain when a subject is completing a memory task in the MRI scanner. Dr. Giovanello suggested that this technique is ideal for investigating the science of mild cognitive impairment and early Alzheimer’s disease because “different imaging modalities give you different types of information.”1 This can give researchers a more complete picture of the biology of normal aging versus the sequential emergence of biomarkers indicating early Alzheimer’s disease. The types of imaging techniques employed include structural MRI (informing brain volume and white matter integrity), functional MRI (revealing communication between brain regions during a cognitive task) and PET (providing information about brain metabolism; Figure 1). One of the research projects currently in progress in the CMN lab measures objective memory recognition (i.e. did you see these two words paired together?) as well as a meta-memory component, which requires research participants to make confidence judgments about their recall (i.e. how certain are you of this decision?). Thus far, the CMN lab has discovered

that people with mild cognitive impairment tend to use extraneous areas in the brain to perform the same tasks as those with normally aging neurophysiological structures.2 This is an especially important finding because those with mild cognitive impairment suffer exclusively from decreased day-to-day Dr. Kelly Giovanello memory capabilities, remaining unimpeded in other cognitive tasks that are included in attention, language and executive functioning. The lab’s recent research findings indicate a significant correlation between subjects’ abilities to perform memory tasks accurately and their abilities to assess their performance on the tasks. Dr. Giovanello and her colleagues have discovered that a disconnect between objective memory (recall) and meta-memory (confidence judgments) may be a primary indicator of mild cognitive impairment in people with early Alzheimer’s disease. As Dr. Giovanello explained, “clinicians will tell you that the individuals they worry about are people that, when they get a memory judgment wrong, are highly confident that they’re right.”1 This discovery has the potential to substantially affect clinical protocols for identifying patients with functional and structural changes in the brain that could potentially lead to a heightened risk for the development of Alzheimer’s disease. Researchers at the CMN lab are looking forward to exploring the relationship between failures to activate meta-memory regions in the brain and poor confidence judgments. Dr. Giovanello noted that with MCI (mild cognitive impairment) patients, clinicians can use the information gleaned from a subject’s confidence judgments in the clinic to determine

Carolina Scientific whether the subject is likely to have meta-memory problems related to the development of Alzheimer’s disease. This new protocol has the potential to evade spending large amounts of money on a brain scan. As with several other chronic and progressive diseases, faster recognition of symptoms allows for earlier intervention, which can ultimately improve conditions for the affected population. When asked about the broader impacts of her research, Dr. Giovanello explained that currently, by the time diagnoses are made, the disease has progressed to such a degree that there is extensive and irreversible structural change in the brain. Furthermore, little is known about effective therapies and interventions in very early Alzheimer’s disease, which is why she and her colleagues have chosen to study patients with mild cognitive impairment. If they can determine the means and the magnitude to which mild cognitive impairment is associated with early Alzheimer’s disease, then it might become possible to implement effective intervention.3 Dr. Giovanello also emphasized the importance of disseminating the laboratory’s research findings in the community. She frequents elderly communities to discuss her research with those who are interested in learning about memory and the processes of normal and abnormal cognitive aging. The CMN lab also presented its findings at the annual UNC Science Expo, which affords students and other community members the opportunity to learn and ask questions about the lab’s work. Alzheimer’s disease research is especially salient as over 5.3 million Americans have this disease, and there is no known cure or even treatment to slow its progression.4 Therefore, the studies that Dr. Giovanello and her team of researchers con-

neuroscience

Figure 1. Example of a PET image from the CMN lab. Image courtesy of Dr. Giovanello. duct are of great significance and produce remarkable implications for the potential revolution in the diagnosis and intervention of Alzheimer’s disease.

References

1. Interview with Kelly Giovanello, Ph.D. 09/24/15. 2. Bear, M. F.; Connors, B.; Paradiso, M. (2015). Neuroscience: Exploring the Brain (4th ed.). Philadelphia: Lippincott Williams & Wilkins. 3. Giovanello, K. S.; De Brigard, F; Ford, J. H.; Kaufer, D.I.; Burke, J.R.; Browndyke, J.N.; Welsh-Bohmer; K.A. J Int Neuropsychol Soc. 2012, 18(5). 4. 2015 Alzheimer’s Disease Facts and Figures. http://www. alz.org/facts/overview.asp (Accessed September 24th, 2015).

Illustration by Smrithi Valsaraj

Image public domain.

neuroscience

Transcranial Stimulation By Carrington Merritt

ess is more – a sentiment that we are all familiar with. Recent research in the UNC-Chapel Hill neuroscience lab of Dr. Flavio Frohlich has found that the saying may even apply to brain stimulation and its effect on cognitive performance. It may seem counterintuitive, but a study first-authored by UNC Neurobiology Ph.D. candidate Kristin Sellers indicated that stimulation of the frontal cortex in healthy human participants resulted in decreased cognitive performance. Sellers’ research in the lab of Dr. Frohlich primarily investigates neural mechanisms underlying attention and other cognitive processes. This study used a form of brain stimulation called transcranial direct current stimulation (tDCS). tDCS is a noninvasive brain stimulation method that applies a weak

electrical current to the brain by placing external electrodes on the scalp.1 The electrical current is applied for a fixed period of time at a constant level and then turned off. Individuals receiving the stimulation feel nothing more than mild tingling of the skin near the electrode. This stimulation slightly alters the natural rhythms of the brain and makes neurons more likely to fire. tDCS is not strong enough to directly activate neurons, but rather provides a small boost in excitability and communication strength of already active cells. In other words, “you’re not going from zero to one hundred,” in terms of neural activity.1 When asked why the study was done, Sellers responded, “There has been a lot of interest in how we can use brain stimulation to aid cognitive per-

formance.”1 The frontal cortex was targeted for this study because it has been associated with several functions of cognition such as Kristin Sellers general and fluid intelligence, working memory and visuospatial reasoning.2,3 The benefits of aiding cognition through transcranial stimulation could include enabling cognitively impaired individuals to regain some of their lost abilities, as well as enhancing cognitive performance of non-impaired individuals. This type of stimulation has been effectively used in treatment of other conditions such as depression and stroke. Many researchers in the field of

Carolina Scientific neuropsychiatry also believe that tDCS offers a new and promising treatment technique for various neuropsychiatric disorders.2,3 Sellers and her research team assessed the effect of tDCS on cognitive performance by comparing IQ test scores of healthy, adult participants who received actual stimulation versus a mock stimulation. The experiment was composed of two sub-studies, one study in which participants received stimulation on both sides of the scalp and one in which stimulation was administered on only the right or left side of the scalp. To establish a baseline, all participants took the IQ test once prior to receiving any form of tDCS. Several days later, participants returned for a second testing session. For twenty minutes prior to the second test session, participants received either actual tDCS to the frontal cortex or a mock stimulation (Figures 1 and 2). As expected, scores from both groups improved on the second administration of the IQ test. However, the participants who received mock stimulation had unexpectedly greater improvement on their scores compared to those who received the actual tDCS. This was true even for the sub-study that only administered tDCS to one side of the scalp. In explaining the results, Sellers indicated, “The change in the scores of anyone who received actual stimulation was significantly different from those who did

Figure 1. The highlighted red area indicates the motor cortex located within the frontal lobe. The tDCS was applied to this cortex because it is easy for researchers to measure the effects of the stimulation. Image by Was a bee, CC-BY-SA 2.1 JP.

neuroscience

Figure 2. The electrical field induced by the tDCS is represented. Areas of blue and green indicate the frontal cortex areas where the electrical current was the strongest. Image from http://www.sciencedirect.com/science/article/pii/ S0166432815002739. not,” with participants who received true tDCS scoring less well.1 From these results, it is clear that tDCS applied to the frontal cortex does not provide the cognitive enhancement predicted. Not only did the stimulation fail to enhance cognitive performance, it rather appeared to diminish the participants’ existing cognitive abilities. These surprising results evoked speculation as to why tDCS had such an effect. Previous studies using tDCS have revealed that this type of stimulation applied to one hemisphere causes decreased blood flow in the frontal lobe of both sides immediately following the stimulation, which could account for decreased cognitive performance. Additionally, there is some evidence that tDCS can cause a temporary “frontal lesion” effect, or impairment, which could also decrease cognitive ability.4 Sellers indicated that even though the results of this study were not as predicted, there are still further avenues for research involving tDCS and cognitive enhancement. Future experiments may involve applying stimulation to different areas of the frontal cortex, altering the length of exposure to stimulation, or even altering the strength of the electrical current. It is also possible that another form of non-invasive stimulation, transcranial alternating current stimulation (tACS), may have a different effect on cognition. Unlike tDCS, which applies one constant current, tACS applies an alternating current that more accurately simulate the natural rhythms of the brain. As far as the results of this study,

Sellers noted, “this study is a bit of a warning that brain stimulation is not a fix-all, cure-all” solution to improving cognition.1 These results are especially relevant, as there is a growing movement toward “do-it-yourself” brain stimulation or “brain hacking” products that claim to improve performance on tasks such as playing video games or studying for tests.1,2 Admittedly, a brain stimulation device that could help someone get to the next level of Call of Duty or perform better on an upcoming biology exam sounds enticing, but it is important to determine if such feats are actually possible with the simple act of placing a few electrodes on one’s head. To those hoping to purchase commercial stimulation devices advertising improved cognitive performance, it is best to wait until the effects of tDCS and other stimulation modalities are better understood in scientific and clinical settings. Until then, improving cognitive performance on tasks such as test taking must be done the old-fashioned way – with lots of caffeine and late night study sessions.

References

1. Interview with Kristin Sellers, Ph.D. Candidate. 09/14/2015. 2. Sellers, K.K.; Mellin, J.M.; Lustenberger, C.M.; Boyle, M.R.; Lee, W.H.; Peterchev, A.V.; Fröhlich, F. Behav. Brain Res. 2015, 290, 32-44. 3. Loo, C.K; Martin, D.M. Expert Rev. of Neuro. 2012, 12, 751-53. 4. Email with Kristin Sellers, Ph.D. Candidate. 09/19/2015.

psychology

Taming Tantrums With Technology By Hannah Jaggers

Illustration by Maddie Fletcher

urprisingly, smartphones can be used for more than just playing Angry Birds and viewing Snapchat stories. Dr. Deborah Jones and her research team at UNC-Chapel Hill’s Department of Psychology are using smartphones as a mechanism of treatment for child behavioral problems in low-income families. Dr. Jones has developed an iPhone application called Tantrum Tamers, which provides parents with resource tools on how to discipline their children and stay connected with treatment goals. With the application ready to use, Dr. Jones hopes to better serve those families that are most in need of treatment. Statistics concerning early-onset disruptive behavior consistently show that low-income families are the majority demographic in need of behavioral treatment for children. However, low-income families are often unable to engage in treatment services due

to obstacles such as money, time and transportation. Early-onset behavioral disorders often predict further antisocial behaviors in adulthood and can lead to medical and criminal justice costs for the families and society as a whole. Child behavioral problems in low-income families can easily become a public health concern if more emphasis is not put on treating children in families without access. “I realized that so much of what we talk about in psychology is based on research with white, middle class, twoparent families and that’s not everyone who’s out there,” Dr. Jones said.1 Twenty-two low-income families participated in Dr. Jones’ pilot study, in which some families received a standard treatment program for early-onset behavioral disorders called Helping the Noncompliant Child (HNC). HNC is a Behavioral Parent Training (BPT) program that focuses on teaching parents the most efficient ways to discipline their

children. The HNC program is individual family-focused and criterion-driven, meaning that families must master a skill before moving to the next Dr. Deborah Jones one. Other families received a Technology-Enhanced HNC program (TE-HNC), which included the use of smartphone functionality that served to keep families engaged in the treatment between in-person HNC sessions. The only difference in treatment between families enrolled in the HNC and TE-HNC programs was the use of smartphone applications that served to increase opportunities for feedback, support and skill modeling between inperson therapy sessions. Families were provided with iPhones throughout the treatment and for 3 months after treatment to determine the extent to which technology helped families maintain

Carolina Scientific treatment gains even after the study was complete. Families in both groups were required to see a therapist at least once a week during the program. “The nice thing about the way we set up the study design is that all of the families get treatment, with half of them also using the technology,” Dr. Jones said. “So my motto is regardless of whether the hypotheses work out the way we think they’re going to, everyday we know we’re being helpful to people.”1 The Tantrum Tamers application was not yet developed in Dr. Jones’ first pilot study, so parents in the TE-HNC treatment program used applications like FaceTime and Survey Gizmo to enhance TE-HNC treatment, such as brief daily surveys of skill practice and progress, text message reminders for next appointments, video recording of home treatment practice for therapist review and coaching, midweek video calls with a therapist to reinforce and/or problem solve use of skills at home and a skills video series, which provided modeling for parents as they practiced and learned to use the skills at home and in the context of their daily lives. The at-home video recordings of treatment proved to be very useful to Dr. Jones and her research team. At one point during the treatment program, parents had to designate a particular time-out chair that was isolated from the rest of the family in a quiet corner of the house. “For low-income families, that might not be possible,” Dr. Jones said. “So, this mom walked us around and said ‘I don’t have what you’re saying, but can you help me pick what makes the most sense?’ and we thought, ‘that’s fabulous!’”1 Dr. Jones said that the main idea behind the use of technology was to ensure that families knew that her research team was supporting them throughout the treatment when they were not faceto-face with the therapist. The technology served to remind the families of what they should be working on with their children and why the task was important. The pilot study revealed that the

TE-HNC treatment group yielded greater program engagement, improved child treatment outcome, and that the TEHNC families required less sessions than the HNC treatment families to complete the program. “For low-income families [the

psychology “There are a lot of people in psychology talking about how technology is going to fix all that is wrong in mental health,” Dr. Jones said. “We just need to be thoughtful about what the technology is, why we are using that technology, what do we want to do with it and why is it most helpful for this group.”1 Dr. Jones also expressed the importance of making sure that technology-based treatment remains applicable beyond research studies. Clinicians must be willing to use unconventional but effective methods in order to better serve families with treatment that is both efficient and directly tailored for individual families. Considering Dr. Jones’ pilot study results, psychologists should expect to see a lot more parents scrolling through their iPhones, but not because they are playing Angry Birds.

Statistics concerning early-onset disruptive behavior consistently show that low-income families are the majority demographic in need of behavioral treatment for children. fewer required sessions] is critically important,” Dr. Jones said. “We have families who drive large distances and might not have money for gas, so the more effective and efficient we can make the therapy, the better.”1 The positive results from her pilot study led Dr. Jones and her research team to conduct a larger study with 102 families. Now that the Tantrum Tamers application has been developed and is available for use during the TE-HNC program, families are using the multiple smartphone enhancements all in one convenient application. Some issues can arise when using technology as a treatment mechanism, namely the fact that increased use of smartphones might take away attention that parents could devote to their children. “We absolutely don’t want to do that,” Dr. Jones said. “So we were very careful to make the things that they were doing on the phone very time limited.”1 One component of the Tantrum Tamers application, for example, is a skills video series. These videos are 3 5 minutes and model and reinforce the skills that the families were taught during their face-to-face therapy sessions. “They can go home with their new video and watch it to remind themselves what they’re learning and why it matters,” Dr. Jones said.1 Dr. Jones said that although she fully supports the idea that technology can help treat many psychological issues, the application of technology must be looked at theoretically before treatments begin.

References

1. Interview with Deborah Jones, Ph.D. 09/17/15. 2. Jones, D.; Forehand, R.; Cuellar, J.; Parent, J.; Honeycutt, A.; Khavjou, O.; Gonzalez, M.; Anton, M.; Newey, G. J Clin. Child Psychol. 2014, 43, 88-101.

Figure 1. Tantrum Tamers application. Image courtesy of Dr. Jones.

psychology

BREAKING FREE FROM ADDICTION studying stress and habit learning BY GRACE GUO

ince the discovery of the mind-altering effects of cocaine, alcohol and other addictive drugs, society has dealt with problems of abuse and addiction caused by “public enemy number one.” The impact of drug use in the United States is huge, affecting not only individuals who use drugs but also their family and friends, the healthcare system and the criminal justice system. One step toward curbing drug addiction is understanding the neurobiology of substance use disorders. At UNC-Chapel Hill, Dr. Charlotte Boettiger, Associate Professor of Psychology and Neuroscience, core faculty member of the Biomedical Research Imaging Center and principal investigator of the Cognition and Addiction Biopsychology Lab (CABlab), leads a group of researchers who use behavioral, neuroimaging and genetic techniques to investigate irregular neurobiological mechanisms associated with addiction. The translational science work done in the CABlab may eventually help improve prevention strategies and treatment plans that make drug rehabilitation more efficient. One aspect of their work is related to habit learning. Habits are useful when they allow an automatic response to familiar stimuli in the environment, enabling the brain to face other challenges. However, habitual behaviors become negative when they continue to occur despite harmful consequences, as in the case of drug addiction. Theresa McKim, a CABlab doctoral student who studies how stress can affect behaviors in both people with a history of drug addiction and in healthy people, commented, “Chronic stress plays a role in how we deal with daily life, and we focus on how it might re-

Image by e-Magine Art, CC-BY-2.0.

late to addiction. People with a history of addiction might take drugs as a result of stress, which is a major proponent of the drug use cycle.”1 These findings could have major implications in the understanding of treatment interventions for substance use disorders, as well as other disorders that are characterized by intractable habits, such as Dr. Charlotte Boettiger obsessive-compulsive disorder. People’s actions are controlled by two main, distinct behavioral systems. The first is goal-directed, or flexible behavior, which involves learning associations between actions and the reward of an outcome. The second is habitual actions that involve learning associations between stimuli and responses. The CABlab’s previous research found that people with a history of addiction showed a propensity to acquire habitual behaviors and had trouble changing these associations. The inability to change habitual behaviors is a risk factor for addiction and could promote relapse during rehabilitation. Individuals may start using drugs because their goal-directed behavior tells them it feels “good.” However, after continuous drug use, it transitions into an uncontrollable habit-based behavior driven by drug cues and environments. McKim also wanted to determine whether acute stress increases habitual responding in healthy people without a history of addiction. To cause stress for a participant in the lab, researchers used the socially evaluated cold-pressor

“Chronic stress plays a role in how we deal with daily life, and we focus on how it might relate to addiction.” Dr. Charlotte Boettiger

Carolina Scientific

psychology

equivalent group of females, but we haven’t tested enough of any other group of females to draw any conclusions about them,” Dr. Boettiger said.3 Furthermore, the biological mechanism of stress promoting habitual behaviors is not exactly clear. “It’s possible that stress is taxing parts of the prefrontal cortex that helps us use goal-directed over habit-based strategy,” McKim said.1 After discovering that stress makes people more likely to show habitual behavior, McKim is enthusiastic about expanding her study. “We know very little about the human neural circuitry of goal directed and habitual behavior, so we want to do the test with fMRI to look at differences in brain function during our task,” McKim said.1 The research of McKim and Dr. Boettiger could lead to the development of pharmacological methods that block the effects of stress, changing behavior to prevent drug addiction and making rehabilitation more successful.

References

1. Interview with Theresa McKim, M.S. 09/14/15. 2. Schwabe, L.; Wolf, O.T. Psychoneuroendocrinology. 2010, 25, 977-986. 3. Boettiger, C. A.; D’Esposito, M. J. Neurosci. 2005, 25(10), 2723-32.

Illustration by Carley West. test (SECPT), in which participants submerge their hand for up to three minutes in ice water while being videotaped and monitored by an unacquainted and unsociable experimenter.2 Previous research has shown that undergoing this stress test makes people favor habitual actions over goal-directed learning. The learning task consisted of viewing stimuli, which were various patterns of colored pixels, and learning the correct button press associated with the stimuli through trial and error feedback.3 Then, participants came back to the lab on a different day to perform their learned stimulus-response (S-R) associations to measure habitual behavior, and were taught new associations to measure goal-directed learning. In part two of this second session, the responses that participants had learned were devalued, meaning that the correct S-R responses were changed. To determine if stress plays a role in learning behavior, participants were randomized to complete the SECPT either before learning the new S-R associations or before devaluation. Habitual behavior is evident if participants continue to push the response previously learned and do not show a change in behavior. On the other hand, people showing goal-directed behavior would use trial and error learning to change associations and overcome what was previously learned. “This is important for disorders like addiction, where individuals need to change their responses to cues that may make them more likely to use drugs or relapse,” McKim explained.1 It was found that exposure to acute social stress before learning new associations has the largest impact on changing learned responses. Even after the stimulus was changed, the participants exposed to stress still had a tendency to respond with the motor response that they previously learned. This suggests that stress can “stamp in the habit.” Results also showed that the effect of acute stress is different between males and females. “While we have detected an effect in males, we have failed to detect an effect in one

Figure 1. (Top) Participants completed the learning tasks in a mock fMRI scanner. Image courtesy of Theresa McKim. (Bottom) A few CABlab members at an fMRI scanner at the Biomedical Research Imaging Center. Image courtesy of CABlab.

neuroscience

VISUALIZING THE BRAIN By Jeffrey Young

ight now as your eyes are scanning across this page, billions of neurons are simultaneously working together, processing light captured by your eyes into words and giving those words meaning. Every thought, action and feeling that we have is controlled by the brain, a remarkably sophisticated organ that gives rise to the human condition. Scientists have been studying this organ for hundreds of years and continue to make new discoveries that enhance our understanding of this complex anatomical structure. Dr. Martin Styner, an Associate Professor in the Departments of Psychiatry and Computer Science at UNC-Chapel Hill, works in the field of neuroimaging and is trying to answer some of the many unsolved questions that surround the brain. Dr. Styner is the Director of the Neuro Image Research and Analysis Laboratories (NIRAL), an interdisciplinary lab that focuses on developing new tools and methodologies for medical image analysis and applying these tools in imaging studies to make novel discoveries. Dr. Styner first became involved in neuroimaging at the Swiss Federal Institute of Technology where he studied as an undergraduate. Trained as a computer scientist, Dr. Styner wanted to create tools that would serve and be used by others. Quoting the founder of the Department of Computer Science at

UNC, Dr. Fred Brooks, Dr. Styner said, “We [computer scientists] are toolsmiths – we create tools that enable others to do something that they otherwise would not be able to do.”1 This mindset led Dr. Styner to work in the burgeoning field of medical image processing and analysis with the goal of enabling researchers to perform studies of the brain that they otherwise would not be able to do. While working on his graduate studies in Switzerland, Dr. Styner’s graduate advisor, Dr. Guido Gerig, was offered a position at UNC. Dr. Gerig invited Dr. Styner to join him, and together they laid the groundwork for what would become NIRAL. When Dr. Gerig left UNC in 2007, Dr. Styner became the Director of NIRAL and has led it since that time. Today, a major focus of NIRAL is developing methodologies for analyzing and characterizing postnatal brain development. Many different models are employed to do this, including humans, primates and rodents. The lab primarily relies on magnetic resonance imaging (MRI) to acquire the images used in their studies (Figure 1, top). A study usually begins with the development of a suitable methodology to quantify the desired measurements. If this methodology is novel, an algorithm and a corresponding implementation in the form of a software tool will be developed by computer scientists. This step is important because not all imple-

Image by Jeffrey Young mentations of the same algorithm are created equal. Perfecting an implementation is often a time consuming process with multiple rounds of testing and validation Dr. Martin Styner required to find the most stable and efficient one. “Different implementations have different properties of stability and reliability,” Dr. Styner said.1 Similarly, the parameters used in an implementation can affect its reliability and robustness. A successful study is predicated on functional, reliable and efficient analytical tools. One of the challenges of having many researchers with diverse backgrounds working together is communicating in a way that everyone can understand. These researchers are experts in their respective fields but may have a limited understanding of other aspects of a comprehensive project. Dr. Styner often serves as an intermediary between researchers. “Often I have to translate… each side knows what they mean but sometimes cannot express their viewpoint in a way that is understood by the other side.”1 Working with postnatal brain development presents some unique challenges as well. At first, it was thought

Carolina Scientific that neonate MRI scans of reasonable quality could not be acquired. “Thanks to the pioneering imaging and image analysis research of Dr. Weili Lin [now the Director of the UNC Biomedical Research Imaging Center], Dr. John Gilmore [UNC professor and Vice Chairman for Research and Scientific Affairs], and Dr. Gerig, we realized we can obtain high quality MRIs even in very young subjects,” Dr. Styner said.1 One of the major challenges to overcome was obtaining a large enough signal to noise ratio (SNR). A large SNR ensures there is enough contrast in the image so that the brain structures are distinguishable. Obtaining a large SNR is made more difficult in neonates because the brain is so much smaller at this early stage of development. Another more obvious hurdle to overcome was ensuring the subjects remained stationary while in the scanner. This was accomplished by imaging infants during natural sleep. One of the main methodologies NIRAL uses to quantify brain development is a technology called diffusion tensor imaging (DTI). Drs. Gerig and Styner were some of the first research-

ers to start acquiring and analyzing DTI images in early brain development. DTI allows researchers to analyze white matter by measuring the direction in which water diffuses along the white matter fiber pathways of the brain, whereas traditional structural MRI images are generally useful for characterizing only gray matter. White matter serves as the connective “wiring” of the brain between its different structures and runs in fibers known as tracts throughout the brain. Analyzing these tracts has proven useful in characterizing brain development and many diseases associated with the brain. DTI images can be captured using a traditional MRI scanner. NIRAL has developed comprehensive toolsets for DTI and structural MRI analysis that are used by researchers around the world including DTIPrep, a tool designed for processing and quality control of DTI images, and SPHARM-PDM, a tool used to analyze shape changes of structures in the brain (Figure 1, middle).2,3 Many of the studies done by Dr. Styner and the NIRAL lab are based on open source and open data principals.

neuroscience This public access philosophy is quite common in the field of computer science, where many collaborators work together on a single piece of software, but exceedingly rare in the field of medical research. Since imaging studies typically cost thousands of dollars per subject, medical researchers are usually keen to keep the data closed so they (and their collaborators) can be the first to find exciting new discoveries from the data they have collected. However, because NIRAL has a multidisciplinary focus, their approach is more open. “I am interested in developing new methods, tools and resources… the creation of the data is a side effect. Without that data I cannot develop my methods and tools,” Dr. Styner said.1 NIRAL has many ways to analyze and quantify the data they gather. For example, with DTI data the focus is analyzing the white matter fiber tracts of the brain. NIRAL has tools to strip away the other brain structures and only look at the tracts. Data from other visualizations can be overlaid on the fiber tract images to create more complex and revealing images. An example of this overlaying technique, as well as other data visualizations, can be seen in the bottom of Figure 1. Dr. Styner and the NIRAL lab are at the forefront of the field of neuroimaging. As an interdisciplinary lab, they have the unique ability to develop and implement novel imaging methodologies. These tools and studies are crucial to unlocking the mysteries of the brain during early childhood – the most rapid and impactful developmental period of our lives.

References

Figure 1. (Top) Side-by-side comparison of a human, rhesus macaque, and rodent brain. (Middle) Example of visualizations created from a DTI scan. (Bottom) T2-weighted atlas of a rhesus macaque, subcortical structures in the atlas space, white matter fiber bundles running through the brain. Images courtesy of NIRAL.

1. Interview with Martin Styner, Ph.D. 09/18/15. 2. Oguz, I.; Farzinfar, M.; Matsui J.; Budin, F.; Liu, Z.; Gerig, G.; Johnson, H.J.; Styner, M. Front Neuroinform. 2014, 8, 1-11. 3. Styner, M.; Oguz, I.; Xu, S.;Brechbühler, C.; Pantazis, D.; Levitt, J.J.; Shenton, M.E.; Gerig, G. Insight J. 2006, 1071, 242-250.

medicine

Ussing chambers used in the Gentzsch Lab to monitor change in CFTR function with addition of drugs. Image courtesy of Dr. Gentzsch.

By Maddie Fletcher

oe to that child which when kissed on the forehead tastes salty. He is bewitched and soon must die.”1 Cystic fibrosis (CF) is an autosomal recessive disease that affects about 30,000 people in the US and 70,000 worldwide. About 1 in 25 people are carriers of the disease. If both parents are carriers of cystic fibrosis, there is a 1 in 4 chance that their child will have the disease. Each year, 1000 more cases are diagnosed and one indicator of this disease is extremely salty sweat.2 The protein that is mutated in CF is a chloride channel that is present in many tissue types and is involved in their function. This protein is called the cystic fibrosis transmembrane conductance regulator, or CFTR. In a healthy lung where the CFTR is functioning properly and is at the cell surface membrane, the channel allows ions to move out of the cell and into the surrounding fluid, and water follows thus hydrating the surface of the lung. Cilia beat and mucus can flow such that viruses and bacteria are transported away. In a person afflicted with cystic fibrosis, CFTR either does not make it to the surface or does not function properly, leading to dehydration of the lung. The airway surface liquid (ASL) is depleted and cilia cannot beat. This results in the buildup of mucus, which leads to an increased possibility of infection.3 Dr. Martina Gentzsch of the Marsico Lung Institute at UNC-Chapel Hill researches cystic fibrosis and is working to better understand its mechanisms to help treat patients. Various mutations affect synthesis, processing, regulation and

conductance of CFTR. Every patient’s disease is unique to them and the vast number of different CFTR mutations (approximately 2000) elicits the need for personalized treatment. As treatments of all of the different classes of CF have not been successfully discovered, Dr. Gentzsch’s lab focuses on treating patients in the best manner possible for their speDr. Martina Gentzsch cific mutations. “What we do is look at cells from patients with different mutations and see what treatments would benefit them with different assays.”3 Dr. Gentzsch continued, “Since we know what can rescue the protein, we are also looking at secondary effects, like how the clearance of mucus is positively affected. But what we are mainly interested in, and what I am very excited about is to develop personalized assays.”3 The lab has recently begun a project in which they receive lung cells after transplant. “We grow lung cells from explant lungs. When people have lung transplants, we obtain their lungs and then we can grow cells in the way that they would grow in the lungs with air above and media underneath. The cells think they are in the lung, so they start making cilia with mucus around.”3 In Ussing chambers, the lab

Carolina Scientific treats cells with different drugs and different doses to monitor change in CFTR function on the basis of current and ion conductance. The lung cells are from patients that have already passed away, but Dr. Gentzsch’s lab hopes to take this information and accommodate patients living with the disease. Deborah Cholon, a research associate in the Gentzsch Lab, explained that they want to run tests on nasal epithelium samples from patients still alive to see what drugs will be likely to work on them. The lab can look at what drugs best helped a lung with a specific mutation, and then take the nasal epithelium of the living patient with the same mutation, and start with the information that they already have. In some cases, only an adjustment in dosage may be needed. The drugs being tested include both corrector and potentiator drugs. Dr. Gentzsch stated that Kaleydeco is a drug currently on the market for patients with mutations that impair channel regulation. This type of drug is a potentiator, and opens the chloride channel in CFTR, allowing it to function more properly. However, the issue is that the most common type of CF mutation is a mutation called ∆F508 in which the protein does not make it to the cell surface. This kind of mutation requires different treatment – the treatment of a corrector to help with misfolding and to get the protein to the surface. The combination of corrector and potentiator drugs is a hot topic for CF researchers right now. One combination drug has received FDA approval after reaching a threshold of 3% improvement of lung function. However, the search is not over. As explained in a paper by Dr. Gentzsch’s team, the combination drug is not as optimal as it could be. When the corrector compound is added, the protein goes to the surface. Furthermore, when the potentiator is added there is a brief increase in function. But when both drugs are added together, there is less response. The group researched this problem further and discovered that the more that is given of the po-

Figure 1. CFTR virally introduced to and expressed in epithelial cells. Cilia is stained blue, cells expressing virally delivered CFTR are green, and CFTR is red. Image courtesy of Dr. Gentzsch.

Figure 2. Mutant CFTR protein, ∆F508, is retained in the endoplasmic reticulum and does not reach the cell surface membrane. Corrector compounds help transfer the mutant CFTR to the membrane, while potentiators increase its activity at the surface. Image courtesy of Dr. Gentzsch. two chromosomes, so you can have all kinds of combinations […] It turns out that there are also modifier genes, so even if two patients have the exact same mutations, they don’t always behave the same way. This is why personalized assays are so important.”3 Not only can the lab take cells and see how well they respond to treatment, they can also look into what other factors in the lung influence how well CFTR can be corrected. “We look at a lot of conditions like inflammation […] to make our culture model more realistic.”3 For example, if a lung is inflamed, this might change the way the CFTR protein acts. Dr. Gentzsch asserted, “[The] aim is to get a model that’s very realistic to predict how drugs will work.”3 By personalizing assays in order to devise more specific and individualized treatment, Dr. Gentzsch and her team are working to better the lives of the many people living with cystic fibrosis.

References

tentiator drug, the more the protein disappears from the surface, thus making it very unstable.4 “This shows that you really need to know how drugs act in order to make them better,” Dr. Gentzsch said.3 Dr. Gentzsch elaborated, “We want to develop individualized assays to test drugs […] because there are a lot of different mutations, but then you have to consider that you have

medicine

1. Welsh, M. J.; Smith, A. E. Cystic Fibrosis. Cystic Fibrosis Foundation, Dec. 1995. https://www.msu.edu/~luckie/cfarticle.html. (Accessed September 22nd, 2015). 2. About Cystic Fibrosis. Cystic Fibrosis Foundation. https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. (Accessed September 22nd, 2015). 3. Interview with Martina Gentzsch. Ph.D. 09/15/15. 4. Cholon, D. M.; Quinney, N. L.; Fulcher, M. L.; Esther C. R. Jr.; Das, J.; Dokholyan, N. V.; Randell, S. H.; Boucher, R. C.; Gentzsch, M. Sci Transl Med. 2014, 6(246).

medicine

Illustration by Julianne Yuziuk

PRINT AND PRACTICE:

3D Printing’s Applications In The OR By Allie Piselli

magine if your physician could perform the exact surgery to fit your specific anatomy, before you even set foot into the operating room. All of the complications and unforeseen pitfalls that happen in surgery could be eliminated – the operating surgeon would have quite literally seen it all before, down to the placement of your arteries and nerves. Dr. Austin Rose, an Associate Professor at the UNC-Chapel Hill School of Medicine who specializes in Otolaryngology-Head and Neck Surgery, had such an idea while studying medical simulation in Israel. Over the past year, Dr. Rose and a team of engineers and physicians have developed 3D models for preoperative simulation of challenging surgeries. The 3Dprinted model is based on a patient’s computed tomography (CT scan), which uses computer processing to create crosssectional images of internal anatomy from a series of X-ray images taken from different angles.1 This 3D modeling technology was recently used in the treatment of an eleven-year-old boy who had a locally de-

structive tumor removed from his middle ear and mastoid space.2 Creation of a patient-specific model allowed Dr. Rose and his team to practice the surgery before ever operating on the child. “When we go into the operating room the next day, there are really no surprises,” said Dr. Rose.1 In the case of the eleven-year-old boy, this was a clear advantage due to his abnormal anatomy from many previous surgeries.3 In addition to these practice surgeries, 3D printing is also applied in the operating room in the form of templates. For example, Dr. Rose recalled “[A child] injured by a hyena in Africa, […] was missing a large portion of his mandible”. The child’s mandibular defect was recreated from his rib cartridge. But to make sure the physician sized it right, the template was designed using “computer-aided design software.”1 The template designed was then built using a 3D printer and sterilized for use in the operating room. It allowed Dr. Rose’s colleague, Dr. Omri Emodi of the Rambam Healthcare Campus in Haifa, to cut out the rib cartridge to the exact size needed.

Carolina Scientific Going beyond patient-specific application, 3D printing’s main contribution to medicine will likely be didactic. In the past, medical students and residents have trained using adult cadaver specimens and computer simulations.3 However, one drawback to these approaches is a lack of training for pediatric cases, where the anatomy is much smaller and quite unique. “Currently, Dr. Rose holding a micro-CT we [have] residents practice hyper realistic 3D print model on cadaver temporal bones with color differentiation [a bone located on the side between the jugular vein and of the skull].”1 As a result of carotid artery. these cadavers not being standardized or representative of the pediatric anatomy, this is a huge limitation to practicing pediatric surgery. 3D modeling can also give medical instructors better insight into the competence of their students. With cadavers, it is often hard to control for the abnormalities found in different bodies when determining students’ skill levels. By 3D printing the same anatomy into multiple models for testing, examinations can be standardized through customization. Accuracy of these models can vary greatly depending on materials used. When based on a patient’s CT scan, the 3D printer can be programmed to use different colors and textures to denote different venous and arterial structures, making them easy to distinguish.3 By running a cadaver temporal bone through a micro-CT scanner and administering a high dose of radiation, resolution is greatly improved. This improves the print’s capacity for a realistic simulation. When basing the 3D print on a micro-CT scanner, the print resolution is detailed to almost the same degree as a real cadaver.1 There are, however, some limitations to 3D printing’s application. The total cost for the personalized 3D model based on the eleven-year-old’s CT scan totaled around $400, a number that is likely to decrease as the cost of printer materials continue to decline.3 At the present time, however, Dr. Rose does not believe that every patient needs a preoperative 3D model.1 “To routinely develop a model for a specific patient and do a preoperative rehearsal or simulation before someone’s surgery is along the order of $1000 dollars.”1 While not expensive in the grand scheme of surgery and medicine, the added cost may not be necessary for a safe surgery. “It may be useful for certain rare cases – certain tumors – but it certainly isn’t something you do for every patient.”1 Cost aside, Dr. Rose also envisions a database filled with different pathological cases that can be printed instead of relying so heavily on cadavers. He envisions a “library of abnormal pathologies so residents can learn how to [approach and identify] challenging anatomy.”1 Dr. Rose also sees the 3D print models applications in medicine across the globe. “There are other places in the world that don’t have access to cadaver temporal bones for

medicine

cultural reasons or otherwise.” To train residents in these areas, Dr. Rose has looked into sharing the 3D print simulations. Dr. Rose’s team has already shared information and educational materials regarding the 3D-printed temporal bone models for the purposes of training and education in countries around the world including Ghana and Taiwan. The application of 3D printing in the operating room and in surgical practice is indeed an evolving field. As more 3D models are built and resolution improves, physicians and residents alike will likely use these modeling techniques more commonly for teaching and standardized testing. The capacity for global impact is high in this project as it seeks to spread knowledge and decrease error in the operating room. Ultimately, Dr. Rose hopes the project will “reduce medical errors and improve patient safety.”1

References 1. Interview with Austin Rose, MD. 09/11/15.

2. Rose, A.; Webster, C.; Harryson, O.; Formeister, E.; Rawal, R.; Iseli, C. Int J Pediatr Otorhi. 2015, 79 740-744. 3. Rose, A.; Kimbell, J.; Webster, C.; Harryson, O.; Formeister, E.; Buchman, C. Ann Otol Rhinol. 2015, 127(7) 528-536.

Figure 1. (Top) A view of the temporal bone lab at UNC used for surgical simulation. (Bottom) The 3D printed model based off of the 11 year old’s CT scan that was printed for pre-surgical practice. Photographs taken by Allie Piselli.

medicine

Human embryonic stem cells by Nissim Benvenisty. Changes were made, CC-BY-2.5.

HUMANS ON MICROCHIPS BY AMI SHIDDAPUR

he cure to cancer could fit in the palm of your hand. Artificial organs are now synthesized on microchips thanks to the new Microphysiological Systems Program (MPS), based in several prominent universities. The MPS program is a five-year partnership between top universities attempting to revise the way that scientists test drugs.1 The current goal of the program is to generate reliable organ models to accurately predict how drugs in the developmental process would work in humans.1 In the future, an integration of the ten major organ systems into one “human-on-a-chip” could revolutionize medicine by creating streamlined solutions to medicine’s most pressing disease problems. Many offshoots of the program at universities around the world are being tasked with creating these different organs. The Allbritton Lab at UNC-Chapel Hill is focused on creating the most efficient, reproducible microchip representation of the human colon.2 But why are new ways of predicting drug toxicity needed? “We don’t even know what the downstream effects of Tylenol in the gut are right now,” said Asad Ahmad – a former graduate student in the Allbritton Lab – when asked about the immediate need for colon modeling. He elaborated, “A human on a chip would be able to map the effects of such medications throughout several organ systems.”3 Current drug testing mostly involves animal models, which fail consistently as predictors of drug interactions in humans. More than 30% of medicines that are satisfactory for animals fail in human clinical trials and lead to unforeseen side effects.1 These failures have served to make the drug testing process costly and time-consuming.4 Microchip organs would streamline the testing process during the drug development

phase, ideally eliminating the need for experiments that claim the lives of up to 90 million animals each year.5 In addition to improving upon human and animal trials, the MPS program offers several advantages over its two-dimensional (2D) and three-dimensional (3D) artificial organ predecessors. ConvenAsad Ahmad tional 2D cell cultures are unable to support live cells and accurately predict drug activities.6 Although 3D models are better at representing spatial complexity, the past 3D models could not react to mechanical stimuli without failing. The earlier 3D models also could not support fluid-based environments, which are critical to modeling human organ function.7 The organs on chips that the Allbritton Lab designed overcame these constraints by integrating the 2D and 3D systems to form a hybrid.8 Because the devices are meticulously engineered, implanted sensors can provide realtime data on cellular conditions, a result not feasible in self-organized 3D cultures. Non-invasive observation is also entirely possible with microchips because the tissues are grown on transparent platforms, and fluorescent proteins are expressed and can be used to identify specific cells.7 The transparent microchips used at UNC are lined with stem cells, which are living cells that can differentiate into multiple cell types. At about 250 micrometers wide, the microchip models of living organ tissues have a variety of functions.1 These microchips contain features designed to repli-

Carolina Scientific cate complex biological processes such as genomic diversity, biomechanical stress responses and intercellular interactions.6 Using cells derived from the large intestine, the Allbritton Lab can model several types of cells on the microchip, including mucus-secreting cells and hormone-secreting enteroendocrine cells.9 The lab successfully formed multi-functional colonic tissue that was sustainable for up to a year.2 Currently, these stem cell microchips can observably respond to stimuli such as stress and compression in the same way that our body’s cells do, and the self-renewal properties of stem cells maintain homeostasis in the microchip.2 This model is incredibly promising for future therapies. If the chips were lined with specific patientderived stem cells, they could provide a way to develop individualized therapies and further the understanding of the genetic determinants of disease.3 This has profound implications for the future of medicine, illustrated by the work on the “colon-on-a-chip” being done at the Allbritton Lab. Currently, researchers believe that the high rate of colorectal cancer in the Western world may arise at the level of the stem cell, and that inflammatory bowel diseases result from attacks on intestinal cells.8 The American population, known for consuming fatty foods that are harder to digest, could benefit from more individualized therapies that focus on their specific food intake patterns and their consequences. The Allbritton Lab was the first to reinvent the microenvironment of the colon using mouse-derived stem cells, and Ahmad specified that a large reason for the success of UNC’s program was their interdisciplinary focus on both biology and engineering. Ahmad, who received multiple degrees in mechanical engineering, asserted that collaboration with bi-

medicine

ologists allowed the program to reach heights it never would have otherwise.3 Many “organ-on-a-chip” projects still rely on the use of cancer cell lines, or specific cancer cells that divide and grow over time. While viable for the project, these cancer cells reflect normal tissue physiology poorly, whereas the Allbritton Lab’s stem cells are very similar to tissue under standard cell culture conditions.3 Over the past two years, the several universities working under NIH offshoots have engineered ten different organ systems separately, including fully functional heart, lung and stomach models. For example, the HarvardWyss team created a “guton-a-chip,” which synthesizes digestive enzymes, hormones and mucus to attempt to treat diarrheal issues.10 The current focus of the MPS has now shifted to integration of the organs to model inter-organ interactions and incorporate multi-system hormonal and immune responses to drug exposure. In July 2014, the Wyss offshoot developed a system to simulate circulation between the different organ systems. Other offshoots at Columbia University and Duke University integrated heart-liver systems and musculo-circulatory systems. The most recent NIH press release, published in September 2014, outlines the future directions that the MPS project will take. Along with tackling organ system integration, the drug trial phases of the project will begin to take place. The chemical testing phase offers an exciting conclusion to the program and boasts the potential to individualize and expedite the way medicines are tested.

Ahmad, who received multiple degrees in mechanical engineering, asserted that collaboration with biologists allowed the program to reach heights it never would have otherwise.

Figure 1. Examples of microchips. Photo by Zephyris, CCBY-3.0.

References

1. FAQ About Tissue Chips. http://www.ncats.nih.gov/ about/faq/tissue-chip/tissue-chip.html. (Accessed August 28th, 2015). 2. Wang, Y.; Ahmad, A.; Shah, P.; Sims, C.; Magness, S.; Allbritton, N. Lab Chip. 2013, 13, 4625-4634. 3. Interview with Asad Ahmad. 09/19/15. 4. Hidalgo, M. Organs on chips. http://www.electroingenio.com/wp-content/uploads/2014/09/organs-on-chiphuman.jpg. (Accessed August 28th, 2015). 5. Dowling, K. 2014. Microchip-size artificial humans may spell end of animal testing. Sunday Times. 2014. 6. Fabre, K.; Livingston, C.; Tagle, D. Exp Biol Med. 2014, 239, 1073-1077. 7. Bhattia, S.; Ingber, D. Nat Biotechnol. 2014, 32, 760-772. 8. Wang, Y.; Ahmad, A.; Gracz, A.; Sims, C.; Magness, S.; Allbritton, N. J Biol Eng. 2014, 8-9. 9. Wang, Y.; Ahmad, A.; Sims, C.; Magness, S.; Allbritton, N. Lab Chip. 2014, 14, 1622. 10. Pasolini, A. Organs-on-chips emulate human organs, could replace animals in tests. http://www.gizmag.com/ organs-on-chips-testing/33337/. (Accessed Aug 28, 2015).

medicine

TARGETING TUMORS FROM WITHIN By Christine Son

ancerous tumors are just like normal tissues; they require blood vessels to survive. Dr. Andrew C. Dudley, Assistant Professor in the Department of Cell Biology and Physiology at UNC-Chapel Hill, is interested in studying the fundamental differences of tumor-associated blood vessels versus normal ones. While attempting to understand how blood vessels feed growing tumors, the Dudley lab discovered a new hidden subpopulation of malignant tumor cells that mimic normal endothelial cells and form their own vessel networks.

Illustration by David Wright

“We are very interested in the non-tumor cells that comprise part of the tumor mass,” said James M. Dunleavey, a graduate student in the Dudley Lab. “While tumors are generally thought of as being made up of mostly tumor cells, there are a number of other cell types that support tumor growth in addition to tumor cells. One type that has received a lot of focus is the endothelial cells that form blood vessels.”1 Vascular endothelial cells line the blood vessels that supply oxygen and nutrients necessary for survival of tissue, including solid tumors. Targeting the vascular system, there-

Carolina Scientific fore, has received attention as a way to treat tumors. For example, anti-angiogenic therapies block angiogenesis, the formation of new blood vessels.1 Yet, these anti-angiogenic therapies have not been very successful in blocking tumor growth in human patients.2 “For years, researchers have used normal endothelial cells as a proxy to understand the endothelium that forms the tumor vasculature. But few labs were actually isolating and characterizing bona fide endothelial cells from tumors in order to formally test this possibility,” Dr. Dudley said.3 Endothelial cells are known to express platelet endothelial cell adhesion molecule 1 (PECAM1), which is found on the surface of the endothelial cells. While trying to isolate endothelial cells from a mouse model of melanoma, Dunleavey used PECAM1 antibodies that should have isolated mouse tumor-associated endothelial cells. However, instead of endothelial cells, he unexpectedly found a population of malignant tumor cells which expressed the PECAM1 protein.1 Interestingly, these PECAM1-positive cells (cells that express PECAM1 protein) from the tumor did not express other endothelial-specific markers, such as vascular endothelial growth factor receptor 2 (VEGFR-2), a major target for anti-angiogenic therapy. This suggested that these vascular-like tumor cells might not respond to VEGF inhibitors that comprise a majority of anti-angiogenic therapies for cancer.2 “[The question was] whether these PECAM1-positive, VEGF receptor-negative cells, that do not need VEGF signaling to survive, could contribute to their own vascular network in a VEGF-independent way,” said Dunleavey.1 Vascular or vasculogenic mimicry refers to a process by which tumor cells supplant endothelial cells and form part of their own vessel walls (Figure 1, right). An initial hypothesis in the study was that PECAM1-positive cells could form PECAM1dependent junctions with endothelial cells. PECAM1 is normally involved in endothelial cell junctions, which led the lab to believe that expression of PECAM1 in endothelial cells could allow tumor cells to interact with endothelial cells. Their role in the formation of a vessel-like network was strongly suggested when the PECAM1-positive cells resulted in about a five-fold increase of tube-like formation compared to PECAM1-nega-

Figure 1. (Left) PECAM1-positive tumor’s relative level of blood perfusion from high (orange) to low (purple). (Right) Visualization of the process of vascular mimicry, the formation of blood vessels by tumor cells. Images courtesy of James Dunleavy.

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James Dunleavy (left) and Dr. Andrew Dudley (right) tive cells (cell that do not express PECAM1) in culture. Additionally, when implanted in mice, PECAM1-positive cells were found in the blood vessel wall, while PECAM1-negative cells were not (Figure 2). The fact that PECAM1-positive cells from tumors were able to form blood vessel-like tubes similar to that of endothelial cells allowed Dunleavey to determine that the presence of PECAM1 was driving vascular mimicry.2 “The next question was ‘do tumor vessel networks evade anti-VEGF therapies?’” said Dunleavey, “And is PECAM1 also sufficient to drive vascular mimicry in living organisms?”1

“If there is any value to our work, it would be that we have developed a model to formally test this possibility.” Dr. Andrew Dudley To determine whether PECAM1 was involved in tumor resistance to therapy, Dunleavey treated tumors with and without an anti-angiogenic agent, harvested tumors of the same size and analyzed them for PECAM1 positivity. In the mice that were treated with the anti-angiogenic drugs, there was a six-fold increase in PECAM1-positive tumor cells. This led to a hypothesis that inhibition of VEGF signaling in tumor cells causes the population of melanoma cells to expand to stabilize the vessels.1 In addition, there was no response to the anti-angiogenic therapy in mice injected with pure, isolated PECAM1-positive tumor cells.2 This showed that PECAM1 expression in the tumor cells was sufficient to drive resistance to these anti-angiogenic drugs.1 “This was the first demonstration that there is a PECAM1-dependent form of vascular mimicry,” Dr. Dudley said. “Researchers have shown vascular mimicry before, and it has been suggested that these tumor cell-lined channels could be

medicine which showed real-time functional differences between the two tumor types in vivo.4 With the blood volume of PECAM1positive tumors being four and a half times greater than PECAM1-negative ones, these studies demonstrated the impact of PECAM1-positive tumor cells on tumor blood vessel function.4 Dr. Dudley and Dunleavey are currently working with the Dayton Lab to further investigate their “serendipitous finding” of these subpopulations of PECAM1-positive melanoma cells. Instead of working with mouse tumor lines, they are now studying human tumors engrafted in mice to examine the role of PECAM1 in human tumors.3 “The main goal is to bring attention to the fact that vascular mimicry may be a conversion process involving the gain of factors that allows tumors two form their own vessel networks which may contribute to the failure of anti-angiogenic therapies,” Dunleavey said. “Targeting these mechanisms could improve the efficacy of these therapies.”1

Figure 2. (Left) PECAM2-negative tumor. (Right) PECAM1positive tumor with tumor cells incorporated into vessel lumen indicated by arrows. Images courtesy of James Dunleavy. one of the reasons why anti-angiogenic therapy might be inefficient, but this has not been demonstrated directly. If there is any value to our work, it would be that we have developed a model to formally test this possibility.”3 Their discovery was further supported by the help of the laboratory of Paul Dayton, Ph.D., a professor in the Department of Biomedical Engineering and member of the UNC Lineberger Comprehensive Cancer Center.3 The Dayton Lab conducted ultrasound imaging studies comparing PECAM1positive tumor vessels and PECAM1-negative tumor vessels,

References

1. Interview with James M. Dunleavey, Ph.D. Candidate. 09/11/15 2. Dunleavy, J.M. et al. Nature Communications 2014, 1-16 3. Interview with Andrew C. Dudley, Ph.D. 09/18/15. 4. Derewicz, M. UNC scientists discover hidden subpopulation of melanoma cells. http://news.unchealthcare.org/ news/2014/october/unc-scientists-discover-hidden-subpopulation-of-melanoma-cells (Accessed September 10th, 2015).

Illustration by Maura Hartzman

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THE SOURCE CODE OF COMPLEX DISEASE The Future of Complex Disease Treatment

By Sage Bauer

Illustration by Kristen Lospinoso

he same treatment of the same disease often results in dramatically different outcomes. Consider, for example, the many types of chemotherapy that cancer patients are routinely subjected to. Some patients respond immediately, while others show no improvement. In order to explain this phenomenon, modern medicine has identified a category called “complex diseases” that many common diseases fall into. Several environmental and genetic factors play a role in the onset and progression of complex diseases. Some common complex diseases include cancer, heart disease and inflammatory bowel disease. In the past, treatment of complex diseases often came down to trial and error. New research has found that different reactions to treatment can be tied to specific differences in the genetic composition of the patient. Genetic research may end the days of trial and error medicine by determining how different people are affected by a disease and its various treatments on a molecular level.1 Dr. Terry Furey, a computational biologist and associate professor at UNC-Chapel Hill, is interested in areas of the genome called open chromatin regions. These areas are where gene expression is regulated, making them responsible for the wide variance and specialization of cells in the human body. If a disease alters these regions, it can result in a cell expressing abnormal traits, causing or assisting the onset and progres-

sion of a disease. “If we can understand the disease better at a molecular level, we can then better understand how to treat it,” Dr. Furey explained.2 Dr. Furey looks at inflammatory bowel diseases (IBDs), including Crohn’s and ulcerative colitis, in a collaboration with Dr. Shehzad Sheikh, assistant proDr. Terry Furey fessor and gastroenterologist at UNC. Combining their expertise in clinical IBD, molecular experimentation and computational analysis, Drs. Sheikh and Furey are attempting to ascertain the most basic impact of the disease on the genome. They do this by comparing colon tissues from patients with and without IBD. “We want to see whether people with the disease have a different chromatin landscape that is contributing to differential expression of certain genes,” Dr. Furey said.2 By looking at the genomes of those who have acquired the disease and comparing them to those in similar environments who have not been affected, it is possible to determine what is going on at the basic cellular and molecular level of cells affected by disease. Dr. Furey focuses on a particular immune cell impacted by IBD called the macrophage. In some patients, chromatin in these cells is programmed to respond to a microbial stimulus from the gut in the wrong way, causing the inappropriate inflammatory response that marks the disease. Dr. Furey’s genomic research may lead to more personalized disease treatment. Instead of treating everyone the same, the physician could first examine the genome of the patient and identify treatments that are more likely to be effective. Mapping the open chromatin of relevant tissues and cells in disease patients is the first step to making this happen. Not only will the effectiveness of individualized treatment increase, but doctors will also get a better idea of what is happening with the disease at a molecular level.

Figure 1. Depending on which proteins are present, chromatin regions are either inactivated, turning off transcription of a particular gene, or open, allowing the gene to be expressed. This results in the specialization of cells. Image by Dynda, adapted from Luong, P., Basic Principles of Genetics, CC-BY 3.0.

References

1. What are complex or multifactorial disorders? http://ghr. nlm.nih.gov/handbook/mutationsanddisorders/complexdisorders (Accessed September 21st, 2015). 2. Interview with Terry Fury, Ph.D. 09/17/15. 3. Furey, T. S.; Sheffield, N. C. Genes 2012, 3(4), 651-670.

health

A Lung in a Box By Shuyan Huang

he air is full of particles that are potentially harmful to human lungs. It is, therefore, important to measure how these airborne pollutants affect people’s health. The Gillings Sampler, designed by Dr. William Vizuete and his colleagues, is a new system that can determine the health hazards caused by air pollutants. Dr. Vizuete, an Associate Professor in the UNC-Chapel Hill Gillings School of Public Health, said, “Atmosphere is a source of toxicity that when particles are put into the atmosphere, they undergo atmosphere chemistry and transforma-

tion and become more toxic than they were originally admitted.”1 In the past, scientists have used air-sniffing monitors to measure the level of air pollutants. These traditional monitors, however, cannot detect the health hazards of airborne pollutants. The Gillings Sampler uses human lung cells to measure the hazard level of airborne pollutants. After an air sample enters the machine through the humidification unit, it blows across human lung cells indented in the Gillings instrument, where electrostatics move the particles out of the air stream and onto the lung

Dr. Vizuete and the Gillings Sampler cells. If the particles are toxic, the cells will send out hormone-like signals. The more toxic the particles are, the more signals the cell will send out. By measuring these signals, scientists can tell how harmful the sample air is to human bodies.1 This new method of testing the toxicity of airborne pollutants is reliable because the machine imitates a human lung. The humidification unit humidifies the incoming air string as the human lung does, and the temperature is controlled to be similar to human body temperature. Also, the particles in the air sample go directly to the lung cells. With the conventional method, called re-suspension, scientists have to re-suspend the particles in liquid and then transfer the liquid onto the cells. “The only difference here is that instead of using a liquid medium, we’re using charges and air. [The Gillings Sampler] is more like a lung because particles are transferred through the air string and then they leave it,” Dr. Vizuete said.1 Dr. Vizuete and his colleagues now have two operational machines. One measures the toxicity of particles in the air and the other measures the gases found in the air. When using both machines, Dr. Vizuette and his colleagues can detect particle toxicity as well as gas toxicity of a full air sample. They have optimized the gas-phased instrument and made one that is field-deployable.

References Illustration by Ivy Somocurcio

1. Interview with William Vizuete, Ph.D. 03/28/15.

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NATURE IS THE BEST GUIDE By Rebecca Landon

magine a cure for a disease that has infected millions since the 1980s. Now, imagine that cure could have been growing in your back yard. The Human Immunodeficiency Virus (HIV), in the last few decades, has slowly propagated across Africa and into other parts of the world. People contract the virus daily, with 35 million people worldwide currently living with HIV/AIDS.1 For decades, scientists have searched for a way to eradicate HIV. Among them is one of UNC-Chapel Hill’s own, Dr. Kuo-hsiung Lee, who is currently researching and testing the activity of gnidimacrin against HIV. Dr. Lee became the Director of the Natural Products Research Laboratories (NPRL) in 1983, a research program currently focused on medicinal chemistry, bioactive natural products, new anti-cancer and anti-AIDS drug discovery and development and Chinese medicine. A natural product is a chemical compound that is produced by a living organism and is found in nature. Dr. Lee is a firm advocate for the use of natural products in science and strongly believes that “nature is the best guide.”2 To better understand HIV treatment, it is beneficial to understand the three stages of HIV infection: acute infection, clinical latency and AIDS. After the virus is transferred into a host, it circulates in the bloodstream until it attaches to a cell, generally a specific type of immune cell. The virus then

Dr. Lee is a firm advocate for the use of natural products in science and strongly believes that “nature is the best guide.” injects its genetic material into the cell, turning it into a ‘factory’ that produces large amounts of copies of the virus. In this first infection stage, a patient may or may not experience severe flu-like symptoms. The infection then progresses to its second stage, in which the virus is still reproducing, but only at a low level. Notably, during this stage, some virus can also form latent reservoirs in infected cells, where it can hide and stay inactive. The only HIV treatment currently available is highly active antiretroviral therapy (HAART). Treated patients can remain in clinical latency with few to no symptoms for the remainder of their lifetimes.1 When used consistently, HAART can allow patients to live longer, healthier lives, reduce (but not eliminate) the risk of transmitting HIV to others and prevent viral progression to acquired immunodeficiency disease syndrome (AIDS). In the last stage of HIV infection, the progression to AIDS, a patient’s immune system is badly dam-

Stellera chamaejasme Harvard University Herbaria

aged causing him or her to be highly susceptible to opportunistic infections.1 However, it should be emphasized that HAART is not a cure and can only suppress, rather than kill, HIV.3 Consequently, a major goal of current HIV research, including that of Dr. Lee, is to pull HIV out of its latent reservoirs and eradicate it.4 Dr. Kuo-hsiung Lee Recently, Dr. Lee and his collaborators, Drs. Chin-Ho Chen and Li Huang of Duke University, analyzed gnidimacrin, a known potent anti-cancer compound, and discovered that it could also activate HIV reservoirs at an extremely small dose. The results suggested that gnidimacrin not only activated these HIV latent reservoirs, but also specifically killed HIV infected cells. However, a mechanism of action has not yet been identified and remains to be determined. Gnidimacrin is a natural product extracted from Stellera chamaejasme, a plant found in Asia. The plant is typically found with no other plants around it, as it is toxic to other plants in close proximity.2 Thymeleaceae, its plant family, includes many different plants from which various daphnane diterpenes, including gnidimacrin can be isolated. Gnidimacrin shares some structural similarities with other anti-HIV compounds such as prostratin, which has also been considered a drug candidate to extract latent HIV for eradication. However, gnidimacrin is a thousand times more powerful than prostratin. This difference makes gnidimacrin a better drug candidate, because a much smaller amount would be needed for treatment.4 Dr. Lee and NPRL have high hopes to eliminate HIV/ AIDS from the population. The research performed thus far profoundly suggests that a natural product could soon be the answer for millions of people who live with the virus. Gnidimacrin might just be the compound in the next new drug that restores normalcy and health to millions infected with HIV across the globe.

References

1. Welcome to AIDS.gov. https://www.aids.gov/ (Accessed September 21st, 2015). 2. Interview with Kuo-hsiung Lee, Ph.D. 09/09/15. 3. What Is Antiretroviral Therapy (ART)? http://www. aidsinfonet.org/fact_sheets/view/403 (Accessed September 22nd, 2015). 4. Huang, L.; Ho, P.; Yu, J.; Zhu, L.; Lee, K-H.; Chen, C-H. PLoS ONE 2011 1-4.

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PICKLES and PEANUT BUTTER:

THE IMPACT OF FOOD CRAVINGS By Aakash Mehta Image public domain.

t’s getting late. Sitting in front of you is a stack of notes for your exam tomorrow morning, and while you are trying to file the masses of information into your brain, you can think of only one thing: food. Everyone has these food cravings, but perhaps some of the most unique food cravings are those experienced by pregnant women. Dr. Kyle Burger and fellow UNC-Chapel Hill researchers at the UNC Gillings School of Public Health are trying to solve the mystery of what causes these intricate food cravings during pregnancy. Women during pregnancy have anecdotally been known to crave specific foods simply for pleasure. Dr. Burger hopes to understand what drives the food intake of women through the second trimester of pregnancy and one year after childbirth. Dr. Burger said that this study is incredibly unusual in the sense that “people always talk about crazy food cravings in pregnant women, but nobody has ever studied the cravings

Figure 1. Typical meal provided before a taste test. Image courtesy of Dr. Kyle Burger.

or systematically asked about them.”1 Much of the work he has done involves observing the behavior of these women through various means. The women are fed a dinner, followed by a taste test, allowing Dr. Burger and his team to determine how much these women eat when they are hungry or full. This can help in predicting future weight gain during or after pregnancy. Dr. Dr. Kyle Burger Burger has also implemented the use of questionnaires that provide insight to these food cravings and to discuss why the women chose to continue eating when full. Sarah Dotters-Katz, a participant in the study, described her first trimester as being carb heavy with chips and cookies, and then transitioned to a second trimester in which she would eat multiple jars of pickles every week.2 In addition to his “eating in the absence of hunger” investigation, Dr. Burger uses functional magnetic resonance imaging (fMRI) technology to look at the women’s brains to see how they react to various foods. The dopamine regions of the human brain are often linked to the reward centers of the brain. Although it is well known that dopamine circuitry is involved in reinforcing the addictive behaviors of drugs and alcohol, many do not understand that food and dietary behaviors follow the same dopamine pathways.2 The brain imaging done by Dr. Burger allows him to see reward regions of the brain become active when pregnant women are given highly palatable foods. He described both the fMRI and taste-test techniques as “extremely novel” because they have not typi-

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“Collecting brain imaging data in combination with behavior and medical record data and getting the full picture is very exciting and informative.”

Figure 2. Left: Food reward regions of the human brain. Right: Active reward regions of the brain while tasting a milkshake. Images courtesy of Dr. Kyle Burger.

Dr. Kyle Burger

cally been used for collecting data from the general population.1 The behavioral and fMRI work of Dr. Burger is only a piece of the puzzle. He is one of many distinguished researchers, seven of whom are here at UNC, who contributes to the Pregnancy Eating Attributes Study (PEAS). A majority of the behavior investigation is done at UNC, but other members of the PEAS project also collect data.3 Biological data are collected through blood samples and information is acquired through focus groups about foods eaten, cravings, triggers and the time-of-day for cravings. Data are also accumulated regarding the children, especially in how the mothers feed their newborns through the early stages of their lives. Dr. Burger is ecstatic about the scale of the project. He said, “collecting brain imaging data in combination with behavior and medical record data and getting the full picture is exciting and informative.”1 The study involves the help of clinics, doctors, the data-coordinating center at the National Institute of Health and the faculty involved at UNC. This holistic perspective through various viewpoints will allow for incredibly concrete conclusions to be drawn.

Sarah Dotters-Katz, a participant in the study, described her first trimester as being carb heavy with chips and cookies, and then transitioned to a second trimester in which she would eat multiple jars of pickles every week.

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Pregnancy is an interesting time in life to change behaviors, because the mothers’ behavior does not only affect themselves but their babies as well. It is also an extremely stressful time for a woman. “A lot of people use food to cope. Reward-driven food intake to cope with stress, whether aware or unaware, can be a serious problem” Dr. Burger said.1 Having to change dietary behavior is a difficult task, but Dr. Burger hopes that with the help of the data acquired from the PEAS study, it will help convince mothers to curtail their diets not only allowing them to lead healthy lives but also allowing healthy lives for their children. Although the testing is only done on pregnant women, which is a very specific group of people, Dr. Burger believes the information learned will help many more than that target group. The study will allow the general population to become aware of how different eating behaviors can affect health and how food is used in their lives. Dr. Burger hopes that the study will not only lead to improved diets in pregnant women and their children, but that it will provide us with an understanding of what drives our Illustration by Kelsey Winchester. food choices.

References

1. Interview with Kyle Burger, MPH, RD, Ph.D. 09/21/15. 2. Pregnancy Eating Attribute Study. www.peasweb.org (Accessed September 26th, 2015). 3. Davis, C. ISRN Obesity. 2013.

“There is no greater high than discovery.” -Edward O. Wilson

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

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scıentıfic Fall 2015 | Volume 8 | 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 as well as the Carolina Parents Council.