Spring 2021 -- Hematologic Malignancies in Malawi

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scıentıfic Spring 2021 | Volume 13 | Issue 2

—HEMATOLOGIC MALIGNANCIES IN MALAWI— full story on page 12 1

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PAST EDITIONS OF CAROLINA SCIENTIFIC Carolina

Carolina Scientific

scıentıfic Spring 2020 | Volume 12 | Issue 2

That Special Sense That Allows Turtles To Travel

—LOHMANN LAB LOOKS AT HOW TURTLES FIND THEIR WAY BACK HOME— full story on page 30 1

Carolina Check out all of our previous issues at carolinascientific.org/.

As the organization continues to grow, we would like to thank our Faculty Advisor, Dr. Gidi Shemer, for his continued support and mentorship.

scıentıfic Fall 2018 | Volume 11 | Issue 1

The Secrets of Space

—USING NUCLEAR FUSION DATA TO IDENTIFY NOVA EXPLOSION PRODUCT— full story on page 26

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Carolina

scıentific

Mission Statement:

Executive Board

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

Editors-in-Chief Andrew Se Divya Narayanan Managing Editor Megan Butler Design Editor Sarah (Yeajin) Kim Associate Editors Janie Oberhauser Maia Sichitiu Copy Editor Mehal Churiwal Treasurer Mehal Churiwal Faculty Advisor Gidi Shemer, Ph.D.

Letter from the Editors: Scientific research, at its most fundamental level, is an endeavor that allows us to ask questions about the world around us. This unrelenting process of posing questions and seeking answers can shed light on our place in the universe, help uncover the inner workings of our minds, and reveal insights that shape future innovations in technology and medicine. At Carolina, original and exciting questions are asked every day. How has the internet played a role in creating both problems and solutions during the COVID-19 pandemic (p. 10)? How does proper nutrition from infancy affect health across the human life (p. 22)?

With this Spring 2021 edition of Carolina Scientific, we hope we inspire you to ask questions of your own. Enjoy!

- Andrew Se and Divya Narayanan

on the cover Dr. Painschab’s main motivation for continuing his work with UNC Project Malawi has been to help treat citizens of Malawi suffering from HIV-associated cancers while also promoting awareness for, and educating... about the diseases and their prevention.

Staff Writers Elizabeth Bennett Sara Bernate Angulo Megan Bishop Henry Bryant Diana Chapman Alisha Desai Hannah Koceja Lasya Kambhampati Sneha Makhijani Aayush Purohit Robert Rampani Alex Reulbach Maddy Stratton Maia Vierengel Designers Gillian Arleth Julia Bay Siona Benjamin Heidi Cao Sarah (Yeajin) Kim Abigail Shuman Cassie Wan Kelly Yun

Full story on page 12.

Illustration by Hannah Kennedy

Email: carolina_scientific@unc.edu Web: carolinascientific.org FB: facebook.com/CarolinaScientific Twitter: @uncsci

Contributors

Illustrators Hannah Kennedy Maddy Stratton

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Copy Staff Gillian Arleth Ambika Bhatt Megan Bishop Coleman Cheeley Elizabeth Coletti Gargi Dixit Maria Esteller AJ Ferido Sally Hassan Nisha Lingam Kirti Nimmala Claire Nolan Elizabeth Redding Alex Reulbach Krithika Senthil Khushmi Shah Maddy Stratton Stephen Thomas Rithika Uppalapati Sreya Upputuri Caroline Webber Alexandra Yarashevich Kelly Yun

Carolina Scientific

contents

Life Sciences 6

Environmental Science 24

Making a Species Using “Magic” Aayush Purohit

Megan Bishop

Physical Sciences 8

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26

Atomic Shape-Shifters Maddy Stratton

Medicine & Health

Psychology & Neuroscience

Modern Problems Require Modern Solutions: The Internet’s Role in the COVID-19 Pandemic Hematologic Malignancies in Malawi Sneha Makhijani

14

Osteoarthritis: Reimagining the “Wear and Tear” Disease Henry Bryant

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The Medical *Potential* of Electrochemical Detection Maia Vierengel

20

Identifying the Drugs Behind Unintended Bleeding Disorders Elizabeth Bennett

22

28

Treating Epilepsy

30

Nicotinamide: A New Form of Rehab?

32

A Novel Approach to Parkinson’s Disease Drug Therapy

Lasya Kambhampati Diana Chapman

Alisha Desai

Tooth Loss: A Potential Side Effect of Obesity Hannah Koceja

16

Predicting Disaster: Using Ecology to Fight Climate Change Alex Reulbach

Robert Rampani

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It’s Complicated: Environmental Crises Reveal the Key to LongTerm Sustainability

Fruits and Vegetables: Promoting Proper Nutrition to Cultivate Better Infant Health Sara Bernate Angulo

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Life Sciences

Making a Species Using “Magic Magic”

By Aayush Purohit Photo by Charles J. Sharp [CC-BY-SA 4.0]

I

t is truly remarkable to know that the planet we call home houses millions of different species, with speciation continuously adding to that amount. Speciation is the reason why the Earth houses such a wide variety of organisms, all sharing common features, while also having unique traits that set them apart from one another. The formation of new species does not happen in the blink of an eye, but rather takes centuries, or even millennia, before noticeable changes come about. Many different factors can account for speciation, ranging from environmental pressures to interactions with other organisms. Identifying and studying these factors can lead to understanding how certain species came to be and predicting what may happen to them in the future.

Dr. Maria Servedio, a professor in the biology department at UNC-Chapel Hill, has spent more than 20 years working on understanding mechanisms

of evolution, speciation, and sexual selection. She and her lab utilize mathematical models—specifically, population genetic models—to understand why organisms behave in certain ways and how those behaviors can lead to evolutionary patterns. Most of the models created by Dr. Servedio are made with the computing system Mathematica, which uses manually inputted parameters with mathematical equations to model evolutionary behavior in a species over future generations. An example of a recent model she constructed in 2020 looked at so-called “magic traits” in organisms. As they are aptly named, “magic traits” are rare traits which have diverged in their expression due to local adaptation, thus potentially determining mating behavior and resulting in non-random mating behavior.2 Dr. Servedio found through her modeling research that, contrary to popular belief, the mating trait, which

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determines mating preferences, has a much stronger effect on an ecological trait, which is related to the ecology of an organism, rather than the other way around. The mere presence of the mating trait is enough to cause local adaptation of ecological traits.2 Dr. Servedio

Dr. Maria Servedio

Carolina Scientific

Figure 1. Example of a magic trait where butterfly wing colors have diverged and this trait affects choice in mate. Figure from article by C. D. Jiggins et al.

remarked that this was an intriguing generations. For example, snails show finding as even “having the mating trait evidence of phenotype matching in at all increased local adaptation quite a relation to the patterning of their shells. lot, which was a direction people usually Snails that feature counterclockwise don’t think of with these magic traits.” spirals on their shells prefer—or are One factor that has a great deal constrained—to mate with other snails of importance in evolutionary biology with counterclockwise spirals, and vice and speciation is mate choice, which versa, serving as a barrier to speciation refers to an organism’s decision of who between the two populations.1 In certain to mate with. Studying mate choice, situations, phenotype matching can which includes sexual selection, is very also be beneficial in bringing about important, since it can affect gene flow— speciation. For example, in a population the transfer of genetic that has a phenotype information— of purple color due to “‘Magic traits’ are rare traits a mixing of the genes between different which have diverged in populations, and thus coding for red and can impact speciation. their expression due to local blue color, individuals Mate choice can adaptation, thus potentially selecting others who make speciation determining mating behavior are more distinctly red more difficult if it and resulting in non-random or blue can result in occurs through a the formation of two mating behavior.” mechanism called separate populations phenotype matching. from the initial one.

Phenotype matching describes the As Dr. Servedio explains, “selection is tendency for organisms to seek out other directional in opposite directions so individuals that share similar phenotypes, there is more red in one population which then results in the passing of and more blue in another.” Numerous those specific traits to subsequent other examples can be seen in nature,

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Life Sciences such as the divergence of butterly wing colors (see Figure 1). Another factor aiding in speciation can be geographical separation, as often times a population in a certain area will have completely different features from a population in another region. Due to this isolation, the populations may continue to diverge further and further apart as there is no gene flow between the two of them. Dr. Servedio’s research is centered around the interconnections between and various approaches to these concepts in evolutionary biology. “Unfortunately, the punch line for a lot of this work is that whether sexual selection helps or hurts speciation depends on geography, how it is working, and various other factors.”1 One of the difficulties with this area of research is that most models produced for predicting evolutionary behavior are forced to be overly simplified due to a lack of knowledge behind the actual genetics of factors such as mating preferences.

Without that concrete evidence to back up mathematical models, they are not able to be as accurate as possible. On top of this issue is the fact that evolutionary mechanisms take very long periods of time to take hold, and collecting data on so many generations is tough, meaning that researchers may not really know enough about what the real world should or will look like to make complex and precise models to predict outcomes. Dr. Servedio sees work on the genetics of preference currently as a “huge black box” and that in the near future, research in the field will improve: “We don’t have good data on which to base assumptions, so I would like to see the field get a much better sense of the genetics of preferences in particular.”1 With this kind of information, there is enormous potential for more complex models to substantially improve our understanding of evolutionary processes such as speciation.

References

1. Interview with Maria Servedio, Ph.D. 02/08/21 2. Servedio, M. R., & Bürger, R. (2020).

The effectiveness of pseudomagic traits in promoting divergence and enhancing local adaptation*. Evolution, 74(11), 2438-2450. doi:10.1111/evo.14056 3. Jiggins, C.D. et al. (2001). Reproductive isolation caused by colour pattern mimicry.

Nature, 411, 302–305

Physical Sciences

Atomic Shape-Shifters The Three Shapes of Stable Nickel-64 Nuclei

By Maddy Stratton

T

he atom remains a mysterious component of reality which modern scientists continue working to understand. Strange phenomena start to occur when analyzing these tiny units of matter—only certain amounts of energy are allowed, one electron can be found in several places at once, and overall, chaos ensues. This leaves scientists pondering how they can approach learning more about the strange world of the atom. For starters, researchers can model the atom in different ways to investigate its properties. The models themselves evolve over time as new information is discovered. J. J. Thomson’s 1904 representation argued the atom consisted of a positively-charged nucleus “soup” with drops of negative charge interspersed to make it look like a plum pudding (the model was appropriately named the “Plum Pudding Model”).1 As researchers continued to learn more about the structure of the atom—namely, that it resembles a sphere, consists of a positively-charged nucleus made up of two types of tiny particles (protons and neutrons), which is orbited by even tinier, negatively-charged particles called electrons—the atomic model changed even further (Figure 1). Today, it is changing again, right now, for nickel-64 (Ni-64).

Robert Janssens, working alongside his team at UNC’s Triangle Universities Nuclear Laboratory (TUNL) and three other nuclear laboratories, has established the existence of three distinct shapes of the stable Ni-64 isotope.2

“There seems to be an aspect of the nuclear force that isn’t yet understood which shows up in neutron-rich nuclei.”

Janssens’s interest in nuclear physics stems from his experience as an undergraduate at the Catholic University of Louvain in Belgium. During his time there, the university was overseeing the construction of a cyclotron, a particle accelerator. Always showing interest in nuclear structure and reactions, Janssens aided in the construction of the accelerator and was inspired to write his thesis in the same domain of nuclear physics during his senior year.3 He gained a PhD in experimental nuclear physics in Louvain before taking Figure 1: Adding or removing neutrons to/from an atom creates an a postdoctoral position in isotope of that atom. Adding/removthe Netherlands. Then, he ing protons creates a new element. moved to the United States.

Today, he and his team of researchers are studying Ni-64 nuclei. Atoms of the same element (which is determined by their number of protons) with differing amounts of neutrons are isotopes of that element. Usually, the nickel atom has 30 neutrons inside its nucleus. Ni-64, however, has 36. This particular isotope of nickel, though less abundant in nature, has stable properties which makes it easier to study in the lab. Janssens’s team and collaborating labs have identified three distinct shapes of stable Ni-64 nuclei, which appear as energy is added to the atom.

Specifically, as energy increases, the nuclear shapes resemble the typical sphere (the ground state), a flattened shape, and an elongated football shape [Figure 2].4 These changes in

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Carolina Scientific

Physical Sciences

similar shapes at different energies. This nucleus may prove tougher to analyze, given it will require more energy to bring out the nuclear shapes. Congruently, the team is also looking forward to future experiments to determine if the shapes are specific to nickel nuclei (also known as 28-proton nuclei) or if the shapes can be generalized for other atoms.

Janssens’ team will begin experiments in the coming weeks with zinc nuclei, which have two more protons than nickel. One more exciting component of the experiments is the potential for Janssens and his team to measure how long the football-shaped nucleus lasts. This could be doable given the relatively longer time the nickel nucleus remains in this specific state. Figure 3: The nuclear reactions However, due to the weak Janssens and his team study take nature of the signal, this place in stars continuously. could prove to be a difficult task.3 Janssens and his team are working hard through setbacks due to the pandemic, which include delayed shipments of materials and the inability to safely work together to build detectors. Their work has big implications for the future knowledge of atomic shapes and structures, since the field is still trying to comprehend the structural results of underlying forces between protons and neutrons inside the nucleus.4 The team’s results will be tied with understanding aspects of the nuclear force, the force that holds the atom together, and will advance our understanding of how the structure of atoms can change. On a final note, learning more about the nuclei means learning more about the stars that produce them, since excited atomic states, neutron-rich nuclei, and many types of reactions Dr. Robert Janssens are present inside stars extremely more frequently than they are here on earth [Figure 3]. Janssens himself states, “the stars shine only because of nuclear physics”.3

Figure 2: Shape coexistence through the chain of Nickel isotopes. This shows the relationship between nuclear shape and excitation energy of the nickel nucleus.

shape are due to the complex ways the protons and neutrons in the nucleus of the atom arrange themselves as the energy that the nucleus is subjected to increases.

The process of finding the nuclear shapes is a matter of adding energy to the atom. After several failed attempts at adding energy to the nuclei, the team found a method that worked: gamma radiation. Gamma rays, the most energetic wavelength of light on the electromagnetic spectrum, are introduced to the top of the nucleus (at high excitation energy) in a “cascade”, causing some energy to be released from the nucleus. The shape of the nucleus can then be interpreted from the energy released.

Specifically, Janssens and his team measure the structure of the nuclei as a function of angular momentum, or the atom’s total energetic motion from each proton and neutron present.2 Nuclei with more neutrons than normal, like Ni-64, react differently to the changes in energy. As Janssens stated in our interview, there seems to be an aspect of the nuclear force that isn’t yet understood which shows up in neutron-rich nuclei, and specifically in ones that contain more neutrons than Ni-64.3 In order to further examine this phenomenon, Janssens and his team needed a new accelerator. The concept for the new accelerator was designed by a large team of scientists, including Janssens, and is currently under construction at Michigan State University. It is set to be operational in 2022. In the meantime, Janssens and the team are asking themselves, “is it really true the same phenomenon appears in stable nuclei [as opposed to only the neutron-rich ones]?”3 The answer: most likely, yes. However, the other stable nuclei would require much more energy to be introduced into the atom for the strange shapes to appear and become detectable, whereas one can see the shapes in neutron-rich nuclei at lower energies in the lab. The three shapes should appear in all nickel nuclei, no matter the isotope of nickel.

Janssens and his team found it experimentally challenging to find the shapes in Ni-64, but the signature for them was very clear once found. The same thing is expected for other stable nickel nuclei.

Now, Janssens and his team are looking ahead to analyzing the Ni-62 stable isotope and seeing if it expresses

References

1. Libretexts. “3.4: Rutherford’s Experiment- The Nuclear Model of the Atom.” Chemistry LibreTexts, Libretexts, 13 Aug. 2020, chem. libretexts.org/Bookshelves/Introductory_Chemistry/Map%3A_ Chemistry_for_Changing_Times_(Hill_and_McCreary)/03%3A_ Atomic_Structure/304%3A_Rutherfords_Experiment-_The_Nuclear_ Model_of_the_Atom.

2.“The Map of Nuclear Deformation Takes the Form of a Mountain Landscape.” Phys.org, Phys.org, 30 Dec. 2020, phys.org/news/2020-12nuclear-deformation-mountain-landscape.html (accessed February 8th , 2021).

3. Interview with Robert Janssens, Ph.D. 02/12/21.

4.“Stable Nickel-64 Nuclei Take Three Distinct Shapes.” Https:// www.energy.gov/Science/Listings/Science-Highlight, Department of Energy Office of Science, Nov. 2020 (accessed February 8th , 2021).

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Medicine & Health

Modern Problems Require Modern Solutions: The Internet’s Role in the COVID-19 Pandemic

By Robert Rampani

Figure 1. The Safer Ways App updates with real time information about COVID-19 guideline compliance

W

hat do psychology, public health, tobacco control policy, the Internet, and the COVID-19 pandemic all have in common? These topics all fuse together to form the research and passions of Dr. Kurt M. Ribisl, a Jo Anne Earp Distinguished Professor in the Department of Health Behavior at the UNC Gillings School of Public Health.

Dr. Ribisl has spent the majority of his adult research life investigating and recommending practices, procedures, and systems to help “evaluat[e] and improv[e] populationlevel efforts to reduce tobacco use with a particular emphasis on policy and information technology.”1 This has manifested in numerous ways throughout his career, from a postdoctoral fellowship at Stanford University, to currently being the Chair of the Department of Health Behavior at the UNC Gillings School of Public Health, and being a CoFounder of Counter Tools. Counter Tools is a nonprofit focused on drawing “on the best available science and an evidence-based model of change to help… partners reduce the impact of products that harm the health of individuals and communities.”2 Today, Dr. Ribisl teaches about health behavior at UNC, and conducts research that is influenced by his experience in combining multiple disciplines of interest.

While reducing tobacco use and encouraging proper health behavior to reduce the spread of COVID-19 may seem like different goals, some of the same underlying principles apply in both preventative measures. Both, in essence, are collective issues that need to be addressed on a large scale. As Dr. Ribisl expressed, “medicine [and] psychology [are] focused on individuals, where public health has a bigger focus on a population approach.”3 The fusion of the

individual, psychological approach and a more collective, populational-behavioral approach is a key tenant of Dr. Ribisl’s work. This interdisciplinary focus, both on tobacco research and now looking at the effects and shortcomings of the response to the COVID-19 pandemic, has yielded an unprecedented level of success. One major success has been in the area of warning labels for tobacco products.

Dr. Ribisl has worked extensively with members of the psychological, communication, visual design, and medical communities to create warnings that explicitly inform and dissuade consumers from using products detrimental to their health (Figure 2).

Kurt M. Ribisl, PhD.

The Internet is another area that links the fight against tobacco and the pandemic. Dr. Ribisl has been investigating the use of the Internet for decades; during his time teaching the class “The Internet & Public Health” at

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Carolina Scientific

Figure 2. New explicit warning labels for tobacco and vaping products in the United States

Gillings, Dr. Ribisl emphasizes, “the Internet and any digital technology is a double-edged sword; there are great digital tools and ways to implement best practices in public health, but they can also be used to spread information and disinformation.”3 This continual battle against disinformation can get incredibly frustrating, as Dr. Ribisl expressed, but its ability to simultaneously be a pipeline for public health officials is at the same time encouraging. Use of the Internet in public health has been firmly rooted as a standard practice for years now, but it was Dr. Ribisl back in 2003 who foresaw that “the Internet is fast becoming a new battleground between tobacco control advocates and pro-tobacco forces” and stressed the importance of further research into the use of the Internet as an advocacy tool for public health officials.4 The interdisciplinary approach of utilizing the Internet for public health measures has contributed to the decrease in tobacco use over the last 20 years, which has been vital to increasing the overall health of the American teenage and young adult populations.5

“The Internet and any digital technology is a double-edged sword; there are great digital tools and ways to implement best practices in public health, but they can also be used to spread information and disinformation.”

team effort with faculty and developers across UNC and the country. Through crowdsourcing, Safer Ways provides up-to-date information on crowd size, social distancing, and mask usage for hotspots both indoors and outdoors at UNC-Chapel Hill. This reliance on the community is a big pillar in bringing the pandemic to a close, as it both holds the public accountable and spreads positive information about vaccination and treatment.3 In everything he does, Dr. Ribisl asks “what are the systems and policies we’ve created?” and “what outcomes do those systems and policies contribute to?”3 While tobacco use may have a more drawn-out answer, the COVID-19 pandemic has given, within just a year, a glimpse into governmental regulation and public health experts’ communicative effectiveness. This demonstration of the importance of bringing multiple branches of the sciences together – both those focused on individual and collective response – and the use of every public channel available to spread information has been a tiring one.

Nevertheless, Dr. Ribisl and his colleagues at Gillings have strived to spread positive scientific research on the use of vaccinations and will continue to do so in other aspects of the health challenges of today. The pandemic has shown the strengths and weaknesses in public health messaging, epidemiology, infectious disease control, distribution channels, and workflow management. Despite the vast room for improvement, interdisciplinary approaches, like Dr. Ribisl’s, have kept the world afloat as it crawls towards a resolution and a return to normalcy.

Dr. Ribisl encourages all members of the Carolina community to remember to follow the COVID-19 guidelines, and to balance their part of the collective fight alongside individual mental health. “People need to find ways to interact and have fun and get outdoors while still following guidelines,” he stressed, to ensure “we don’t become isolated and shut-in.”3 As undergraduates hope to return to campus this fall, it is increasingly important to remember that the most successful approaches to modern problems require cooperation between experts in every field, as well as everyone outside of the scientific community. Dr. Ribisl’s work is simply one example of the importance of collective response to the challenges of 2021 and beyond. Everyone now serves as a member of the collective to return to what is now called pre-pandemic life.

References

The Internet during the COVID-19 pandemic has made the transfer to working and learning at home possible. The importance of the Internet in maintaining a productive society cannot be overstated. Nevertheless, the disinformation about the pandemic has been a real fighting point for Dr. Ribisl and other public health experts across the globe. One way Dr. Ribisl has utilized the Internet to the advantage of public health officials is through an app called “Safer Ways,” which was developed as a vast

Medicine & Health

1. UNC Gillings School of Global Public Health. Kurt M. Ribisl, PhD. https://sph.unc.edu/adv_profile/kurt-m-ribisl-phd/ (accessed February 20th, 2021) 2. Counter Tools. https://countertools.org/ (accessed February 20th, 2021) 3. Interview with Kurt M. Ribisl, PhD. 02/19/21 4. Ribisl, K. M. Tobacco Control 2003, 12.1, i48-i59 5. United States Centers for Disease Control. Health, United States 2019 Comprehensive Review. https://www.cdc.gov/ nchs/data/hus/hus19-508.pdf (accessed March 10th, 2021)

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Medicine & Health

Hematologic Malignancies in Malawi

By Sneha Makhijani

Illustration by Hannah Kennedy

F

ew people would have thought that it is possible to develop cancer by simply sharing their spoon of ice cream with a friend.

However, the common human herpesvirus Kaposi’s sarcomaassociated herpes virus (KSHV) is transmitted through saliva (for instance on a spoon), sexual contact, or transfusion of contaminated blood or tissue. The virus hides in the body and does not usually cause problems unless the immune system is weakened in cases such as in those with human immunodeficiency virus (HIV). KSHV can cause multicentric Castleman disease (MCD) in some patients with HIV. MCD is a rare disease that presents with similar symp-

toms to lymphoma.

The HIV/AIDS (acquired immune deficiency syndrome) epidemic greatly affected the African country of Malawi. The prevalence of HIV among adults is around 9% and before the link between HIV and cancer was well understood, many people living with HIV mysteriously suffered from lymphoma and other cancers.

In 1990, the UNC Chapel Hill Institute for Global Health and Infectious Diseases, in collaboration with the Malawi Ministry of Health (MOH), formed Matthew Painschab, MD UNC Project Malawi in order to focus research and training around HIV and other sexually transmitted diseases (STDs). Since 1990, UNC Project Malawi has spearheaded treatment and research on HIV and STDs in Malawi with physicians like Dr. Matthew Painschab at the forefront. Dr. Painschab’s main research Figure 1. A representative lymph node biopsy from a patient with multicen- focus has been on HIV and its association with hematologic maligtric Castleman disease in Malawi demonstrating a) the classic convulted nancies, specifically the two blood cancers leukemia and lymphoma. germinal center surrounded by b) Kaposi sarcoma herpesvirus (KSHV)Dr. Painschab has always had a passion for public health and infected plasmablasts that stain brown for a protein made by KSHV. medicine as a first-generation college student with interests in biol-

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Carolina Scientific ogy and international development. After completing a research fellowship in Puno, Peru during medical school, he pursued a career in oncology with a focus on global health. In his career, Dr. Painschab hopes to deliver cancer treatment and research that will have a tremendous impact on communities. He states, “[Standardized] treatment protocols go a long way in saving lives…so that the children and young ones don’t become orphans.” 1 During his Hematology/Oncology fellowship, he began to work with UNC Project Malawi, where he has further developed his interest and passion for his medical and research work.

Dr. Painschab first became involved in research with UNC Project Malawi through his fellowship research mentor, Dr. Satish Gopal. Throughout his clinical career, Dr. Painschab’s primary area of research has focused on HIV-associated cancers and implementation of cancer care in low-resource settings. His main motivation for continuing his work with UNC Project Malawi has been to help treat citizens of Malawi suffering from HIV-associated cancers while also promoting awareness for, and educating the citizens of Malawi about the diseases and their prevention.

Optimizing treatment and spreading awareness are two critical aspects of patient care in Malawi.

Medicine & Health

of diseases like tuberculosis and several forms of cancer. Tissue biopsies are a major diagnostic tool for confirming the presence of MCD in patients, and using new tissue biopsy facilities constructed by UNC Project Malawi, the team has been able to better diagnose and treat MCD. Since MCD is rare in high-income countries, it has not been extremely well-studied. KSHV is a common virus endemic to Sub-Saharan Africa. Up to 80% of the population is reportedly infected with KSHV, which can cause MCD, Kaposi sarcoma, or lymphoma in those with immunodeficiencies. MCD causes marked inflammation in the body which leads to severe anemia, extreme bleeding events (due to low platelets), and dangerously low blood pressure, ultimately resulting in high mortality rates without treatment. MCD can be controlled with chemotherapy, but relapses are common and new therapies, such as a medication called rituximab, are urgently needed and are being studied by the team at UNC Project Malawi.

Figure 3. Kaplain-Meier survival curves showing time to disease relapse or death in patients with multicentric Castleman disease after treatment with a) chemotherapy and b) rituximab, demonstrating the clear superiority of rituximab.

Figure 2. One of the UNC Project Malawi nurses preparing chemotherapy.

While working in Malawi, Dr. Painschab was exposed to MCD, one of the most common lymphoproliferative diseases treated and observed in the studies from UNC Project Malawi at the National Cancer Treatment Centre at Kamuzu Central Hospital in the capital city of Lilonge, Malawi. There are two types of MCD: idiopathic MCD, which has no known cause and is more frequently found in the U.S., and KSHV-associated MCD, which is more common in Sub-Saharan African populations due to the high prevalence of both KSHV and HIV in this region. For example, the U.S. National Cancer Institute has had approximately 60 cases of MCD over a 15-year period, referred from all over the United States. On the other hand, since starting to collect patient samples and recognize the disease seven years ago, Malawi has already seen over 35 cases. With new advancements in healthcare, Dr. Painschab and his fellow research team are able to improve MCD detection and are improving the diagnosis of MCD as it is thought to be underdiagnosed in the region. Further, Dr. Painschab and his team are also working on improving patient recovery after MCD. When the project first started, Dr. Painschab and his team found that patients in Malawi affected by MCD experienced symptoms characteristic of lymphoma, such as fevers, loss of appetite, weight loss, and night sweats. It was difficult to recognize MCD because it could have easily been mistaken for a plethora

Rituximab, an alternative to chemotherapy, is an antibody medication used to treat certain autoimmune diseases and some types of cancer. Rituximab has already worked well in high-income countries like in the U.S., but it has also shown promising results in low-income countries like Malawi, showing positive results in greater than 90% of treated cases. This medicine has side effects; for example, Malawian patients that had been treated with rituximab showed a much higher risk of malaria than nonrituximab patients. Dr. Painschab’s team is currently working on measuring the efficacy and side effects of rituximab for MCD in Malawi as this can have huge implications for many other diseases as well.

Through the intersection of research and patient-care, Dr. Painschab makes a difference not in the lives of his patients both in the United States and in Malawi. He hopes that by studying HIV, lymphomas, and MCD, the team at UNC Project Malawi will make a difference in the field of medicine and help people throughout the world lead longer and healthier lives.

References 1. Interview with Matthew Painschab, MD. 02/24/2021

2. Shin, D.-Y.; Jeon, Y.K.; Hong, Y.-S.; Kim, T.M.; Lee, S.-H.; Kim, D.-W.; Kim, I.; Yoon, S.-S.; Heo, D.S.; Park, S.; et al.

Leuk. Lymphoma 2011, 52, 1517-22.

3. Gopal, S.; Fedoriw, Y.; Montgomery, N.D.; Kampani, C.; Krysiak, R.; Sanders, M.K.; Dittmer, D.P.; Liomba, N.G. Lancet 2014, 384, 1158.

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Medicine & Health

Tooth Loss: A Potential Side Effect of Obesity

By Hannah Koceja

S

tress eating, decrease in outdoor activity, and higher food insecurity - causing Americans to eat poorer quality foods - are factors heightened by the 2020 pandemic that caused the obesity rate to go over 40% in 2020.1 The obesity rate in 2020 was 42.4% for American adults, 26% higher than in 2008.1 For the past decade, the U.S. adult obesity rate has been leaning towards 40%; however, the rate did not go over 40% until after 2019.1 With obesity comes a number of health risks, such as heart disease, high blood pressure, and diabetes, but other lesser known side effects are still present and should not be neglected by the media. One such side effect being found is tooth loss.

Cristiano Susin, DDS, MSD, PhD, is an associate professor in the Division of Comprehensive Oral Health and chair of UNC Chapel Hill’s Department of Periodontology since

Figure 2: Missing tooth X ray Photo taken by Theodor Negru

2018. In his most recent study located in Porto Alegre, Brazil, Dr. Susin along with 6 other researchers conducted research showing that obese individuals were significantly more likely to experience tooth loss over nonobese individuals.

Since 2001, Dr. Susin has aided research in the Porto Alegre study to provide evidence that a legitimate correlation between obesity and tooth loss exists; the study was finalized and then published in 2020. Obesity is thought to possibly cause periodontitis, or inflammatory gum disease, which can eventually lead to tooth loss.⁴ However, little research showing the direct connection between obesity and tooth loss has been conducted on this topic prior to Dr. Susin’s study.

Research has implied that obesity can cause tooth loss but, since few studies were carried out, the obesity health risk of tooth loss was never widespread in the media. Dr. Susin and

Figure 1: Tooth loss graph regarding to sex, periodontitis, and smoking. Photo by original research journal article

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Medicine & Health

his team’s research provides the evidence, which will hopefully cause more people to become aware of the hidden health detriments of obesity.

Dr. Susin and his team conducted their study over 5 years and examined 1,586 individuals from ages 14-64 as a starting point. A baseline for one’s body mass index (BMI) was then calculated for each individual to determine which individuals were considered obese in this cohort study. In addition, periodontal status, smoking habits, sex, education, socioeconomic status, dental care, and number of teeth were all variables measured at the beginning, throughout, and at the end of the study.3 These factors were assessed to make the cohort study controlled and more accurate. The 5-year timespan of the study was also an adequate amount of time even when considering the long process of tooth loss. “For the study, a large population was followed for 5 years, making it extremely difficult to have more than 50% of a participation rate as a result, which is pretty much what we have. To have the study take place over 10 or 20 years seems more ideal; however, after 5 years participation goes down very precipitously,” explained Dr. Susin.2 The large starting population and 5-year timespan allowed for a sufficient number of subjects’ data to be collected even with the almost 50% participation rate (755 subjects).

The results from their data then showed that 47.1% obese individuals recorded at least one tooth loss while 32.4% normalweight individuals experienced at least one tooth loss over the 5 years.3 This gives obese individuals in the study a 31% higher risk than participants who were normal-weight.3 Obese and overweight females were also significantly more likely to have a recorded tooth loss than obese and overweight males (Figure 1).3

because of better habits and better behaviors when it comes to teeth,” which supports the normal-weight tooth loss results but not the obese.2 This is because, as mentioned in the study, past literature has indicated that the sex differences in those who are obese may cause dissimilar side effects in chronic diseases. Varying sex hormones and different inflammatory responses between the sexes are two possible reasons mentioned for why females who remained obese reported higher tooth loss results than males of the same category, even though females are known to have better dental care.3 Although these results showed that tooth loss was more common if the subject fell into one of these categories, it is noted that individuals that did not fit into these categories and were solely obese were still found to have higher rates of tooth loss. An obese male without periodontitis who has never smoked is still more likely to experience tooth loss over his nonobese counterparts (Figure 1).3 Dr. Cristiano Susin Though the study originated in Porto Alegre, Brazil, the results found on obesity affecting tooth loss are applicable to individuals on an international level. Dr. Susin states, “Diet and lifestyles are different across the world. There will be slight differences in other studies globally, but the same trend exists. When looking at studies on this topic from other populations, you see different strengths of the association, but the results are ultimately going in the same direction. Knowing this, along with having multiple adjusted factors in our own research, it is fair to say that we are looking at a true effect that will be generalizable through multiple populations.”2 Because of this study, researchers, dentists, periodontists, and individuals can further aid others in achieving better dental care. In addition, general awareness of these results can help individuals who are obese or overweight be more conscious about how to improve their own dental health. Whether an individual is obese or overweight due to stress eating, genetic illnesses, hormonal imbalances, etc., knowing that obesity could be another factor to cause tooth loss can help them plan and prevent additional dental issues in the future.

Figure 3: Gums being examined with a periodontal measuring probe. Photo taken by Sodel Vladyslav

References

Out of the 47.1% of obese individuals who reported having tooth loss, the types of subjects most prominently found within this percentage were females, smokers, or those who had periodontitis (Figure 1).3 These results are surprising, particularly for sex, since the data shows that females who remained normal-weight were less likely to experience tooth loss over males who remained normal-weight. Dr. Susin notes, “Males and females behave differently when it comes to dental care. For instance, females tend to have better oral hygiene

1. Warren, M. Trust for America’s Health: The State of Obesity 2020: Better Policies for a Healthier America. https://www.tfah. org/report-details/state-of-obesity-2020/ (accessed February 23rd, 2021).

2. Interview with Cristiano Susin, DDS, MSD, Ph.D. 02/18/2021.

3. Vallim A.C.; Gaio E.J.; Oppermann R.V.; Rösing C.K.; Albandar J.M.; Susin C, Haas A.N. J Clin Periodontol. 2021, 48, 15 - 24.

4. Mayo Clinic: https://www.mayoclinic.org/diseases-conditions/ periodontitis/symptoms-causes/syc-20354473 (accessed February 28th, 2021).

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Medicine & Health

Osteoarthritis: Reimagining the “Wear and Tear” Disease

By Henry Bryant

Image by Manuel González Reyes .[CC0]

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lthough rheumatoid arthritis may be more recognizable to many, osteoarthritis actually affects more people; it is the leading cause of pain and disability in older adults.1 Rheumatoid arthritis is an autoimmune disease, meaning the body’s immune system mistakenly tries to destroy healthy tissue. For rheumatoid arthritis, this includes cells in joint tissues. Osteoarthritis, on the other hand, is commonly misidentified as the “wear and tear” arthritis due to the disease’s prevalence in older individuals, especially after joint injury.2 However, recent research has uncovered complex, intertwined molecular signaling pathways and feedback loops involved in osteoarthritis, changing the medical community’s perception of the disease entirely. These pathways, rather than strictly the mechanical erosion of joint tissues, cause the joint pain and disability associated with the disease.

Dr. Richard Loeser Jr., MD

Dr. Richard Loeser, an Eminent Professor of Medicine in the Division of Rheumatology, Allergy, & Immunology at UNC-Chapel Hill and Director of the Thurston Arthritis Research Center, has played a central role in this shift. Dr. Loeser’s lab uses a combination of human joint tissue and mouse models to study osteoarthritis. Joint tissue taken from both healthy young patients and older patients with osteoarthritis facilitate the discovery of physiological processes and potential biomarkers of the disease. Researchers in the Loeser Lab also activate cellsignaling molecules in healthy tissues in an attempt to study relevant pathways when osteoarthritis is induced.

Both techniques highlight molecules and pathways of interest that present starting points for further investigation.

The researchers then explore the complex interactions of these signaling pathways in mouse models.

Mouse models provide a more realistic picture of what happens inside the human body that tissue samples alone cannot emulate, and many mouse pathways mirror pathways found in the human body. Additionally, an array of biochemical techniques elucidate upstream and downstream molecules in the signaling pathways for a more complete biological picture in mice. One of these techniques involves knocking out specific genes in a pathway to see the effects on other molecules downstream.

Together, these studies led Loeser and his lab to discover a specific positive feedback loop that contributes to osteoarthritis. First, mechanical trauma, over-

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Carolina Scientific use, and other factors partially destroy the extracellular matrix (ECM) that makes up the majority of a patient’s joint cartilage. The ECM normally consists of proteins and other biomolecules outside of individual cells, giving the joints their strength and providing low-friction surfaces for bones to glide over. However, as fragments of cartilage break off they bind to receptors on the surface of joint cells, causing inflammation and the release of enzymes that break down the ECM further.3 These effects perpetuate the feedback loop; as more of the ECM breaks

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to define osteoarthritis phenotypes. In other words, patients with osteoarthritis may differ from one another and represent different subtypes of the disease.

Dr. Loeser has not only made great strides in the advancement of osteoarthritis knowledge; he has also been a mentor for many undergraduates, graduate students, medical students, and post-doctoral fellows.

He allows his students to pursue the research in this lab they find most interesting and helps guide the next generation of researchers by assisting them in creating their own projects. Dr. Loeser loves to share his knowledge with others; he describes it as “the fun part” of his work.⁵ By sharing his work with others, he has informed other researchers and clinicians who now better understand the signaling pathways of osteoarthritis and the role aging plays in the development of osteoarthritis. While Dr. Loeser’s goal is ultimately to help people with osteoarthritis live better lives, he also hopes to inspire young scientists to continue his legacy.

Figure 2. A simplified representation of the positive feedback loop discovered by Dr. Loeser’s lab that contributes to osteoarthritis.

down, more fragments bind to cell receptors, amplifying the damage that exacerbates osteoarthritis.

Dr. Loeser’s lab also studies the potential role of reactive oxygen species and the gut microbiome on signaling pathways related to osteoarthritis. Both reactive oxygen species and the gut microbiome induce inflammation, which may contribute to the release of enzymes that destroy the ECM and initiates the ECM destruction feedback loop.⁴,⁵ While many questions surrounding the role of joint components in disease progression and the degree of interdependence between osteoarthritic signaling pathways remain, the Loeser Lab’s work has reshaped how scientists and healthcare providers approach and understand the disease. Dr. Loeser hopes that increased knowledge of the disease can aid researchers to develop effective treatments for osteoarthritis by targeting one of the many molecules involved in the pathways central to the disease such as ROS. Dr. Loeser has recently started a drug discovery project based on his work that will help facilitate the development of new therapeutics.⁵ Dr. Loeser’s work to improve the lives of those suffering from arthritis extends beyond the lab; he also juggles many other roles serving as Director of the UNC Thurston Arthritis Research Center and treating patients in the clinic. Dr. Loeser’s clinical research builds upon the knowledge gained by his lab, seeking to treat patients that have knee osteoarthritis with exercise and weight loss. He also participates in a multidisciplinary project

Figure 3. Current and future management and treatment options for osteoarthritis. Items with blue stars are recommended treatment options by the American College of Rheumatology (2019). Red items are being developed and do not currently exist.

References 1. Loeser, Richard F., et al. “Osteoarthritis: A Disease of the Joint as an Organ.” Arthritis & Rheumatism, vol. 64, no. 6, 2012, pp. 1697–1707., doi:10.1002/art.34453.

2. Katz, Jeffrey N., et al. “Diagnosis and Treatment of Hip and Knee Osteoarthritis.” JAMA, vol. 325, no. 6, 2021, p.

568., doi:10.1001/jama.2020.22171.

3. Loeser, Richard F. “Integrins and Chondrocyte–Matrix Interactions in Articular Cartilage.” Matrix Biology, vol. 39, 2014, pp. 11–16., doi:10.1016/j.matbio.2014.08.007.

4. Coryell, Philip R., et al. “Mechanisms and Therapeutic Implications of Cellular Senescence in Osteoarthritis.” Nature Reviews Rheumatology, vol. 17, no. 1, 2020, pp. 47–57., doi:10.1038/s41584-020-00533-7.

5. Interview with Richard F. Loeser, Jr., MD. 02/18/21

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Medicine & Health

The Medical *Potential* of Electrochemical Detection Improved glucose monitor holds greater implications

By Maia Vierengel Image courtesy of Wikimedia Commons

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t is estimated that one billion chemical reactions occur in a single cell of your body every second! Within such a complex system, it is extremely difficult to measure just one type of molecule at a time, but for people living with diabetes, it is essential for scientists to be able to measure on this micro-level quickly and accurately.

Diabetes is a disease which affects roughly 10% of the U.S. population, causing glucose levels to fluctuate between lower or higher levels than normal.1 Glucose is the body’s most basic sugar, which cells use to make energy. If glucose levels are left unchecked, a diabetic can easily become hypoglycemic or hyperglycemic, both of which are seriously dangerous conditions. A healthy person’s blood glucose levels typically hover around 140 mg/dL. Hypoglycemia occurs when blood glucose levels dip below 70 mg/dL; this condition can become critical within 10-15 minutes, with the possibility of seizure or loss of consciousness. Conversely, hyperglycemia occurs when blood glucose levels are elevated above 180 mg/dL, which rapidly causes nausea or shortness of breath.2 Thus, it is imperative that diabetics continually monitor their blood glucose levels.

Most commonly used glucose monitors are electrochemical, as they are inexpensive, rapid, portable, and user-friendly.3 However, current commercial monitors must be replaced regularly as biofouling causes them to degrade over time. Biofouling happens when biomolecules such as proteins and cytokines stick to and cover the electrode surface, making it less sensitive and less reliable.

Additionally, modern monitors use Figure 1. A depiction of glucose levels rising in the blood to cause hyperglycemia. Image courtesy of Blausen Medical Communications

amperometry or voltammetry which use high currents to make measurements and thus are more disruptive to living cells.3 Enter Jeffrey E. Dick, PhD, and his graduate student, Nicole L. Walker. These two UNC scientists specialize in nanoelectrochemistry and single-cell biology, and set out to combine the two fields in order to make great strides in biosensor technology. Nanoelectrochemistry investigates electrical properties of materials on the nanoscale level, while single-cell biology studies genomics, proteomics, and metabolism within a single cell. In their recent publication, Dick and Walker outline a new type of glucose monitor: one that is reliable, versatile, specific, and miniturizable.

The glucose sensor, an oxidase-loaded hydrogel potentiometer, utilizes oxidase enzymes and a chitosan hydrogel measure electric potential instead of amperage or voltage.3 Electric potential is the amount of work needed to move a unit of electric charge, whereas voltage refers to a difference in potential and amperage refers to an amount of current. The enzymes are embedded in the selfassembling gel, which is laid over the electrode surface as shown in Figure 3. When a glucose molecule comes in contact with one of the enzymes, it oxidizes to form glucanolacetone and hydrogen peroxide, or H₂O₂. When the peroxide reaches the electrode surface, it signals a change Figure 2. A diabetic using a in potential to the monitor, commercial glucose monitor. measuring a change in Photo by David-i98. glucose concentration.

After experimentation, the lab proved that the detector is both highly selective and versatile. This means that the detector only signals when glucose is near the sensor and that in the future it could detect other metabolites important to medical technology. The latter part of Dr. Dick’s paper on

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Figure 3. A depiction of the sensor design; on the electrode surface, the chitosan hydrogel keeps the oxidase enzymes in place, while allowing the glucose and hydrogen peroxide (H₂O₂) to move freely. Figure from article by N. L. Walker and J. E. Dick.

oxidase-loaded hydrogel potentiometers demonstrated how the same system could be used with galactose, a different kind of sugar. The expansion of the detector to measure galactose levels may be applicable to monitoring individuals with galactosaemia, a genetic disorder that affects one’s ability to metabolize galactose. Furthermore, this potentiometer is miniturizable, meaning it can continue to yield accurate results on the nanoscale. Miniturizability is critical when considering the invasiveness of any kind of medical device.

For diabetics, a glucose monitor such as Dr. Dick’s would mean a less-invasive device, faster results, and more accurate readings of glucose levels. Potentiometric biosensors are easy and inexpensive to create, which would make them most accessible to diabetics. Considering the other costs associated with diabetes, such as insulin which can be hundreds of dollars per month, a less expensive monitor could ease the financial burden. Beyond the scope of diabetes or galactosaemia, the monitor could be used specifically for a number of other metabolites; all that’s needed is an enzyme specific to that metabolite, that causes an oxidation-reduction reaction and causes a change in potential.

Figure 4. A depiction of low blood sugar levels during hypoglycemia (on the left) and normal blood sugar levels (on the right). Image courtesy of Scientific Animations.

This device did not come to fruition easily; the team had to overcome more than a few hurdles to bring the idea to reality. One of their biggest challenges was Mixed Potential Theory, which Dr. Dick mentioned tends to be a problem

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when measuring within a complex organism.⁴ “You have to deal with Mixed Potential Theory, the fact that other things are going to contribute to the potential signal that you’re measuring, like oxygen reduction. Because of that, if you stick an electrode in a cell, you have lots of things Jeffrey E. Dick, PhD that can happen, lots of reactive species that could affect that potential. So, we have to be able to mitigate that.”

A single cell contains many chemical reactions, and the presence of oxidative species like oxygen (O₂) can complicate the potential signal. To resolve this problem, they tinkered with different materials for the electrode surface, and found that peroxide specifically reacts favorably on the surface of platinum, making it a great electrode material.

When asked about the impact of his device and its research as it pertains to other fields, Dr. Jeffrey Dick insisted that single-cell detection is the future of disease medicine and will impact lots of other fields. “There are extensive heterogeneities between cells. Take the pancreas, for instance; it’s really difficult to diagnose pancreatic cancer because pancreatic cells are very heterogeneous in nature, and understanding how they interact with each other on a single-cell level could lead to that one cell that becomes pancreatic cancer. It’s really necessary to understand disease on the most fundamental level: the cell.” As with most other things in life, generalizations can cause very important details to be washed out!

Concerning collaboration, Dick reported that the lab is working with UNC biomedical engineering professor Koji Sode, a world expert on glucose sensors and enzyme manipulation. Additionally, they have compacts with scientists at the UNC Medical school to reach their next goals: lowering limits of metabolite detection, enhancing sensitivity, and understanding how the detector can be applied to different diseases, including those within the worlds of oncology, virology, and stem cell differentiation.

Dr. Dick’s research and his inventive ideas clearly show the broad implications of the intersection of electrochemical detection and single-cell biology. Though he has only just begun, his research and innovations could lead to a ripple effect in the lives of ordinary people in addition to the fields. of biochemistry and medicine.

References

1. National Diabetes Statistics Report 2020. US Department of Health and Human Services 2020.

2. Hypoglycemia, Hyperglycemia: Symptoms and Causes. https:// www.mayoclinic.org/diseases-conditions/hypoglycemia/symptoms-causes/syc-20373685 (accessed March 1st, 2021) 3. Walker, N.L.; Dick, J.E. Elsevier: Biosensors and Bioelectronics 2021, 178.

4. Interview with Jeffrey E. Dick, Ph.D. 2/16/21

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Biology

Identifying the drugs behind unintended bleeding disorders

By Elizabeth Bennett

Image credit: Pexels

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edications are a powerful and important tool at a physician’s disposal, but they can become problematic when the full extent of their behavior is unknown. Many drugs come with long lists of known side effects, yet unintended reactions to prescribed medications, called adverse drug reactions (ADRs), are a leading cause of death worldwide. Associated with numerous drug classes, uncontrollable bleeding is a particularly dangerous and common ADR presented by patients. Identifying the risk of drug-induced bleeding disorders associated with specific medications would represent a vital step toward reducing the hospitalizations and deaths associated with drug-induced bleeding disorders.1 Although antithrombotic drugs, or blood thinners, understandably confer the greatest risk of drug-induced bleeding, ADRs associated with the use of blood thinners tend to be predictable and manageable. Scientists know how these drugs interfere with coagulation, through targeting the vitamin K cycle, and understand how to counter their effects.

In contrast, other drugs such as anti-inflammatory medications, antibiotics, anti-depressants, and chemotherapeutic agents pose bleeding risks that are not predictable or controllable.1 Understanding how these medications interfere with coagulation and which of them could cause bleeding disorders would save lives, rendering many ADRs preventable and controllable. The Stafford Lab at the University of North Carolina at Chapel Hill hopes to achieve this goal.

The Stafford Lab seeks to investigate “the structure and function study of enzymes in the vitamin K cycle and…vitamin K-dependent proteins involved in blood coagulation.” 2 The lab, located in UNC’s Biology Department, used its own cell-based assay, developed in 2013 by Dr. Jack Tie & Dr. Da-yun Jin, to screen the drugs—a testament to years of carefully researching the vitamin K cycle.3 In a recent study led by Xuejie Chen, a postdoctoral researcher in the Stafford Lab, the group “established a cell-based, high-throughput approach for screening drugs that have bleeding risks caused by off-target inhibition of vitamin K redox cycling,” a process involved in blood coagulation.1

Figure 1: Bleeding disorders can occur when the vitamin K cycle is disturbed. Image source: RicHard-59, CC BY-SA 4.0, via Wikimedia Commons.

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Dr. Xuejie Chen

Carolina Scientific Vitamin K is a fat-soluble vitamin and a necessity for many of the body’s regulatory functions. Vitamin K-dependent proteins, including many responsible for coagulation, cannot properly function without vitamin K acting as a cofactor for their enzymatic modification. Yet despite the body’s need for vitamin K, its storage capacity for the nutrient is very small. Instead, the body recycles the vitamin through the vitamin K-epoxide cycle, which greatly reduces the amount of vitamin K an individual must intake each day.4 The vitamin K-epoxide cycle involves a series of redox reactions that takes vitamin K through three forms, only one of which, vitamin K epoxide (KO), is usable as a cofactor.4 After KO is used by the body’s proteins, VKR and VKOR enzymes transform the vitamin back into its reduced form, hydroquinone, in two steps; first VKOR reduces KO to vitamin K, and next both enzymes reduce vitamin K to its reduced form. From there, hydroquinone can be oxidized to KO.1 Anti-coagulants like Warfarin, the most commonly prescribed vitamin K antagonist, reduce clotting by inhibiting VKOR, disrupting the vitamin K cycle. Without VKOR to reduce KO back to vitamin K, the vitamin cannot progress through the cycle and return to its usable form. Therefore, Warfarin is intended to limit the body’s ability to produce coagulation factors.1

“Identifying the risk of drug-induced bleeding disorders associated with specific medications would represent a vital step toward reducing the hospitalizations and deaths associated with drug-induced bleeding disorders”

Biology

of vitamin K capable of rescuing VKR off-targeting. 2 The Stafford Lab also hopes “to build screening systems, to not only test drugs that target the vitamin K cycle directly, but to also test drugs that affect vitamin K absorption, transportation, and metabolism.” 2

Figure 2. Drugs interfering with KO reduction stop the enzyme VKOR from reducing KO to vitamin K. Image sourced from PDBe (EBI), CC0, via Wikimedia Commons.

For the present, experts in the field expressed in a commentary article that the cell-based assay system “could serve as a high-throughput platform to screen novel drugs for druginduced bleeding resulting from…interaction[s] with the VK cycle.” 5 The ability to screen for specific aspects of a drug’s behavior and flag detrimental interactions is crucial to ADR prevention; while vitamin K antagonists are powerful drugs physicians can use to help patients, their effects are dangerous if unintended.

With the Stafford Lab’s tools in hand, physicians will have more options to rescue and reduce bleeding related to vitamin K cycle off targeting.

However, drugs that are not blood thinners can also act as vitamin K antagonists by “off-targeting” the vitamin K cycle. Identifying these would-be blood thinners represents an important aspect of “preventing and controlling bleeding disorders associated with ADRs.” 1 The Stafford Lab used their cell-based assay to screen compounds from the NIH Clinical Collection Library of drugs for unintended interference in vitamin K-dependent coagulation. Out of 727 compounds, the lab identified nine drugs as vitamin K antagonists. The drugs were also found to impact the cycle in three ways: they either interfered with KO reduction, vitamin K reduction, or the availability of vitamin K. 1 However, the identification of drugs capable of antagonizing the vitamin K-epoxide cycle and of inducing bleeding is only the first step towards reducing ADR-related deaths and hospitalizations. Chen and the Stafford Lab also study how to counter the effects of vitamin K antagonists. The method of interference matters: Chen’s study confirmed that the effects of VKOR-targeting drugs in the study—including Warfarin, Nitazoxanide, and Lansoprazole—can be countered by simultaneously giving patients vitamin K supplements, effectively bypassing VKOR’s reduction of KO. Unfortunately, drugs targeting VKR present a problem without a simple solution.1 Chen explained that the reduced form of vitamin K, “cannot be used to rescue VKR off-targeting, as it is unstable.” 2 An ongoing, NIH-funded study in the Stafford Lab seeks to address the problem of VKR targeting by synthesizing a form

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Figure 3. (left) Warfarin is a vitamin K antagonist and used as a blood thinner.

Image sourced from Calvero, Public domain, via Wikimedia Commons.

References

1. Xuejie Chen, Caihong Li, Da-Yun Jin, Brian Ingram, Zhenyu Hao, Xue Bai…Jian-Ke Tie (2020). A cell-based high-throughput screen identifies drugs that cause bleeding disorders by off-targeting the vitamin K cycle. Blood, 136 (7): 898–908. https://doi-org.libproxy.lib.unc.edu/10.1182/ blood.2019004234 2. Interview with Xuejie Chen, Ph.D. 09/24/20 3. Tie J.K., Jin D.Y., Tie K., & Stafford D.W. (2013). Evaluation of warfarin resistance using transcription activator‐like effector nucleases‐mediated vitamin K epoxide reductase knockout HEK 293 cells. Journal of Thrombosis and Haemostasias. Aug;11(8):1556-64.

4. Higdon, J., Drake, V. J., & Delage, B. (2000). Vitamin K. Linus Pauling Institute. https://lpi.oregonstate.edu/mic/ vitamins/vitamin-K 5. Mettine H. A. Bos, Felix J. M. van der Meer (2020). Vitamin K therapy to reduce bleeding. Blood; 136 (7): 780–782. doi: https://doi.org/10.1182/blood.2020006563

Public Health

Title Fruits and Vegetables for

By Firstname Lastname Infant Health

By Sara Bernate Angulo Photo by Heather Annette Miller, CC-BY-NC-2.0

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besity—a disease of staggering severity, though unfortunately much too familiar in this day and age. As rates increase among both adults and children, the obesity epidemic continues to worsen in the U.S.1,2 Obesity is associated with increased risk for diseases and decreased quality of life. Thankfully, researchers worldwide have made strides to understand and address this public health concern, identifying factors such as diet and exercise for prevention and treatment. Research has indicated that the risk of obesity can stem from diet and eating behaviors as early as the first two years of life.3,4 As such, improving infant diet is a major focus for preventing the development of obesity later in life.

This is precisely the focus of Dr. Heather Wasser, a nutrition assistant professor in the Gillings School of Global Public Health at the University of North Carolina at Chapel Hill (UNC-CH). She earned her BS from Fontbonne University, her RD credential from Cornell University, and both her MPH and PhD from UNC. In addition to her education, her extensive experiences working as a clinical dietitian and a project specialist, coordinator, and nutrition consultant for the N.C. Department of Health and Human Services have cultivated a professional focus on behavioral nutritional interventions that promote infant and toddler health. “Almost all of my research comes from life experiences and observation,” Dr. Wasser shared.5 Indeed, her interest in public health began with an observation. In undergraduate school, as a nanny for a wealthy family and an intern for a public health organization that provided summer meals for children of low-income families, Dr. Wasser had a first-hand account of the wide-ranging racial, economic, and health disparities of St. Louis, Missouri, where she lived at the time. After earning her RD credential and MPH, Dr. Wasser’s involvement with the state and local health departments

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to improve nutrition in childcare centers led her to identify child health promotion as her field of specialization. Yet it wasn’t until she spoke with UNC-CH researchers about a study assessing infant care risk of obesity that Dr. Wasser identified nutrition research as her intended professional career.

In the early years, Dr. Dr. Heather Wasser Wasser’s research looked at infant temperament and feeding behaviors. Previous studies had suggested that caregivers use fussiness as a cue to begin complimentary feeding, defined as the feeding of food and drinks in addition to breastmilk or formula. In a cross-sectional study with a cohort of lowincome black mother-infant pairs, Dr. Wasser assessed the association between maternal perception of infant temperament and complimentary feeding. The results found that babies who are perceived as fussy are more likely to be introduced by caregivers to complimentary foods before four months of age, a practice that does not adhere to feeding guidelines and recommendations.6 In fact, professionals recommend exclusive breastfeeding for the first 6 months of life, followed by complimentary feeding.7 The study also found that caloric intake may be higher for infants receiving complimentary feeding before 4 months of age, which may result in infant weight gain and, subsequently, obesity.6 Thus, these results call for maternal perception of infant behavior to be accounted for as an important factor for infant feeding in future research. They also call for the development of counseling

Carolina Scientific methods that equip mothers with the knowledge to respond to infant behavior in ways that promote healthy feeding. Additionally, since most interventions targeted one primary caregiver, usually the mother, Dr. Wasser then studied how feeding practices vary by the type of caregiver, such as mothers, fathers, and grandparents. Her findings showed that non-maternal caregivers are highly involved in infant feeding, and as such, may increase the intake of obesity-related foods and drinks and decrease the likelihood of exclusive or continued breastfeeding.8 Thus, the results supported interventions that target multiple family members, not just mothers.

In accordance with these results, Dr. Wasser will be testing a multi-component, family-based intervention through Growing Healthy Together, a randomized controlled trial that aims to promote healthy infant size and growth during the first two years of life.9 Her target population is African American families, as the literature shows that African American infants have a higher prevalence of obesity.10 The intervention’s components include home visits, newsletters, an information toolkit, and text messages, all of which provide guidance

Figure 1. Mother feeds baby complimentary foods. Photo courtesy of Wikimedia Commons, CC-BY-SA-4.0

and support for breastfeeding, responsive and complimentary feeding, addressing sleep and crying, and limiting infant TV/media exposure.9 There are two groups, each composed of infants, mothers, and the mothers’ identified study partners: the intervention group, which will receive the intervention, and the control group. This 5-year study will collect data starting from each woman’s 28th week of pregnancy, continuing until the infants are 15 months old. The results of this project will determine which intervention components, or combination of components, best improves fruit and vegetable intake and minimizes junk food intake. This determination is critical in informing public health initiatives for obesityprevention in infants. As for Dr. Wasser, she shares, “If I can help parents feed kids under the age of five vegetables and make progress on vegetable intake in children, I’ll feel like I’ve had a successful career.”5 In the future, Dr. Wasser is interested in shifting her research focus toward parents. There is growing evidence on the negative impact of maternal postpartum depression (PPD), a form of depression that occurs after having a baby, on maternal and infant health.11

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Public Health

Figure 2. Healthy infant and toddler feeding is the foundation for optimal child and adult health. Photo by Alexas_Photos, Pixabay

For mothers, PPD impairs their psychological health, caregiving ability, relationships, and overall quality of life. For infants, PPD negatively impacts their cognitive, social, and physical development. Notably, PPD disturbs feeding practices and result in infants who are fed inadequately, some of whom may become overweight and develop obesity later in life.12 These consequences have highlighted a need to develop interventions that address mental health, especially in low-income families.

Additionally, Dr. Wasser notes the importance of involving non-maternal caregivers in interventions that aim to optimize infant health. Fathers, grandparents, siblings, and even childcare centers and providers contribute to the way children are raised and the foods and behaviors to which they are exposed. Thus, Dr. Wasser hopes to work on developing interventions to reduce postpartum depression and improve co-parenting for healthy infant diet and growth.

References

1.Hales, C.M.; Carroll, M.D.; Fryar, C.D.; Ogden, C.L. NCHS Data Brief, no 360. https://www.cdc.gov/nchs/data/databriefs/db360-h.pdf (accessed February 24, 2021).

2.Hales, C.M.; Carroll, M.D.; Fryar, C.D.; Ogden, C.L. NCHS Data Brief, no 288. https://www.cdc.gov/nchs/data/databriefs/db288.pdf (accessed February 24, 2021).

3.Baird, J.; Fisher, D.; Lucas, P.; Kleijnen, J.; Roberts, H.; Law, C. BMJ. 2005, 331(7522), 929.

4.Thompson, A. L.; Bentley, M. E. Soc Sci Med. 2013, 97, 288–296.

5.Interview with Heather Wasser, Ph.D. 2/24/21 6.Wasser, H.M.; Bentley, M.E.; Borja, J.B.; Goldman, B.D.; Adair, L.S.; Thompson, A.L.; Slining, M. Pediatrics. 2011, 127(2), 229-237.

7.Recommendations and Benefits: Breastfeeding. https://www.cdc. gov/nutrition/infantandtoddlernutrition/breastfeeding/recommendations-benefits.html (accessed February 24, 2021).

8.Wasser, H.M.; Thompson, A.L.; Siega-Riz, A.M.; Adair, L.S.; Hodges, E.A.; Bentley, M.E. Appetite. 2013, 71, 7-15 9.Wasser, H. M.; Thompson, A. L.; Suchindran, C. M.; Hodges, E. A.; Goldman, B. D.; Perrin, E. M.; Faith, M. S.; Bulik, C. M.; Heinig, M. J.; Bentley, M. E. Contemp Clin Trials. 2017, 60, 24–33.

10.Taveras, E. M.; Gillman, M. W.; Kleinman, K.; Rich-Edwards, J. W.; Rifas-Shiman, S. L. Pediatrics. 2010, 125(4), 686–695.

11.Slomian, J.; Honvo, G.; Emonts, P.; Reginster, J. Y.; Bruyère, O. Women’s Health (London, England). 2019, 15.

12.Gaffney, K.F.; Kitsantas, P; Brito, A.; Swamidoss, C.S.S. J Pediatr Health Care. 2012, 28, 43-50.

Environmental Science

It’s Complicated: Environmental Crises Reveal the Key to Long-term Sustainability

By Megan Bishop

Image by Adonyi Gabor [CC0]

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umans engage in constant conversation with the environment; human prosperity is contingent upon having clean water to drink, pure air to breathe, and rich soil to harvest food. Perhaps, the Earth is our oldest friend. UNC-Chapel Hill environmental anthropologist Dr. Caela O’Connell first acquired this realization as a child attending nature camps. It was her volunteering with local stream water management testing that sparked her interest in the disconnect between people’s relationship with the environment and the environmentally harmful consequences of their actions.1 Though decisions pertaining to sustainability can quickly fall into the polarizing categories of “good” and “bad”, Dr. O’Connell knows human behavior is much more complicated than this. Her research is motivated by trying to understand this complication in which humans must both utilize and protect the environment—particularly as the environment undergoes unprecedented changes—so that long-lasting sustainability efforts can be put into place. By analyzing communities as they navigate environmental crises, Dr. O’Connell uncovers what secret, underlying environmental struggles surface amidst difficulty so that these issues can be addressed, resulting in resilient sustainability efforts.

When UNC students think of Jordan Lake, they may immediately think of beautiful scenery and hiking trails. However, underneath the water, there is an ongoing crisis threatening the sustainability of local drinking water.

In 2012, Dr. O’Connell began analyzing the problem of nutrient pollution in Jordan Lake—the primary source of drinking water for Cary and Apex, NC—in order to evaluate Dr. Caela O’Connell why current alleviation efforts are

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failing.2 The simple answer to this, is in fact, not so simple. Dr. O’Connell studied why mass disapproval of Water Quality Trading (WQT) policy implementation was evident within the Jordan Lake Watershed agricultural community, despite the extent of water pollution in Jordan Lake. Dr. O’Connell utilized ethnographic interviews with ninety farmers that revealed that only 26% of farmers would agree to be involved in the WQT program, but before jumping to the conclusion that they do not care for the environment, consider their situationally complex justifications.2 Farmers showed concern regarding the financial burden of losing property value, increasing income tax, and the fairness of doing more on their farms specifically so new business and housing developments could do less to protect the water.2 In fact, the interviews revealed that farmers supported policies to purify Jordan Lake, yet simply could not risk the financial or moral trade-offs. Identifying these complications is essential in order to establish sustainability practices that can fit the needs of a community in the long term, and therefore offering a permanent solution to an ongoing crisis.2

“There’s this idea that sometimes when

there’s a point of disaster or crisis it brings to the surface things that are going on all the time” The struggles of a community that prevent environmental action are not always ongoing; Dr. O’Connell has found that observing communities undergoing a more sudden crisis exposes underlying socio-environmental dilemmas that the community may not have been aware of before. Dr. O’Connell explains, “There’s this idea that sometimes when there’s a point of disaster or crisis it brings to the surface things that are going on all the time.” 1 Currently, Dr. O’Connell has taken the semester

Carolina Scientific off from teaching to focus on studying how the COVID-19 pandemic has influenced local food system resilience. For 8 months, Dr. O’Connell and her team of students from the Socio-Ecological Change Research (SECR) lab, conducted ethnographic interviews with organizational, nonprofit, and local government leaders involved in the food industry as well as food producers and distributors across Orange and Chatham counties. The interviews were semi-structured, meaning that though there were some prepared questions, the interviews could diverge to become more personal. This allowed Dr. O’Connell to better understand the specific changes individuals had seen, what their personal worries were, and discern whether or not issues from pandemic are blown-up version of issues that they face in times of non-crisis. As she listened to the stories of these leaders, she considered: “Are there any lessons that we can learn to help us to think about what makes our food system stronger even during times of non-crisis?”1 By conducting her research through interviews, O’Connell is able to specifically hone in on the reasoning behind people’s decision-making process to better identify their needs.

In evaluating these community responses, Dr. O’Connell’s team has found trends that may be indicators of underlying food resilience issues as well as potential, long-term food resilience solutions. Interview data indicated struggles within the elderly population due to their vulnerability to COVID-19; when a trip to the grocery store or food bank becomes a life-threatening event, food security is not sustainable. She also noted that individuals with more contingent labor situations struggled with food security when restaurants and small businesses faced closures to enforce safety precautions. These jobs have less of a financial safety net, so this demographic was also more vulnerable. By identifying which demographics struggled the most with food sustainability during difficulty, permanent changes focusing on the needs of these communities could increase the resilience of food systems long-term.

Figure 1. Food distribution in a local farmer’s market during the COVID-19 pandemic.Photo by Don Mason In addition to identifying these specific complications, Dr. O’Connell observed solution methods that could be successful long-term. She found that food producers and distributors who were plugged into a community, such as a network of farmers or a food council, were able to better communicate strategies for navigating the pandemic. By learning from each other’s successes and mistakes, they had an easier time adapting to feed the community. This finding is a huge testament to the power of interpersonal relationships in implementing successful, sustain-

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Environmental Science

able practices. She also discovered that the new technology that had been rapidly implemented to limit in-person contact might be here to stay. For restaurants, this technology manifested itself as an online ordering system, while for food banks and pantries, volunteers and donations were organized online. In both cases, leaders in local food distribution had previously been hesitant to adapt technology due to the financial risk; however, these leaders were willing to innovate their technological systems in order to operate safely. As a result, they discovered that using technology tends to increases the sustainability of local food systems, and can provide organizational and accessibility benefits that have been needed for years.

Figure 2. A Puerto Rico banana farm taken shortly after Hurricane Maria; image courtesy of Dr. Caela O’Connell Dr. O’Connell’s interviews uniquely acquire information on the complexity of environmental decision-making. Many factors must be considered when implementing sustainable, environmentally resilient practices: consumer cost, distributor cost, health, safety, etc. By identifying both the problems and solutions that arise in agricultural communities during crisis, O’Connell hopes to help food system leaders establish sustainable practices that can withstand difficulty. Though this information can be communicated scientifically, it is most directly applied when shared with local communities. O’Connell wants to ensure that “the research is good, the science is there, but also the communication of [her] findings goes beyond publications.”1 It is important that she not only analyzes the needs of the community but also answers them. Soon, she is giving a series of informal talks with a network of North Carolina farmers markets to discuss the problems and solutions that this study revealed about local food system resilience. That way, local farmers can adapt their strategies to serve the communities in a way that has proven beneficial. When communities are aware of both the potential issues and possible solutions that can arise during socioenvironmental hardship, they can implement sustainability efforts that are strong enough to endure unprecedented difficulty.

References

1. Interview with Dr. Caela O’Connell. February 12, 2021 2. O’Connell, C.; Motallebi, M.; Osmond, D. L.; Hoag, D. L. Trading on Risk: The Moral Logics and Economic Reasoning of North Carolina Farmers in Water Quality Trading Markets. Economic Anthropology 2017, 4(2), 225–238.

Photo by Jim Maragos [CC BY-NC 2.0]

Ecology

Predicting Disaster:

Using Ecology to Fight Climate Change

By Alex Reulbach

Coral providing shelter from predation to reef fish.

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apidly rising temperatures and adverse human activities have ravaged habitats across the world, and efforts to slow the pace of destruction have been futile. As the climate crisis continues to irreversibly alter many crucial ecosystems globally, innovative techniques are required to curb the extensive damage that has been done to the environment. Due to the onset of climate change that has wreaked havoc on both terrestrial and marine ecosystems in the last several decades, conservation ecology has largely been a reactive science. One approach championed by marine ecologists Dr. John Bruno and Dr. Mark Bertness suggests that, for conservation ecology to become a predictive rather than reactive science, the conceptual framework of the science of ecology has to be reconfigured. The researchers argue that conservation ecology must focus on positive instead of negative interactions between species if it is to develop into a successful predictive science that prevents future ecological disasters.

Dr. Bruno, a marine ecologist and Professor in the Department of Biology at the University of North Carolina at Chapel Hill, has studied ecology for over 25 years. Dr. Bruno’s journey into conservation ecology began when he was working to earn

his Ph.D. at Brown University back in the late 1990s.¹ At Brown, he conducted his research in the Department of Ecology and Evolutionary Biology under the guidance of his mentor and Ph.D. advisor Dr. Bertness. It was during a conservation ecology symposium honoring Dr. Bertness’s retirement that the two colleagues joined forces with fellow conservation ecologists Dr. Andrew Altieri and Ph.D. students Hallie Fischman and Sinead Crotty to try to fundamentally alter the landscape of conservation ecology.

To understand why the team’s push to focus on positive species interaction is so groundbreak-

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Figure 1 : Hawk competing with with a mouse for limited resources.

Carolina Scientific

Ecology

ing, a brief summary of the history of ecology is would not normally survive.² Foundational species necessary. Since the science of ecology blossomed are extremely important to ecosystems because under Darwin’s influence in the 19th century, ecol- they reduce or remove an environmental stressor ogy has attempted to from the ecosystem. “...researchers argue that conservation explain the processes As Dr. Bruno explains, ecology must focus on positive instead of and patterns we see in negative interactions between species if it “Foundational species nature. The “struggle is to develop into a successful predictive like coral, mangroves, for existence” principle science that prevents future ecological trees, and grasses are that Darwin proposed essential to the health disasters.” drives evolution has of every ecosystem also driven the science of ecology.¹ To explain the they are a part of. If you do not have the foundacomplex structures and processes seen within tional species, then you do not have a functioning ecosystems, ecologists have relied on the study of habitat.”¹ Ecosystem models that rely on positive negative interactions between species. Competi- species interactions do not require an ecosystem tion between species for a limited number of re- to be in equilibrium since foundational species are sources in an ecosystem at equilibrium – meaning able to create habitats and expand ecosystems and the ecosystem is unchanging – is the major princi- the resources available in an ecosystem through ple of negative interaction.² Ecologists believe that facilitation. This is exciting because it allows scienit is the negative interactions between species that tists to more accurately study ecosystems across are responsible for how ecosystems are shaped. the world that are in a constantly changing state of Even though ecologists use models that rely disequilibrium.

While Dr. Bruno does not plan to expand on on negative interactions between species in an unthis research in the changing ecosystem to study ecosystems, Dr. Bruno argues that, “Most ecosystems exist in a state future, he believes of disequilibrium. Human activities are constantly it has many applicachanging ecosystems from their natural state.”¹ tions for future conSince the principle of competition between speservation ecology.

The most important cies that is integral to negative interactions relies application of this on an ecosystem being at an unrealistic equilibresearch is the recrium Dr. Bruno and his team believe that positive ognition that founinteractions between species play a much more central role in shaping ecosystems. Such positive dational species interactions, also known as facilitation theory, ocmust be protected at all costs if there cur when a species benefits from another species Dr. John Bruno, PhD. and neither species receives a disadvantage.² An will be any chance example of this would be the facilitation that oc- for the future survival of both pristine and degradcurs between coral and reef fish. Reef fish rely on ed ecosystems. Dr. Bruno and his team hope that the extensive, complex structure of corals for pro- more accurate studies of ecosystems using models tection from predation. based on the principles of facilitation theory will One of the main goals for Dr. Bruno and his transform ecology into a predictive science that reteam with the project was to change the current searchers can utilize to conserve ecosystems across conceptual framework of ecology so that more the world before it is too late. emphasis is placed on facilitation theory when studying ecosystems. The main principle of facili- References tation theory is that foundational species, species 1. Interview with Dr. John Bruno 02/15/21 that are abundant and provide habitat structure, 2. A. Altieri; M. Bertness; J. Bruno; S. Crotty; H. Fisallow other organisms to exist in places where they chman. Frontiers in Marine Science 2019, 6, 10.3389

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Psychology & Neuroscience

Treating Epilepsy

BY LASYA KAMBHAMPATI

Image from Yale Medicine, 2019

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pilepsy is one of the most common neurological disorders, affecting over 3.4 million people in the U.S. alone.2 There are over a dozen different types of epilepsy, which makes it hard for doctors and researchers to determine the exact cause of each type.5 Epilepsy’s mysterious origins make the task of finding a cure or effective treatment significantly harder.

Dr. Erin Heinzen, an associate professor at the University of North Carolina at Chapel Hill, is on a mission to change the outlook of epilepsy research. While in pharmacy school, Dr. Heinzen recognized the lack of effective treatments for neurological diseases. “Instead of trying to make the old medications that weren’t great work better,” Dr. Heinzen decided to “retrain as a human geneticist to figure out what causes epilepsy better.” In doing so, she would be able to eventually design better medications for epilepsy.1 This realization inspired her to take a step back and join the effort to create better medicines, particularly for epilepsy.1 Specifically, she hopes to identify the genetic cause of neocortical focal epilepsy, a condition characterized by seizures that originate in the neocortex and are restricted to a certain section of the brain. The lack of definition of brain lesions that cause neocortical seizures makes it difficult to identify and target problematic regions for treatment.6 Dr. Heinzen identifies genetic variants associated with neocortical focal epilepsy by sequencing samples

taken from human patients with the disease.1 As a last resort for patients consistently struggling with seizures, doctors perform a procedure in which they remove the part of the brain that is ‘acting up.’ The Heinzen Lab receives some of these samples and analyzes them for genetic anomalies that could represent causal factors of epilepsy.

Dr. Erin Heinzen Interestingly, the Heinzen Lab has identified inconsistencies in the genetic mutations found throughout the brain. In order to determine whether these mutations are somatic or inherited, they compared the genetic sequence to the DNA sequence in blood samples from the patient.1Oftentimes, identified mutations proved to be unique to specific parts of the brain and were not found throughout the whole body.

These mutations present in a mosaic fashion and are believed to have occurred during development.3,4 The earlier in development the mutation arose, the more widespread the variant would become. The Heinzen Lab hypothesizes that neocortical focal epilepsy might result from these localized mutations. To verify this, the lab seeks first to identify mutations of interest. However, many of the samples that the lab receives have 10-15 somatic variants, making it difficult to determine which

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Carolina Scientific

Psychology & Neuroscience

Figure 1. Neuronal cells viewed under fluorescent microscopy gene(s) contribute to epileptic behavior. To narrow down the pool, Dr. Heinzen’s team uses a complex probability calculation based on known information about the gene and its function to determine the gene’s likelihood of causing epilepsy.

One example of a mutation identified by the lab’s probability calculation falls in the SLC gene, which encodes a protein product responsible for the transportation of galactose from the cytosol to the Golgi in a process called glycosylation.4 When the amount of galactose transported to the Golgi is reduced, glycosylation decreases. Since glycosylation plays an important role in protein regulation, this reduction significantly impacts hundreds of proteins throughout the entire cell.

As a result, this specific mutation acts as a lethal gene on the X-chromosome. Males conceived with this mutation usually do not survive, as every cell would have this deficiency .1,4 Women have two X-chromosomes, one of which is inactivated as a Barr body. This fact increases their likelihood of survival even with the mutation, which presents itself in a mosaic pattern: active in some cells and inactive in others.

However, the Heinzen lab’s findings present new problems. One of the main challenges and critiques that Dr. Heinzen faces relates to the lab’s use of patient samples.1 Since surgery represents a last resort technique to help patients and technological advancements have steadily reduced the need for surgical intervention, acquiring large numbers of patient samples has grown increasingly difficult.

Lacking samples to test for mutations makes the

research process very difficult. Additionally, since the samples only originate from epileptic patients, the lab does not have access to control samples. Many of the somatic mutations identified by the Heinzen Lab may be present in the general population, but because there is no control group, there is no way to confirm each mutation acts as a differential factor between healthy and epileptic individuals. The lab seeks to circumvent this problem by using samples from deceased donors and tumor cohorts to construct a core genome. Then, they can statistically estimate the likelihood each identified somatic mutation is the causal factor of neocortical epilepsy.

Dr. Heinzen hopes to continue pursuing this research in the coming years by looking for more epilepsy-linked genes in the somatic and germ line.

The discovery of new mutations might someday lead to the development of life changing therapies to combat epilepsy. A development like this would help the millions of people suffering with epilepsy by providing them with effective treatments.

References

1.Interview with Erin Heinzen, Ph.D. 2/9/21.

2.CDC. Epilepsy Fast Facts. https://www.cdc.gov/epilepsy/about/fast-facts.htm 3.Campbell I.; Shaw C.; Stankiewicz P.; Lupski J.; CELL PRESS. 2015, 31, 382-390.

4.Heinzen E.; GENETICS & DEVELOPMENT. 2020, 65, 1-7.

5.Columbia Neurosurgery. Neocortical Epilepsy. https:// www.columbianeurosurgery.org/conditions/neocorticalepilepsy/

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Psychology & Neuroscience

Nicotinamide: A New Form of Rehab?

By Diana Chapman

Photo by Marco Verch [CC-BY 2.0]

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he number of drug disorders and deaths is continuing to skyrocket, with more than 70,000 Americans dying from drug overdose in 2019 alone, but unfortunately the majority of people who do seek help before it is too late often fall back into the cycle of relapse following treatment.1 Rehabilitation can help many patients maintain abstinence from substances, but not all people can afford or access treatment options; the lengthy, daunting, and emotional process of rehab can also frighten some people with addiction away altogether. Furthermore, many people who have been treated for drug addiction still have lingering effects that can lead to relapse later on in life. The effects include psychological and physiological cues that researchers have discovered can tap a part of a former or current patient’s brain and drive them to relapse.2 These cues may come from work stress or even something as simple as walking down a street where one bought or took drugs before. This part of recovery is extremely difficult for many people to get through, but Emily Witt, a neuroscience graduate researcher at UNC-Chapel Hill, is working to see how a form of Vitamin B3 may help prevent the notion of needing to respond to these pervasive cues using animal research.

Nicotinamide, or NAM, a pharmaceutical used mostly for acne and dermatological treatments, has recently Figure 1. Chemical structure come into light as a possible of nicotinamide [PubChem] aid in the treatment of sev-

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eral animal forms of neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases (Figure 2).3 One of the ways NAM is thought to improve the effects of these disorders is through inhibition of an enzyme called PARP, or poly(adp-ribose)polymerase.⁴ Interestingly, researchers have also seen the activation of this enzyme in those suffering from addiction, prompting some to anecdotally indicate NAM as a possible avenue of addiction treatment.⁵ These arguments pointed at the conclusion that NAM could possibly be used to prevent drug relapse, but Witt and Dr. Kathryn Reissner, a UNC psychology professor, wanted to give a firmer conclusion to the rumors floating around the scientific community.

The pair set out to create an experiment to see if NAM specifically diminished the responses caused by a cue. To do so, they first induced an association between cocaine and an environmental stimulus in an animal model. 225 male and 175 female Sprague-Dawley rats were trained to press a lever for cocaine self-administration, causing a presentation of a tone and light illumination for five seconds.3 Over time, Pavlovian conditioning occurred, in which the light and tone presentation induced the behavioral response even in the absence of cocaine administration. Then, following the 12-day conditioning period and a 15-day abstinence period, the rats individually went through a process of receiving the light stimulus in order for researchers to see if the rats pressed the lever. Half of the rats were given NAM injections prior to this process; in the first two sessions of the process, the response of the lever press from the rats resulted in the concurrent light and tone presentation, and, in the last sessions, the lever press

Carolina Scientific resulted in a dose of cocaine instead.3 This way, the researchers could look at not only cocaine use as a response but also take into account general conditioning caused by the cue. “Both [cocaine and cue-primed reinstatement] relate to the reasons why humans relapse…. an individual may be able to maintain [sobriety] until they see some environmental cue that they associate with the drug… [or] they take the drug again,” Witt explained.⁶ Without the NAM, the rats would generally respond to the cue of the light or cocaine and continually press the lever throughout the entire session. The end goal was for the researchers to see if a decrease occurred in lever presses in rats that were administered NAM, as that would show a correlation between taking the therapeutic and not responding to the stimulus.

Figure 2. Results of female rats’ lever presses. Figure provided by Emily Witt.

how men and women become addicted and get treated for addiction. Witt also took particular interest in the gender disparity, stating, “I find any difference between males and females to be fascinating. History shows that research is mainly performed in male individuals, including in the animal research world. These days the scientific world has recognized this issue and the differences people are discovering are amazing.”⁶ Reissner and Witt concluded their study saying the next step from the evidence they collected would be to see why there is this difference in response in males and females. Witt herself explained, “I always like to keep in mind just how little we know about the brain! …

Because I’m always keeping in mind the fact that my hypothesis could be wrong, I’m always thinking of what the next step could be to develop or test a new hypothesis.”⁶ This study is promising in showing what experiments to begin in the future and what to look at next in the realm of relapse preventative medicine.

The relevance of this work could not be any greater.

Cases of drug disorders and abuse are continuing to rise in America; drug use and misuse cost Americans more than $700 billion a year in healthcare costs, crime, and lost productivity.1 In light of these statistics, drug rehabilitation has not changed in years, and many of the programs created around rehab are solely behavioral. Witt affirmed, “A single treatment that prevents drug relapse for all drugs is ‘the dream’ but, I predict, a highly unlikely outcome…. Behavioral therapy in addition to a pharmacological treatment will, I think, always be a part of overcoming addiction.

Medication is fine, therapy is fine, but the two together likely produce the best outcomes for individuals.”⁶ While there is no one-size-fit-all solution to addiction and recovery, with Witt’s research, there is hope for a guaranteed and more accessible way to help put an end to one’s drug addiction and the drug pandemic around the world.

References

Figure 3. Results of male rats’ lever presses. Figure provided by Emily Witt.

The study eventually ended with inconclusive but helpful evidence toward the use of NAM. While the female rats showed almost no difference in number of responses between NAM administration and no NAM administration, the male rats did show a difference in lever presses when administered NAM daily (Figure 3,4).3 This evidence is interesting, as it possibly leads the way into looking at how biological differences in the brain can further variation in

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Psychology & Neuroscience

1. National Institute on Drug Abuse. Overdose Death Rates. https://www.drugabuse.gov/drug-topics/trends-statistics/ overdose-death-rates [accessed 2021 Feb 27].

2. Fricker RA, Green EL, Jenkins SI, Griffin SM. The Influence of Nicotinamide on Health and Disease in the Central Nervous System. International Journal of Tryp.

2018;11. https://pubmed.ncbi.nlm.nih.gov/29844677/. doi:10.1177/1178646918776658 3. Reissner, K.J.; Witt, E.A. Psychopharmacology. 2020, 237 (3), 669-680 4. Scobie KN, Damez-Werno D, Sun H, Shao N, Gancarz A, Panganiban CH, Dias C, Koo J, Caiafa P, Kaufman L, Neve RL, Dietz DM, Shen L, Nestler EJ. Essential role of poly(ADP-ribosyl)ation in cocaine action. PNAS. 2014 Feb 4. https://www.pnas.org/content/111/5/2005. doi:10.1073/ pnas.1319703111 5. Namazi MR. Nicotinamide: a potential anti-addiction weapon. Med Hypotheses. 2004;62(5):844-5. doi: 10.1016/j. mehy.2004.01.020. PMID: 15082118.

6. Interview with Emily Witt. 2/20/21.

Psychology & Neuroscience

A Novel Approach to Title Parkinson’s Disease Drug Therapy By: Alisha Desai

By Firstname Lastname

Image by Waleed Alzuhair [CC BY-NC-SA-2.0]

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hemical signals in the brain influence how we production of dopamine is dependent upon dopamine move, think, feel, and interact. Considering the receptor interactions. There are five dopamine complexities of the brain, it’s easy for something receptors, and each receptor type signals for different to go awry. While drug development has come a responses. The Frankowski Lab currently works with long way in the treatment of neurological diseases, three of the five receptors, however, their research is in many areas, the path to these solutions can often the most advanced with the dopamine D3 receptor. spark a new issue in another part of the brain. The key This receptor specifically regulates movement, mood, to finding solutions is isolating the problem rather reward, and reinforcement.2 Dr. Frankowski hopes to than generalizing it. Dr. Kevin develop dopamine D3 agonists, Frankowski, professor at the UNCwhich are molecules that are able Chapel Hill Eshelman School of to mimic dopamine and bind to Pharmacy, has been researching dopamine receptors. While there dopamine receptors with the hope are currently D3 agonists in the of creating a new drug that could market in the form of drugs such efficiently treat Parkinson’s Disease, as Ropinirole, these agonists are without stimulating adverse side not selective for just D3 and can effects. also bind to the D2 receptor due Dopamine is one of a to the highly similar structures select group of neurotransmitter of the two receptors.2 This lack of molecules produced in humans and selectivity can result in impulse other animals. Neurotransmitter control problems, including bingemolecules transmit various eating and substance abuse.2 chemical signals in the brain and These negative side effects have these signals instruct the body led to the search for a highly on how it should physically or selective D3 agonist, and after mentally act.1 The over- or under- Figure 1. The image depicts dopamine years of optimization and analysis, production of dopamine can cause and dopamine receptor interactions. the Frankowski Lab has found a Licensed with CC BY-SA 3.0 promising compound which could numerous neurological and mental health disorders.1 These can include Parkinson’s be useful in the Parkinson’s disease treatment plan.

Frankowski’s work with developing a novel D3 disease, Alzheimer’s diseases, restless leg syndrome, Schizophrenia, and substance use disorders. The receptor agonist began when he collaborated with

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Carolina Scientific the National Center for Advancing Translational Sciences (NCATS) and National Institute for Neurological Disorders and Stroke (NINDS), who were conducting a screening of about 400,000 compounds from the NIH compound collection.

This screening evaluated a large variety of Dr. Kevin Frankowski, PhD compounds, including many inspired by compounds that are naturallyoccurring in the body.1 With the help of this data and funding provided through the Eshelman Institute for Innovation, the Frankowski Lab partnered with the Sibley lab at NINDS to begin their search for a highly selective D3 receptor agonist. When asked about the hardest part of his work with D3 agonists, Frankowski stated, “the biggest hurdle was finding the resources to properly analyze and optimize the results of the highthroughput screening.”1 This is why Dr. Frankowski is so grateful for the Eshelman Institute for Innovation. It was their funding that allowed his research group the ability to dedicate the time and resources to utilizing the data obtained from the screening. The lab initially tested the 400,000 compounds to determine if they were able to activate the D3 receptor.2 There were 4165 compounds that activated the D3 receptor, and upon eliminating those that interacted with D2 receptors, they were left with approximately 2500 compounds.2 Eventually, the lab focused on one compound as the most promising and selective for the dopamine D3 receptor. This compound was further optimized through a process of new compound synthesis and dopamine receptor testing which led to the current compound, ML417.2 Similar to most other drug discovery research projects, the final goal for the Frankowski Lab is succeeding in clinical trials and distribution of their drug to the public. Clinical trials are research studies in which potential therapeutics are tested on humans for the first time. In preparation for submitting this drug for clinical trials, the Frankowski Lab is now working on toxicology, safety profiling, and pharmacokinetic studies.1 These studies will give information regarding proper dosage forms, and drug half-lives. According to Frankowski, these next steps in the research process “is where we often see promising molecules fail.”1 However, if this new compound is successful, it could be used to aid in treating restless legs syndrome, and the movement related symptoms of Parkinson’s disease.

In addition to his work with dopamine D3 receptor agonists, Dr. Frankowski has also collaborated

Psychology & Neuroscience

with the Sibley lab to discover dopamine D1 receptor positive allosteric modulators. An allosteric modulator also regulates receptors, but instead of binding to the receptor’s primary binding site, allosteric modulators bind elsewhere on the receptor. Allosteric modulators offer an approach to develop highly selective receptor modulators and also amplify the effects that occur when molecules bind to the binding site.1 Dysregulation of the dopamine D1 receptor has been observed in cognitive decline diseases.3 These include Alzheimer’s disease, Schizophrenia, dementia, and the mental aspect of Parkinson’s disease.3 D1 receptor activation has demonstrated utility for restoring lost cognitive function, but D1 receptor agonists possess clinically limiting side effects. Additionally, overactivation of D1 receptor signaling leads to suboptimal cognitive function which presents a challenging dosage situation. The goal of this research project is to amplify D1 receptor signaling and regulate the timing and duration of D1 signaling. The research team has also discovered two D1 positive allosteric modulators.4 Further optimization efforts are underway and Dr. Frankowski is hopeful that this approach may lead to new treatment options for cognitive decline.3 Dr. Frankowski’s work with D3 and D1 receptors provides a promising future for the treatment of these common neurological disorders. By optimizing the novel D3 agonist, common side effects that plague the available drug therapies may be alleviated, resulting in a brighter future for Parkinson’s disease treatment.

Figure 2. Graph displaying the high selectivity of the optimized compound 20, for the D3 receptor. Courtesy of Dr. Frankowski’s Lab

References

1. Interview with Kevin Frankowski, Ph.D. 02/12/21.

2. Moritz, A. E.; Free, R. B.; Weiner, W. S.; Alkano, E. O; Gandhi, D; Abramyan, A; Keck, T. M.; Ferrer, M.; Hu, X.; Southall, N.; et al. J. Med. Chem 2020, 63, 5526-5567.

3. Luderman, K. D.; Jain, P.; Free, R. B.; Conroy, J. L.; Aube, J.; Sibley, D. R.; Frankowski, K. J. Bioorg. Med. Chem. Lett.

2021, 31, 127696 4. Luderman, K. D.; Conroy J. L.; Free, R. B.; Southall, N; Ferrer, M; Sanchez-Soto, M; Moritz A. E.; Willette B. K. E.; Fyfe, T. J.; Jain, P; et al. Mol. Pharmacol. 2018, 94, 1197-1209.

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Megan Butler Managing Editor

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“Science and everyday life cannot and should not be separated.”

- Rosalind Franklin

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

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Spring 2021 Volume 13 | 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.

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