Spring 2016 -- Uncovering the Secrets of our Universe by Carolina Scientific

Carolina

Carolina Scientific

sc覺ent覺fic Spring 2016 | Volume 8 | Issue 2

UNCOVERING THE SECRETS OF OUR UNIVERSE a worldwide search for the neutrino and its long-lost counterpart full story on page 44 1

Carolina

scıentific 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 UNCChapel 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 Editor: Science is perhaps the greatest labor of love. Every article in this issue of Carolina Scientific, from the science behind “hanger” (page 30) to a look in the life of a behavioral ecologist (page 24), represents the blood, sweat, and tears of dedicated researchers whose work deserves to be shared with the world. Research can be exhausting and frustrating, but the moment when it works is beautiful. In these pages we celebrate those researchers who work tirelessly so that we may share in their beautiful moments as they aim to make our lives better. You’ll read about the latest in recovery for stroke victims (page 8) as well as blood platelet research, told through the metaphor of a sports car (page 4). We hope you read through these articles and come away with a newfound appreciation for the astounding work being done in the UNC-Chapel Hill community as we did. Enjoy! -Parth Majmudar

on the cover Dr. Reyco Henning is a physicist and member of Project Majorana, a team dedicated to finding the neutrino and its antimatter counterpart. Full story on page 44.

Executive Board Editor-in-Chief Parth Majmudar Managing Editor Tracie Hayes Associate & Copy Editor Ben Penley Associate Editor Kimberly Hii Treasurer Karthika Kandala Design Editors Rachel Quindlen Jui Naik Nirja Sutaria Publicity Chair Jonathan Smith Fundraising Chair Sahana Raghunathan Online Content Managers Tirthna Badhiwala William Howland Faculty Advisor Gidi Shemer, Ph.D. Contributors Staff Writers Copy Staff Ashley Cruz Sarah Dweikat Sara Edwards Suzy Gleaves Hailey Gosnell Callie Hucks Hannah Jaggers Madison Kennedy Margaret McAllister Aakash Mehta Carrinton Merritt Cameron Pharr Allie Piselli Annaleigh Powell Nathan Raynor Nicholas Rewkowski Akshay Sankar Bri Sikorski Elizabeth Smith Jacob Smith Ben Twery Lynde Wangler Jeffrey Young

Design Staff Naomi Breitenfeld Hannah Jaggers Juhee Kim

Illustration by Naomi Breitenfeld.

Nicole Affleck Misbah Ahmad Ashley Cruz Jason Gershgorn Jie He Shuyan Huang Aakash Mehta Adesh Ranganna Akshay Sankar Ami Shiddapur Patrick Truesdell Ben Twery Wilfred Young

Illustrators Andrew Bauer Naomi Breitenfeld Anja Burjak Alex Cecil Hailey Gosnell Laura Hamon Linnea Lieth Kristen Lospinoso Victoria Long Dave Mossman Megan Perritt Sean Stickel Abbey Vinson Smrithi Valsaraj Carley West May Wang David Wright Julianne Yuziuk

Carolina Scientific

contents Medicine and Health

Sports Cars of the Vascular System

A Permanent Viral Shield

Psychology and Neuroscience

Got Hanger?

Conditioned Immune Response

A â&#x20AC;&#x153;Strokeâ&#x20AC;? of Luck

Breaking the Poverty Cycle

Addressing the Burn Crisis

Good Vibrations

Drugs in Disguise

The Neural Network

Preventing PTSD

Nathan Raynor

Cameron Pharr

Aakash Mehta

Akshay Sankar

Allie Piselli

Biology

Margaret McAllister Lynde Wangler Hailey Gosnell Ben Twery

Carrington Merritt Ashley Cruz

Computer Science

Sea-ing 20/20

Madison Kennedy

Uncharted Fields

A New Age of Accessibility

Keeping Up With the Kinases

Visualizing Traffic Pollution

The Predictable Within the Chaos

Sarah Dweikat Jacob Smith

Holy Crop!

Annaleigh Powell

A Snapshot of Field Research

Fish Evolution

Killing More Cancer

Sara Edwards

Miscellaneous

Suzy Gleaves

Nick Rewkowski

The Mysteries of the Neutrino

Learning for the Real World

Elizabeth Smith Jeffrey Young

Bri Sikorski

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

Hannah Jaggers Callie Hucks

medicine

Platelets:

the  sports cars of the vascular system By: Nathan Raynor

Image by ZEISS Microscopy, CC BY-NC-ND 2.0.

ports cars move at fast speeds and their drivers must have quick reflexes to respond to obstacles in the road. Platelets are the same… except they have no driver. Platelets are cell fragments that lack a nucleus and are known for their role in clotting blood. They develop from cells in the bone marrow and normally circulate for about Dr. Wolfgang Bergmeier five to ten days.1 The fragments race around your body at speeds up to 160,000 lengths per second (scaled to the size of the average sedan, that would be 1,770,000 miles per hour!).2 Platelets circulate in a non-adhesive state, but when they arrive at a site of blood vessel injury, they respond within milliseconds to stick, form a plug, and prevent blood from leaking into the surrounding tissue. This requires a signaling machine (engine) that is well balanced so the platelets can be sensitive enough to stop bleeding quickly, yet not so sensitive that they form blood clots in uninjured blood vessels.3 Dr. Wolfgang Bergmeier, a platelet researcher at the UNC-Chapel Hill School of Medicine, studies the signaling ma-

chinery in platelets. “I compare platelets to fancy sports cars, vehicles with an extremely powerful engine that is optimized for speed. Platelets sense a change in the vasculature and boom, off they go (well, in this case, they will stick), just like when you touch the gas pedal of a sports car! But in order for that to be viable, a platelet also relies on a powerful braking system.”4 Dr. Bergmeier’s lab has identified proteins in the platelet that act as the engine, gas pedal, and brake as Rap1, CalDAGGEFI, and Rasa3, respectively. Rap1 is a member of a family of proteins called small GTPases. They serve as switches in the cell, cycling between an on- and off-state. Rap1 is in the onstate when bound to Guanosine Triphosphate (GTP), and in the off-state when bound to Guanosine Diphosphate (GDP). The difference between GTP and GDP is an extra phosphate. This can be thought of as fuel. Rap1 is active when bound to Guanosine Triphosphate because it has enough fuel. Rap1 becomes inactive when GTP is converted to Guanosine Diphosphate, because there is one less phosphate. CalDAGGEFI and Rasa3 are GTPase regulators, meaning they activate and deactivate Rap1 by adding or removing that phosphate. As the platelets circulate through the blood, Rasa3 (brake) prevents the platelets from sticking by ensuring that Rap1 (engine) is in its inactive form. When the platelets are stimu-

Carolina Scientific lated by vascular trauma, a protein called P2Y12 releases the brake, and CalDAG-GEFI (gas pedal) is activated to turn Rap1 (engine) into its active form and make the platelets stick and plug the leak.4,5  Disruption of this balanced mechanism can lead to complications such as blood clots or prolonged bleeding. “You step too hard on the gas pedal, or your brake doesn’t work, and you end up in a ditch,” said Dr. Bergmeier.4 One such disruption is cancer cells. Studies show that cancer can increase chances of thrombotic disease. Cancer cells express proteins that can trigger platelets to see injury where there is none and form clots. Researchers are not sure of the mechanism, but cancer cells can also use platelets like a camouflage and hide from the body’s natural defenses. This facilitates their ability to spread to other parts of the body.3    Dr. Bergmeier studies the effects of genetic and environmental factors on the CalDAG-GEFI – Rasa3 balance. The long-term goal of these studies is to improve the balance so platelets are not overactive, but still prevent bleeding. He hopes to do this either by developing better drugs or by improving the use of available drugs. Dr. Bergmeier is interested in the concept of personalized medicine. This idea revolves around developing tests to analyze a patient’s risk and then using this information to provide more effective care for the patient. Cellular mechanisms can be very complex and many times, physicians prescribe medications and wait to see their effects before reassessing their treatment plan. Personalized medicine would test the patient first to better understand the problem before treating it. “Knowing about the balance in an individual patient’s platelets would allow us to optimize treatment, i.e. to decide which cocktail of drugs to give. Our goal is to develop a simple test that would provide this critical information.”4 This method could drastically improve the effectiveness of treatments for platelet-related diseases, reducing instances of heart attack, pulmonary embolism, and strokes. The Bergmeier lab has many great ideas in the works, but sometimes research is limited by the information and technology available. When studying new cellular processes, there is no way to identify potential candidates for the machinery except by randomly looking at which proteins are being transcribed. But as more discoveries are made, researchers can use the databases of information to further their own re-

medicine

Figure 2. (Top) Vascular trauma causes blood vessel to rupture and leak blood cells. (Bottom) Platelets activate and bind to Fibrin and each other to form a hemostatic plug and prevent further loss of blood. Images from Med-Health.net. search. “Sometimes you have to wait for the puzzle pieces to come together. I work on my area in one corner and let someone else work in another area.” In the case of this signaling system, the gas pedal, CalDAG-GEFI, was found by accident by psychologists studying Huntington’s disease. The studies following this initial discovery set Dr. Bergmeier’s lab on the path to find the brake. To identify Rasa3, they took advantage of existing data on the expression of different proteins in platelets, which showed that the expression level of Rasa3 matches that of CalDAG-GEFI.4  Dr. Bergmeier is inspired by both the complexity of these types of machinery and the clinical benefits of understanding them. In the future, he hopes to make more important discoveries that will lead to better medical treatments. “The project is never done. Every discovery leads to three new questions you have to answer.”

References

1. Harker L.A. et al. Blood. 2000, 95(8): 2514–2522. 2. Tortora, G.J.; Derrickson, B. Principles of Anatomy & Physiology, 13th. John Wiley & Sons, Inc. 2012. Print. 3. Bergmeier, W.; Stefanini, L. Oncotarget. 2015, 6, 19922– 19923. 4. Interview with Wolfgang Bergmeier, Ph.D. 02/02/16. 5. Stefanini, L.; Bergmeier, W. J Mol Med. 2015, 94, 13–19.

Figure 1. The pathway of activation and deactivation of platelets with RAP1. Drugs like  Clopidogrel can be used to inhibit P2Y12 and prevent clotting.5

medicine

A Permanent Viral Shield By Cameron Pharr

Illustration by Julianne Yuziuk

ucus is the body’s barrier that can separate infection from immunity. When a person thinks of mucus, sickness and discomfort – likely involving a runny nose – are brought to mind. These examples of mucus are just the body working overtime to fix a problem such as an infection. However, even when a person is healthy, mucus has the important task of fending off foreign pathogens that constantly bombard the lungs, gastrointestinal tract, and female reproductive tract. One such invader is the Human Immunodeficiency Virus (HIV). HIV is a virus that is transmitted through bodily fluids and can persist in the body for life. It is impossible to cure this infection using current medical techniques and, although treatment exists to suppress HIV to low levels in the body, a better solution is to avoid contracting it.1 Current strategies for preventing HIV through sexual contact with an HIV-positive partner, such as using condoms or taking medications, do not always work due in large part to poor user adherence.1 Dr. Samuel Lai, a UNC Eshelman School of Pharmacy professor, and his research group have been working on a new method for preventing the transmission of HIV before it can even infect someone. Dr. Lai focuses his research on mucosal surfaces such as the female reproductive tract, which is coated with cervicovaginal mucus (CVM).2 This layer acts as

the first barrier to HIV infection in the female reproductive tract after sexual intercourse with an HIV-positive partner. If HIV is not stopped in mucus, it can easily reach and infect the underlying cells (Figure 2). Antibodies are an important part of the immune system responsible for preventing infection from outside pathogens.2 They play a crucial role in identifying what is foreign as opposed to what is not by attaching to pathogens and subsequently orchestrating the most effective immune response (Figure 1). Antibodies are present throughout the entire body, but large quantities are found in mucus layers, including the

Figure 1. Antibodies are proteins that bind tightly to a select few molecules. Image public domain.

Carolina Scientific

medicine

“We hope that over time, more and more scientists will understand that antibodies in the mucus protect in the way we have discovered.”

CVM.2 When an HIVspecific antibody encounters an HIV virus, it will attach to the virus. The interactions between an HIV-bound antibody and the vaginal mucus are what Dr. Lai studies. Dr. Samuel Lai and Timothy Wessler H I V- s p e c i f i c antibodies are only weakly attracted to mucus while bound to a virus.2 However, in their studies with mice, researchers in the Lai lab discovered that if enough antibodies are attached to a virus or even to a highly motile bacteria, they will attach to the mucus lining, thereby immobilizing the pathogens and preventing infections altogether.3 In this way, mucus stops the virus in its tracks so that it cannot infect any cells past the CVM, effectively preventing the transmission of HIV to the woman. The Lai lab found that, without antibodies that can bind HIV, the virus can penetrate CVM and arrive at the vaginal epithelium in minutes.2 Through computational modeling using experimental data, the Lai group confirmed that antibodies could indeed immobilize HIV in the CVM before reaching and infecting cells (Figure 3). “For decades, scientists were puzzled by what function antibodies could play in mucus and thus overlooked the potential protection if HIV-specific antibodies are present in CVM” explained mathematics graduate student Timothy Wessler, who assisted in generating the infection computer model. “We hope that over time, more and more scientists will understand that antibodies in the mucus protect in the way we have discovered.”4 The computational simulations developed to model

Timothy Wessler the interactions between the antibodies, HIV, and the CVM can be easily adapted to represent mucus anywhere in the body. For example, in addition to vaginal transmission, the model “can also [simulate] rectal transmission [because the mucus] is similar,” Wessler said.4 Also, the model is not restricted to viruses, as it can be applied to both bacterial infections and drug delivery. To get the antibodies inside the CVM in the first place, a device similar to an intrauterine device (IUD) or a vaginal ring could theoretically be inserted into the vagina to slowly release antibodies for weeks to months.4 A startup that spun out of the Lai lab, Mucommune, Figure 3. Viruses entering has recently received a conthe CVM encounter antibodtract from the NIH to develop ies that can immobilize them. such a product. Although no Reprinted with permission clinical trials are yet in sight, from the American Chemical the impacts of this research Society: ACS Infectious Disare far-reaching. eases. Copyright 2015 AmeriThe opposite problem can Chemical Society. is encountered when modeling drug delivery, Wessler claimed.4 Instead of trying to stop a virus from infecting a cell, a drug could be designed to deposit its contents where and when the drug is needed. An applicable example of this is inside the lungs, where mucus is of great importance. In this case, Wessler pointed out, a drug developer would want the “most penetration possible through the lung mucus.”4 The open-ended nature of the impacts of this research, as well as the program created for its analysis, provides countless directions in which future explorations can go. One can dream that, with the help of research like Dr. Lai’s group, infectious diseases such as HIV could become a thing of the past.

References

1. HIV/AIDS Prevention. 2016. Retrieved from http://www. cdc.gov/hiv/basics/prevention.html 2. Chen, A. et al. Biophys J. 2014. 106(9). 2028-2036. 3. Wang, Y-Y. et al. Mucosal Immunol. 2014, 7, 1036-1044. 4. Interview with Timothy Steven Wessler, Ph.D. Candidate. 02/04/16.

Figure 2. Artist’s depiction of a virus, such as HIV, infecting a target cell. Image by J Roberto Trujillo, CC BY-SA 3.0.

health

A “Stroke” of Luck By Aakash Mehta

here is one thing familiar to most students at UNCChapel Hill: walking. Whether it is making the trek from Hinton James dorm to north campus, or just the casual stroll between classes, students walk an incredible amount throughout the day. Now imagine that a student’s walking was limited, and someone noted that it was because every step he or she took was wrong. This is what those who have suffered from a stroke often experience. With the wide range of physical impairments that arise after a stroke, many abnormalities go unnoticed by patients, particularly asymmetrical walking patterns. Dr. Michael Lewek in the Physical Therapy department of the UNC-Chapel Hill School of Medicine is developing new strategies for the rehabilitation of walking in individuals recovering from stroke. Stroke is the leading cause of disability in the United States, with nearly 6.8 million Americans living after suffering from a stroke.1 Additionally, approximately half of the individuals who have survived a stroke have asymmetrical walking patterns.2 Dr. Lewek aims to help stroke victims realize and understand their unbalanced movements and eventually change them. Clinical studies suggest that the movements of patients after stroke are difficult to change, but he hopes to help individuals get back to the activities they want to engage in and “increase their participation in the world.”3 To analyze the walking patterns of patients, Dr. Lewek utilizes state of the art technology in the Interdisciplinary Human Movement Lab. The main piece of equipment is a dual belt treadmill. Dr. Lewek’s team has programmed the treadmill

to be responsive to patient movement, and the two belts may be run at different speeds to account for asymmetry in the walking patterns of patients. Additionally, there are eight cameras directed at the treadmill, and motion-capture technology similar to that used in video game and movie animation is used to track patient movement. Dr. Lewek emphasizes the importance of helping people realize that they Dr. Michael Lewek have problems in their movement patterns. “If people do not perceive something is abnormal, they cannot make efforts to change. Coming to this realization is the first step to improving mobility.”3 The process of helping patients understand their asymmetric walking patterns is best understood when thinking first about an individual without stroke. When the dual belt treadmill and the belts are run in sync, an individual without stroke will walk normally. Even a subtle difference in the speed of the belts may be noticed. But for many who have had a stroke, they do not notice the different speeds. This is because the imposed asymmetry feels normal to them. It takes a much larger difference in the belt speeds for many individuals who have had a stroke to notice that walking has been perturbed. As a control to test the responsiveness of the treadmill belts to variations in gait symmetry, preliminary testing was done on unimpaired individuals that had an ankle weight on one leg. This simulated the lack of balance and asymmetrical

“If people do not perceive something is abnormal, they cannot make efforts to change.” Dr. Lewek

Figure 1. (Left) Dual belt treadmill used to analyze patient walking patterns. (Right) A weight is used to mimic the effects of gait asymmetry of a stroke victim. Photos courtesy of Dr. Lewek.

Carolina Scientific

health

them realize what is happening. Fortunately, making patients aware of their gait asymmetry is often all it takes to jumpstart their rehabilitation. One patient, who came in twenty years after his stroke, doubled his walking speed after working with the dual belt treadmill. Another was able to go grocery shopping with his wife for the first time in three years. Perhaps one of the most substantial improvements in regaining mobility involved a patient who was able to play a full round of golf (using a cart) after extensive work in the Interdisciplinary Human Movement Lab and working on his gait. Increasing awareness of walking imbalances can have an enormous impact on the daily life of someone who has had a stroke. It not only plays a role in improving walking for aesthetic purposes but more importantly reduces the risk of future injury and pain caused by muscular fatigue and imbalances. “The general perception of post-stroke life, and what is sadly still told to patients by some doctors, is that the way someone recovering from stroke is moving at 3-6 months post-stroke is the way their mobility will be forever.”3 Dr. Lewek’s research is clearly defying that myth.

References

1. Go A.S. et al. Circulation. 2013, 127, e6–e245. 2. Patterson, K.K.; Gage, W.H.; Brooks, D.; Black, S.E.; Mcilroy, W.E. Gait Posture, 2010, 31(2), 241-246. 3. Interview with Michael Lewek, PT, Ph.D. 02/05/16. 4. Wutzke, C.J.; Faldowski, R.A.; Lewek, M.D. Phys Ther. 2015, 95(9), 1244-1253.

THE MEREDITH

Figure 2. Stroke is caused by severe reduction of blood flow to a region of the brain, often by a clogged artery. Photo from Wikimedia Commons, Blausen Medical Communications Inc.

PRE-HEALTH POST-BACCALAUREATE

CERTIFICATE

walking patterns that stroke victims deal with but are completely unaware of. There are a number of ways that Dr. Lewek tries to help patients realize their asymmetry. For some patients, it is as simple as talking to them – telling them their movement errors and ways to fix the issues. For others, it requires using the dual belt treadmill to either exaggerate or fix their gait asymmetry. The toughest task facing any physical therapy study is that every patient is different. “Stroke is different from other diseases due to the wide range in severity of their post-stroke symptoms, and even more so in the varying responses to treatment.”3 Dr. Lewek recognizes that it is impractical to find an intervention that works for all patients. Some methods may help half, or even three-quarters of all patients, but there is no treatment that is 100% effective in helping every patient regain a balanced walking pattern. There are other obstacles that Dr. Lewek faces in his work as well. Studies have low sample sizes, often about 30-40 individuals. It is also difficult to make conclusions when there are patients from such an extensive age bracket and wide ranges of walking imbalances. Dr. Lewek hopes that his work can lay the foundation for future training studies that involve actually manipulating the movement patterns of patients, rather then simply helping

Go strong for health care. Meredith’s one-year coeducational program is the only one of its kind in the Triangle. We offer small classes. Hands-on clinical experiences. Individualized advising. MCAT prep. And with a graduate placement rate above 90 percent, our program prepares students to get into their top schools.

Learn more. meredith.edu/graduate/pre-health 16-062

health

ADDRESSING THE BURN CRISIS By Akshay Sankar

n explosion at Dey Hall on January 20th, 2016 left over half the campus without electricity and a UNC-Chapel Hill employee with a burn.1 Fortunately, UNC-Chapel Hill is home to one of the most comprehensive burn centers in the nation. Dr. Bruce Cairns is the John Stackhouse Distinguished Professor of Surgery and Director of the North Carolina Jaycee Burn Center. Embracing his role as a surgical investigator, Dr. Cairns serves as a middleman in medicine using scientific and clinical knowledge to improve the lives of burn patients. Dr. Cairns centers his clinical and research efforts on the burn patients. He stresses that the research and other activities of the Jaycee Burn Center cannot be understood without tying the progress to the larger context of serving the burn patients and the greater public good in North Carolina. According to the 2007 National Burn Repository report, the Southern United States accounts for approximately 42% of all reported burn cases.2 Yet, geographic access to burn centers in the Southeast is limited.3 Unfortunately, hospitals are still closing down burn centers – they are expensive to operate and maintain – as the annual number of burn hospitalizations continues to rise. For example, the Jaycee Burn Center has seen a 2.5-fold increase in annual admissions between 2003 and 2014.4 Furthermore, a burn is an extremely complex injury to understand and treat. In fact, a burn injury “evokes, to an exaggerated degree, all of the systemic responses seen in other injured patients, [making] the patients with such an injury the

Illustration by Smrithi Valsaraj universal trauma model.”5 Consequently, the treatment of a burn requires careful thought in elementary, translational, and clinical research, as well as in medical practice. Burn research focuses on the physiological and genetic changes that arise from a burn injury. The Cairns lab explores all facets of biology and mediDr. Bruce Cairns cine from functional genomics and proteomics to stem cell biology to obtain a holistic understanding of burn issues. Over the last fifteen years, the Cairns lab has focused on the immune system changes after an injury, inhalation injury, microbial growth and infection (particularly burn sepsis), tissue engineering, and stem cell treatments. He is joined in these research efforts by his Burn Center clinical colleagues – Dr. Samuel Jones, Dr. James Hwang, and Dr. Felicia Williams. The Cairns lab determined the immune system achieves homeostasis at an active (or heightened) state while recovering from a burn injury. This heightened immune system state can cause complications during treatment, especially related to skin graft surgery. The treatment of a burn patient is further complicated by the patient’s pre-existing medical problems and the treatment center’s quality. In the mid-2000s, the Cairns lab developed a minimal

Carolina Scientific perforation mesher, which provides the optimum amount of perforation to facilitate the entry of much needed antimicrobial fluid to a burn wound and the drainage of other burninduced secretions during burn treatment. When combined with Integra, a synthetic skin developed at the Massachusetts Institute of Technology, it has been able to dramatically improve the prognosis of burn injuries. In one instance, a patient suffering from an extensive burn injury completely regenerated most of their skin with the application of Integra combined with the minimal perforation mesher, and could bend their arm without the skin adhering to their joints. Currently, the Cairns lab is working on a “spray-on-skin” treatment which applies epidermal cells to the burn wound to regenerate skin – these efforts are led by Dr. James Hwang. Aside from tissue engineering endeavors, the Cairns lab also focuses on using genetics and proteomics to describe the immune system after a burn injury, especially its association with burn sepsis, a complicated and fatal symptom of burn injury. Researchers are investigating the gene expression profiles in the blood of burn patients to uncover vital clues in the area of burn research. Additionally, inhalation injury and subsequent infection of the lung pathways is major area of research in the Cairns lab and is a major focus of Dr. Samuel Jones, Director of the Burn Intensive Care Unit. Burn injuries can severely suppress immune function by creating a cesspool of pathogenic fungus and microbes in the lungs. Pneumonia is a major cause of death in burn patients, and the Cairns Lab has worked with Dr. Peden at the EPA to identify protein and genetic changes in burn patients and their relationship to infection. Aside from the tremendous amount of research into a plethora of subfields related to burn injury and prevention,

health

the Jaycee Burn Center has coordinated several partnerships to improve global public health under Dr. Cairns’ leadership. The center has worked with the United States Special Forces to train military health personnel in burn treatment, and their team effort has helped create the Physician Assistant program at UNC. Recently, the center developed a burn unit in Malawi in partnership with Johnson & Johnson to train medical professionals to optimize care with a limited amount of resources. Regionally, the Jaycee Burn Center has one of the largest aftercare programs in the region, specializing in psychological and physical trauma for burn patients. “Once you’re a burn patient, you are a burn survivor for life” said Dr. Cairns, stressing the psychological trauma that persists well after a burn injury has been treated. This burn center has developed several advocacy and prevention programs to create a safer environment for the people around the state: “We would like to prevent burns altogether and our job would be over someday.”1 Dr. Cairns continues to work towards improving burn prevention programs, extending the Jaycee Center’s reach to rural communities, and furthering his research endeavors to tackle burns from both basic sciences and clinical approaches.

References

1. Staff. “One UNC Employee Injured in Dey Hall Accident; Power out on Central Campus.” The Daily Tarheel, 20 Jan. 2016. Web. 16 Mar. 2016. 2. American Burn Association. Annual Report: National Burn Repository. Chicago, IL. 2007. 3. Klein, M.B. et al. JAMA. 2009, 302(16), 1774-1781. 4. Interview with Bruce A. Cairns, M.D. 02/02/2016. 5. Pruitt, B.A. J Trauma. 1984, 24(6), 463-70.

EXCEED YOUR GOALS. By joining the U.S. Army health care team, you can expand your education and explore new areas of your specialty. Army health care professionals are leaders that inspire others to succeed, all while providing outstanding care for Soldiers and their families.

Visit goarmy.com/cy91 to learn more or call us at 919-875-1530.

medicine

The image on the right is a transmission electron microscope (TEM) image of the drug delivery system. The picture on the left is the schematic of the nanogel delivery system. Image courtesy of NCSU.

Drugs In Disguise:

How platelet membranes are improving cancer drug treatments

By Alexandra Piselli

eople often say “the cure is worse than the disease,” referring to the emotional and physical pain associated with various chemotherapies and radiation dosages needed for cancer treatment. For these reasons, it is not surprising that there is a lab at UNC-Chapel Hill interested in alleviating the pain of treatment, while also making the treatment more effective. Through the research of Dr. Zhen Gu and his lab on the use of platelet membranes in administering cancer treatments, methods have been found that allow chemotherapy drugs to last longer in the body, achieve active targeting ability to attack both primary and circulating tumor cells, and alleviate immune response. With labs at both NCSU and UNC, Dr. Gu and Quanyin Hu (a graduate student also working on the project) have been developing this idea since it was found recently that platelets could help circulating tumor cells (CTCs) survive in the blood stream and migrate to other places for development and growth. The aggregation of platelets surrounding CTCs helps them survive in the bloodstream and spread to new tissues. Using this knowledge, they devised the strategy of using platelet membranes to help deliver chemotherapy drugs. Quanyin explained that “the idea [of using platelet membranes to encapsulate the cancer drug being administered] is inspired by the natural role of the platelet […]. We hypothesize that if the drug delivery system could mimic the behavior of a natural platelet, it could be very effective in treating cancer.”1 Much like pieces of a puzzle fitting together, the plate-

let encapsulating the cancer drug attaches to the CTCs. This attack specificity severely decreases general chemotherapy side effects of nonspecific drug distribution, such as inducing unsuspecting harm on main organs.1 Using the platelet membrane to disguise the drug can dramatically enhance the accumulation of the drug at the tumor site and thus decrease the Dr. Zhen Gu unwanted side effects.1 Though optimal drug dose will ultimately be affected by many factors based on different tumor types, size, and stage, this is certainly a positive step in the fight against cancer.1 In the lab, the patient specific platelets are collected and treated so that the membranes can be extracted and coated in a nanoscale gel containing anticancer drug doxorubicin (Dox). Dox is a drug that attacks the nucleus of a cancer cell. Because the platelets are patient-specific, they are not identified as foreign objects, allowing the encapsulated cancer drug to last up to 32 hours in the bloodstream. Without the coating, the drug circulates only six hours in the bloodstream. Quanyin stated: “Due to the long circulation time of pseudo platelets [referring to the platelet-treatment hybrids], they could stay much longer in the body after administration compared with free drugs, and thus the administration frequency could be significantly reduced.”2 He went on to clarify that this will allow for

Carolina Scientific “a much lower dose of cancer drug to treat the cancer compared with drugs without platelet membrane coating.”1 After injection, these “pseudo-platelets” accumulate at the tumor site due to active targeting based on the affinity between PSelectins (a cell adhesion molecule) expressed on the platelet membrane and receptors on the cancer cell. This affinity allows drugs to not only attack stationary tumors but also those circulating in the bloodstream – attacking new tumors before they begin proliferation. The “pseudo-platelets” undergo a series of natural processes when coming in contact with the tumor to release the treatment inside. First, P-selectin proteins on the platelet membrane bind to the CD44 proteins on the surface of the cancer cell, effectively locking it into place like a puzzle piece. Second, TRAIL, one of the most important extracellular activators of programmed cell death (apoptosis) expressed on the platelets’ membranes, attacks the cancer cell membrane. TRAIL induces apoptosis of the tumor cells by binding to death receptors on the cell surface. Third, the platelet is swallowed by the larger cancer cell. The acidic environment inside the cancer cell then begins to break down the pseudo-platelet – allowing the Dox inside to directly attack the cancer cell’s nucleus and trigger apoptosis. This platelet technique has only been tested on mice, but Quanyin and Dr. Gu have big expectations for the future. When using fluorescence testing to see how much of the Dox treatment had found its way to the tumors, increased fluorescence was seen in the case of Dox treatments coated in platelet membranes, indicating that the treatment was more targeted and effective than non-platelet membrane coated Dox administration. In addition, no obvious pathological abnormalities were observed on normal organs under platelet membrane encapsulated Dox treatment. While complete tumor eradication cannot be promised with this method due to metastasis, recurrence, and drug resistance, these methods are a hopeful contribution to the realm of cancer treatment. Quanyin explained that the treatment is soaring in potential; the platform could be adapted to many different types of cancer as well as a multitude of cancer-specific drugs.1 Because of the stability of the serum, the specificity of targeting, and the ease of generation, the concept of platelet membrane delivery could even, in the future, work to deliver other proteins that act on the tumor cell membrane. The platelets also play a key role in several physiologic and pathological processes such as hemostasis and thrombo-

medicine

Illustration by Dave Mossman sis by forming plugs that seal injured vessels and stops bleeding, holding promise for developing this platform for treating vascular disease. Currently, Dr. Gu and Quanyin are moving forward with this project by evaluating the safety and treatment efficacy of the platform on large animal besides mice, and trying to extend application of the platelet membranes to vascular disease. With all of the possible applications and efficacy of this project thus far, it certainly holds promise for further development.

References

1. Interview with Quanyin Hu. 01/27/16. 2. Hu, Q.; Sun, W.; Qian, C.; Wang, C.; Bomba, H.; Gu, Z. Adv Mater. 2015, 27(44) 7043-7050.

Figure 2. Schematic design of drug-loaded PM-NV. The main components of TRAIL-Dox-PM-NV: TRAIL-conjugated platelets membrane derived from platelets; Dox-loaded nanovehicle (Dox-NV). I: centrifugation of whole blood; II: isolation of platelets; III: extraction of platelets membrane. Image courtesy of Quanyin Hu.

biology

Sea-ing 20/20

Zebrafish Leading the Pathway to Sight By Madison Kennedy

hile sitting in a movie theatre watching the latest horror film, you wait as quiet fills the room. You can hear your own breath until a harsh noise breaks the silence. Before you know it, your eyes are shut and you are screaming amongst the audience. Escaping visual stimuli by shutting your eyes may seem like a simple task, but there is actually a complex pathway that controls your retina so that when you shut your eyes, you no longer see that evil clown that popped up on the movie screen. This pathway is particularly interesting, as it happens within 100 milliseconds.1 Dr. Ellen Weiss, a professor at UNC-Chapel Hill, has taken on the research of this pathway. Her research may help further our understanding of visual pathways and also shed some light on degenerative eye diseases. Dr. Weiss’s main concern is to understand how vision adapts to changes in light. In the eye, light comes through the lens and focuses on the retina, which is the inner periphery of the back of the eye. Two types of photoreceptor cells – rods and cones – are then activated. Rods are responsible for dim light vision and cones are responsible for color and daylight vision.1 Dr. Weiss is specifically interested in the differences between these two cell types. This interest led her to look at the proteins that interact with the receptor proteins, called opsins, in the membranes of rods and

Photo by Thierry Marysael, CC BY-NC-ND 2.0.

cones. There are different biochemical properties between the opsins present in cones and rods, but these differences do not account for the diversity between the structure and function of these two photoreceptor cells. The “shut off” pathway for these opsins allows the eyes to look at new images without leaving a residual imDr. Ellen Weiss age. This pathway includes a G proteincoupled receptor kinase (GRK) that phosphorylates the opsin. Phosphorylation causes arrestin, another protein, to bind to the opsin and shut off signaling. GRKs are found in both rods and cones. Dr. Weiss’s research focused initially on the 13-lined ground squirrel, an interesting little mammal that led to the discovery of a new GRK in cones: GRK-7. Previous research indicates that the first discovered GRK, GRK-1, is present in the cones of most mammals including mice and humans. Following the research done on the 13-lined ground squirrel, Dr. Weiss found that GRK-7 is also present in human cones, along with GRK-1. This discovery is thought to account for major differences between rods and cones because of heterogeneity, or

Dr. Weiss’s main concern is to understand how vision adapts to different changes in light.

Carolina Scientific diversity, in the present GRKs.1 The discovery of GRK-7 is also an important one due to the model organism currently used for research on cones: mice. Mice, unlike humans, only express GRK-1 and not GRK-7 in cones. This lack of congruency between mice and humans could mean that the current standard for research may soon shift to a surprising model organism, zebrafish. Dr. Weiss explained, “Zebrafish express both GRK-1 and GRK-7 in cones much like humans do, and so we are currently using zebrafish to look at the differences between these two kinases.”1 Dr. Weiss used non-invasive electrophysiology to knock out either GRK-1 or GRK7- and look at the differences between these GRKs in living larval zebrafish.2 By looking at the resulting visual signaling, Dr. Weiss can tell if the absence of one of these GRKs affects how well the opsin is shut off. This is an important discovery, as cone function can now be studied in a living organism. Additionally, Dr. Weiss found that these GRKs are phosphorylated by a protein called cAMP-dependent protein kinase (PKA). This phosphorylation modulates GRK activity so that it can no longer turn off the opsin as efficiently, thereby shutting down visual signaling in the eye. To further look at the effect of GRK phosphorylation in vivo, Dr. Weiss used genetically mutated mice whose GRK phosphorylation sites are “always phosphorylated” or are “always un-phosphorylated.” By performing immunocytochemistry, a lab technique that tags proteins using antibodies, Dr. Weiss can visualize the phosphorylation in these retinas. Using a test called a pairedflash paradigm, Dr. Weiss determined the rate of recovery of photoreceptor cells following light stimulation. The phosphorylated GRK should be the less-functional kinase and a delay in the recovery of the second flash would be expected. For the un-phosphorylated mutant, a faster recovery would be seen because the GRK is “turned on” and can more quickly phosphorylate the opsin protein.1 Dr. Weiss is excited about the results to come in the next months, “It’s so obvious [phosphorylation of GRKs] is im-

Figure 2. Mice are used in Dr. Weiss’s lab to study retinitis pigmentosa through an analogous mutation known as rd10. Photo by Yu-Chan Chen, Aug. 23, 2015. Image public domain. portant for something, but whether or not we have figured out what it is important for, I don’t know.”1 This innovative research may have practical implications for a degenerative disease: retinitis pigmentosa, which causes the inflicted individual to go blind. Dr. Weiss elaborated on the disease, “There are no therapies for retinitis pigmentosa. It is a genetic disease and there are many different mutant genes that cause it – a large number of mutations are in rhodopsin. One in every 4,000 individuals worldwide may have retinitis pigmentosa.”1 Dr. Weiss spent a year studying this disease with RTI International. Through mice models and mass spectrometry, she has determined that the top three statistically significant compounds in the diseased retinas are unknown compounds. The mass spectrometry readings received from the retinas had never been identified before, and so their functions remain unknown. Uncovering the structure and function of these compounds may have a huge impact on how this degenerative disease is treated. “Five years ago, we wouldn’t have been able to do this project with the retinas that we have, but mass spectrometry keeps getting more and more sensitive so hopefully we will keep moving with the technology,” Dr. Weiss added.1 Dr. Weiss has made significant advances in the understanding of the visual pathway and soon will have more results from her cutting-edge research. In the future, zebrafish may become an increasingly popular model organism for research as Dr. Weiss’s team further uncovers the function of GRK-7. So, the next time you shut your eyes to sleep or escape a scene in a scary movie, be thankful for this complex pathway that has yet to be fully understood.

References Figure 1. A novel protein, GRK-7, was discovered in the 13-lined ground squirrel. Photo by Phil Myers, Museum of Zoology, June 28, 2002. Image public domain.

biology

1. Interview with Ellen Weiss, Ph.D. 01/27/16. 2. Chrispell, J.D.; Rebrik, T.I.; Weiss, E.R. J Vis Exp. 2015, (97), e52662. 3. Osawa, S. et al. J Biol Chem. 2011, 286(23), 20923-20929.

biology

Uncharted Fields plant science and cellular signaling By Sarah Dweikat

nyone who has ever been involved in serious competition can recall the intoxicating effect of adrenaline. For some, adrenaline fuels perfection. For others, it creates pure nausea. But how exactly are cells able to recognize and respond to adrenaline, or any other type of neurotransmitter or hormone? All signaling chemicals – whether it be dopaDr. Alan Jones mine, norepinephrine, serotonin, or testosterone – are capable of causing dramatic changes in how the human body thinks and feels. These changes, however, can only occur if the chemical signals are properly perceived by individual cells. The simplest, and most accepted, early models for signaling recognition proposed that a chemical like adrenaline would be acknowledged by a receptor on the cell that, in turn, would activate enzymes within the cell to cause the intended reaction. In reality, the cell receptor recognizes adrenaline and stimulates a component called ‘G protein,’ which then stimulates cellular enzymes. G proteins, therefore, are critically important molecules for signaling in cells; and their dysfunction can result in several human diseases including blindness, allergies, diabetes, depression, cardiovascular disease, and some types of cancer. Human cells have close to 850 G protein coupled receptors, and nearly half of present-day drugs target these receptors. It is this complex system that allows for detection of light, hormones, drugs, and growth factors. Dr. Alan Jones, Kenan Distinguished Professor of Biology at UNC-Chapel Hill, is a highly renowned expert in the function of G proteins. While most people in the field of G proteins were studying these proteins using animal cells growing in culture, Dr. Jones began his research on G proteins using the genetic model Arabidopsis – a small plant that has many advantages for basic research. As it turns out, plants also use G proteins in their cellular signaling, and these complexes play critical roles in essential biological processes like cell proliferation. “Arabidopsis offers a multicellular context which has been lacking in the G protein field. When I decided to research G proteins they said ‘well, what are you going to teach us with that plant? We alIllustration by Carley West

Carolina Scientific ready know everything.’ But we have made some major discoveries in Arabidopsis that have human impacts.” Dr. Jones explained that the fact that these discoveries could only have been made using plants is often overlooked or underappreciated.1 When Dr. Jones thinks about the field of cell biology at large, he thinks about a field at an exciting juncture, a field in transition. “Some think the signal transduction era is over, but I think it is just getting started.” He said, “now is the fun part because we have completed the parts list, allowing us to focus on how all the parts interact in time and space; we are understanding the multidimensionality of the system.” A recent, exciting discovery by the Jones lab has revealed the unusual way that G proteins evolve. When a cell experiences a change in environment, perhaps by a change in hormone levels, G proteins are activated by receptors on the cell surface. This activation involves converting guanosine diphosphate (GDP) to guanosine triphosphate (GTP) on the G protein. This reaction is accelerated by the Regulator of G protein Signaling (RGS).2 This series of reactions represents one crucial way in which a cell responds to the signals that it receives, serving as an “on” switch for the process. Because this activity is so crucial to how cells perceive their environment, components of the process are similar even across distantly related animal and plant species. It was, therefore, surprising when scientists discovered that grass species do not have the RGS protein. The grass family of plants not only lack the RGS protein, but also have a mutation on their G proteins at precisely the site where RGS binds to affect the GTP conversion reaction. Dr. Jones and his collaborators reasoned that during evolution, an ancestor of the grass family must have undergone a mutation in the G protein so that RGS could no longer bind. When this happened, and the RGS protein could no longer be useful, it was lost. What was even more surprising, however, was that the Jones group then discovered one type of grass, the foxtail millet (Setaria italica), that still had an RGS protein. When they looked at the G protein of this unusual millet, it also had the G protein mutation that was found in other grasses. So if

Figure 2. Foxtail millet. Image by jennyhsu47, CC BY-NCND 2.0. foxtail millet had the G protein mutation, they wondered how it could also have the RGS protein. The Jones group reasoned that when the G protein underwent mutation in the millet line, the RGS was not rendered inactive but, instead, underwent a compensating mutation so that the new mutated RGS could work together with the new mutant G protein.1 This discovery revealed something important about how evolution occurs among proteins that must interact in special ways: changes to one component can result in a loss of the other interacting component (as was observed in most grass species), or changes to one component can lead to compensating changes in the other (as was the case in the foxtail millet).2 Dr. Jones becomes noticeably more animated when he talks about the emerging era of plant science, where scientists now have the opportunity to dissect and understand the many components of plant function. Part of his excitement stems from the power of a model system like Arabidopsis, which permits the scientist to mutate nearly every gene, one at a time, to learn how each contributes to the plant’s behavior. “Genetics in a system like Arabidopsis lets the scientist tease out each component by knocking out the gene, so that what we have really done is tugged at a net without cutting a single string.”1

References Figure 1. Yeast cells with fluorescent G proteins. Image by ZEISS Microscopy, CC BY-NC-ND 2.0.

biology

1. Interview with Alan Jones, Ph.D. 02/09/16. 2. Urano, D.; Dong, T.; Bennetzen, J.L.; Jones, A.M. Mol Biol Evol. 2015, 32, 998-1007.

biology Lander, A.D. BMC Biol. 2010, 8(40).

KEEPING UP WITH THE KINASES how cell signaling pathways complicate cancer treatments By Jacob Smith

ost of us have played the game telephone, but how does it relate to cancer cells? Signaling within cells can be a lot like a game of telephone, as in telephone signalers must pass along messages from one part of the cell to another, or from one cell to another. However, signals failing to consistently and accurately pass their message to their targeted disease is almost a guarantee. These signalers are often proteins, and the message they carry often comes in the form of a phosphate molecule. Compared to proteins that contain thousands of atoms, phosphate molecules are comparatively miniscule with only one phosphorus and four oxygen atoms. Amazingly, they can cause huge changes in protein activity (if and when complications arise). Two major classes of proteins carry out the transfer of phosphate molecules: kinases, which attach phosphate molecules, and phosphatases that remove them. Since cell signaling is so important in cancer, kinases are often the key to developing a therapy. In the same way that the genome is the entire collection of genes in an organism, the kinome represents the entire collection of kinases. In some sense, kinases are the trees that make up the forest of the kinome. In his research, Dr. Gary Johnson in the Department of Pharmacology hopes to avoid mixing up the forest for the trees when devel-

oping cancer therapies. Dr. Johnson is a Kenan Distinguished Professor and Chair of the Department of Pharmacology at UNC-Chapel Hill. His lab employs advanced chemical analysis techniques to determine the effect of kinase inhibitor drugs on the entire kinome. One Dr. Gary Johnson process, known as Multiplexed Inhibitor Bead/mass spectrometry (MIB/MS), allows researchers to analyze the impact of a drug on the entirety of kinome activity.1 This process involves breaking open cells that have been treated with a drug and pouring their innards over a column lined with molecules that are known to bind different kinases. The kinases can then be collected, and the effect of the drug on the entire kinome can be evaluated. This large scale, or â&#x20AC;&#x153;global,â&#x20AC;? analysis of protein activity has provided key insights into cancer research. There are several advantages to analyzing global kinase activity in a cell instead of focusing on a specific protein. For instance, the effect of a drug on many different kinases can be detected simultaneously.1 This can reveal important informa-

Carolina Scientific tion about how cancer cells adapt when a drug blocks a single pathway. Knowledge of this process helped to determine the mechanism behind what is known as kinome reprogramming, which occurs in breast cancer along with several other cancers. Kinome reprogramming can make some cancer treatments ineffective.1 Kinome reprogramming is the result of the inherent complexity of signaling within cells.1 In some cancer cells, blocking one type of kinase is not enough. When only one kinase is blocked, other kinases can be expressed that can block the drug used to treat the tumor. In effect, the cancer cell is taking what should be a road block – the inhibitor – and turning it into a detour. Knowledge of this mechanism made it possible to design a combination drug therapy to treat a group of tumors known as triple negative breast cancer (TNBC). The MIB/MS approach can be used to gather global information of kinome activity in other cancer cells. Dr. Johnson admits we are not there yet, but envisions using this information as a diagnostic tool and sees it as a step towards advancing personalized medicine. He stated, “You could actually do this in personalized medicine where you could understand an individual’s tumor, how it responded to therapy, and how you might change that therapy.”2 In fact, it is already being used to screen patients’ tumors at UNC Hospitals.2 In the future, tumors exhibiting kinome reprogramming could be detected by identifying biomarkers, molecules that are associated with a certain kinase pathway. This could mean that tumors that require a combination of drugs to be treated could be detected and treated right away instead of a physician providing a patient with ineffective drugs and allowing the tumor to grow

Figure 1. Summary of the MIB/MS process and a diagram of kinome activity. Red spheres indicate kinases whose activity increased relative to a baseline reading when treated with inhibitor. Blue spheres indicate kinases whose relative activity decreased. Image from Stuhlmiller, T.J.; Earp, H.S.; Johnson, G.L.; Clin Pharmacol Ther. 2014, 95(4) 414.

biology

“I still get pleasure when people in my lab do a really good experiment, and they’re really proud of it, and they need to realize that they may be the first person in the history of the world that has ever discovered that.” Dr. Johnson further. Starting out with the right treatment plan is critical when fighting cancer since mortality rates are significantly higher for patients whose treatments begin in later stages. The obvious complexity of kinase signaling networks demands a multifaceted approach of investigation. UNC is an ideal place for this research based on work being conducted in the pharmacy, medical, and public health schools, as well as by many researchers in fields like physics, computer science, and statistics that contribute to biomedical research. Dr. Johnson understands the importance of having experts in many disciplines in one place, explaining that he gets to interact with “basic scientists, translational scientists, clinical researchers, and people in the clinic… you can be right at the edge of development of new therapies.”2 It is not just making discoveries that Dr. Johnson finds rewarding, but also that his students go on to make important discoveries: “I still get pleasure when people in my lab do a really good experiment, and they’re really proud of it, and they need to realize that they may be the first person in the history of the world that has ever discovered that.”2 Dr. Johnson and his colleagues’ work highlight the importance of networking, both in cellular activity and in academia. Collaboration is the key to unraveling these highly integrated cellular signaling pathways and using this information to develop practical treatments. This research is representative of the field of pharmacology in general, too. It lies at the convergence of many fields, and thus pharmacological studies can have a broad impact on both pure research and applied health science. Using global kinome activity to develop better therapies demonstrates how esoteric knowledge gained from research can have a real impact on people’s lives. The work of Dr. Johnson’s lab helps bridge the gap between scientific research and medical application.

References

1. Stuhlmiller, T.J.; Earp, H.S.; Johnson, G.L.; Clin Pharmacol Ther. 2014, 95(4), 413-415. 2. Interview with Gary L. Johnson, Ph.D. 02/11/16.

biology

the predictable within the

CHAOS By Suzy Gleaves

magine being in a bustling room humming with people and noise, and lots of it. You faintly hear someone beckoning at you from across the room – but there is no direct path to that point. You would think that it is nearly impossible to hear, much less to respond, when surrounded by this much chaos and noise. However, this is a glimpse of what it is like inside the dynamic cell, and mathematical equations can help explain your response to the signal you heard. Mathematical modeling is crucial to researching and predicting cell behaviors. The field of computational biology is a mash-up of mathematics, statistics, and computer science to approach problems in biology dealing with things like threedimensional protein structures, gene expression, metabolic pathways, protein interactions, gene regulation, and more.1 According to Dr. Tim Elston, “Computing and quantitative approaches are now in every aspect of cell and molecular biol-

Illustration by Alex Cecil

ogy. While you do not have to be an expert, if you want to be successful in this type of research, you have to know something about computational biology or bioinformatics – there’s just no way to avoid it.”2 Dr. Elston works in the Department of Pharmacology in the UNC-Chapel Hill School of Medicine, and heads Dr. Tim Elston the Bioinformatics and Computational Biology program. His primary interest is in systems biology, a field that focuses on how proteins work together to function, respond to their environment, and make decisions. Dr. Elston uses his extensive knowledge of stochastic processes (random behavior) and simultaneous equation sets to collaborate with labs on campus as well as at Duke on numerous projects.

Carolina Scientific

Figure 1. (Top) Fluorescent proteins can be attached to native yeast proteins to make them easier to see. Here, the effectiveness of some fluorescent proteins are tested in increasing dilutions at increasing temperatures. Images courtesy of Dr. Elston. (Bottom) Two different proposed models of how chemicals help determine polarity. Images courtesy of Goryachev, Pokhilko, and Klunder. In fact, to help with modeling these busy, random systems, Dr. Elston helped create BioNetS, the Biochemical Network Stochastic System. It is a software that captures the random “noisy” behavior of cell parts to see the effect of that random noise and study its consequences during experiments. Primarily, he uses this software to tackle the big questions in signaling pathways and polarity establishment in the yeast S. cerevisiae.

biology

helped discover that small cells like yeast do not have receptors scattered evenly across their surface, as researchers initially hypothesized. While larger cells can notice differences in receptor activity on opposite ends of the cell, small cells do not have the diameter to do that.3 Receptors on a majority of the cell surface would attach to the target molecule at the same time if they were evenly spaced, and thus the cell would not know which direction to go. Rather, their receptors are very mobile and, like a compass, point towards the strongest concentration in their environment. Setting the “head” and “tail” of a cell is more important than one would imagine. Just as a dog would swim in the direction that its head is facing, with its tail trailing behind it, cells move headfirst with the “tail” on the opposite side. Determining which part of the cell will form the head (and thus the tail) is known as polarity establishment – like the North and South Poles. Cells with multiple heads usually die off rather quickly or, if they survive, suffer greatly and lead to diseases.4 Oftentimes, the cell will start off with several small heads at different points on the cell surface. However, if one head has even the slightest advantage over the others, it will rush to fully develop while others will die off. The search to find a mathematical model that works is a long process. There are just so many variables that come into play. However, Dr. Elston constantly reminds his students that “failure shouldn’t be considered a bad thing—we learn something new and understand the system a bit better whenever a model fails. It just requires patience.”

Signaling pathways are comparable to electric circuits. If you know how to build a circuit and alter the electrical flow, then you can describe precisely how it works with a mathematical equation. Signaling pathways are comparable to electric circuits. If you know how to build a circuit and alter the electrical flow, then you can describe precisely how it works with a mathematical equation. It is the same way with cell processes – if you can find the equations that capture the behavior of the molecules or proteins of interest, then you can predict future behavior, and perhaps even manipulate the equations to create new behaviors. In this case, the Elston lab is helping figure out how a cell builds and uses its receptors to know where higher concentrations of key molecules are located in its surroundings, and how it signals its internal machinery to move towards those molecules. Mobile cells use receptors on their surface to detect where a particular chemical has a stronger concentration and moves towards it; however, the specifics of this process are not fully understood. The Elston lab has

Figure 2. S. cerevisiae captured under a microscope. Image public domain.

References

1. Computational Biology. Retrieved from https://bscb. cornell.edu/about/computational-biology 2. Interview with Timothy Elston, Ph.D. 02/08/16. 3. McClure, A.W. et al. Dev Cell. 2015, 35(4), 471–482. 4. Wu, C.F. et al. Elife. 2015, 4, e11611.

biology

HOLY CROP! how gene editing can produce better plants By Annaleigh Powell

Illustration by Laura Hamon

lant cells talk to each other, but their words often get lost in translation. If we learn how they communicate with each other, we can gather information to better understand their machinery. Dr. Zachary Nimchuk, Assistant Professor at UNC-Chapel Hill, aims to understand plant language by studying their genomes and maDr. Zachary Nimchuk nipulating them to affect gene expression. Gene editing is a hot topic in biology with incredible prospects in solving real world problems like curing genetic diseases and increasing crop production. Though gene editing has a history of ethical controversy, advancements in this area enable a safe and reliable way to practice and utilize this technology. Dr. Nimchukâ&#x20AC;&#x2122;s research focuses on how cell-to-cell communication controls development in plants.1 He studies the rules that plants abide by to perform simple functions, such as the types of cells made and how those cells specialize.1 He experiments with Arabidopsis thaliana plants, which share similar genes with crops we eat such as tomato and maize.1 The larger focus of Dr. Nimchukâ&#x20AC;&#x2122;s work is to apply knowledge about Arabidopsis to agricultural crops to increase crop production and potentially alleviate problems associated with exponential human population growth in the future. Dr. Nimchuk uses a cutting edge technology to edit and modify plant genomes to elucidate gene functions. The method Dr. Nimchuk employs is derived from the genome of Streptococcus pyogenes, the bacteria responsible for causing strep throat.2 Many bacteria and archaeans possess an adaptable immune system found in their own genetic makeup called clustered regularly interspaced short palindromic

Carolina Scientific repeats (CRISPR). CRISPRs are repeated sequences in bacterial DNA that have unique genetic sequences sandwiched between them.2 These unique portions of the bacterial genome are pieces of invading viral DNA retained by the bacterium to fend off future infections.2 An enzyme called Cas9 (CRISPR-associated protein 9) works together with CRISPRs to create an efficient and precise defense mechanism.2 Cas9 is specifically from the bacteria Streptococcus pyogenes.2 Cas enzymes pick up RNA molecules created from CRISPR sequences that correspond to specific viruses.2 The Cas-RNA pair travels around the bacterial cell to recognize and destroy corresponding viral DNA, which ceases viral replication. This naturally occurring phenomenon is utilized in biotechnology for gene editing and is called the CRISPR/Cas9 system.1 Scientists, like Dr. Nimchuk, give Cas9 a specific RNA sequence to edit the genome of an organism of interest.2 CRISPR is preferred over older methods of gene editing due to its superior precision and efficiency. “We have a CRISPR/Cas9 genome editing technology to precisely modify the plant genome in a way that does not introduce any foreign DNA to the plant,” explained Nimchuk.1 CRISPR has incredible potential for crop production and many other subfields of biology. Dr. Nimchuk has made important discoveries using the CRISPR/Cas9 system. By removing genes that change stem cell development, larger and more desirable plants can be created.1 For example, a large tomato differs from a cherry tomato in both size and taste due to a mutation in stem cell production that causes a large tomato to grow more tissue than a cherry tomato. Such mutations create a larger crop that is more suitable for feeding more people. These genetic differences extend into Dr. Nimchuk’s work with stem cell growth in Arabidopsis. Arabidopsis CLV3 mutants exhibit extra stem cell production, which causes increased root growth, similar to how a tomato may experience more tissue growth (Figure 1).3 Humans have unknowingly been manipulating the DNA of crops for centuries. Long before any knowledge about DNA, humans bred crops with more desirable traits. If a crop developed a random mutation that made it a better food for consumption, its seeds were used to make more crops of the same type. Though creating better crops certainly is not a new goal, Dr. Nimchuk’s work can create better crops in a more efficient and systematic way. It is projected that by 2050, the human population will have increased by 2.4 billion people.4 Dr. Nimchuk believes that his research will give insight on how we can modify plants to yield a larger amount of crops and avoid an increased global food shortage. “The idea here is that we have this global problem. We need to feed the increasing number of people on the planet. If we can figure out some way to control the genes and alter the way plants grow to improve crop production, we can take on some of the challenges we will be facing in the upcoming years.”1 “If everything goes perfectly, you end up with a new set of questions” Dr. Nimchuk said.1 There is no end to scientific research. We will likely never find the precise genetic recipe to yield the perfect crop for human consumption, but we get closer every day.

biology

Figure 1. (Top) Stem cell niche showing CLV1 receptor. (Middle) A wild type CLV3 Arabidopsis plant. (Bottom) A mutant CLV3 Arabidopsis plant. All images courtesy of Dr. Nimchuk.

References

1. Interview with Zachary L. Nimchuk, Ph.D. 02/08/16. 2. Cong, L. et al. Science. 2013, 339, 819-823. 3. Email with Zachary L. Nimchuk, Ph.D. 02/10/16. 4. Block, B. UN Raises “Low” Population Projection for 2050. Retrieved from http://www.worldwatch.org/ node/6038

waking up to rain: a snapshot of field research By Bri Sikorski

Illustration by Linnea Lieth

ince 1995, Dr. Karin Pfennig has driven hundreds of miles and chased storms through the deserts of Arizona for a single furtive moment. Throughout the summer, the spadefoot toads have spent their time burrowed under these hot sands in a sleepy stupor. When isolated storms form during the night and rain begins to fall, the toads wake up and congregate in these newly formed pools. Into the desert night the chorus of whining calls fill the cooling night air. Their songs may become deafening when the ponds swell with calling males. Often they just have this one fleeting night to find a mate and lay their eggs before the July sun dries the pool come morning. With their simple appearance, spadefoot toads are assuming as to their stunning adaptations to the harsh desert environment. Their small and stout bodies, their wide and calm eyes, and their smooth skin speckled like a bird’s egg develop at an astonishing pace. Their eggs only last two days before they must hatch or face the threat of the looming sun. In as little as a week or two the tadpoles escape the shrinking ponds to burrow into the sand. This makes them “the most rapidly developing amphibian on the planet,” according to Dr. Pfennig.1 The New Mexican and Plains spadefoot toad populations may be isolated from one another; however, in overlapping areas, these toads can and do hybridize. This is where Dr. Pfennig’s research peers into the secretive life of these reclu-

sive toads. In their development, the tadpoles can mature into two different morphs: one feeds upon plant matter and the other cannibalizes other tadpoles. To bear witness to the habits of these creatures, Dr. Pfennig must prepare months in advance. Reservations for staying at the Southwestern Research Station are made in the early months of the year for these few weeks in July. When she first started this annual migration, she was just a graduate student. Now with her husband, Dr. David Pfennig, and their children, they make the drive out west, eat at the same Subway, and stop at the same grocery store before entering Portal, Arizona every year. As they drive down the highway, they peer from the mountains over the valley where their research will take place. The first years she was there, she stayed in the “bachelor quarters where as many as six people would be in a very big room with one bathroom and bunk beds. Honestly, we camped in the early days because it was more pleasant to live in a tent.”1 With the addition of her family, she now stays in the rustic family housing that still breathes the old southwestern charm of cabin lodging and has a microwave and a fridge. Meals are served at three set times during the day in the large communal dining area where geologists, archaeologists, naturalists, and biologists can socialize.2 Owned by the American Museum of Natural History, the station has teemed with these kinds of researchers since 1955.2 Around

Carolina Scientific the humble dormitories and cafeteria of the research station, the staggering view of the Chiricahua Mountains engulfs the skyline. The station sits in a valley pocket surrounded by the rugged desert and mountain environments, where the mountain lions skulk about and the coyotes howl at night. Tucked away in their burrows for the other part of the year, toad and reDr. Karin Pfennig searcher alike begin to quiver in anticipation of the summer storms. Before the days of radar, they would pack their dinner. Dr. Pfennig said they would “drive thirty, forty, fifty miles and watch the skies. You see lightening and you drive towards it. You were storm chasing in the oldfashioned way and it could be exhausting.” Now with access to the Internet and radar, they continuously and compulsively check the readings throughout the day to chart their course. When the rain falls, that is their only chance to reach the area and collect samples. It is up to firm planning and decisionmaking to know what to do when they see lightning or hear thunder in one or more areas. How should they decide where to go? Would they divide into two groups? What if they could only choose one spot? Once they detect an isolated night shower, Dr. Pfennig and her team rush to meet the rain. “We spend a lot of time driving. You’re just putting hundreds of miles on your car at night,” Dr. Pfennig explained.1 Along rural roads, they quietly approach ponds saturated with toads. Extinguishing the headlights of the cars and with only flashlights to see, they are enveloped in a chorus of roaring wha wha wha calls. Even in the stillness that night brings, where most animals rest and the earth seems empty, around these ponds only frenzy exists. For the male toads, their one chance to mate has them calling until exhaustion and even death. In the clamor of the songfilled and busy night, males may accidentally overwhelm a female, drowning her in their attempt to reproduce. For Dr. Pfennig and her team, frustration can rise when the pond is too deep to enter, toads escape their reach, or communication becomes impossible over the roar of calls. But even in timedriven panic, when there’s just a few toads and with the stars stretched overhead it is “very peaceful, relaxing, and meditative.” With recorders in hand, researchers collect samples of the mating calls that fill the desert night as well as other data. Some years, researchers collect toads for further experiments focused on their behaviors. After a night of chasing and calling, the pond becomes still once again. In clusters, the eggs of the toads can be seen rapidly forming tadpoles twirling within, later to hatch and form a “tadpole soup.” The trying conditions of the desert are what spur so much of the behavior that Dr. Pfennig has come to understand and publish. She has assessed how in these populations, males must call differently if both New Mexican and Plains spadefoot toads are present to ensure species recognition. Females also prefer different calls if they come from a population of just their own species versus a pond where both species are calling, even preferring to hybridize in some instances. This choice to hybridize is complex as the two spe-

biology

cies have different developmental times. While hybridization may be beneficial for one species when the pool is shallow, it can be deadly for the other. Other influencing factors include the survival and success of detritus eating tadpoles compared to those that hunt and cannibalize others. Each of these factors are interwoven and change based on the environment, the depth of the pools that mating occurs in, the presence of one or both species, the fitness of the males, the presence of parasites, and female preference. All within the fleeting moment of a night these factors come together to influence the next generation and spur on further research in areas of character displacement, mate choice, and behavioral ecology. Once the warm baths of July showers have ended, Dr. Pfennig and her family make the journey home to the piedmont of North Carolina. Nights once again are spent sleeping, where they listen to the occasional rainfall and across the country the spadefoots wait for the summer of next year.

Figure 1. The Chiricahua Mountains and their peaks tower over the flats of the valley where the ponds form. Photo by Gregory Smith, CC-BY-SA 2.0.

Figure 2. The Plains spadefoot toad can be in isolated populations or mate in the same areas as New Mexican spadefoot toads. Photo by Andy Teucher, CC-BY-SA 2.0.

References

1. Interview with Karin Pfennig, Ph.D. 01/28/16. 2. About SWRS. Retrieved from http://www.amnh.org/ourresearch/southwestern-research-station/about

biology

Fish Evolution Revealed by Fine Scale Genetics

By Hannah Jaggers

iology textbooks might need some serious revision. Current genetic testing is revealing that one of the most celebrated examples of sympatric speciation is not quite what it seems. Sympatric speciation is the evolution of a new species without the assistance of geographic barriers or isolation by distance. This process, discovered by Charles Darwin, was so controversial that it was virtually dismissed by scientists throughout the 20th century. It was not until the 1994 discovery of the Cameroon crater lake cichlids, a type of fish from the Cichlidae family, that scientists began to seriously consider sympatric speciation as a possible evolutionary driving force in nature. Genetic evidence revealed that different assemblages of cichlid fish in Lake Bermin and Lake Barombi Mbo, two crater lakes specifically targeted for study, appeared to descend from a single common ancestral species that invaded the crater some time ago. Lake Bermin contains nine different cichlid species and eleven were identified in Lake Barombi

Mbo. Considering the lakes are no longer connected to rivers that could possibly carry in new fish species and both lakes are small and uniform, preventing the formation of isolated pools within the lake, scientists concluded that these species must have evolved sympatrically. Today, the crater lake cichlids are still considered a rare example of sympatric speciation in nature.1

ticular interest in the crater lake cichlid populations. “It’s a crater that’s the size of campus,” Dr. Martin said. “Within this crater that’s only two million years old, you have all of these fish species. Up to eleven species within this one little crater and they’re found nowhere else in the world.”2 Dr. Martin utilized population genomic analyses to study the crater lake fish populations. This analysis can distinguish more complex scenarios of colonization and hybridization that occur during periods of gene flow, or the transfer of genes from one population to another.1 “The older methods for looking at [gene transfer] were not up to the task,” Dr. Martin said. “So we used newer genomic methods to ask ‘Do all of these species share the same common ancestor?’ Unfortunately, it looks like the lake has been colonized more than once, which just makes the story more complicated.”2 Dr. Martin’s genetic analysis of the two cichlid radiations in Lake Bermin and Lake Barombi Mbo produced

“Within this crater that’ s only two million years old, you have all of these fish species. Up to eleven species within this one little crater and they’ re found no where else in the world.” Dr. Martin However, evolutionary biologists might reconsider this designation after speaking with Dr. Christopher Martin, UNC-Chapel Hill assistant professor in the Department of Biology. Dr. Martin has been fascinated by fish evolutionary biology since childhood and took a par-

Carolina Scientific

Dr. Christopher Martin more than 350 million DNA sequences which were then used to re-do the phylogenetic analysis, or evolutionary relationships, among the fish. Dr. Martin found that the descent from a common ancestor, or monophyly, of the two fish radiations was actually weaker than previously thought. As monophyly is crucial evidence for sympatric speciation, this finding was certainly unexpected.3 His studies also indicated that a substantial amount of gene flow was occurring between some of the species in each of the two fish radiations and also between the species in the lake and different “out-group” species found in rivers outside of the lakes. These findings suggested that there had been multiple invasions of the crater lakes by ancestors of the cichlid fishes and contradicted the idea of a single common ancestor forming multiple species in the lake.3 “There was a lot of hybridization,” Dr. Martin said. “It does make it look like overall there was a single common ancestor, but when you start to get into the fine-scale genetics, it suggests that repeatedly there were riverine fish getting into that lake.”2 Dr. Martin’s findings support the

Figure 1. Crater Lake Cichlids. Image by Dr. Martin.

conclusion that while sympatric speciation might be occurring to some extent in the fish populations, the true evolutionary history of the crater lake cichlids is much more complex and involves a certain degree of gene flow caused by riverine fish invading the crater lakes. As to how these riverine fish are getting into the isolated lakes is still a mystery to Dr. Martin. “It’s up in a crater, so it’s not like a storm washes them in from the river into the crater,” Dr. Martin said. “Maybe the eggs – the eggs are pretty big too – but maybe the eggs were being carried around. I don’t know. But then, over a million years, maybe that’s quite likely to happen.”2 Dr. Martin’s research also indicated that the crater lakes do in fact have some different ecological niches, which could contribute to speciation within a small area. Speciation in this case was facilitated by an environmental gradient, meaning that sympatric speciation alone did not produce the variance of species found in the lakes. Furthermore, some cichlid species appeared to mate at particular times and places within the lake. The tendency of a cichlid fish to associate time of mating and location of mating is called a “magic trait.” These traits also enable speciation in that fish that tend to mate in certain areas of the lake produce offspring that mate with those nearby, eventually leading to a type of geographic isolation based on fishes’ preference for particular parts of the lake for mating, or their “magic trait.”3 Dr. Martin’s conclusion is that a variety of ecological forces are at play in these crater lakes. “I think there’s a diversity of things going on,” Dr. Martin said. “Some of the species are facilitated by having an influx of new fish every now and then. I think others are helped by specializing in a particular habitat. All of these different ecological factors are playing a role in terms of shaping how far along towards a fully separate species you can get.”2 Although Dr. Martin said that he received no pushback from the scientific community during his time spent researching in Cameroon, the cichlid species themselves receive no protection in

biology

Figure 2. Lake Bermin and Lake Barombi Mbo.3 Cameroon. “All of the habitats I study are threatened by climate change, invasive species, and habitat loss,” Dr. Martin said. “Some of the species I have in the lab are extinct in the wild already.”2 Dr. Martin equates the loss of a species due to extinction to the loss of a research question that he can address. He believes that every biological question can be answered by studying a particular organism that potentially contains the answer to the research question. As species continue to go extinct through human destruction of ecosystems, the answers are slowly fading away. “It’s this very narrow window that we have in the next twenty or thirty years to even study these ecosystems and species and address these fundamental questions in evolutionary biology before our ability to ask those questions goes extinct.”2

References

1. Martin C.H.; Crawford J.E.; Turner B.J.; Simons L.H. P R Soc B. 2016, 283, 23-34. 2. Interview with Christopher H. Martin, Ph.D. 02/03/16. 3. Coyne, J. Cameroon lake cichlids probably did not speciate sympatrically: Part 1 & 2. Retrieved from https://whyevolutionistrue.wordpress. com/2015/06/25/cameroon-lakecichlids-probably-did-not-speciatesympatrically-part-1/

biology

Killing More Cancer, Using Less Chemo By Callie Hucks cancer cells without the toxicity of Taxol.”2 The primary purpose of this exosomal treatment is to spare the healthy cells and kill cancer cells, while protecting the drug from the body’s immune system. Taxol is currently used to treat various types of lung, breast, and ovarian cancers.1 It works by inducing an “arrest” of a certain area of cells, which eventually kills all the affected cells, and often includes many healthy, non-cancerous cells. Exosomes are different from common cancer treatments, in that they come from the white blood cells of a human immune system.1 This keeps white blood cells from attacking the exosomes that carry the drugs and, in turn, allow the exosomes to carry out the process of targeting and only attacking cancer cells. For these reasons, Dr. Batrakova and her colleagues have high hopes for the potential of their new drug treatment: “Since we can make exosomes find only cancer cells, it allows us to significantly increase the efficacy of this drug.”2 Despite this, the research still has a long way to come before exoPXT can be introduced as cancer treatment. The next step is finding another animal model to confirm their research. Following this, toxicology studies will need to confirm that the drug treatment’s side effects do not outweigh its ability to kill cancer cells.2 Finally, manufacturing guidelines will need to be established before clinical trials can begin. Dr. Batrakova shared that this is a difficult part of their research because they want to see the patients get help, while also ensuring that the patient’s safety is considered.2 Despite the challenges that come with the research, exoPXT seems to have proved itself as a powerful therapeutic tool. Dr. Batrakova mentioned that this research could not have been completed without the outstanding support from the Eshelman School of Pharmacy. “It’s a fantastic department… they helped develop budgets and communicate with companies.”2 When asked of her hopes for the future of this drug, Dr. Batrakova discussed her plans for clinical trials. “In clinic, we are aiming to take a patient’s white blood cells, inject the exosomes with the drug, then re-inject the patient with their exosomes.”2 This would provide a natural and more effective way of killing cancer cells. Regardless of where the drug ends up, Dr. Batrakova’s research is of great significance to current medical procedures. The results of the studies produce remarkable implications for a possible revolution in the treatment of cancer.

References

1. Kim, M.S. et al. Nanomedicine. 2016, 12(3), 655-64. 2. Interview with Elena Batrakova, Ph.D. 02/08/16. 3. Weaver, B.A. Mol Biol Cell. 2014, 25(18), 2677-2681.

Illustration by Sean Stickel

ou have cancer - This statement is applicable for many and will continue to plague people of different backgrounds across the world. Cancer is costly to victims and, despite years of efforts, continues to affect children and adults alike. However, researchers at UNC-Chapel Hill are working on a new treatment that Dr. Elena Batrakova could revolutionize the current forms of chemotherapy. According to Dr. Elena Batrakova and her colleagues, exosomes, a “natural nanoparticle,” are being used as drug delivery vehicles, and might be the answer to minimizing some of the damages caused by chemotherapy. Exosomes are spherical particles derived from white blood cells, which can be found in various bodily fluids such as urine or saliva. They are used to carry messages throughout the cells in the form of RNA and proteins. However, Dr. Batrakova has discovered a new way to utilize these messenger cells, which were once thought of as “trash bags” and unusable by other researchers.1 Dr. Batrakova’s research seeks to use exosomes as transport vesicles for anti-cancer drugs, but in a way that targets cancer cells specifically, sparing other cells from the toxic medicine. In explaining this process, Dr. Batrakova noted, “Anti-cancer agents are very toxic [and] when they accumulate in the normal tissues [there are] bad side effects. The goal [is to] use the exosomes to deliver the drug only to cancer cells and spare normal cells.” Though the research has not gone to clinical trials yet, current research has promising results for the future of both cancer and neurological treatments. First, researchers took canine kidney cells and injected some of them with dyed exosomes from the white blood cells of mice. These are then compared with non-exosomal drugs currently on the market, such as Taxol, to see the overall effect they had on the harvested cells. After doing this experiment in petri dishes, Dr. Batrakova and her colleagues noticed that they could use fifty times less drug with their treatment to achieve the therapeutic effects of market drugs. When this comparison yielded promising results, they were able to move the experiment on to mice. When the treatment, called exoPXT, was used on mice, the exosome vesicles were found to target the drug-resistant cancer cells. The exosomes were injected with another anti-cancer drug and dyed again, so that they could be tracked through the lungs of the mice. When compared to Taxol, Dr. Batrakova thinks this drug holds a lot of promise: “When we inject exosomes in mice, [we are] able to completely eliminate

Carolina Scientific

TRUE MEDICINE

TRUE. SGU is the #1 provider of doctors into first-year US residencies for the past 6 years combined, including 850 US residencies to date in 2016.*

TRUE. SGU has a network of over 13,000 graduate physicians who have impacted health care worldwide.

TRUE. SGUâ&#x20AC;&#x2122;s US and Canadian students achieved a 97% first-time pass rate on the USMLE I in 2015.

St. Georgeâ&#x20AC;&#x2122;s University, located on the tip of the True Blue peninsula, is committed to the belief that One Health, One Medicine is the portal to a comprehensive medical education. Since 1977, more than 13,000 School of Medicine graduates have gone on to successful careers in medicine and public health. Find your true calling. sgu.edu/md | 800.899.6337 *According to published information as of April 2016

Got Hanger? By Margaret McAllister

he Snickers ad campaign that popularized the phrase “You’re not you when you’re hungry” is sure to produce a smile with its comical representations of beloved figures experiencing hunger-based mood shifts. While these portrayals of hunger shifting emotions are a bit dramatic, researchers Dr. Kristen Lindquist and Jennifer MacCormack from UNC-Chapel Hill’s Department of Psychology and Neuroscience are beginning to unravel the psychological principles that may drive this phenomenon. In their research, they explore how

The close relationship between hunger and anger stems, in part, from their overlapping physical states.

hunger may influence anger, resulting in an emotion called hanger. Past research has explored these phenomena by finding that judges’ legal rulings are more severe prior to lunch than after, that low blood sugar can drive aggression, and that hunger predicts impulsive behaviors.1,2,3 One specific study conducted by Bushman and colleagues gave couples a voodoo doll meant to represent their spouse and a box of pins that they were asked to use at the end of each day. The study found that individuals with lower blood sugar stuck their voodoo doll with more pins each evening, suggesting that the lower the participants’ blood sugars were, the more frustrated or aggressive they felt towards their partners. The primary hypothesis behind Bushman and others’ work is simple: the hungrier one is, the harder it is to regulate negative emotions. Dr. Lindquist and MacCormack have taken this idea a step further. They hypothesize that there is an additional factor in the relationship between hun-

Photo by m01229, CC BY-NC 2.0 ger and anger. Growing evidence from psychology research suggests that emotions emerge when bodily feelings, context situational feedback, and Jennifer emotion knowlMacCormack edge combine. In any given instant, the mind and brain are automatically and effortlessly combining these three streams of information to construct a coherent emotion experience such as anger. The close relationship between hunger and anger stems, in part, from their overlapping physical states. Some symptoms of hunger, in addition to “hunger pangs,” include shakiness, sweating, dizziness, and a pounding heart. Many of these sensations are also felt during anger. Although this discomfort arises from distinct causes (i.e., hunger from not eating versus anger from a frustrating experience), it is

Carolina Scientific easy to misattribute or misinterpret this discomfort as caused, not by hunger, but by other people or events. The combination of an ambiguous arousal like hunger and the lack of conscious recognition of emotions may increase the intensity of anger experienced (Figure 2). To study this, Dr. Lindquist and MacCormack randomly assigned participants to either fast for more than five hours or to eat a full meal less than one hour prior to lab arrival. To test if hunger decreases self-regulation, all participants completed a boring visual task and were told they could stop whenever they wanted. Afterwards, participants were randomly assigned to either do an angry, sad, or unemotional storytelling task. This task was meant to either make individuals think of specific kinds of emotions (anger or sadness) or did not reference emotions at all (Figure 2). Finally, participants completed a frustrating computer-based task 100 times before a pre-programmed crash screen appeared on the screen (Figure 1). The experimenter blamed the participant for the crash and said they would have to complete the task all over again. While the experimenter was in another room “fixing” the computer, the participant was asked to anonymously evaluate the performance of their experimenter and report their own emotions. Results from this study show that, contrary to previous work, hunger did not decrease self-regulation. This would suggest that hangry behaviors may be a product of more than just an inability to regulate negative emotions. The results also support a misattribution story: when participants had thought

Figure 1. An example of the crash screen that appeared on participant’s computer. Courtesy of Jennifer MacCormack.

psychology

Figure 2. (Top) Random assignment of participants into individual treatmentgroups. (Bottom) The process of misattribution. Diagrams created by Jennifer MacCormack. about emotions (either anger or sadness), they were not likely to experience their hunger as hanger, likely because thinking about emotions allowed them to regulate their feelings and behaviors. However, when participants were hungry but were not able to explicitly link their feelings to an emotional cause, their feelings of hunger influenced their emotions and behaviors. It was only hungry individuals who had done the unemotional storytelling task who reported feeling more hateful, stressed, and negative. These participants also viewed the experimenter as more judgmental, as compared to the perceptions of satiated participants. Dr. Lindquist and MacCormack have replicated these findings in follow-up studies. It is clear that bodily states like hunger, fatigue, or illness can impact emotions and perception of others’ intents. When hungry participants’ attention was directed away from their body and emotions and towards the experi-

menter, they became hangry. However, automatically assuming that someone else is responsible for a negative emotion when hungry does not have to occur. This research also suggests it is possible to avoid misattribution: hungry individuals who focused on emotions before the frustrating task did not show signs of becoming hangry. By simply focusing more on emotions and internal state, you can still be you when you’re hungry.

References

1. Danziger, S.; Levav, J.; Avnaim-Pesso, L. PNAS. 2011, 108(17), 6889-6892. 2. Bushman, B.J.; DeWall, C.N.; Pond, R.S.; Hanus, M.D. PNAS. 2014, 111(17), 6254-6257. 3. Fessler, D.M.T. J Med Ethics, 2003, 29, 243-247. 4. Interview with Jennifer MacCormack. 02/04/16.

neuroscience

Conditioned Immune Response a novel application of the placebo effect By Lynde Wangler

he concept of cramming is familiar to almost anyone who has survived an exam week in college. For many students, staying up late to absorb as much information as possible in a short timeframe describes the quintessential college technique for studying. However, no matter how many times materials are reviewed prior to taking an exam, the information always seems to slip away after a few weeks. Fortunately, the immune system has a better long-term memory than most college students. Every time the immune system fights off another antigen, it generates memory cells that allow the body to recall when and how to fight a pathogen for several years after the initial exposure. It is therefore unsurprising that any time a foreign substance is introduced into the body, an immune response is generated to assess the situation. In addition

Illustration by Victoria Long

to responding to the internal environment (i.e., pathogens in the body), the immune system also has the capability to respond and become associated with benign external environmental stimuli, evoking what is known as a conditioned immune response. Christina Lebonville, a third-year Ph.D. student in the Behavioral Neuroscience program who conducts research in the laboratory of Dr. Donald Lysle at UNC-Chapel Hill, is especially interested in this phenomenon and focuses her research on discovering the memory mechanisms underlying this effect. 1 In the Lysle lab, researchers are using an animal model to study the immune consequences of opioid use. Many of their studies involve injecting rats with opioids – either heroin or morphine – and then challenging their immune systems to assess how well they are functioning after exposure to these drugs. The researchers focus on investigating the mechanisms mediating alleviation of immune consequences of drug use, aware that opioid users have been identified as having exceedingly high rates of infection and a high risk of contracting HIV. Lebonville suggests that the use of opioids in hospitals for pain relief is of great concern because immunosuppression (a decrease in functioning of the immune system) while recovering from surgery, trauma, or any other ailment has the potential to increase the likelihood of infection. There are instances, however when immunosuppression is considered favorable from an evolutionary standpoint in medical situations. For example, in cases of organ transplant, pregnancy, and cancer patients undergoing chemotherapy, decreased activity of the immune system actually facilitates the intended medical outcomes. Scientists recently used this knowledge to create an experiment in

Lysle Lab which they administered immune-suppressant drugs paired with a strawberry smoothie to cancer patients undergoing chemotherapy. They hypothesized that pairing the drug with the smoothie enough times would engender an implicit association in which the immune system would “remember” that suppression came subsequent to smoothie consumption. Therefore, drinking the smoothie alone without the drug would be able to inhibit the immune system. The scientists were correct – after sufficient pairing, just drinking the smoothie alone suppressed the patient’s immune system! This finding has the potential to change medical protocol for cancer and other chronic disease patients; the drugs administered for treatment often leave the patient with debilitating side effects, whereas consumption of a smoothie could provide a solution

This method of treatment has greater potential to succeed in clinical settings because it does not rely on variable personality characteristics of the individual.

Carolina Scientific

The experiment demonstrates that the immune system is reacting to the external environment rather than solely to the internal conditions of the body. for inducing immunosuppression without any side effects at all – with the exception of a possible brain freeze. Because this phenomenon is made possible through an implicit association between the patient’s immune system (resulting in immune suppression) and the smoothie (or any paired substance benign in nature), this procedure is divorced from and unaffected by the expectation bias that is regularly associated with implementation of the placebo effect. Therefore, this method of treatment has greater potential to succeed in clinical settings because it does not rely on variable personality characteristics (i.e., susceptibility to suggestion) of the individual receiving the treatment.2 In the Lysle lab, another animal model is used to demonstrate a variation on this initial project. In this experiment, rats are injected with opioids and then placed in behavior chambers for several timed trials. It is important to note that the only time that the rat is exposed to the box is when the rat has received a drug injection and that the context of the chamber does not change from trial to trial. One week later, the rats are placed in the chamber without receiving any opioids and are subsequently injected with a substance used to challenge their immune systems. This experimental design allows the researchers to measure the rats’ immune responses to being placed in the chamber while controlling for other effects (including any opioid effects). Their results have shown that, after sufficient pairing of a specific context (being inside the behavior chamber) and the drug, placing the rat in the chamber is enough to cause a conditioned immune response. The experiment demonstrates that the im-

mune system is reacting to the external environment rather than solely to the internal conditions of the body. With this knowledge in mind, Lebonville and her colleagues intend to investigate the neural mechanisms related to associative memory by studying regions such as the hippocampus (known to be involved in associative memory) as well as the nucleus accumbens and ventral tegmental area (known to be involved in addiction and reward sensation). Lebonville is excited

neuroscience to continue her work in this field and expand the lab’s procedural techniques for acquiring data regarding the neural circuitry underlying the conditioned immune responses, as well as the ways in which this knowledge might one day be applied to humans.

References

1. Interview with Christina Lebonville, Ph.D. Candidate. 02/04/16. 2. Albring, A., et al. Clin Pharmacol Ther. 2014, 96: 247–255.

At this moment, hundreds of thousands of young men and women serve in America's Navy. As a Navy Chaplain and Officer, you will serve and work alongside them. Build friendships. Share in their trials and their triumphs. And be ready to lend a listening ear - or offer spiritual insight in the moment it's needed most. The need is real. The rewards are bountiful. And the calling is great. Are you ready to serve both God and country as a Chaplain in America's Navy? There's never been a better time to find out. WANT TO LEARN MORE? CONTACT YOUR NAVY OFFICER RECRUITER TODAY. 800-662-7419 JOBS_raleigh@navy.mil

psychology

Illustration by Abbey Vinson

Breaking the Poverty Cycle increasing adulthood status attainment in disadvantaged background with intelligence and personality traits By Hailey Gosnell

ccording to humanistic psychologist Carl Rogers, people constantly strive to become the best versions of themselves that they can be. However, universally defining what would be considered the “best” or “most successful” life is next to impossible. While the definition of “success” is complex and subjective, objective factors can be used to measure individual status within society. Dr. Mike Shanahan, a professor of sociology at UNC-Chapel Hill, sought to understand the factors that emerge in childhood to impact adulthood attainment – a dependent variable he measured by considering education level, annual income, and occupational prestige. The issue that lay ahead, however, was determining what factors would play a role in deciding what socioeconomic status (SES) children would take on as adults.

The traditional model for predicting status attainment has been a one size fits all, focusing mostly on parental SES and rote cognitive ability. Dr. Shanahan recognized the importance of molding predictive theories to fit a diverse array of individuals by adding personality traits to the list of SES factors.2 Dr. Shanahan shed light on his interest in his statement: “I’ve been look- Dr. Mike Shanahan ing at personality with colleagues – it’s a very standard way of thinking about and measuring people’s behavioral patterns across very different types of situations.”1 Dr. Shanahan’s work adds to prevailing evidence that person-

Carolina Scientific ality traits have measurable effects on socioeconomic status, potentially enabling intergenerational mobility. The cycle of poverty that plagues so many is perpetuated by the inequalities that arise between classes. Those born to poor families tend to stay poor because they lack the resources and opportunities to rise to a higher SES. Intergenerational mobility, a phenomenon in which there is a shift in socioeconomic status among different generations of the same family, is all too rare. Well-compensated careers in the stratified American job market that yield a high SES require individuals to have extensive levels of education and social capital, networks of relationships within a microcosm of interest. Those born into high SES households with one or more college-educated, white-collar working parents tend to have a leg up on their peers. This is because parents push for their children to be placed in advantageous activities for academic and extracurricular development and expect them to acquire post-secondary education.1 However, the sociological studies that isolate traits capable of helping children from underprivileged households get the assistance they need to attain a higher socioeconomic status are clarifying ways that the cycle of poverty can be changed. With this knowledge of class discrepancies and their effects on SES, Dr. Shanahan and his peers sought to understand whether personality traits and intelligence factored into adult SES and, if so, to what degree. The team used surveys from a random sample of 81,000 participants in grades 9-12 to elucidate relationships between SES and the factors of interest. They considered three outcomes for personality and intelligence in relation to SES: that these traits were more accurate predictors of adulthood status at lower parental SES, more accurate predictors of adulthood SES at higher parental SES, or unrelated.2 They assigned scores for individuals based on their responses to the Project Talent Personality Inventory (PTPI), a test that measures personality in terms in ten areas: vigor, calmness, maturity, impulsiveness, self-confidence, culture, sociability, leadership, social sensitivity, and tidiness. Addressing fifteen questions for each category, participants rated how well the statements provided described them on a scale of one to five (extremely well to not very well). The researchers correlated student responses to the PTPI to raw scores for the five dominant personality traits: extraversion, conscientiousness, agreeableness, neuroticism, and openness.1 The multifaceted approach Dr. Shanahan and his team took to define and assess personality traits, as well as the large number of participants, made his study results comprehensive and strong. Of the personality traits tested, Dr. Shanahan and colleagues found a correlation between extraversion, agreeableness, and conscientiousness in comparison to each of the measures of adulthood attainment: education level, annual income, and occupational prestige. Without controlling for intelligence, the researchers found evidence of compensation of extraversion for lack of resources in all three categories.2 However, when cognition was factored out, “only the interaction between conscientiousness and parental SES when predicting annual income had statistical significance”.2 Though extraversion paired with intelligence is a strong predictor for adulthood attainment by all three measured factors, only con-

psychology

scientiousness stands alone in its ability to influence SES, albeit by impacting one factor. Separating personality traits from effects of intelligence in predicting adulthood attainment is important in this study because personality traits stand alone in their development while intelligence is heavily impacted by family background. Thus, lower SES background individuals stand to benefit more from possessing conscientiousness than their higher SES counterparts who already possess status dependent advantages.1 Lower SES background students, for instance, will be able to find mentors to support their endeavors if they seem meticulous and thorough, while higher SES students use their outgoing personalities and tailored intelligence to achieve the same ends. There is, however, a catch. Although lower SES background individuals benefit more from possessing conscientiousness, the environments in which they are raised do not tend to foster this trait.1 Upbringing in the lower SES environment shapes the individual to be less inclined to develop favorable personality traits for the educational environment and later the workforce. According to Dr. Shanahan, “[conscientiousness] emerges in middle to late childhood from childhood temperament. The temperament is innate but also a product of interactions with parents. While less educated parents tend to take a hands-off approach to developing the child’s worldview, more highly educated parents work with different temperaments to encourage the right values.”1 To even the playing field, educators of young children should try to encourage the development of favorable personality traits while minimizing anxiety to promote a healthy learning environment for all students. At the college level, effects of diverse backgrounds and the personality traits that result are deeply felt. Upon being asked how his study results directly influence UNC as a community, Dr. Shanahan stated, “We think that intelligence, personality traits, social supports, and financial assets are the reason we succeed or fail in school, but, in reality, latent behavioral propensities that stem from these factors are just as important.”1

References

1. Interview with Michael J. Shanahan, Ph.D. 09/15/15. 2. Damian, R. I.; Su, R.; Shanahan, M.; Trautwein, U.; Roberts, B. W. J Pers Soc Psychol. 2015, 109(3), 473-89.

Illustration by Hailey Gosnell

GOOD VIBRATIONS By Ben Twery

ain is an unavoidable and necessary fact of life. Humans feel pain for a reason; it functions as a signal to the brain that something is wrong and deserves attention. Chronic pain, however, is not as useful. Chronic pain is any pain that lasts three months or longer, and according to a 2011 report from the Institute of Medicine, more than 100 million people suffer from chronic pain every day in the United States alone. Attempting to relieve that pain leads to an annual bill of over $600 billion in terms of health care and lost productivity.1 According to Dr. Mark Hollins, a psychologist and neuroscientist at UNC-Chapel Hill, current treatments for most types of chronic pain are only partially effective. Drugs that are powerful enough to relieve intense pain, such as opioids, can have harmful side effects. Patients who rely on opioids to alleviate pain run the long-term risk of dependence, and may increase their pain over time.2 Dr. Hollins researches pain processing and the interactions between pain signals and signals from other sensations, such as touch. Pain and touch receptors are physically and functionally distinct; while they often occupy the same general area, they are not the same nor do they carry the same messages. For Dr. Hollins, pain research is scientifically important not only because of its potential clinical applications, but also because pain is extremely changeable compared to other sensory experiences. He says the malleability of pain can be understood by contrasting it to vision. If an individual looks at a spoon while they are in a good mood, it looks about the same as if they looked at it while in a bad mood. This is not the case for pain. If an individual stubs their toe while happy, it

Illustration by Megan Perritt

hurts. If they stub their toe while unhappy, it really hurts!2 The flexible nature of pain reflects the fact that pain pathways are complicated. Previous research has shown that there are many more neural connections, called synapses, for a pain signal traveling to the brain than for a similar touch signal. The brain requires quick and accurate information about the physical properties of a touch stimulus, answering the Dr. Mark Hollins question: “what is it?” Conversely, the brain primarily needs information about the significance of a pain stimulus, determining the appropriate way to react to that pain.3 Dr. Hollins explained, “Pain is a motivational stimulus. All those synapses are places where the pain message can be hacked and can be made stronger or weaker depending on what your needs are.”2 Consequently, pain is suppressed in an emergency but grows gradually stronger if an attention-worthy stimulus is continuously ignored. For example, if someone had to run on a broken leg to get out of a burning building, the leg would not hurt until the emergency was over, at which point the pain would strengthen and ensure the injury was attended to. Pain perception can be altered by mood, attention, or stress. Even vibration can alter pain, a phenomenon called vibratory analgesia. It is similar to rubbing a bruise – the pain feels a little better after some mechanical stimulation. While

Carolina Scientific vibratory analgesia is physiologically different from the relief of rubbing an injury, the result is similar. Consequently, understanding vibratory analgesia is important to Dr. Hollins’ pain processing research. Although scientists have known about it for several decades, vibratory analgesia is still poorly understood. Dr. Hollins is using new approaches to gain additional insight into how vibrations on the skin can impact our perception of pain. Dr. Hollins induces vibratory analgesia using an apparatus that applies painful pressure to a finger while vibrating a nearby region of the palm (Figure 1). Previous studies found that the inhibitory effects of vibration on pain sometimes decrease over time. This reduction occurs because vibration (touch) receptors have high sensory adaptation; they become decreasingly responsive to an ongoing vibratory stimulus and thus are less able to inhibit pain.4 In order to learn how to amplify the effects of vibratory analgesia, Dr. Hollins is investigating a few different possibilities. One technique he and his group are exploring is called intermittent vibration. He hopes that by only introducing vibration for short periods of time, the vibration receptors will

psychology

tion have different effects on pain, this may give us clues to underlying mechanisms; and if we understand these, we may be able to increase the effectiveness of this method of pain modulation.”2 Further, Dr. Hollins believes it is possible that vibration optimized in terms of frequency, intensity, and location, could be used by patients to temporarily relieve chronic pain on an as needed basis. While Dr. Hollins believes his work with intermittent vibration and different vibration frequencies is promising, he cautions that his research is still far from clinical application. He says that typically in the field of sensation and perception, scientists first use behavioral methods to study a sensory process in order to work out the principles that describe it. Electrical recording or neuroimaging can then be utilized to learn what neural processes underlie those principles. If Dr. Hollins’ findings remain promising, the next step may be to partner with electroencephalogram (EEG) researchers to see how vibratory analgesia impacts the normal electrical rhythms of the brain. Such studies may lead to discoveries that have clinical applicability. Understanding pain processes is the first step toward the ultimate goal of finding new ways to alleviate chronic pain.

“If different frequencies of vibration have different effects on pain, this may give us clues to underlying mechanisms; and if we understand these, we may be able to increase the effectiveness of this method of pain modulation.” Dr. Hollins

Figure 1. Dr. Hollins’ experimental setup for inducing vibratory analgesia. Photos by Ben Twery. not adapt to the signal and the analgesia will maintain its effectiveness. Additionally, Dr. Hollins and his lab are studying the effects of different frequencies of vibration on vibratory analgesia. He is finding that not all frequencies have the same inhibiting effect on pain; some frequencies of vibration appear to make pain worse. While at first this may appear to be an indictment on the usefulness of vibratory analgesia, Dr. Hollins thinks the opposite. “If different frequencies of vibra-

References

1. The National Academies of Sciences, Engineering, Medicine. 2011. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: Pizzo, P. 2. Interview with Mark Hollins, Ph.D. 01/05/16. 3. Hollins, M. Annu Rev Psychol. 2010, 61, 243-71. 4. Hollins, M.; McDermott, K.; Harper, D. Perception. 2014, 43(1), 70-84.

Investigating the Neural Network By Carrington Merritt

he necessity for communication extends far beyond everyday interactions with others. In fact, the most vital communication processes begin within the brain. It may seem intuitive that our brain is made up of intercommunicating networks. However, the organization and dynamics of communication between these networks vary depending on the task at hand. Dr. Jessica Cohen, of the UNC-Chapel Hill Department of Psychology and Neuroscience, aims to explore how such brain networks interact with each other in response to various cognitive tasks including working memory, learning, and impulse control. Dr. Cohenâ&#x20AC;&#x2122;s research studies the functional networks of both healthy individuals and patient populations such as children diagnosed with attention deficit/ hyperactivity disorder (ADHD).1 Dr. Cohen uses neuroimaging to map the different brain networks, which can vary among individuals (Figure 1). Dr. Cohen primarily studies healthy individuals to determine how the communication patterns within and between distinct brain networks change in response to specific cognitive processes. With the help of previous brain atlas studies,

Illustration by David Wright

Dr. Cohen has identified specific networks to focus on depending on the type of cognitive task her subjects are performing. The cingulo-opercular and fronto-parietal networks are two distinct networks involved in tasks requiring working memory.2 These networks display high functional connectivity and during working memory tasks, they undergo dynamic changes Dr. Jessica Cohen that increase integration between the two networks.2 In other studies conducted by Dr. Cohen involving healthy individuals, subjects were asked to perform both complex memory and simple motor tasks. During these tasks, functional magnetic resonance images (fMRI) of the brain were taken to delineate network organization. The complex memory tasks of this study were designed to require greater cognitive control than the simple tasks. The fMRI data collected indicated that increased need for cognitive control

Carolina Scientific

neuroscience

This finding suggests that between-network communication is critical for proper cognitive functioning.

Figure 1. (Top) An fMRI scan taken during a working memory task. The areas of cortical activation are shown in red. Image courtesy of Dr. Cohen. (Bottom) Brain network structure during a complex memory task. Each sphere represents a region of the brain, each line represents communication between two brain regions, and each color is a different brain network. The structure displays connections both within and across brain networks. Image by John Graner, Neuroimaging Department, National Intrepid Center of Excellence, Walter Reed National Military Medical Center, public domain. led to increased integration of network systems.1 This means that increases in task complexity are associated with greater communication between brain networks. Additionally, when studying the network properties during the simple tasks, it was found that inter-network integration decreased but intranetwork communication increased.1 This finding indicates that some brain circuits may be specialized for specific low demand tasks. In addition to gaining insight into the communication and organization dynamics of functional neural networks, Dr. Cohen’s research has also led to a better understanding of dysfunctional networks within clinical populations such as ADHD patients. In a study of children between the ages of 8 and 12 years old suffering from ADHD, Dr. Cohen found certain network characteristics that may be linked to the demonstration of the disorder’s symptoms. This particular study focused on the brain’s intrinsic networks, meaning the natural organiza-

tion that is observed while the patient is at rest. While in this resting state, fMRI scans were taken of the subjects’ brains in order to identify any abnormalities. Dr. Cohen observed that “networks seemed to be more segregated and less able to communicate with each other in children with ADHD than in typically developing children.”1 This finding suggests that between-network communication is critical for proper cognitive functioning. “I suspect that one of the causes of ADHD may be dysfunctional communication across networks.”1 As Dr. Cohen continues her research, she hopes to investigate how certain drug treatments for ADHD affect network organization. Based on the findings regarding abnormalities in network communication of children with ADHD, Dr. Cohen is looking forward to studying how some stimulant drug treatments may change or normalize such networks. Additionally, in future ADHD studies, Cohen plans to concentrate on a specific brain network known as the default mode network. It is theorized that this network is more active during nonspecific cognitive actions, such as mind wandering. During focused cognitive activity, this area generally decreases in activity.1 Based on this theory, Cohen seeks to understand the communication activity between this network and other task-specific networks in order to determine if the default mode network is in fact hyperactive in ADHD patients. Dr. Cohen’s continued work is promising for better understanding functional neural networks and greater insight to the origin of disorders such as ADHD.

References

1. Interview with Jessica R. Cohen, Ph.D. 02/10/16. 2. Cohen J.R.; Gallen C.L.; Jacobs E.G.; Lee T.G.; D’Esposito M. PLoS ONE 2014, 9(9), e106636.

Illustration by May Wang

psychology

Preventing PTSD

he eyes cannot detect all wounds. After a severe traumatic event, one may experience a form of chronic anxiety and fear known as PostTraumatic Stress Disorder (PTSD). PTSD is an anxiety disorder that is known to affect a wide range of people. In America alone, this disorder is observed in about 7.7 million people, of which around 17% are combat veterans.1 Dr. Donald Lysle of the Department of Psychology and Neuroscience at UNC-Chapel Hill is researching the potential effects of morphine in preventing PTSD in an animal model known as stress-enhanced fear learning (SEFL). Two years ago, Dr. Lysle and Dr. Jennifer Thomson, a postdoctoral fellow in his laboratory, read a paper regarding the administration of morphine to treat traumatic injuries sustained in the military. By analyzing the detailed medical records of soldiers, they discovered a relationship between morphine and the prevention of PTSD. Dr. Lysle and Dr. Thomson took these clinical findings and applied them to an animal model to study what exactly prevented the formation of PTSD in a laboratory setting. The animal model used SEFL in rats to mimic human PTSD. SEFL can cause symptoms of human PTSD such as a response to future fear.1 The overall goal of this experiment was to study the impact that the protein interleukin-1 has on the development of SEFL. Interleukin-1 is a cytokine, a protein responsible for cell signaling, and is known to be associated with sleep disorders, anxiety, and lack of socialization. Dr. Lysle wanted to see if morphine reduced interleukin-1 in the brain, since the enhanced expression of interleukin-1 after a trauma leads to the development of PTSD. In the SEFL study, rats received a trauma, known as foot shock, and then were observed one week to several months later to see if they were affected by the mild traumatic event.2

Three experiments were conducted on the rats. The first experiment looked at the amount of time needed for interleukin-1 to cause signaling in the brain after the stressor in SEFL was administered. In the second experiment, an antagonist receptor to interleukin-1 was used to block cell signaling in order to study its effect Dr. Donald Lysle on the development of SEFL 48 hours after the stressor was administered. The third was to study if morphine decreased the levels of interleukin-1 after SEFL. The findings of these experiments concluded that morphine does in fact block the development of SEFL, meaning that the medication stopped PTSD-like behaviors in rats. Other conclusive findings were that morphine must be given 48 hours after a trauma in order to be effective in preventing the development of prolonged fear. If morphine was given immediately after the traumatic event, it had no effect on the development of SEFL.2 Even though morphine can prevent PTSD-like symptoms in rats, there are still no pharmaceutical treatments for PTSD. Many diagnosed with PTSD are prescribed medications for anxiety. These medications, however, only alleviate symptoms and do not cure the disorder. According to Dr. Lysle, “what makes PTSD difficult to treat is that once that neuroplasticity has taken place, it’s much harder to reverse it.”1 Meghan E. Jones, a graduate student under the direction of Dr. Lysle, also contributed to the PTSD findings. She studied traumatized rats in a plus-sign-shaped maze and observed their reactions. The maze had both an open and a closed side. Jones discovered that the anxious rats would not go to the open arms of the maze and would instead spend their time in the closed area. In addition, she witnessed that the rats expressed the “stretched attend” posture when exiting the closed section of the maze. This posture allows the rats to stretch out of the closed arm of the maze and look to see if they want to enter one of the open arms, which indicates that the rats might have been conflicted about venturing out because of potential danger.1 A person can develop PTSD if he or she experiences a traumatic event that affects his or her long-term response to stress and fear. As Dr. Lysle mentioned, “one thing that separates PTSD from other anxiety disorders is that you must have experienced the trauma,”meaning there has to be an environmental stimulus for one to be diagnosed with PTSD.1 PTSD still has no treatment at this moment, but because morphine is now known to help prevent the occurrence of PTSD, perhaps these findings can be applied to any traumatic event, such as a bombing or a serious injury.

References Illustration by Anja Burjak

By Ashley Cruz

1. Interview with Dr. Donald Lysle, Ph.D. 02/02/16. 2. Jones, M. E.; Lebonville, C. L.; Barrus, D.; Lysle, D. T. Neuropsychopharmacol. 2015, 40(5), 1289-96.

Carolina Scientific

biology

A New Age of Accessibility By Nick Rewkowski

hile computers are an integral part of our daily lives, there are many who are still unable to use them effectively. Although our society is now one of widespread access to technology, there is still an important slice of the population that does not share this liberty: those with disabilities. While computer access may be something many of us take for granted, it is still not so simple for those whose needs are not satisfied by “traditional” means of access. However, it seems that access for all is finally being brought to the forefront of computer research. Every spring, Dr. Gary Bishop of UNC-Chapel Hill’s Computer Science Department and his students organize a large event called “Maze Day,” during which people with disabilities can experience first-hand the ways in which research is attempting to meet their needs. At first, this event was simply a project designed by students in Dr. Bishop’s “Enabling Technology” class, who asked a group of children with disabilities to test out a life-size, interactive maze simulaDr. Gary Bishop tion. However, the demonstrations drew much more attention than anticipated, which led Dr. Bishop to create the annual event. The feedback has been so positive that the event has grown larger each year and continues to attract the attention of over 100 students and adults. To Dr. Bishop, his students, and the attendees, Maze Day is much more than just an assessment for those with disabilities – “My main goal for Maze Day is for the kids who visit to have fun and see the possibilities that technology affords. My second goal is that our students get a chance to show their work to a receptive audience and get feedback. It serves both of those functions,” said Dr. Bishop.1 As emerging technologies spill into society, Maze Day provides an excellent way to test new devices as well as a way to gauge their usefulness and application. Some examples of such emerging technology include 3D sound generation, affordable virtual reality headsets, and haptic feedback mechanisms that can simulate various senses in a human body. These innovations not only expose the flaws of previous methods of providing access to those in need, but also reveal new techniques to engage target audiences. One may wonder why events such as Maze Day have only begun to appear recently, considering the fact that disabilities have been a major concern for computer scientists since their field’s beginnings. It seems that many of the roadblocks to accessibility research and understanding have been

Photo by Andrew Bauer

built into society itself and have only recently begun to be broken. “Inclusion in schools is helping [the modern] generation see that we’re all just people with various abilities and disabilities. The more we know people, the more receptive we are to helping,” said Dr. Bishop.1 As this mentality of acceptance for people of all abilities becomes more widespread, accessibility for all demographics may be further realized. The possible correlation between tolerance and accessibility may require further research that, hopefully, events such as Maze Day can provide. Another roadblock that has traditionally slowed progress in accessibility is a lack of funding. Because the inclusion of children with disabilities has only recently been funded extensively through the Americans with Disabilities Act Amendments of 2008, adequately resolving accessibility issues continues to be a struggle. “We’ve got to get out of the zero-sum thinking that dominates, such as if we spend money on this disabled person, we won’t have it for something else. The fact

“My main goal for Maze Day is for the kids who visit to have fun and see the possibilities that technology affords.” Dr. Bishop is, we buy whatever we want; billions on potato chips, trillions blowing up Iraq,” said Dr. Bishop.1 Perhaps events such as Maze Day can serve as evidence to policy makers that computer accessibility technology truly is worth paying for. Dr. Bishop and his students are continuing the battle for equal accessibility through their work developing technologies to help the disabled. The upcoming Maze Day event should assist with not only the introduction of emerging technologies to those in need, but should also provide enough data through interactions, results, and reactions to finally set an appropriate technological standard for widespread accessibility. As society becomes more accepting of both different people and different types of technology, complete accessibility will become a much more tangible goal.

References

1. Interview with Dr. Gary Bishop. 02/09/16. 2. “ADA AMENDMENTS ACT OF 2008.” Americans with Disabilities Act Amendments Act of 2008. U.S. Equal Employment Opportunity Commission, 25 Sept. 2008. Web. 22 Mar. 2016.

computer science

VISUALIZING TRAFFIC POLLUTANT HOTSPOTS where research intersects policy

By Sara Edwards

t’s invisible, it’s deadly, and it’s in your backyard. Air pollution, according to the World Health Organization, is the world’s largest single environmental health risk.1 Those who live in urban environments are especially at risk because they are surrounded by a major source of emissions: traffic. A team of researchers at the UNC-Chapel Hill Institute for the Environment (IE) has developed a program that can make estimating exposure to air pollution from traffic easier. The program, called C-Line, is a web-based geographic information system (GIS) application similar to Google Earth.

Figure 1. Dispersion of NOx (nitrogen oxides) at peak morning traffic during summer (top) and winter (bottom). Image courtesy of C-Tools, Brian Naess.

Image public domain.

C-Line is one of a suite of similar tools designed to estimate the spread of pollutants like carbon monoxide and nitrogen oxides, which can be hazardous to human health. It models the concentration of traffic pollutants around roadways based on the condition that the user chooses. Brian Naess, a lecturer and IT research developer for the IE, helped Brian Naess create the program. “I’m really interested in places where research intersects with policy and community outreach, and so what I see in this tool is something that a nonprofit or community group can use to evaluate how roads are affecting their health in terms of pollution,” he said.2 What makes C-Line unique is that it runs on a webbased platform, which means it can process information and produce results in a matter of minutes. Another advantage is the program’s simplicity: anyone can use it. The tool is designed to be easy for non-scientists to understand, making its applications “pretty much limitless,” according to Naess.2 If a city planner wanted to see the concentrations of traffic-generated pollutants on a specific road, he or she would simply type in the desired conditions and C-Line would visualize it. Additionally, that planner could run a series of “what-if” scenarios by changing the pollutant, time of day, season, and meteorology inputs (Figure 2). In this way, the tool could provide more nuanced information that could be used to predict conditions in the future. The model works by collecting data such as the number of vehicles on the road, the types of vehicles, and the speed of vehicles, and combining it to create hourly or annual concentrations along a roadway for a specific pollutant (Figure 3).2,3 “For each segment of the road, we’ll calculate a concentra-

Carolina Scientific tion because each segment has different parameters – they can have different traffic, they can have different speeds,” explained Naess. After determining the parameters for each segment, Naess plots the concentrations of different pollutants for an imaginary network of points in space based on the segment closest to each point. After all of the information is gathered, the model produces a map that can be overlaid onto a Google Maps background (Figure 1).2 Since the model relies on many sources of data to produce results, the accuracy of the concentrations it calculates can be variable.3 But the model, which leaves out factors such as the landscape of an area and pollution mixing, is meant to be simplified. Naess explained that it was more of a screening tool. “It’s not designed to be like, ‘this is the concentration at this exact point,’” said Naess. The ability of the tool to run quickly is an advantage, but also a limitation.2 The tool’s simplified design and utility make it applicable to many aspects of community management. Through C-Line, anyone could access air quality predictions, including non-scientists. Organizations and local governments could use the tool to estimate how a change in the road network, such as a widening of a highway, might affect the health of nearby residents. Since children are the most sensitive to poor air quality, planners could use the program to determine the best location for a new school by seeking the areas with the lowest concentrations of pollutants.2,3 The program is still being improved and it is likely that more uses for the tool are yet to be discovered and applied. “We’re always looking at usability in the tool. We’re working at incorporating some census-level data to try and produce a more simplified output that people could even download and put into a GIS,” Naess said. In addition to C-Line, which applies specifically to roads, the team has developed a similar model called C-Port, which focuses on emissions from shipping lanes and railways. And soon to come is a model that will track airport emissions.2 The important thing about the field of GIS and spatial

computer science

Figure 2. In C-Line, conditions including pollutant type, weather, and time of day can be used to calculate hourly concentrations. Image courtesy of C-Tools, Brian Naess. data is that it is constantly evolving. Like with the suite of CTools, Naess said, “You have to keep on top of the latest technology, and you can’t settle for one version of one model because each one has its own plusses and minuses.” The key is to keep improving and looking for new ways to implement the spatial data. With today’s technological advances like smartphones with GIS capabilities, this type of data is becoming accessible to more people. “I think the possibilities for real scientific breakthroughs – especially in planning and in smart cities – is really exciting,” said Naess.2

References

1. 7 million premature deaths annually linked to air pollution. Retrieved from http://www.who.int/mediacentre/ news/releases/2014/air-pollution/en/ 2. Interview with Brian Naess, M.S. 02/03/16. 3. Snyder, M. et al. Int J Environ Res Public Health. 2014, 11, 12739-12766.

Figure 3. The average vehicle speed on each road segment in the Detroit area. Snyder, M. et al. Int. J. Environ. Res. Public Health, 2014, 11, 12739-12766. Creative Commons. Illustration by Alex Cecil

physics

Illustration by Naomi Breitenfeld

The Mysteries of the Neutrino By Elizabeth Smith

eutrinos are particles that have baffled modern scientists since their discovery. Scientists have long been interested in finding methods to determine their mass, understand the mechanisms through which they work, and examine their candidacy as a constituent of dark matter. These inconceivably small particles exist in every corner of the universe and millions of them stream through our bodies every second, but not much is known about their fundamental nature. Most common particles, such as electrons and protons, are made out of matter. However, the majority of these particles also have an antimatter counterpart, such as the positron and antiproton, that have opposite properties. Currently, scientists treat neutrinos and antineutrinos as two separate

particles, but there is a great deal of speculation about whether or not this is actually the case. Neutrinos may in fact be their own antiparticles â&#x20AC;&#x201C; a result that would revolutionize our understanding of particle physics and cosmology. Current research into this speculation is led by the Majorana project, a multinational experiment centered in Lead, South Dakota. Dr. Reyco Henning, a particle physics Dr. Reyco Henning researcher at UNC-Chapel Hill and a member of the Majorana project, gave an in-depth explanation of the project.

Carolina Scientific Dr. Henning explained that the major focus of the experiment is to search for evidence of a type of decay known as neutrinoless double beta decay (NDBD). Typical beta decay emits one electron or positron through the transformation of a proton into a neutron or vice-versa, whereas neutrinoless double beta decay releases two protons and two electrons. Though the reaction does not produce any real neutrinos, the physical principles behind the decay mechanism only allow the decay to happen if the neutrino is its own antiparticle. Based on fundamental conservation principles, researchers can therefore conclude that the neutrinos are their own antiparticles if NDBD is detected. Detecting NDBD is no simple task. Only a handful of elements are expected go through this still undetected type of decay. Out of these elements, researchers working on the Majorana experiment chose to use Germanium-76, a rare isotope of germanium that has a half-life on the order of 1027 years (trillions of times as old as the universe itself ). The number of decays observed increases proportionally to the number of atoms that are studied, so researchers must gather large samples of Ge-76 to counteract the fact that its tremendous halflife vastly reduces the probability of observing NDBD. Up to 30 kilograms of detectors enriched in Ge-76 are kept in large copper cryostats intertwined with strings of detectors ready to measure signatures of NDBD. “The thing that we are doing that is very different is the low reactive backgrounds. [Detecting the NDBD] is easy, we know how to do this. The hard part is that there are a lot of things that can look like a double beta decay,” explained Henning. Limiting the effects of background radiation is thus crucial to the success of the Majorana experiment. Cosmic rays, a

Figure 1. Workers must wear protective suits while building the detector in order to prevent contaminating the equipment with radiation from the human body. Image coutesy of the UNC Physics Department. form of high-energy radiation that originates from supernova explosions far outside the solar system, constantly bombard the surface of the Earth. This pervasive radiation can overwhelm detectors searching for the subtle radiation emitted from Ge-76 samples. Therefore, the Majorana project was built a mile below the surface of the Earth, beneath several layers of bedrock that reduce the radiation from cosmic rays to accept-

physics

Figure 2. Construction of the detector takes places 1 mile underground to minimize background radiation. Image coutesy of the UNC Physics Department. able levels (Figure 2). Unfortunately, even this extreme measure cannot block out all background radiation. The experiment still has to cope with a significant amount of radiation originating from other sources, including potassium in the human body, uranium decay in the concrete walls, and even plastics and metals used in detector components (Figure 1). The most distressing problem with radiation is that when a charged particle enters the detector, it can stick to the detector’s metallic surface, decay, and then become embedded in the metal. Once buried in the surface, the particle can continue to cause problems and must be removed. Henning explained that the Majorana project does not actually spend most of its time working on the mechanics behind the experiment, “We spend probably about 99% of our time developing low-radioactive materials and low-radioactive material processing”. The conceptual development of the Majorana project began twelve years ago, and the construction of the detector lasted five years. Since then, the detector has been through several successful test runs and will begin collecting data and publishing results by the end of this summer. During its expected five year run time, the Majorana project will also study the feasibility of building a much larger NBDB experiment. Ultimately, the Majorana experiment seeks to resolve the mystery of why there is more matter than antimatter observed in the universe. Our current model of the Big Bang and development of the universe gives no explanation for this imbalance, but neutrinos existing as both matter and antimatter could explain the discrepancy. “This is very important because if there wasn’t this big asymmetry, the universe would just be filled with a sea of photons and very diffuse gas. There would be no galaxies, or planets, or people, so it’s a pretty profound question to understand why there is this asymmetry.”

References

1. Interview with Reyco Henning, Ph.D. 02/05/16. 2. Efremenko, Y.; Abgrall, N.; Arnquist, I.J. Int J Mod Phys A. 2015, 30, 262-269.

education

Illustration by Kristen Lospinoso

Learning for the Real World By Jeffrey Young

he process of learning is not something students typically give much thought to. Students assume that if they listen to a lecture or read from a textbook, then afterwards they have “learned” that material. Recently however, the process of learning – especially in the classroom – has come under closer scrutiny. More attention is being placed on how students learn, and how to best enable students to learn and succeed in large classrooms common at many universities. Here at UNC-Chapel Hill, one of the professors at the forefront of reshaping the way classes are taught is Dr. Thomas Freeman, a STEM Lecturer in the Department of Chemistry. Dr. Freeman’s focus is on leveraging research being done at various universities, including UNC, to change traditional lecturestyle classes and find new and innovative ways to teach students. Dr. Freeman sees learning as a collaborative process; a conversation between the student, the professor, and perhaps most importantly, their peers. To enable this style of learning, Dr. Freeman uses a “flipped classroom” style of teaching. In this paradigm, students spend time before class reading the textbook and watching videos about the topic to be covered in class. Then, during class time, students work collaboratively in groups on problems that focus on applying the knowledge they have learned. Professors using this model can also use the extra class time they have as a result of students

preparing before class to answer questions and clarify the more challenging concepts presented. “When you interact with your peers it is very different; it creates a different feeling. Students can speak a ‘language’ with each other and say things to one another in a way that a professor cannot necessarily do,” said Dr. Freeman.1 This in turn changes the way Dr. Thomas that students can interact and engage Freeman with the material. This flipped classroom style of teaching also has other benefits. “I try to create an environment that reflects what the real world is like… working with other people, coming up with solutions on your own, these are skills employers expect graduates to have because problems in the real world do not always follow a ‘textbook definition’” said Dr. Freeman.1 A flipped classroom exposes students to these types of situations in a relatively stress-free environment, while still holding them accountable through exams and grades. Technology has also helped Dr. Freeman facilitate an active style of learning in the classroom. Tools, such as a wireless tablet, allow him to project his writing to the screen in real-time, and also allows students to write their solutions to a

Carolina Scientific

Figure 1. These charts show the differences in the failure rate between an active and lecture style classroom. This meta-study concluded that an active learning classroom led to better learning outcomes for the students.2 problem and show their peers how they solved it. One of the biggest pieces of enabling technology for the active classroom is the classroom space itself. In the fall of 2015, professors at UNC, including Dr. Freeman, had the opportunity to teach in the renovated Greenlaw 101 classroom. This was the first interactive lecture hall at UNC and was designed specifically to facilitate an active classroom. Each chair is on wheels and can fully rotate, allowing students to easily form groups to collaborate with one another. Additionally, students can project their laptop displays to large screens in the classroom (there are seven), allowing for students to work on problems together. All around the country, there has been a focus on developing more of these learning spaces that are designed to redirect the focus from the front of the classroom to a more active, collaborative learning amongst peers. Ongoing research is also proving the efficacy of an active learning paradigm. A meta-analysis of 225 studies done on active learning found that classes taught in this manner had lower failure rates and higher scores on standardized tests across the board (Figure 1).2 From his own anecdotal evidence, Dr. Freeman said that students also tend to enjoy this format, “Students are more engaged than they have been… they are understanding what is going on at a deeper level.”1 However, not all professors are hurrying to implement these changes in their own classroom, even when confronted with the concrete evidence. Many faculty members, especially those with research obligations who are not full-time lecturers do not have the time required to invest in overhauling the curriculum for a flipped classroom. For professors in this situation, which is especially common at large research universities such as UNC, Dr. Freeman tells them to “make incremental changes… pick the topic that you have identified as the most difficult one for students to grasp and flip that one. Then the next semester, flip another one.” Another way to help professors make the switch to a flipped-style classroom is a mentor-apprentice model that has been implemented within the Chemistry Department at UNC. In this model, a professor who has experience in flipping a classroom to a more active style of learning teams up with an “apprentice,” a professor who may have research obligations and is accustomed to teaching with a traditional lecture-style format, to co-teach a flipped classroom. This gives the apprentice valuable experience with teaching an active learning class

education

without having to implement the changes on their own. Although flipped classrooms have shown positive learning outcomes for students, there are still opponents to implementing these changes. The flipped classroom has been criticized for reducing the amount of instructional time by the professor, and being more difficult for students to catch up if they happen to fall behind. While no teaching method can be perfect for every student, research has shown that this teaching method can, “enhance learning, improve outcomes, and fully equip students.”3 Change is coming to the methods of teaching science classes at the university level. Although adoption has been much quicker at smaller liberal arts colleges, these changes are beginning to percolate up to larger research universities. “We are starting to build some momentum. We will see a lot more changes coming, especially in STEM courses,” Dr. Freeman believes. “Even a Nobel Laureate, Carl Weiman, has committed his efforts to help reshape science education. I hope those who are resistant to these changes, which are now obviously for the better, will step out of the way and not prevent change from happening.”1

References

1. Interview with Thomas Freeman, Ph.D. 02/05/16. 2. Freeman, S. et al. PNAS. 2014, 111, 8410-8415. 3. McLaughlin, J. et al. Acad Med. 2014, 89(2), 236-243.

NC STATE UNIVERSITY Interdisciplinary Physiology Graduate Program The Interdisciplinary Physiology Graduate Program at NC State University provides a wide-range of opportunities to help students reach their goals, whether they pertain to Biological Research or health-related professional school admission. The Physiology Graduate Program at NC State serves the pre-health population as an "academic enhancement" program. The ability to custom-tailor your degree program with courses that interest you and apply directly to your specific needs are part of what makes this graduate program unique and valuable in the current job market. The Physiology Graduate Program offers two different degrees:

• Master of Physiology, Non-Thesis Option • MS: Masters of Science (thesis-based) For a wonderfully detailed and informative explanation of Post-Baccalaureate Pre-Professional Programs, please see the following website:

physiology.grad.ncsu.edu

“Nature composes some of her loveliest poems for the microscope and the telescope.” -Theodore Roszak

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

Carolina

scıentıfic Spring 2016| Volume 8 | Issue 2

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.