SPRING 2022 | Volume 15 | Issue 2 —TEST STRIP FOR SARS-COV-2 WEARS THE SUGARY HAIRSTYLE OF HUMAN CELLS— full story on page 10 scıentıfic FALL 2021 | Volume 14 | Issue 1 Carolina
2 PAST EDITIONS OF CAROLINA SCIENTIFIC Check out all of our previous issues at issuu.com/uncsci. As the organization contin ues to grow, we would like to thank our Faculty Advisor, Dr. Lillian Zwemer, for his continued support and mentorship.
3 Carolina Scientific PAST EDITIONS OF CAROLINA SCIENTIFIC
Designers
Copy Staff Matthew Shelton TanishaZiyunChoudhuryTang Illustrators "I wanted to make an impact. Not just work on basic discoveries, but also discoveries and innovation that would be applied, and actually reach the public in one way or another.” Dr. Ronit Freeman and her team have developed a costeffective alternative to RT-PCR: a paper-based test strip called FullGlycoGrip.storyon page 10. Illustration courtesy of Matthew Shelton Editors-in-Chief Divya MeganNarayananButler Design Editor Sarah (Yeajin) Kim Copy Editor Gargi Dixit Web Editor Heidi Cao & AssociateTreasurerEditors Robert Rampani Maddy Stratton & Publicity Chair Isaac Hwang Managing Editors Megan Bishop Faculty Advisor Dr. Lillian Zwemer
CarolinascıentificWiththeongoingpandemicandclimatecrisis, we are increasingly in need of high-caliber scientific communication. Carolina Scientific prides itself on being both a vehicle for conveying scientific information to the public and a place where scientific communicators are made. In this issue, we hope you appreciate the breadth and depth of scientific research happening at UNC. From designing revolutionary COVID-testing (p. 10), to creating urban jungles (p. 32), to figuring out how to most effectively study (p. 54), we want this magazine to convey the successes and difficulties of scientific research – and of living in a constantly changing world. We hope you enjoy!
Founded in Spring 2008, Carolina Scientific serves to edu cate undergraduates by focusing on the exciting innova tions 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 knowl edge 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. the
Sarah (Yeajin)
Editors: Staff Writers Amil SprihaaAnnoshkaCharismaSimranKrutiGillianAgarwalArlethBhargavBhatiaHenryBryantAnnaCristDanielDeshpandeHannahGarnerSarahGiangPrimaGurjarBreannaHuxIsaacHwangMeitraKazemiKolanukuduruRyanLiptonSnehaMakhijaniKishanPatelBelleRetkoClaireSniderNeilSudRebeccaTurnerAshleyVillaneuvaJadanZawieruchaZhiyueZhang facebook.com/CarolinaScientificinstagram:carolina_scientific@unc.educarolinascientific.org@carolinascientific -
Divya Narayanan and Megan Butler
CorinneRidhiAmeliaEmmaChoudhuryCraverVarnerCassieWanYiwenXuYarlagaddaKellyYunCassieWanMaryannBowyerNicholasBoyerDrabenstottAJFeridoMeitraKazemiNishaLingamClaireNolanLucasRallsAroraRohrbachKirinaShahJasmeetSinghStephenThomasSreyaUpputuriAllieYarashevichKellyYun
Kim Tanisha
on the cover ExecutiveContributorsBoardMission Statement: Letter from
4
5 Carolina Scientific contents 16 It's All About Context: Psychopharma ceutical Use in Military Populations Claire Snider Health & Medicine Life Sciences 10 A First Step towards Precision Medicine Sneha Makhijani126 Test Strip for SARS-CoV-2 Wears the Sugary Hairstyle of Human Cells Zhiyue Zhang Immuotherapy is Revolutionizing Breast Cancer Treatment Annoshka Deshpande Old is Gold: Using an Old Antibiotic to Defeat Modern Multiresistant Bacteria Kruti Bhargav18828 Psychology & Neuroscience2220 The Data Shows Current Opioid Abuse Prevention is Ineffective Kishan Patel Contraceptive Discontinuation in African Populations Ryan Lipton Comprehensive Healthcare: Broadening the Healthcare Perspective Henry Bryant 14 Environmental Science Waging War in our Bodies Issac Hwang PhysicalPreventingScienceHIVwithout Daily Supplements Amil Agarwal 2426 Responsibility in our Genes: Helping Children with Rare Genetic Diseases Belle Retko 32 The "Lab Rat" Caterpillars of the Entomology World 34 The Urban Jungle Dilemma Rebecca Turner The Sweet Spot of Inner-Tidal Oysters Breanna Hux Rearranging the Vinyl on the Shelf Sarah Giang 3052 Counterfactual Thinking: Turning What-ifs into Stress Busters Simran Bhatia 36485038 Growing Tall: Stem Cell Research in Arabidopsis Plants Charisma Daniel 40 Gene on, Cancer off, Gene off, Cancer on Prima Gurjar Cohesin: How to Catch a Culprit in Cancer Jadan Zawierucha 4244 Dynamic Benefits of Fundamental Sleep Sprihaa Kolanukuduru 46 The Potential of the Arabidopsis Thaliana in Genetics and Plant Biology Research Neil Sud Invisible Ink: A Systematic Exploration of Noncoding Genes Ashley Villanueva Overcoming the Odds: How Early Childhood Adversity Influences Brain Development Gillian Arleth Are Bilingual and Monolingual Brain Structures like Apples and Oranges? Hannah Garner Death by Review: Why Restudying is Not the Best Strategy for Your Memory Meitra Kazemi 54
6
Image by juliendn, Flickrhealth & medicine
Clopidogrel was, at one time, one of the most commonly used blood thinning medications. It works by blocking the P2Y12 receptor and impairing platelet aggregation. This medication is crucial to anyone who has had a heart attack or a stent placed to open up their veins, because if platelets are not inhibited, they can form blood clots and consequently, possibly a fatal heart attack. Clopidogrel is especially useful in high-risk patients as they are more prone to blood clots and have a greater risk of bad clinical outcomes like thrombosis and hemorrhage. Clopidogrel is a ‘prodrug’ that has to be metabolized in the liver to its active form, which is the antiplatelet drug. It turns out that about a third of people do not metabolize it well and those individuals often have low levels of the active form of the drug.Dr. Rick Stouffer is an interventional cardiologist at UNC Hospitals who enjoys the procedural aspect of the specialty as well as the spectrum of patients he sees from outpatient to the ICU. He loves working with all cases within the cardiology patient population but has always had a specific fascination for platelets. Several years ago, his colleague Dr. Joe Rossi helped steer his interest into looking at genetic control of Clopidogrel metabolism and helped launch a research effort that has continued for approximately 10 Clopidogrelyears.was approved by the FDA in the late 1990s and has been an important medical asset ever since. However, as aforementioned, some individuals in the general population do not respond to the drug. At the time of this discovery, medical practitioners looked intently into the mystery of these non-responders and wondered why this was occurring. Some researchers used ex vivo platelet function assays to identify non-responders while other groups looked at genetic factors. The reasoning for looking at genetic influences was that Clopidogrel is metabolized by a cytochrome P450 pathway in the liver (the CYP2C19 pathway) and it was known that different genotypes of this enzyme predict different responses of that pathway. Others used platelet function assays, a group of assays that can measure the ability of platelets to aggregate and promote clotting in a sample of blood. Through these assays, researchers looked at genetic factors, like familial heritage, health issues, etc. After extensive study, researchers concluded that Clopidogrel is metabolized by a cytochrome pathway in the liver, a pathway which has the function of hormone synthesis and breakdown. This was not known before and helped to contribute to the information as to why non-responders may behave the way they do. It is known that there are different genotypes, codes in our DNA, that predict different responses to that pathway. The group of non-responders was of particular interest for the research. In fact, UNC Hospitals at Chapel Hill was one of the first hospitals in the country to investigate this group and use genetic testing to guide the selection of anti-platelet medications to track clinical outcomes based on CYP2C19 genotyping.Thiseffort has been a multidisciplinary one. Dr. Stouffer has worked closely with Dr. Craig Lee, Associate Professor and Vice Chair of the Division of Pharmacotherapy and Experimental Therapeutics in the Eshelman School of Pharmacy. Dr. Lee has been actively involved in this research since the beginning and has helped lead many studies including those that showed a twofold difference in the risk of bad clinical outcomes in patients treated with Clopidogrel who had specific CYP2C19 genotypes. This research led UNC to establish algorithms to help physicians choose the best anti-platelet medications based on the genotype results. Around the nation, more and more hospitals are using this personalized approach. Today, Dr. Stouffer, Dr. Lee, Dr. Rossi and their colleagues continue this research at UNC. They are also involved with other studies being performed in collaboration with the University of Florida and a National By Sneha Makhijani
A first step towards precision medicine
Dr. Rick Stouffer, MD Figure 1. Kaplan-Meier curves describing cumulative event rates for major adverse cardiovascular and cerebrovascular events (MACCE) in patients ≥70 years of age (A) and P2Y12 inhibitor group (IM/PM clopidogrel, NM/RM/UM-clopidogrel, or prasugrel/ticagrelor) [IM = immediate metabolizer; PM = poor metabolizer; NM = normal metabolizer; RM = rapid metabolizer and UM = ultrarapid metabolizer; clop = clopidogrel; taken from Pharmacotherapy. 2021;00:1–8]. Photo courtesy of Dr. Rick Stouffer
3. Lee et al. Clinical Outcomes and Sustainability of Using CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Inter vention. Circ Genom Precis Med. 2018 Apr;11(4):e002069. doi: 10.1161/ CIRCGEN.117.002069. PMID: 29615454; PMCID: PMC5889089.
2. Wood et al. Effects of aging on clinical outcomes in patients receiv ing genotype-guided P2Y12 inhibitor selection after percutaneous coronary intervention. Pharmacotherapy. 2021 Jul 9. doi: 10.1002/phar.2611. Epub ahead of print. PMID: 34242414.
health & medicine
7 Carolina Scientific Institutes of Health (NIH) sponsored group that has participants across the US. These studies have corroborated the results found at UNC - patients who have specific CYP2C19 genotypes that do not metabolize Clopidogrel normally were found to have worse clinical outcomes if treated with this medication. These patients do better if treated with alternative anti-platelet medications that do not require metabolism by the CYP2C19 pathway. Looking at the individual’s genotype to determine the best route of medical treatment improves outcomes and shows the promise of personalized medicine. Being able to prescribe based on these results which UNC has been doing for many years, allows the physician to choose the best medication for the patient.Infact, the UNC Hospitals were among the first hospitals to use genetic testing to guide anti-platelet therapy. One of the things that made it easier for Dr. Stouffer and his team to conduct such tests was the ability of the clinical laboratory at UNC Hospital (McLendon Laboratories) to provide the test results. The genotype can be ordered through EPIC, the electronic health record, and the results reported there. The implementation of this test was led by Dr. Karen Weck, who is Director of the Molecular Genetics Laboratory. When a patient comes to the hospital with an acute coronary syndrome and/or the need for an intracoronary stent, genotyping can be readily ordered and performed which provides the clinicians with information necessary to prescribe the best medication. The research efforts in this field are still continuing. Additional studies are being performed at UNC looking at clinical outcomes in various subgroups of patients. The UNC investigators are optimistic that as data accumulates showing the benefit of genotyping, national and international guidelines will change to incorporate the recommendation to use genotyping prior to treating patients with Clopidogrel. The ability of genotyping to guide anti-platelet therapy in patients with disease outside the heart is also being investigated. One of the current areas being studied is patients who have undergone neuro-interventional procedures. Another area of active research is how best to convey the implications of genotype results to physicians who use Clopidogrel but are not familiar with CYP2C19 genotyping. Widespread dissemination of this knowledge will help further the investigators’ efforts to truly personalize selection of medications.
Figure 3. P2Y12 inhibitor maintenance therapy by CYP2C19 status. A, Study popu lation summary by CYP2C19 genotype availability, loss-of-function (LOF) allele status, and maintenance therapy. B, CYP2C19 phenotype distribution in genotyped patients: ultrarapid (UM: n=40; 4.6%), rapid (RM: n=196; 22.6%), normal (NM: n=369; 42.5%), intermediate (IM: n=239; 27.5%); poor (PM: n=24; 2.8%) metaboliz ers. The IM [*1/*2=190 (21.9%), *1/*3=1 (0.1%), *2/*17=48 (5.5%), *3/*17=0 (0%)] and PM [*2/*2=24 (2.8%), *2/*3=0 (0%), *3/*3=0 (0%)] phenotypes included multiple genotypes. C, Maintenance therapy distribution (clopidogrel, prasugrel, or ti cagrelor) by CYP2C19 status [NG = not genotyped; PCI = percutaneous coronary intervention; Pras = prasugrel; Ticag = ticagrelor; IM = immediate metabolizer; PM = poor metabolizer; NM = normal metabolizer; RM = rapid metabolizer and UM = ultrarapid metabolizer; clop = clopidogrel; taken from Circ Genom Precis Med. 2018;11:e002069]
References 1. Interview with Rick Stouffer, MD. 09/15/2021
Pharmaceuticals can produce varying results due to many factors such as genetic differences, body size, underlying medical conditions, and other influences. However, physiology alone cannot account for the effects that a drug may have on one’s body: the context in which the medication is used is crucial.
Since 2016, Dr. Chua has been familiarizing herself with the culture of United States military institutions and exploring the intricacies of medication use on soldiers during the wars in Iraq and Afghanistan.2
By Claire Snider
To navigate the complexities of medication use during or after deployment, researchers must have an understanding of the military experience. With funding from the National Science Foundation and the Wenner Gren Foundation, Dr. Chua’s team has been conducting focus groups, interviews, and archival research, drawing on personal narratives from the United States Army to identify patterns and outstanding experiences regarding medicationFirst-handuse.1
8
Prescribing medication is not as simple as identifying an illness and choosing the corresponding drug.
Psychopharmaceuticals, for example, are drugs that are used to treat mental and behavioral health. The involvement of psychopharmaceuticals in military populations requires special assessment and discussion due to the contexts in which they are used.1 Rooted in the UNC-Chapel Hill Department of Anthropology, Dr. Jocelyn Chua and her team of undergraduate and graduate UNC students, some of which are student veterans, have taken up this challenge.
It’s All About Context:
Psychopharmaceutical Use In Military Populations
Figure 1. Artistic depiction of collaboration and
Photo by Pixel
Max
Jocelyn Chua, Ph.D. Figure 2. Molecular model of Modafinil, a stimulant commonly prescribed in the U.S. Air Force. Photo by Wikimedia Commons the integration of human stories.
accounts indicate that medications may work differently in deployment compared to in civilian contexts due to its stressful and operationally dynamic environment.2 Psychological and behavioral changes which result from pharmaceutical use in this population require additional clinical and operational considerations
While many used medications or witnessed its prescribed use, some accounts involved the use of pharmaceuticals without a proper prescription. The individual’s specific role within the military influenced their unique experience with pharmaceuticals.2 For example, the use of a medication is more likely to involve greater risks for a soldier and their team if that soldier is regularly leaving their installation or engaged in combat, as might be the case for an infantry soldier. The same drug may have less risk for a cook who never leaves the base. Therefore, the larger context in which pharmaceuticals are used must also be considered by commanders, clinical practitioners, and policy makers who actively make decisions regarding medication use in the military.Notonly do psychopharmaceuticals have different effects on those in the military, but also social implications.
Figure 3. Mental health specialist working with military personnel. Photo by Flickr.
Dr. Chua states that medication use is not solely about the individual, but it is a “collective experience” in the military community.2Medication use in deployment has most often been considered from a bioethical or philosophical perspective, and thus in abstract terms.2 The absence of soldiers’ own experiences with medication use in deployment has motivated Dr. Chua to listen to military personnel about their experiences with pharmaceuticals. Her research has found that the relationship between pharmaceuticals and the military is extremely nuanced and complex, so there is no clear answer as to when medications should be used in deployment. However, the narratives that have come out of this project provide a first-hand account of the benefits and risks of the use of medications in a deployed environment, allowing for more informed decisions for clinical practitioners. Dr. Chua seeks to bring these issues to the public eye— by raising awareness of how the complexities of medication use in the military can influence policies and encourage more research in this field.
One veteran Dr. Chua interviewed recalled his sergeant’s nickname, “Rattlesnake,” which referenced the recognizable rattling noise from the pill bottle in her pocket.1 Constant interaction between soldiers may also allow them to recognize when their colleagues undergo behavioral changes from medication use.2 Consequently, soldiers are often very aware of who is taking medications, as well as why they are taking them. This awareness of medication use means soldiers often work with one another to navigate, absorb, and adjust to the effects of medication use of others. While mental health is still generally stigmatized in the US military, it is also true that soldiers learn to live and work with the medication use of their peers in deployment.
Public perception is often stigmatized around mental health in the military.2 Fear of social and professional consequences of medication use is common, but there is more to the story. Dr. Chua’s research has shown that military personnel are typically deeply aware of their peers’ medication use in deployment due to tight living and working quarters.2 Her study relies on the experiences of military personnel and veterans who have used pharmaceuticals or witnessed medication use in their peers while deployed in the wars in Iraq and Afghanistan. She states, “The corporate ways of living in deployment mean that both the use and the potential effects of medications are borne by the social group more so than they might be in many civilian contexts.”2 Privacy is limited in a deployed environment, so it can be difficult to hide pharmaceuticals.
2. Interview with Jocelyn Chua, Ph.D. 2/18/22.
Acknowledgement of medication use in the military also stimulates discussion of larger issues.2 People’s views on pharmaceuticals in the military often lead them to question agency, control, mental health, and military care. Further discourse can even create reconsideration of their role as a soldier, the process of recruitment, and the nature of the conflicts they are fighting in as a whole. Dr. Chua’s studies can help contribute to a comprehensive understanding of the military experience, which will hopefully be supported by more concrete research in the future.
9 Carolina Scientific health & medicine
and risk assessment given the crucial information and equipment accessed by the military. Military personnel and veterans have expressed a range of experiences with the nature of prescription drug use within their ranks.
References 1. Chua, J. Taylor & Francis. 2016, 37, 17-31.
technology—RT-PCR—depends on highly skilled laboratory personnel and expensive instruments. Now, at the Applied Physical Sciences department of UNC-Chapel Hill, Dr. Ronit Freeman and her team have developed a costeffective alternative to RT-PCR: a paper-based test strip called GlycoGrip.2Themain difference between RT-PCR and GlycoGrip lies within their mechanisms of virus detection. The structure of the coronavirus is a protein shell enclosing RNA molecules, which are genetic materials causing the infection and disease.
By Zhiyue Zhang
Illustration by Matthew Shelton, Dr. Freeman Lab health & medicine
While RT-PCR recognizes the RNA inside, GlycoGrip recognizes the protein spikes on the virus shell, similar to how the virus itself infects human cells. To invade a human cell, the virus must anchor to specific harbors on the cell surface, called receptors. However, instead of a smooth surface where receptors are exposed, cells are actually quite hairy. They are coated with huge hairs made of sugars called glycopolymers. Dr. Freeman reasoned that for viruses to enter cells, they have to latch onto those sugary hairs first, so there has to be unique binding between the virus coat and the cell surface. Therefore, she decided to mimic the cell surface by putting the glycopolymers onto a test strip (Figure 1).3
COVID-19 is the most prominent global health crisis of this century. At the time of writing, more than 400 million cases have been reported worldwide.1 Despite the unprecedented rate of mass testing, many low-income or rural communities remain undertested and relatively invisible in pandemic statistics. This is because the most widely used testing
10
Test Strip for SARS-CoV-2 Wears the Sugary Hairstyle of Human Cells
Dr. Ronit Freeman
Glycopolymers have been under-researched as capture agents for viruses in the past, partly because of their non-specificity, which means they recognize most viruses or bacteria that come near. However, Dr. Freeman took advantage of this trait, as it allows GlycoGrip to detect all variants of SARS-CoV-2, including ones that may emerge in the future. Another significant component of GlycoGrip is anti-spike antibodies, which enable GlycoGrip to still detect coronaviruses selectively. Antibodies are important blood proteins in the human body; each type of antibody recognizes a specific class of viruses or bacteria and induce the necessary immune responses to fight the infection. Here, anti-spike antibodies specifically bind to the protein spikes on the virus shell, allowing GlycoGrip to detect coronaviruses with high accuracy. Since these antibodies are also labeled with gold nanoparticles, they give out a wine-red color easily viewed by eye or by a Together,detector.glycopolymers and anti-spike antibodies effectively recognize SARS-CoV-2 and its variants. The final product of GlycoGrip looks like a simple strip of paper (Figure 2).2 When the saliva sample flows through the strip, it first encounters a pool of anti-spike antibodies, and then migrates towards a forest of glycopolymers at the test line. If coronaviruses were present, they would bind to the red antibodies, and then be captured by glycopolymers, resulting in the emergence of a red color at the test line within minutes. Since this paper-based assay is cheaply manufactured, easily stored, and requires only easy visual inspection, no specialized personnel or expensive instruments are required. Overall, GlycoGrip is a sensitive, rapid, and cost-effective testing technology for SARS-CoV-2 and its variants.
“I wanted to make an impact. Not just work on basic discoveries, but also discoveries and innovation that would be applied, and actually reach the public in one way or another” health medicine
&
GlycoGrip is inseparable from Dr. Freeman’s collaboration with diverse scientists. One of the lead scientists in the project, Dr. Sanghoon Kim, joined her lab for his experience with paper-based biosensors. Since Dr. Kim is a Korean citizen, Dr. Freeman wrote a special request for him to fly across the borders during the pandemic. She has also worked closely with Dr. Rommie Amaro at UC San Diego, whose team performed the computational modeling of GlycoGrip.⁵ Until this day, they have only been meeting through Zoom. “I think the pandemic brought together people that might have not been working together otherwise,” Dr. Freeman said. “There was something interesting about how scientists came together from all over the world in order to try and provide solutions and make an impact. It shined a really beautiful light on the role of scientists in helping to overcome a challenge like this.” When asked about the future of GlycoGrip, Dr. Freeman said her team is in the process of clinical validation. They extract patient samples from the UNC sample bank, test them with GlycoGrip, and compare the results to the commercially available tests to confirm performance. Then, they will partner with companies that can manufacture, and hopefully commercialize the test strip in about 6 months to a year from now. Due to its low cost and usability without the need for expensive and customized lab equipment, GlycoGrip could potentially improve the accessibility of testing technologies for medically underserved populations.
3. Interview with Ronit Freeman, Ph.D. 02/01/22 4. Freeman Lab. https://freeman-lab.com/ (accessed Feb ruary 19th, 2022)
11 Carolina Scientific
Dr. Ronit Freeman’s interdisciplinary training was essential for the innovation of GlycoGrip. Originally from Israel, she has focused her graduate studies on designing nanoparticle-based diagnostic devices. “I wanted to make an impact. Not just work on basic discoveries, but also discoveries and innovation that would be applied, and actually reach the public in one way or another,” she said. She completed a postdoc fellowship at Northwestern University Feinberg School of Medicine, where she broadened her research to regenerative medicine. Now, the Freeman Lab designs biomaterials that mimic the environment around biological living systems including cells and viruses, and uses these materials for biomedical applications, such as nextgeneration sensors (e.g., GlycoGrip), nanorobots, novel drugs, and clinicalFurthermore,tools.⁴
2. Kim, S. H.; Kearns, F. L.; Rosenfeld, M. A.; Casalino, L.; Papanikolas, M. J.; Simmerling, C.; Amaro, R. E.; Freeman, R. GlycoGrip: Cell Surface-Inspired Universal Sensor for Betacoronaviruses. ACS Central Science 2021, 8 (1), 22–42.
Lastly, Dr. Freeman gave advice to undergraduate students seeking to pursue innovation. While there are multiple routes, she said the most important one is to have the courage to ask questions on things one does not understand, to branch out of just a textbook, and to read scientific literature on the state-of-the-art findings in one’s fields of interest. She advised students to become motivated by the discoveries they want to make by asking what, why, when, and how. She asked them to think about what they want to study, why they are motivated, at what time point they want to make an impact—a year or a lifetime, and how they plan to execute such an idea. She emphasized that students must connect their work with a real passion, and learn from the inevitable failures rather than becoming derailed. Through taking the road less travelled, one may contribute to making the change one wants to see in the world.
Figure 1. Graphical illustration of (A) virus interaction with glycopolymers on the cell surface and (B) on the GlycoGrip test strip. Kim, S. H.; Kearns, F. L.; Rosenfeld, M. A.; Casalino, L.; Papanikolas, M. J.; Simmerling, C.; Amaro, R. E.; Freeman, R. GlycoGrip: Cell Surface-Inspired Universal Sensor for Betacoro naviruses. ACS Central Science 2021, 8 (1), 22–42.
References 1. WHO COVID-19 Dashboard. Geneva: World Health Organization, 2020. https://covid19.who.int/ (accessed February 19th, 2022)
Photo of using GlycoGrip in the Freeman Lab. Photo by Caro line Bittenbender
By Kruti Bhargav
Dr. Gauri Rao and her lab at the UNC Eshelman School of Pharmacy primarily focus on repurposing old antibiotics to combat multidrug resistance, as there are not many new drugs against gram-negative pathogens (bacteria that do not retain crystal violet stain used in Gram staining) currently. Her research, published in November 2021, concentrates on how optimal antibiotic treatments can be designed against highly resistant pathogens in critically ill patients.
Antibiotic resistance has evolved into one of the most alarming threats to global health today. The use of a diverse range of antibiotics has led to the emergence of multidrug resistant and pan-resistant bacteria, rendering it almost impossible to treat a patient with solely one drug.
Dr. Rao and her team focused on polymyxin B, an old antibiotic drug that has existed for over 50 years. Its usage is complicated as it never underwent the current FDA approval process– it was not put through the rigorous clinical trials required prior to entering the market. The team was permitted a National Institutes of Health (NIH)-funded clinical trial for polymyxin B, specifically in critically ill patients. They obtained the various pharmacokinetic (PK) models (drug exposure over time once the drug is administered into the body) of the drug previously published in literature. They then determined whether these models could be repurposed into a new PK model in this new set of Polymyxinpatients.B
possesses certain features that made it important to broaden the research conducted. According to Dr. Rao, polymyxin is a narrow therapeutic index drug– the concentration required for efficacy is extremely close to that associated with toxicity. Therefore, an overdose could lead to nephrotoxicity (damage to the kidneys and renal functions at high concentrations), while underdosing could fail to treat the target condition and ultimately lead to death. Hence, the team focused on methods of identifying an optimum dosage for patients. Additionally, the drug shows variable efficacy in different individuals–administering the same drug to different patients results in a range of responses. Consequently, they wanted to determine if certain patient characteristics, such as body weight, could explain the variability and are currently examining how dosage could be narrowed based on patient characteristics. This entire research project maintains a strong focus on multidrug resistant bacteria. Critically ill patients already possess weak organ systems for which they may already be taking medication. Therefore, treatment with a single drug becomes almost impossible. When two or more drugs with different mechanisms are used to cripple the infection, it could lead to further bacterial resistance. Exposure of the drug to suboptimal conditions or an incorrect dosage may lead to further bacterial resistance, further complicating treatment. Therefore, identifying the PK profile of polymyxin B would allow physicians to prevent such problems. The team collaborated with many individuals and institutions over the course of the research project. According to Dr. Rao, “science is a collaborative field and individual clinical research can be challenging.”1 They worked with clinicians from Rutgers University and The University of Michigan because of their expertise in polymyxin B mechanisms and usage. They also worked with an infectious disease clinician, who was instrumental in providing greater insight into the condition of
12
Old Is Gold: Using Old Antibiotics to Defeat Modern Bacteria
Dr. Gauri Rao
Photo
by Pixabay health & medicine
13 Carolina Scientific the patients. Additionally, they collaborated with researchers in Brazil, specifically Sao Paulo and southern Brazil, because of the high population of patients undergoing polymyxin B treatment in the region. The research has far-reaching applications not only for the pharmaceutical industry and drug development, but in the medical field as well. According to Dr. Rao, its most notable impact is on patient care.1 With greater knowledge on the PK model and the behavior of the drug within different bodies, it empowers physicians to provide more precise doses to improve efficacy and determine the required dose at an earlier time to reduce the recovery period. It also allows for a reduction in unnecessary adverse effects, as polymyxin B is a nephrotoxic drug. Another important application is determining the most efficient method of introducing the drug into the patient’s body–drug delivery. For instance, if a certain drug does not enter the lungs effectively, pharmaceutical and research companies can identify alternate formulations of the drug based on its PK profile in the patients, that ensures it is administered in an appropriate concentration to the lungs. However, no major experiment is exempt from obstacles. Over the course of their research, patient recruitment was a major hurdle the team faced due to the onset of the pandemic. Initially, their research protocol stated that patients must not have been infected with any multidrug resistant bacteria (including COVID-19) other than the one contributing to their critically ill condition. However, this severely limited their range of possible candidates during the time. Therefore, once the pandemic began, they altered the protocol such that if the patients had been infected with COVID-19 and the physicians provided consent, the individuals could be included in the study. Additionally, in 2019, their research population did not include South American patients as they were focusing on recruitment from other clinical sites. However, patients in these other regions either had not been treated with polymyxin B for a sufficient amount of time or their families were hesitant to consent to participation. The team then expanded the protocol to include South America as many patients in the region were being treated with the drug at the Currently,time.
Figure 1. Visualization of how bacterial resistance occurs. Image courtesy of ZME Science
3. Puiu, T. What is antibiotic resistance: everything you need to know. https://www.zmescience.com/medicine/ antibiotic-resistance-0423423/ (accessed: 02/14/2022)
Dr. Gauri Rao and the team on a lab outing. Image courtesy of Dr. Gauri Rao health & medicine
Dr. Rao’s research is an extension of her work on polymyxins. Her work is focused on understanding if different drugs could be combined with polymyxin B to produce more efficient action against multidrug resistant pathogens. “Using polymyxins alone, as the resistance of the pathogens increases, will soon be insufficient as an effective treatment,” Dr. Rao said.1 For instance, her lab is investigating whether polymyxins could be combined with phage therapy for improved treatment. With greater research into such novel treatment methods, we may be progressing towards a world where the global threat of antibiotic resistance may not seem as alarming as it does today.
References 1. Interview with Dr. Gauri Rao, Pharm.D., M.S. 02/15/2022
2. Hanafin, P. O.; Nation, R. L.; Scheetz, M. H.; Zavascki, A. P.; Sandri, A. M.; Kwa, A. L.; Cherng, B. P.; Kubin, C. J.; Yin, M. T.; Wang, J.; Li, J.; Kaye, K. S.; Rao, G. G. Assessing the Predictive Performance of Population Pharmacoki netic Models for Intravenous Polymyxin B in Critically Ill Patients. CPT: Pharmacometrics & Systems Pharmacology 2021, 10 (12), 1525–1537. doi: 10.1002/psp4.12720
&
14
Dr. Miriam Braunstein – PI studying tubercu losis and other NTMs.
By Isaac Hwang
Photo by Nick Youngson CC BY-SA 3.0 Alpha Stock Images
During the COVID-19 pandemic, viral mutations are constantly on the front page of news outlets, and people often forget about bacterial mutations. Mutations that make bacteria resistant to commonly used antibiotics decrease the effectiveness of these regimens, thus increasing the financial cost for the patients needing them. As a result, diseases that have mutated become practically untreatable, making new treatment options—such as phage therapy— the only viable solution. The Braunstein Lab at UNC-Chapel Hill studies the use of bacteriophages, viruses that target and kill bacteria, to fight harmful bacteria that cause disease in our bodies. Specifically, Dr. Braunstein studies Mycobacterium tuberculosis, a deadly bacterium that infects our lungs and causes tuberculosis (TB), as well as other, nontuberculous mycobacteria (NTMs). These mycobacteria live in macrophages of our lungs, which are immune cells involved in detecting and destroying foreign bacteria and other harmful organisms.1, 2 M. tuberculosis has typically been treated through a cocktail of pharmaceutical drugs to prevent antibacterial resistance. NTMs are opportunistic bacteria, a class of bacteria that take advantage of people with preexisting conditions such as chronic immuneor(COPD),pulmonaryobstructivediseaseolderage,aweakenedsystem.3 M. tuberculosis and NTMs are able to survive in macrophages by releasing proteins that block the destruction of the bacteria within the host cell. typicallyMacrophagesfunctionby enveloping foreign objects into a cocoon-like structure known as a phagosome, which goes on to fuse with a lysosome, a separate structure in the macrophage with destructive proteins that destroy the foreign object. By blocking the fusion of the two cocoons, M. tuberculosis and NTMs survive within macrophages of our lungs.1Dr.Braunstein utilizes the natural abilities of bacteriophages to infect and kill antibioticresistant bacteria that reside in macrophages. Bacteriophages are naturally occurring viruses that infect bacteria and destroy them, but each bacteriophage can only infect a very specific set of bacteria. The goal is to completely destroy M. tuberculosis and NTMs with bacteriophages as an alternative to antibiotics. Each bacteriophage has been naturally selected to be extremely effective at eliminating bacteria. For instance, there is a case report of a 15-year-old patient on the brink of death due to an NTM infection treated with injections of NTM-specific bacteriophages. The patient showed clinical improvement with the novel therapy.⁴ The study’s success suggests that the bacteriophages may have the ability to infiltrate the macrophages and then infect the bacteria inside.1 The study helps prove that a bacteria-infecting virus can be effective at treating bacterial infections that are resistant to all other treatments. For stronger, antibiotic-resistant strains of bacterial infections, bacteriophages may be able to save countless lives where antibiotics have failed. Although the research surrounding bacteriophage therapy is limited, the field is ripe for expansion. With more antibiotic-resistant strains of bacteria rendering present
Waging War in our Bodies
Photo courtesy of Nan Friedman Figure 1. A scanning electron micro graph photo of Mycobacterium tuberculosis. Photo courtesy of Miriam Braunstein and Sherry Kurtz. health medicine
2. Saldana, J. Macrophages. 3.phagespublic-information/bitesized-immunology/cells/macrohttps://www.immunology.org/(accessedMarch2,2022).LearnaboutNTMLungDisease.https://www.lung.org/ lous-mycobacteria/learn-about-nontuberculosis-mycobaclung-health-diseases/lung-disease-lookup/nontubercu
health
5. Antibiotics: Side Effects. 2022).tions/antibiotics/side-effects/https://www.nhs.uk/condi(accessedFebruary12th, Figure 2. The mechanism in which bacteriophages are thought to infect, lyse, and kill bacteria. The Braunstein laboratory is currently evaluating the ability of the bacteriophage to act in different environments associated with infections: macrophages, biofilms, and mucus. Figure courtesy of Miriam Braunstein
References
4. Dedrick, RM; Guerrero-Bustamante, CA; Garlena, RA; Russel, DA; Ford, K; Harris, K; Gilmour, KC; Soothill, J; Jacobs-Sera, D; Schooley, RT; et al. Engineered bacterio phages for treatment of a patient with a disseminated drugresistant Mycobacterium abscessus. Nature Medicine. 2019, 25(5), 730-733.
Figure 3. A fluorescence microscopy image of an infected macrophage with Mycobacterium abscessus, an intracel lular Nontuberculous Mycobacteria (NTM). M. abscessus is & medicine
To solve this issue, Dr. Braunstein collaborates with Dr. Hickey in UNC’s Eshelman School of Pharmacy to create an inhalerlike system. The treatment can be delivered straight to the infected cells in the lung through inhalation. The process is hypothesized to be highly efficient since nearly all of the medicine is immediately delivered to infected cells rather than the gut, saving precious time and energy. Additionally, these inhalers can be 3D printed, resulting in an extremely cheap mode of delivery. The bacteriophage study and new inhaler delivery system are vital to Dr. Braunstein’s research in creating new and effective solutions to M. tuberculosis and NTM disease.1Members of the Braunstein Lab at UNC are approaching bacterial warfare through a groundbreaking approach. As antibiotic-resistant strains of bacteria continue to occur and treatment prices rise, Dr. Braunstein believes that the next step in the fight against bacteria is through their natural enemies: bacteriophages. Through her research and the broader field, bacteriophages may emerge as the cure for TB and NTMs. They may even uncover breakthroughs in which bacteriophages can fight off other infections. Perhaps to win the battle against tuberculosis and NTM disease, individuals must wage battle in their own bodies.
In order for the implementation of bacteriophage treatment, researchers must come up with a way for bacteriophages to be delivered to the infected macrophages. As in the case of M. tuberculosis and NTM diseases, the bacteriophages need to be delivered to lung macrophages.
teria (accessed February 12th, 2022).
15 Carolina Scientific antibiotics largely useless, scientists like Dr. Braunstein are searching for more resilient methods to fight infection. The highly specific nature of bacteriophages reduces the chance of medical side effects. Antibiotics destroy all of the bacteria in the gut, including those vital for proper digestion. As a result, this can lead to gastrointestinal side effects and digestion problems. Rather than killing all of the bacteria in the body, bacteriophage therapy selectively eliminates only the targeted harmful bacteria.⁵
1. Interview with Miriam S. Braunstein, Ph.D. 02/04/2022.
Discontinuation in African Populations
16 health &
Wmedicineithsomuch
WikimediaContraceptive
The results show the different underutilized contraceptives in Francophone West Africa (FWA), Anglophone West Africa (AWA), and East Africa (EA), along with the probability of pregnancy after discontinuation based on the method type and region. Francophone West Africa was an area of interest because of its low level of contraceptive use and its dominant cultural norm to procreate. On the other hand, regions in Anglophone West Africa and East Africa have higher rates of contraceptive use and generally welcome family planning. The most discontinued form of contraception was birth control pills in FWA, and injectables in both AWA and EA.² This is interesting because injectable hormones have been popular in AWA and EA, since “about 12 million women between the ages of 15 and 49 in sub-Saharan Africa, roughly 6% of all women in that age group, use them.”³ Furthermore, there was a lower chance of pregnancy 12 months after By Ryan Lipton
Figure 1.
seeming to be at the tip of our fingers nowadays, there are millions of people without this luxury that lack proper knowledge and access to effective birth control. The stigmas around pregnancy and contraceptive methods are apparent all over the world but are uniquely significant in certain African populations. There are various misrepresentations regarding the use of contraceptives in Africa which ignites this stigma and fear. Having inadequate access to contraceptive information, fear surrounding the topic of family planning, and societal pressures to have a child soon after marriage contribute to relatively low modern contraceptive use in sub-Saharan Africa. A majority of the youth population in specific African communities fear that contraceptives will lead to a delayed return to fertility, especially after hormonal contraceptive use. For those women who are using contraceptive methods, they “are now using modern birth control rather than traditional methods (such as abstinence and withdrawal) or nothing at all.”¹ In this instance, these modern birth control methods are extremely beneficial, yet cause widespread hesitation and anxiety to those using them.
Janine Barden-O’Fallon is a researcher in the department of Maternal and Child Health in the Gillings School of Public Health who has a strong passion for the sociological aspect of fertility and public health. Her goal has been to conduct research in public health that has practical applications, which she has done in countries around Central America and Africa. Dr. Barden-O’Fallon along with other researchers, explored the concept regarding which forms of contraception are most underutilized in specific African communities. Their study was focused on Francophone West Africa (French speaking African countries), Anglophone West Africa (English speaking African countries), and East Africa. Data for this study came from the Demographic and Health Survey (DHS). This is a nationally representative household survey that gives data on various health outcomes, like family planning. Within this study, women of reproductive age (1594) gave reasons for their discontinuation of certain methods of contraception on a reproductive calendar.²
Dr. Janine Barden-O’Fallon Different kinds of birth control pills. Commons
References 1. Newey, Sarah: Africa’s women embrace modern birth control as experts hail rapid rise in contraception use.
17 Carolina Scientific health & medicine
discontinuation in FWA compared to AWA and EA. While the probability of pregnancy after contraceptive discontinuation in FWA and EA were both high, it was the lowest in FWA. Dr. Barden-O’Fallon postulated that this could be because more women in FWA discontinued contraceptives in order to become pregnant than they did in other regions.⁴ In addition, she stated that there is a chance the women were migrating and not co-residing, thus separating men and women and making the possibility of pregnancy rate lower than in the other African
temberEastation2021.2.modern-birth-control/.https://womendeliver.org/press/africas-women-embrace-(accessedOctober2,2021).O’FallonJB,SpeizerIS,CalhounLM,MoumouniNA.Returntopregnancyaftercontraceptivediscontinutobecomepregnant:apooledanalysisofWestandAfricapopulations.BiomedCentral.[accessedSep14,2021];18(141):1-10.https://reproductive-healthjournal.biomedcentral.com/articles/10.1186/s12978-0213.01193-w#citeas.Belluck,Pam. The NY Times. 4.OctobervZ6H6BPzHlosLtr_uAF-DIovMaAiLiEALw_wcB.yJBhDTARIsABKIcGaVmbgPvcBgHF_pBB3fr102-UbSmBkeywords=auddevgate&gclsrc=aw.ds&gclid=Cj0KCQjwm9com/2011/10/04/health/04hiv.html?.?mc=aud_dev&ad-https://www.nytimes.(accessed2,2021).InterviewwithJanineBarden-O’Fallon,Ph.D.9/28/21.
Figure 2. Which contraceptive methods were discontinued and the number of women who discontinued contraceptives to become pregnant. Image courtesy of Biomed Central.
Althoughcommunities.⁴thisstudywas successful in its goal, it did have its limitations. For example, the contraceptive calendar could have introduced recall bias of women who were unable to remember exactly when reproductive events took place. In addition, discontinuation was self-reported, and the analysis does not consider the outcome of pregnancy events.² In this instance, the analysis does not shed light on whether the method used before discontinuation affects whether pregnancies resulted in a live birth, miscarriage, or stillbirth. Furthermore, the governing cultural ideals to conceive in FWA as opposed to the less strict values of conception in AWA and EA could impact these differences in frequency of pregnancy after contraceptive discontinuation. Colleagues of Janine Barden-O’Fallon in Niger requested the information from her research because they wanted to know if there was any reason for this fear of infertility among African women.⁴ Moreover, the results can be used to aid training of providers on method counseling for youth. Dr. O’Fallon maintains that honest information regarding contraceptives is important to promote, including that “you may not get pregnant right away, as it is common for it to take a few months.”⁴ Also, this information could impact broader community-based activities in these regions where concerns about infertility or delayed return to fertility are common reasons for non-use and where providers may not recommend hormonal methods to young women. Dr. Barden-O’Fallon claims that “health care providers know there are a lot of rumors surrounding contraceptives, and hopefully this research contributes to more efforts to think about counseling methods”.⁴ Sentiments against contraceptive use may continue to spread through Africa as well as in other regions where conception is highly prioritized. This hesitation is in part due to the mistrust of biomedicine. This can cause certain nations’ people to experience more hazards to their health if they turn away medicine methods to further their wellbeing. It is important to reflect on the advantages the West experiences because of its access to biomedicine and how this knowledge can be expressed in other nations where some philosophies of medicines are less understood.
Omedicineneofthe
Dr. Rahima Benhabbour Photo by Pixabay
Figure 3. Artistic depiction of the HIV .virus. Photo by Bruce Blaus [CC-BYSA-4.0]
these PSIs using a three-step process: phase inversion, micronization, and compression. The phase inversion step is crucial as it allows the drug to be dissolved in the polymer solution and allows for the removal of organic solvents and other additives making the PSI a solvent-free biodegradable implant. An important benefit of this process is that the PSI can be used for a few months before another has to be implanted since the micronization and compression result in a smaller implant allowing for more of the drug(s) to be added. The implant’s biodegradable nature means that the PSIs do not require surgical removal after complete drug diffusion and only require a new PSI to be administered to allow largerthereducesmicronizationtreatment.continuousforThestepthesizeofdrugsothataamountcan be loaded into the PSI. Lastly, the tablet compression technique is used to form the implant that will be administered to an individual.1 Altogether, these steps result in the drug(s) with a certain polymer encasing it. As the research progressed, Dr. Benhabbour and her lab hope that this new technology can be used as a viable option for numerous medications.1
recent developments, the problem of accessibility and efficacy can be abated to some extent. A UNC professor, Dr. S. Rahima Benhabbour MSc. Ph.D., and her lab have been working to create a new method of delivering medicinal drugs to prevent HIV through the use of biodegradable implants rather than a daily supplement. This novel method is a Polymeric Solid Implant (PSI), which diffuses the HIV antiretrovirals slowly over time without requiring a pill to be taken daily.2 These polymeric solid implants are composed of a polymer and the drug. Currently, the lab is focusing on the implant’s use for the treatment and prevention of HIV, but Dr. Benhabbour says that this delivery system can be generalized for multiple viral illnesses.1 Using a PSI is different from a daily medication since the implant allows the drug to be used for a few months without the need to remove the implant after use given diffusioninneedusedcaninoutcomenature.biodegradableitsThisresultsanimplantthatbewidelywithoutthetointerjectbetweentheprocess.2Thelabcreated
Using a PSI is different from a daily medication since the implant allows the drug to be used for a few months without the need to remove the implant after use given its biodegrad able nature.
modern world’s deadliest viruses (HIV) can now be prevented. A new implant has been created to keep people safe by preventing viral infections such as HIV. HIV is a virus (Figure 3) that consequently causes Acquired Immunodeficiency Syndrome (AIDS), a common illness that predominantly affects women in developing countries such as those in Sub-Saharan Africa. The virus is the sixth leading cause of death in the world and is more prevalent in developing countries due to their lack of accessibility to health care resources such as HIV antivirals. Antivirals are a category of drugs that suppress the symptoms of the virus if taken daily. Due to the lack of a health care system and the cost of these medicines, it is difficult for most people to acquire a steady
supply.With
Biodegradable Implants Are The Key To Preventing HIV By Amil Agarwal
18 Image courtesy of ESO/S. Brunier, CC BY 4.0 health &
The lab conducted studies on BALB/c mice to determine the effectiveness of these implants, testing different methods of creating the implant along with the effect other drugs may have on the PLGA in the same PSI.2 The BALB/c mice used are immunodeficient mice bred specifically for laboratory research. Two types of PSIs were implanted into the BALB/c mice and were observed to determine which could provide the best outcomes in drug diffusion. Both types of PSIs contained two antiretrovirals (Dolutegravir (DTG) and Rilpivirine (RPV)).2 One type involved the micronization of the PLGA with both drugs into a powder followed by the compression to form a PSI. The other type of PSI was created through multiple compressions to create a PSI with layers of the two antiretrovirals observed, which can be seen in (Figure 2).2
19 Carolina Scientific health & medicine
References 1.Interview with Rahima S. Benhab bour, MSc. Ph.D. 01/28/2022 2.Panita Maturavongsadit, Roopali Shrivastava, Craig Sykes, Mackenzie L. Cottrell, Stephanie A. Montgom ery, Angela D.M. Kashuba, S. Rahima Benhabbour* Biodegradable polymeric solid implants for ultra-long-acting vdelivery of single or multiple antiret roviral drugs, Int J Pharm, 2021, doi:10.1016/j.ijpharm.2021.120844605.
As Dr. Benhabbour and her team conducted the study, they observed that the difference in diffusion times for both types of PSI was minimal (Figure 1). Using the results along with further studies, the lab was able to conclude that for the PSIs with multiple drugs, the characteristics of each of the drugs could slightly affect diffusion times.2
Figure 1. Data of the diffusion of antiretrovirals in BALB/ mice. Data by S. Rahima Benhabbour
Figure 2. PSIs with different drugs and production methods. Photo by S. Rahima Benhabbour
Some of the antiretrovirals tested (Dolutegravir and Rilpivirine) were hydrophobic meaning that those compounds do not dissolve readily in water. In order to incorporate high amounts of the drug(s) in a small size PSI, the team had to change the design of the polymer and the chemical makeup of the PSI.1 This change in polymers allowed the lab to create a more diversified use of the implant which can extend to other drugs, and the possibility of having more than one drug in a single implant. Dr. Benhabbour and her lab then observed the diffusion of the drug and what steps need to be taken to prepare a viable implant for use.1When the PSI is implanted into the body, the drugs are diffused for the first few days whereas the poly(DL-lactide-co-glycolide), known as PLGA, can begin to degrade at around day 30.2 PLGA is used due to its biocompatible nature and its ability to control the drug release kinetics.
As Dr. Benhabbour and her lab conducted the study on mice, they were able to determine how the dosage should be administered. The size of the PSI (Figure 2) and the number of implants administered depends on the amount of the drug needed. A highly potent drug requires only a small dose making the resulting PSI smaller.1 Similarly, a less potent drug requires a greater dosage resulting in a larger PSI and more frequent implants. To calculate the amount of the drug that needs to be implanted, the speed of diffusion, the dosage needed, and the time between each implant being introduced into the person need to be taken into account.1 Dr. Benhabbour states that “Currently my lab is focusing this technology for HIV prevention and treatment and as a multi-purpose prevention technology.”1 When asked about other applications, Dr. Benhabbour states that “it can be used for treatment of diseases that can highly benefit from long-acting drug release and as a multi-purpose prevention technology for other STIs and infectious diseases, not only HIV.”1 This shows that the viability of these implants isn’t restricted only to HIV. Using the methods of phase inversion, micronization, and compression, a PSI containing the HIV antiretrovirals at a high concentration can be produced.2 Implanting this PSI in the human body will lead to the slow diffusion of the HIV antiretrovirals and will potentially provide the person with a similar level of prevention as daily medications. Some future steps involve generalizing the PSI for other antiretrovirals and the production of these for use in non-human primates and eventually in human clinical trials. Applying the PSI to other STIs and viral infections will reduce the need for daily medications to be administered, improving the quality of lifestyle for individuals who could potentially be affected.1 With the use of a polymeric solid implant, viral infections can be prevented in a large portion of the population leading to a much lower infection rate if implemented at a wider scale.
A lymphocyte is a type of white blood cell that protects the body against foreign substances, known as antigens, which have the potential to cause harm by infecting cells. Lymphocytes are classified into two types: B-lymphocytes and T-lymphocytes. B-lymphocytes produce antibodies to neutralize antigens. Neutralization is a process in which antibodies prevent antigens from altering their shape and binding to receptors on the surface of target cells. Conversely, T-lymphocytes directly attack foreign substances, such as cancer cells, by releasing chemical messengers called cytokines that eventually destroy the antigen.2 A CD8+ cytotoxic T-cell is a special type of T-lymphocyte that helps defend against tumor cells and serves as a good prognostic marker for breast cancer.
20
Dr. Abdou used this technique to investigate the presence and location of CD8+ T-cells in the breast tissue of white and black women. Results demonstrated that on average black women have a higher density of CD8+ T-cells in their breast tissue compared to white women. However, these results are not consistent with the trend of black women suffering higher By Anooshka Deshpande
1.
ImmunotherapyRevolutionizingIs Breast Cancer Treatment
health & medicine
Figure 2. Breast cancer tumor cells.
Figure Cytotoxic T-cells prepare to attack a cancer cell. Image source: Wikimedia Commons.
Breast cancer rates have sharply risen in recent years, yet treatment options remain limited. According to the World Health Organization, breast cancer has become the most common type of cancer as of 2021.1 Furthermore, racial differences in breast cancer tumor biology have resulted in lower survival rates among black women compared to white women. Dr. Abdou, an assistant professor in oncology and an oncologist at the University of North Carolina Lineberger Comprehensive Cancer Hospital, is engaging in translational research with her team to devise treatment therapies for breast cancer. Translational research is the application of discoveries made during research studies to improve patient lives through better diagnosis and treatment options. Her approach to developing treatments focuses on immunotherapy, which involves the use of the body’s own defenses to battle breast cancer. As a clinical researcher, she not only aims to prolong her patients’ lives but also to reduce the “morbidity and suffering” that her patients endure.
CD8+ T-cells can be detected with immunohistochemical staining, a popular technique used by cancer researchers to detect certain immune cells in the tumor microenvironment.
health & medicine
4. Interview with Yara Abdou, MD, 02/17/22.Yara Abdou, MD. “We need more representation of minority women in clinical research, in order to develop interventions that translate into real-world use and that are efficacious in different populations.”
References 1. Breast Cancer Facts and Statistics, https://www.breast 2.cancer.org/facts-statistics.“B-cellsvs.T-cells:What’s the Difference?”, https://www. cancercenter.com/what-are-b-cells-vs-t-cells (accessed March 6, 2022).
21 Carolina Scientific mortality rates from breast cancer than white women. Dr. Abdou explains that this could be an effect of T-cell exhaustion, in which CD8+ T-cells are present but are no longer functional if they have been fighting chronic antigen stimulation for a long time, such as chronic infection or cancer. She continues to investigate markers of T-cell exhaustion to determine if they are existent in these particular tumors.
3. Walens, Andrea; Olsson, Linnea T; Alsten, Sarah; Carey, Lisa A; Troester, Melissa A; Abdou, Yara. Journal of Clinical Oncology 2021, 39:15_suppl, 594-594.
Dr. Abdou has experienced numerous successes and obstacles in her research. One of her many
breasttomoretheconductandbreasthaveoffightfieldincludesaccomplishmentsworkingintheofimmunotherapytobreastcancer.Afewherimmunotherapiesbeenapprovedforcancertreatment,shecontinuestomoretrialswithgoalofapprovingimmunotherapieswidentherangeofcancertreatments.
Figure 3. Immunohistochemical staining sheds light on differences in CD8+ Tcell density in White and Black women. (B) CD8+ T-cell density in Black women. (D) CD8+ T-cell density in White women. Image courtesy of Dr. Yara Abdou.
However, underrepresentation of minority women in cancer research and clinical trials remains a formidable obstacle. There are many barriers to minority women recruitment including lack of awareness amongst minority populations and possible diminished trust in the healthcare system. However, she states “it’s a challenge I plan to face whole heartedly. This has been an ongoing challenge for years and it’s time for us as clinicians and researchers to step up and find ways to overcome it; we need more representation of minority women in clinical research, in order to develop interventions that translate into real-world use and that are efficacious in different populations.”4 She believes that this challenge can be overcome through better communication, transparency, and logistical support. Dr. Abdou applies her immunotherapy research to treating patients by studying their tumor microenvironment, which enables her to customize their treatment. By understanding the tumor’s biology, she can predict how it may behave and respond to certain treatments. Dr. Abdou collaborates with breast cancer researchers on a daily basis in order to make her clinical research efforts successful. She states that “at UNC, we’re a multidisciplinary team, where every doctor brings their area of expertise together, whether it’s the medical oncologist, surgical oncologist, the radiation oncologist; we all meet to discuss every patient and we all contribute to their care.”4 As researchers across different subdivisions of oncology unite and develop immunotherapies, there is no doubt that breast cancer treatment will soon be revolutionized. With ongoing research efforts, the next generations of breast cancer patients may have much lower mortality rates.
Additionally, Dr. Abdou examines the tumor biology of her patients in order to enhance their outcomes through novel treatments. A gene known as BIRC5 codes for a protein called survivin, which is present in relatively high amounts in black women and is associated with more aggressive types of breast cancer.3 In order to improve patient outcomes primarily in black women, she is currently developing clinical trials utilizing vaccine treatments that allow the immune system to play a role in targeting survivin. Dr. Abdou also aims to use checkpoint inhibitors, which is a type of immunotherapy involving the use of drugs that ensure T-cells are able to successfully mount an immune response against cancerous cells.
Dr. Fu uses these viral vectors to look at neurogenetic diseases affecting the central nervous system (CNS), which constitutes the brain and spinal cord. One of the main issues with the treatment of genetic disorders in the brain and spinal cord is the blood-brain barrier (BBB). This is a layer of protec tive blood vessels and tissue where cells are tightly packed, leaving very small pores and preventing more than 99% of molecules (both small and large) from entering the CNS. When asked about the biggest challenges she has faced in her Dr. Haiyan Fu
22 health &
AAV is common throughout humans but has no patho genesis recorded (meaning it cannot cause disease). It is also a latent virus that can persist within cells. Once inside a cell, the virus transcribes proteins but not cause diseases. AAV vectors were developed by Richard Jude Samulski, part of the gene therapy faculty at UNC, in the early ‘80s. The majority of the viral genome was cut out of the AAV, leaving only the essential pieces—inverted terminal repeats—which cap the DNA and are critical for replication.. The replication process begins at one of these inverted terminal repeats and continues to the other end. AAV vectors have 96% of the viral genes cut out, making it an extremely safe tool for gene therapy. Its persis tence also allows it to provide treatment with long-term ben efits. These vectors also have broad tissue tropism, meaning they have the ability to access cells in a variety of organs and cell types, giving researchers tools for the treatment of a vari ety of different organs and even diseases that affect all organs.
Responsibility in genes: Gene Therapy for Rare Neurodegenerative Diseases
Gmedicineeneticdisorders can be devasting for both those affect ed and their families. Dr. Haiyan Fu, part of the research faculty in the Department of Pediatrics at UNC-Chapel Hill, has been studying gene therapy since the ‘90s. She is an investigator at the gene therapy center and has been part of the faculty on campus for almost three and a half years.
Dr. Fu lab
By Belle Retko
Dr. Fu’s research specializes in treating rare neuroge netic diseases (conditions caused by defects in chromosomes or genes that affect the brain, spinal cord, and nerves), specifi cally a category called “lysosomal storage diseases.” Lysosomal storage diseases are caused by genetic defects or mutations, creating a build-up of toxic material in the cells. Gene therapy has long been considered an ideal tool for the treatment of such diseases. For example, Taye-Sachs and Krabbe’s disease. The therapy would allow doctors to target the root cause of a disease, replacing the defective gene with a normal one. Through the use of viral vectors, researchers are able to carry the therapeutic gene to administer to target organs and cells. DNA cannot enter a cell alone. However, viruses are able to enter cells and cause sickness, replicating and multiplying until eventually the cell bursts. Viral vectors allow researchers to use a virus’s ability to enter a cell, without the negative effects of the virus. Scientists use nonpathogenic (not disease-caus ing) viruses that can infiltrate the cell and persist there. Once inside, the viruses begin replicating the DNA that was added. These vectors are more specifically called Adeno-Associated Virus Vectors (AAV Vectors).
Those families with kids who… need 24/7 care from the family... go from appearing to be normal to this. And, they are treatable... It’s our responsibility to develop this treatment and improve the quality of life, not only for the sick children but also for their families.”1 “It’s a situation that makes you think, ‘If I could do it, to change it, I should… or I must.’ And I think I can.”1 Dr. Fu goes on to explain that her products have proved to be a cure in the mice she has tested when they are treated early-on, and she insists that research must move forward in order to treat these diseases in children. This effort to better the lives of people, combined with her love of science and drive to advance the field, make up Dr. Fu’s inspiration.
1. Interview with Haiyan Fu, Ph. D. 2/21/2022
2. This is Engineering. (2019). Scientist Putting Petri Dish Under Microscope. Pexels. This is Engineering. Retrieved April 9, 2022, from lecularPrevention3.tist-putting-petri-dish-under-microscope-3912365/.https://www.pexels.com/photo/scienC.D.C.(2020).ThisCentersforDiseaseControland(Cdc)scientistwasshownimplementingmotesting.Unsplash.CDC.RetrievedApril9,2022,
Dr. Fu’s success can be seen in her FDA approvals; three ap proved clinical trials for three diseases. She then points at pic tures of children she has treated with the gene therapy, smil ing. “I hope our treatment will go on to help newborns before the diseases even begin manifesting.”1 After discussing her research, Dr. Fu explained the ef fect COVID had on her research. It had a huge impact; they were asked to shut down the lab for three months at the be ginning of the pandemic, meaning they had to close down the animal breeding program for their mouse models. This pause in the breeding program has had longer effects than the initial three months, as it took time to get the program at peak per formance again. Although her lab was mostly closed (she still had a few people going in), she never stopped working with grant applications and applications and paperwork for clinical trials. She also emphasized funding, explaining most of their funding comes from the families and communities affected by MPS, as this was also an issue in general, but especially during the pandemic.Therecent advances in the field of gene therapy for neurogenetic diseases are astounding. With researchers like Dr. Fu working on gene therapy treatments, the future for the field is bright. Her dedication is a lesson to all, “If I could change it…"
When Dr. Fu spoke about why she is interested in this topic, why it is important, and what her broader goals are, her answers all circulated around the same thing: helping people. She jokingly calls her story “not very inspirational”1,emphasizing that she wanted to do research that can benefit patients. She believes the research she is do ing today will achieve that. “My research is actually funded in a pretty large scale by the families and communities of patients with MPS [muco polysaccharidoses].
23 Carolina Scientific health & medicine research, Dr. Fu has said, “For gene therapy, the blood-brain barrier.”1 Currently, diseases that are primarily located in these regions have no treatment. Diseases affecting this region are scattered throughout the CNS. Ensuring meaningful benefits involves treating as many cells as possible throughout the en tire region. The issue stems from the impermeable structure of the human brain. The brain is designed to prevent infiltra tion and the spread of viruses and pathogens, with the BBB as a main shield. The lack of entrances creates the almost im permeable BBB, making it difficult to find a way to administer gene therapy treatments to the brain and spinal cord: even when administered directly, there is little to no spread due to the construction of the brain. This stronghold system, meant to prevent damaging viruses and infections, is another obsta cle in treating neurogenetic diseases.
In a similar manner, when asked what progress she is proudest of making a contribution towards, she jokingly said, “I’m not normally proud of myself very much.”1 Research takes a long time, usually involving more troubles than successes.
AAV-9 has been the saving grace for neurogenetic gene therapy. Discovered 15 years ago, its natural ability to cross the BBB created more feasible research into gene therapy treatments for neurogenetic diseases. “Before AAV-9, we were trying different techniques to manipulate the blood-brain barrier and delivery methods or routes to get past it.”1 com mented Dr. Fu. She is working with Dr. Munzer, who brings her translation research into a clinical setting. Dr. Fu says they are working on new products and are hopeful they will work at the clinicalAnotherlevel.problem facing gene therapy is antibody de pletion. When someone is infected with any other virus, AAV-9 triggers an immune response and spurs the development of antibodies. These antibodies make the treatments ineffective and the patient ineligible for the study. More pressingly, AAVantibodies are present in humans, found in up to 80% of the population. Even if a patient had been eligible for the first dose of treatment, by the second dose, they would have high levels of these antibodies. About 80% of the population would not be eligible for treatment, and the 20% that would be eligible could not receive a second dose. Dr. Fu is striving towards a solution. She describes the process of uncovering more about antibody depletion; finding what levels of antibodies will ren der treatment ineffective, and then affirming she has found a possible solution. When this new treatment is given alongside the gene therapy treatment in animal models, the gene ther apy was found effective. She hopes to move this forward to clinical application adjunct with the gene therapy treatments she has been developing, hoping to ensure treatment for all those who might need it.
References
medicine
New Strategies in the Battle to Prevent Opioid Abuse
When making an effort to accomplish a goal, one can choose to “Lock-In,” focusing down into a narrow approach and process to successfully achieve an end goal in situations from athletic competition to an academic endeavor. Yet, while this can be beneficial in some circumstances, when it comes to the healthcare and injury prevention realm, locking into a single focus is not an effective strategy. Applying this logic to someone struggling with opioid addiction, it appears that they should be “locked” into an approach that limits their access to the medication, yet new data suggests that this strategy is not as effective as it may seem.
Medicaid “Lock-in” programs (LIPs) are used by health care providers nationwide to restrict patients’ access to opioids by requiring beneficiaries to use a single prescriber to obtain them. LIPs are used for a specified amount of time. For example, one year. When examining the periods before, during, and after the LIP, it was shown that patients exhibit varying usage patterns with a sharp increase of opioid usage in morphine milligram equivalents (MME) before the LIP, and either a decrease, increase, or no effect in MME dosage after the LIP.1 UNC - Chapel Hill researcher Dr. Rebecca Naumann aims to study both this pattern and MME disposal, with respect to the LIP’s effectiveness.
Dr. Naumann further builds on her interest and experience using Systems Science, an interdisciplinary field working Rebecca B. Naumann, Ph.D.
By Kishan Patel
Figure 1. UNC Injury Prevention Center Building on MLK Blvd. In Chapel Hill, NC. Photo courtesy of Kishan Patel. &
health
Dr. Naumann is a distinguished assistant professor in the Department of Epidemiology at the Gillings School of Global Public Health at UNC, as well as a member of core faculty at the UNC Injury Prevention Research Center. Dr. Naumann’s research in the fields of road traffic injury and drug overdose prevention has allowed her to work with local and state coalition partners to promote innovative injury prevention efforts. With a history in injury prevention and epidemiology, the roots of Dr. Naumann’s passion stem from a singular class in her undergraduate studies at the University of Georgia.1 By taking an epidemiology class, Naumann became intrigued in the field and went on to work through internships in epidemiology with a focus on car crashes and traumatic injury.1 She gained her master’s in public health, concentrating on transportation injury, gained overdose prevention experience in Atlanta at the CDC Injury Center, and earned her Ph.D. at UNC.1 Wanting to stray from academia and go into research, today Dr. Naumann’s lab aims to spend its time split 50/50 with road safety and overdose prevention.1 Her lab’s research has contributed to multiple policy reforms and she would love to continue seeing a tangible impact of her work in the real-world.1
24
2. Naumann RB; Marshall SW; Gottfredson NC; Lund JL; Ringwalt CL; Skinner AC. Pharmacoepidemiol Drug Saf. 2018, 28, 16-24.
25 Carolina Scientific on complex systems in the natural environment. She applies this in fields like engineering and medicine, to analytically pursue methods in injury prevention research in her lab. When studying the LIPs, Dr. Naumann uses a form of statistical analysis dubbed “latent class growth analyses” to help account for underlying variate factors in user demographics such as, age demographics and if the patient has previously used medication assisted treatment. She can then effectively cluster similar patients among the beneficiaries of NC Medicaid that follow approximately the same trajectory with opioid usage. What resulted from a cohort of beneficiaries enrolled in the NC Medicaid LIP (n=2,701) were 5 different trajectory patterns displaying heterogeneity: “(1) start at a high level of MMEs, end at a high level of MMEs (13.1% of cohort); (2) start medium, end medium (13.2%); (3) start medium, end low (21.5%); (4) start low, end medium (22.6%); and (5) start low, end low (29.6%).”
2
Figure 3. Photo of typical opioid prescription.
health & medicine
2
References
1. Interview with Rebecca B. Naumann, Ph.D. 10/4/2021
All 5 classes displayed a spike in daily MME dispensed 6 months prior to joining the LIP—a plausible trigger for enrollment. Classes 1, 2, and 5 have a stable level of MME’s before the spike, while classes 3 and 4 have greater variability—class 3 being the only one with a decreasing level of MME pre-spike.2 In classes 1 and 2, Dr. Naumann explains how different covariate factors help match the classes together. Beneficiaries in classes 1 and 2 were older and had higher chronic pain levels, while the beneficiaries in class 1 were younger on average and had lower pain levels.2 Therefore, class 1 demonstrated a higher disposal of opioids due to the underlying factors of higher pain levels and olderaged individuals.2 When looking into classes 2 and 3, both starting in the medium MME range, class 2 displayed sustained levels of MME after the LIP and class 3 demonstrated a large decline.2 Beneficiaries in class 3, however, had the highest prevalence of overdoses and a history of MAT (Medication Assisted Treatment). Deductively, this explains for the decrease of MME’s because the individuals in the class have had experiences with other overdose prevention efforts and were used in programs with similar intent to the LIPs.2 Lastly, classes 4 and 5 began at low initial MME levels, while the MME levels in class 4 became elevated and those of class 5 remained low. Factors in class 4 contributing to increased MME levels included “a higher prevalence of beneficiaries receiving Medicaid benefits due to a disability [and] a higher prevalence of severe pain diagnoses.”2 Class 5 witnessed the highest history of MAT use—almost 5 times the levels of class 4. Varying factors like pain type and age contribute to different use cases for opioids.1 Dr. Naumann explains how her findings suggest a limited impact of LIP on the average trajectories of MMEs dispensed.1 The only class that actually demonstrated a decline was class 3, yet the class was already demonstrating a decline prior to the LIP.1 Naumann suggests that her team’s findings can be useful for future improvement and installation into LIP programs. For example, extensive MAT history demonstrated generally low MME trajectories. Therefore, LIP programs can “consider comprehensively integrating a range of substance use disorder assessment and treatment services throughout LIP pre-enrollment and enrollment periods.”
Figure 2. Foyer Sign Located Inside the UNC Injury Prevention Center. Photo courtesy of Kishan Patel.
2 The 5 classification solution came from the best of multiple models used to fit the beneficiary’s data into different hidden classes. Dr. Naumann’s team determined that the 5 classes had an entropy level of 0.97, meaning that beneficiaries had a high level of belonging to one class and not any others.
“Dr. Dave’s lab breaks from this traditional approach by getting the community involved through evaluations.”participatory Image courtesy of Health eCareers. Integration of multiple facets of healthcare leads to overall better patient outcomes. medicine
26
Dr. Gaurav Dave, MD, DrPH,
Disease prevention and health disparities
Broadening the Healthcare Perspective
health, decrease illness, and alleviate some of the burden on clinicians.Dr. Dave has experienced the burden clinicians feel during his own time as an ER physician in Mumbai, India, serving some of the country’s most impoverished regions. He noticed that much of the community was in a “vicious cycle” of poverty, which led to worsening health conditions and further disease progression before seeking treatment due to lack of prevention measures. These worsening health conditions and lack of disease prevention in turn led to more poverty within the community. Dr. Dave wanted to “make a change [to] affect a larger population” through “systemic changes.” He decided to transition to public health so that “rather than treat[ing] individuals, [he could] treat communities.”1
ComprehensiveBryant
Doctors, nurses, and treatment clinics are central tenants of the healthcare field. However, healthcare permeates every aspect of of life—from foods, to physical activity, to occupation. Individuals and communities focus more on the relatively quick results of immediate patient problems and less on the more hidden aspects of disease prevention. Because these prevention measures require longterm consistency and usually lack immediate benefits, they are often overlooked. Although a single fast-food meal has minimal health consequences, a lifetime of unhealthy eating can increase risk for obesity, diabetes, heart attacks, and many other diseases. Most healthcare systems primarily emphasize the retroactive treatment of diseases after diagnosis, and seldom put effort into the upstream prevention of these diseases. Without emphasis on disease prevention, clinicians are increasingly burdened with patients with otherwise preventable
community’sresearchcommunity-basednovelresearch.andofaSchoolCarolinaUniversityEpidemiologyMedicinetheAssociateGauravconditions.Dave,anProfessorinDivisionofGeneralandClinicalattheofNorthatChapelHill’sofMedicine,ispioneerinthefielddiseasepreventionpublichealthDr.Daveusesapproachesoftohelpaoverall
By: Henry
Dr. Dave’s lab focuses on disease prevention through health disparities. Historically, health disparities research has been implemented by researchers who decide which changes to implement in a community for study. While the approach may or may not yield positive results, its inherent flaw is that the community does not have input on the issues addressed. Thus, the community does not feel as included in the research study and may be less likely to participate.
Healthcare:
health &
References
2) Cathorall, M.L.; Xin, H.; Aronson, R.; Peachey, A.; Bibeau, D.L.; Schulz, M.; and Dave, G. Health Culture and Society. 2015, 8, 87-96.
1) Interview with Gaurav Dave, MD, DrPH, MPH. 02/07/21.
health
Dr. Dave also mentors many students, including graduate, undergraduate, and even high school students. He is very excited about helping the future generation of public health researchers develop innovative research methods. He encourages his students to employ methods outside the box, such as using poetry to spread information about HIV, or using photo competitions of people’s hardships to better understand community issues. Dr. Dave also helps to motivate his students through the challenges of systemic change toward healthcare equality. Progress can be very slow, and the daunting task of tackling healthcare inequality can be overwhelming. However, there is a comfort in the fact that even though expanding the scope of healthcare beyond treatment is slow progress, the world continues to move in the right direction: toward a better tomorrow.
3) The Tuskegee Timeline. Centers for Disease Control and Prevention. https://www.cdc.gov/tuskegee/timeline.htm (accessed Month Day, Year).
Dr. Dave also believes that it is his “obligation and duty” to share the results of the experiments with the community who provided the data.1 He published a study in 2015 demonstrating the significant impact of “neighborhood deprivation” on the blood glucose levels of communities.2 The study suggests that environmental factors from under-privileged neighborhoods contribute to higher blood glucose which is correlated with diabetes and high blood pressure.Participatory evaluations require trust between the researchers and the studied community. Building trust can often be a slow and difficult process due to the historic injustices inflicted by the scientific community. For example, during the Tuskegee Syphilis Study, African American males were intentionally denied treatment so that the CDC and US Public Health Service could study disease progression. Without knowledge of the true experimental purpose, over 100 of the nearly 400 syphilis patients died.3 This is just one of many instances that contribute to minoritized communities’ hesitancy toward participating in research studies. In addition to his research on health disparity factors, Dr. Dave also works to connect communities with medical information. One study found that parents and caregivers could function as informal health advisors to help reduce the risk of HIV in African American youth.4 Dr. Dave uses information gained from his research to aid his work as Director of Evaluation for the Translational and Clinical Sciences Institute (TraCS). The institute works to accelerate the dissemination of biomedical research to patients and communities, helping streamline the research-to-implementation pipeline. Through this, people can more quickly benefit from the newest advancements in biomedicine.
27 Carolina Scientific
Dr. Dave’s lab breaks from this traditional approach by involving the community through participatory evaluations.
Participatory evaluations give a voice to community stakeholders who are the beneficiaries of the research projects, allowing them to work with researchers to design experiments. By allowing the community to vocalize the concerns they have, the research can be adapted to community needs so that they address the most pressing difficulties. The approach allows for empowerment of those who directly benefit from participating in the study.
4) Ritchwood, T.D.; Dave, G.; Carthron, D.L.; Isler, M.R.; Blumenthal, C.; Wynn, M.; Odulana, A.; Lin, F.C.; Akers, A.Y.; Corbie-Smith, G. AIDS Care. 2016, 28, 537-42. PMID: 26573538. PMCID: PMC4764414. DOI: 10.1080/09540121.2015.1112348. Figure 2: A participant in the Tuskegee Syphilis Study getting blood drawn. & medicine
28
physical science
Previous examples of similar
The conventional approach to polymer synthesis, as described by Dr. Zhuk hovitskiy, is a forward-thinking process2 Polymer synthesis starts with established chemical molecules and then uses known polymerization methods to arrive at a new material. Many polymerization methods are quite straight forward, combining monomers to create a polymer3. However, the approach that Ditzler and Dr. Zhukhovitskiy showcased in their work is exactly the opposite — a ret rosynthetic process. The system begins with a target polymer and then destructs it, piece by piece into its original building blocks. The core of the retrosynthetic strategy taken by Ditzler and Dr. Zhukhovitskiy is backbone editing⁴. Backbone editing can be defined as the reshuffling of existing polymeric mate rial’s bonds, or the connection between mol ecules, to create an entirely new polymer.
“Vinyl polymers are important for the future of sustainability as their resistant carbon backbone allows for broad utilization and development.”
offocusedhovitskiyprocess,Torialshazardousficientfieldaretransformationsscarceintheandareineforutilizemate(Figure2)⁴.optimizethetheZhukgrouponaclassreactionscalled sigmatropic rearrangements, which are reac tions that take place in a concerted process where single and double bonds shift, simul taneously2.Sigmatropic rearrangements are ideal for polymer editing because the transforma tions are simple, mild, and do not break poly mer chains during reactions. To achieve the goal of creating vinyl polymers from a new and possibly more sustainable pool of nonvinyl polymers, Ditzler and Zhukhovitskiy turned to a type of sigmatropic rearrange ment called the Ireland-Claisen rearrange ment (ICR)2. This process is highly studied in small-molecule chemistry but has not been explored in a polymer context. Using the retrosynthetic thinking pioneered by Ditzler and Dr. Zhukhovitskiy, a synthetic polymer called polyester can be derived from a class Dr. Aleksandr Zhukhovitskiy and Rachael Ditzler
A Retro Take on Vinyl New technique on synthesizing vinyl polymers
By Sarah Giang Illustration by Ziyun
The word “vinyl” may be associated with vintage records, but in chemistry, the term opens the door for a more sus tainable future. Polymers are found in ev eryday life; in plastic bags from local grocery store, in common adhesives, and clothing fabric1. Polymers are defined as a class of substances composed of natural or synthetic large molecules which are also known as monomers, or macromolecules that can be used as building blocks for larger chemical units. The vast majority of synthetic poly mers are not biodegradable, taking upwards of 400 years to completely degrade. With such a slow degradation process the heap ing number of plastic items will eventually lead to catastrophic effects. Some of the ef fects are seen now, in the destruction of coral reefs and marine habitats, and human health hazards related to the consumption of mi croplastics, which are plastic debris smaller than five millimeters. Today, littering, and plastic pollution are immense problems and efforts to combat this issue seem modest in comparison. However, what if one could edit a polymer’s chemical makeup to enhance its biodegradability? What if one could upcycle existing plastics to boost its value, and there fore motivate future investment into sustain ability? These are some of the questions the Zhukhovitskiy Group here at the University of North Carolina, are aiming to answer.
Dr. Aleksandr Zhukhovitskiy stud ied Chemistry and Mathematics as an un dergraduate at Northwestern University, and from there, he earned a PhD from Massachu setts Institute of Technology working with Professor Jere miah Johnson to advance the chemis try of vitskiyDr.Subsequently,networks.andmodificationsurfacepolymerZhukhocarried out his postdoctoral studies in catalysis and organometallic chemistry with Professor Dean Toste at the University of California, Berkeley. Since the Zhukho vitskiy Group’s beginning in the summer of 2019, they have published two manuscripts in the Journal of the American Chemical Society, pioneering the concept of skeletal rearrangements in polymers. Authored by group member and PhD candidate Rachael Ditzler with Dr. Zhukhovitskiy, their most re cent publication takes a step in the direction of sustainable plastics (Figure 1).
A. Sigmatropic Rearrangements of Polymer Backbones: Vinyl Polymers from Polyesters in One Step. November 22nd, 2022. Accessed February 10th, 2022. https://pubs.acs.org/ doi/10.1021/jacs.1c09657 4. Gellner Industrial Website (January 20th, 2018) accessed February 16th, 2022. https://www.gellnerindustrial.com/partpolymer%20based%20paints.the%20raw%20materials,personal%20favorite%2C%20onepolymersdailylife/#:~:text=Polymers%20become%20
Figure 3. Ditzler and Dr. Zhukhovitskiy’s full rearrangement.
29 Carolina Scientific physical science of monomers called lactones. Then, from polyester, one can derive vinyl polymers through ICR. The specified lactones can be derived from a biological and sustainable stock, created in reactions between two ac ids. Vinyl polymers are important for the fu ture of sustainability as their resistant carbon backbone allows for broad utilization and development⁵.Withtheir retrosynthetic process in place, Dr. Zhukhovitskiy and Ditzler first synthesized the polyesters and studied their rearrangement. The ICR proved to be highly efficient with virtually all units of the polymer rearranged as expected (Figure 3)2. The result of the new vinyl polymers is sup ported by extensive nuclear magnetic reso nance spectroscopy (NMR) analysis. NMR spectroscopy works to determine the mo lecular structure and purity of a material and was used to assign the new structure of the rearranged polymer⁶. The properties of the new material changed considerably com pared to the original polyester. For example, differential scanning calorimetry (DSC) es tablished that the rearranged plastic’s glass transition temperature, which is temperature when the material turns from bring glass like and fragile, to rubbery and bendable, had increased by 60° Celsius⁴. Furthermore, the thermal stability, defined as the ability of a material to resist heat, rose greatly⁴. This retrosynthetic process of synthesizing vinyl polymers from lactones, unlocks the door to making vinyl polymers from sustainably de rived monomers.Polymerbackbone research is just one of many approaches that the Zhukho vitskiy Group is investigating. Real world obstacles the group is interested in inves tigating include how to depolymerize, or break down tire rubber, decreasing rubber pollution, and creating valuable small mole cules in the process2. On top of their research goals, the group earnestly works in service and outreach within the surrounding com munity, sharing their passion for chemistry and polymer science. Group members have been able to perform chemistry demonstra tions in local schools and Dr. Zhukhovitskiy is also starting his own program to train teach ers in scientific research and give them the tools to encourage the younger generations appreciation for science. Dr. Zhukhovitskiy’s goal as a professor is to elevate the skills and knowledge of his students and broader community through immersive and experi ential techniques, and to foster in them the chemistry between people and polymers.
5. Interview with Dr. Aleksandr Zhukhovitskiy on February 10th, 2022. 6. NMR Lab Website accessed February 16th, 2022. http://chem.ch.huji.ac.il/nmr/whatisnmr/whatisnmr. 16th,7.containing%20known%20compounds.(NMR)%20spectroscopy,analyze%20mixtures%20html#:~:text=Nuclear%20Magnetic%20Resonance%20TheZhukhovitskiyGroupWebsiteaccessedFebruary2022.https://www.zhukogroup.com 2/10/22.
Figure 2 (above): Previous examples of rearrangement vs. Ditzler and Dr. Zhukhovitskiy’s.
Ultimately, Dr. Zhukhovitskiy, Rachael Dit zler, and the group’s main ambition, is to examine the knowledge and techniques of composing new polymeric materials and ex panding upon them to create a more viable tomorrow⁷. References 1. Encyclopaedia Britannica. Polymerization chemical reaction definition. n.d. Accessed March 13th, 2022. https://www.britannica.com/science/polymerization 2. Delplace, V., Nicolas, J. Degradable vinyl polymers for biomedical applications. September 22nd, 2015. Accessed March 13th, 2022. https://www.nature.com/ 3.articles/nchem.2343Ditzler,R.,Zkukhovitskiy
By Anna Crist
UNC-Chapel Hill’s Dr. Joel Kingsolver is an example of such a scientist. He has been enamored with ecology since his undergraduate years at Duke. In addition to conducting experiments on Manduca, his lab works on butterfly preservation with the Mason Farm Butterfly Project, where non-scientist citizens can observe and collect data on butterflies at the local Mason Farm Biological Reserve. Not only does this give the lab data to work with, but it also makes it easy for local North Carolinians (and even UNC students) to go engage with some of the insects Kingsolver’s work focuses on.
environmental science
Tobacco hornworms go through four main developmental stages. They begin their lives as eggs laid on the undersides of the leaves of plants in the Nightshade family; these include tomatoes, potatoes, peppers, and tobacco. Once hatched, the larvae shed their skin five or more times as they get progressively larger, with the mature caterpillars being a little over three inches in length.1 Then, their bodies harden into a pupal stage, and lie dormant in the soil, often over winter. Finally, they emerge from their pupas as tobacco hawkmoths, who feed on nectar and fertilize flowers (Figure 3). Tobacco hornworms also have an interesting relationship with a tiny parasitoid wasp about the size of a small ant. The wasps insert their eggs into young hornworms, which serve as portable homes and food sources for the wasp larvae once they hatch inside. When ready to pupate, the tiny wasp larvae emerge from the hornworm’s skin and spin white, fuzzy cocoons on top of the caterpillar. If you’re a gardener, perhaps you have even seen this bizarre sight before (Figure 1)! These two attributes make tobacco hornworms an excellent candidate for those looking to examine bug life stages and inter-species relationships. In fact, hornworms have been a popular choice for insect experiments since the 1950s; their large size and ease of domestication make them easy to experiment on, while their vegetative diet means that the experiment results can apply to a wide range of herbivorous insects. The Kingsolver lab has an ongoing colony of tobacco hornworms that was derived from an NC state colony that started in the 1960.
These “Lab Rat” Caterpillars Are Helping Scientists Measure the Effects of Climate Change
30
If you have gardened in the southeastern U.S., you might be familiar with the hornworm, a species of chubby green caterpillar whose strong appetite can quickly decimate rows of tomato and pepper plants. Named after the spiky protrusion on its rear, the tobacco hornworm—Manduca sexta—might be an irritant to those with green thumbs, but they are an incredibly useful bug for scientists.
Figure 3. A tobacco hawkmoth. Photo courtesy of Kingsolver lab Figure 1. A parasitized tobacco hornworm with soon-to-emerge wasp cocoons. Photo by Judy Gallagher
31 Carolina Scientific
5. Geoffrey G. E. Scudder; Chapter Two. In The Importance of Insects, Second Edition; Robert G. Foottit, Peter H. Adler; John Wiley & Sons: 2017; Volume I, Pagination
Figure 2. An example of a thermal performance curve. Different life phases of Manduca have differing optimal temperatures. Graph courtesy of Kingsolver lab Dr. Joel Kingsolver environmental science
References 1. Featured Creatures. tures/field/tobacco_hornworm.htmhttps://entnemdept.ufl.edu/crea(accessedFebruary 16, 2.2022).Interview with Joel G. Kingsolver, Ph.D. 02/17/22.
Regarding the purpose of their lab, Dr. Kingsolver says that he is “interested in how insects respond and adapt to environmental changes in the real world.”2 Kingsolver focuses particularly on the effects of climate change on insects, of which Manduca is an effective model. In a 2011 paper, Kingsolver found that because of differences in size and habitat, each Manduca life stage lives in a unique microhabitat and microclimate. For example, the tiny Manduca eggs live on the surfaces of leaves, which emit cooling water vapors that can lower the temperature of the leaf’s surface by 7.2-14.4 °F, often preventing temperature-induced egg mortality.3 Manduca pupae are similarly shielded from temperature fluctuations by living underground, where the dirt proves an effective insulator. Manduca larvae, however, are often subject to greater temperature variations, because they are much bigger than eggs. Data taken in the southwestern U.S. indicates that larvae tend to be 1.8-7.2 °F warmer than the air surrounding them.3 As the different developmental stages of Manduca are used to their respective microclimates, climate change has the potential to affect each stage differently. These findings are significant because most multicellular organisms undergo development in distinct stages. Furthermore, it indicates that the effects of climate change might be more complex to measure than previouslyCurrently,thought.the Kingsolver lab conducts research in two main ways: Their lab experiments attempt to isolate the effects of heat on Manduca physiology, while their field experiments observe how these mechanisms play out in the real world.
Although these findings may seem hyper-specific, they have many broader applications. To understand their underlying causes, the challenges of measuring ecosystem health must first be acknowledged. Ecosystems are composed of the extremely complicated and dynamic interactions between living and non-living factors in an area. Since these relationships are so numerous and nuanced, it’s impossible to measure the effects of climate change on every species in an ecosystem. This is where the hornworm comes in. Ecologists use model species—such as Manduca sexta—to make observations and predictions that can be broadly applied to many species. It is particularly important to examine the health of insect populations as they are a critical indication of ecosystem health; as the “biological foundation” for many ecosystems, bugs “cycle nutrients, pollinate plants, … maintain soil structure and fertility … and provide a major food source for other [organisms].” Manduca’s role as a model species means their performance in experiments reveal important information about the health of entire populations of insects. The hornworm may be unpopular among farmers. Among ecologists and entomologists, however, it is a muchappreciated experimental tool whose utility seems unlikely to fade anytime soon.
3. Joel G. Kingsolver; H. Arthur Woods; Lauren B. Buckley; Kristen A. Potter; Heidi J. MacLean; Jessica K. Higgins. Symp. 2011, 1, 1-14. 4. Interview with Meggan Alston and Katherine Malinski, 02/11/22.
Graduate and postgraduate students Meggan Alston and Katherine Malinski are two of the lab’s researchers. Their research seeks to expand on the findings of Kingsolver, as they examine the physiological specifics of how temperature affects Manduca fitness and alters the relationships between the caterpillars, the plants they eat, and the wasps that parasitizeMuchthem.isstill left to be discovered about the tobacco hornworm. Alston’s research has identified that heat shocks negatively affect fertility, the broader reason remains a mystery. She said it was especially “puzzling” because it seemed to affect both male and female Manduca. “Typically, heat induced infertility is often associated with males and sperm,” she pointed out.⁴ Malinski is also replicating some of Alston’s research with less extreme temperature intervals, to see how that may change the data.
Most people see trees as a method of combating climate change and creating greener air. Planting trees is seen as a “fix” for carbon emissions, and large forests are where carbon sink. However, even forest activity contributes to the climate crisis and poor air quality in an unintended way.
Dr. Jason Surratt, a professor in the Department of Environmental Sciences and Energy as well as in the Department of Chemistry at UNC, focuses his research on the atmospheric formation of secondary organic aerosol (SOA).1 Sunlight-driven chemistry occurring in the earth’s atmosphere leads to SOA formation. In this process, organic gas molecules produced from forests during the day react in the atmosphere and convert from the lighter gas phase to the heavier condensed phase, where they become particles. The same gases that give pine trees or flowers their scent are those reacting secondarily in this process.
SOA is a significant problem, as it is one of the most abundant elements of fine particulate matter. Fine particulate matter is a dangerous pollutant to health because of its size and ability to enter the body and affect the lungs and heart. Furthermore, SOA particles can absorb a wide range of photons of sunlight, which can potentially lead to warming on the surface or cooling if it makes cloud droplets. Both man-made and natural sources produce the organic molecules that react to form SOA, which led to Professor Jason Surratt’s interest in this area. He wanted to investigate how byproducts of human activity, such as emissions from burning coal or driving vehicles, affect the environment. His most recent collaboration with other professors and scholars involved the investigation of a molecule called isoprene-derived epoxydiols (IEPOX), a compound that is nearly as abundant in the atmosphere as methane. IEPOX is produced by the atmospheric oxidation of isoprene tree emissions from trees, so the compound is entirely natural. However, solely because the compound is naturally produced from trees as a result of photosynthesis does not necessarily mean it is beneficial, as IEPOX is highly reactive in the air when it reacts with human pollution. IEPOX is more reactive when in the presence of highly acidic particles from emissions.2 Specifically, the reaction of IEPOX with various forms of atmospheric sulfur pollution from the usage of coal and diesel leads to SOA formation. The products of IEPOX and sulfur compounds, both organic and inorganic, continue to react in the atmosphere and change for two to three weeks after formation. The extent of reactions between IEPOX and humanderived sulfur emissions continues to be researched. A recent study focused on the reactive uptake of IEPOX and how that reaction affects the conversion of sulfur compounds from inorganic to organic forms.3 In areas with higher ratios of IEPOX to inorganic sulfur, the conversion of inorganic to organic sulfur is greater. The effects of this conversion on public health and the climate system remain unclear at this time and continue to be an active area of research. Secondary atmospheric reactions are especially noteworthy in locations where dense forests are science
environmental
Jason D. Surratt, PhD. Photo by Wikimedia Commons
TheDilemmaJungleUrban
32
By Rebecca Turner
While the clouds disappeared, these small particles, which can be grouped into the category of fine particulate matter, remained. Fine particulate matter is one of the most harmful forms of pollution for human health because of its minuscule size. Thus, health issues caused by the inhalation of fine particulate matter can be especially prevalent in communities affected by onandenvironmentaltheSOAstartedSincerolelikelyatmosphericForestsissecondaryunderstandingwildfires.Scientists’ofthisprocessstillrelativelynew.reactingwithpollutionplayanimportantinclimaticchanges.scientistsonlyinvestigatingformationwithinlast15-20years,modelspoliciesbasedthosemodelsare lacking. However, research in this field has already proved that regulations have been beneficial. Currently, Surratt’s lab focuses on isoprene and IEPOX reactions. Their findings reveal that through regulations on coal and diesel emissions, the overall amount of SOA particle pollution can be reduced. Further research into atmospheric chemical reactions of IEPOX remains necessary, particularly in developing countries. Much of the research scientists have conducted thus far has been in the United States and the Amazon. In the future, Surratt hopes that scientists can go to Southeast Asia and to the Congo Basin in Africa in order to investigate IEPOX reactions in other rainforests.
Additionally, smog chambers are useful for mimicking the conditions of places without robust tools for data collection, like the Amazon rainforest. The Amazon is of particular interest because isoprene is so common in the atmosphere due to the tree cover. With deforestation and urban development threatening the rainforest, the chemistry in the region is changing.Surratt and his team have studied the chemistry of wildfires and have found fascinating results about the reactions. Organic gases and particles are released into the atmosphere after wildfires. Some molecules are water-soluble and enter clouds. Through the FIREX campaign, the Surratt group simulated wildfires in the lab in order to evaluate this chemistry.4 They discovered submicron particles will likely form once these wildfire emissions are processed in cloud droplets that then evaporate leaving behind these airborne particles.
Figure 2. Look Rock Ground Site where gaseous, particle, and meteorological measurements are taken in Look Rock, Tennessee. Image courtesy of Surratt Research Group.
Figure 3. Smog Chamber in Pittsboro, North Carolina. Image courtesy of Surratt Research Group.
Professor Surratt and his research group have furthered SOA research here at UNC through the use of smog chambers (Figure 3). Smog chambers are a vital tool for mimicking atmospheric chemistry in the lab as every variable from light to humidity, to pressure, can be changed.
33 Carolina Scientific close to residential and urban areas, like the Southeastern U.S. Here, dense tree cover and forested areas lie near busy cities, and both IEPOX and sulfur concentrations are high. Researchers conducted field measurements from the Smoky Mountains, to Southern cities like Birmingham and Alabama, to nearby in the Research Triangle (Figure 2).
References 1. Interview with Jason D. Surratt, Ph.D. February 10, 2022.
3. Matthieu Riva, Yuzhi Chen, Yue Zhang, Ziying Lei, Nicole E. Olson, Hallie C. Boyer, Shweta Narayan, Lind say D. Yee, Hilary S. Green, Tianqu Cui, et. al. Environmental Science & Technology 2019, 53(15), 8682-8694.
environmental science
It is his hope that nations like the U.S. will recognize the importance of these reactions on the global environment and climate, and thus fund this crucial research elsewhere as well.
2. Cassandra J. Gaston, Theran P. Riedel, Zhenfa Zhang, Avram Gold, Jason D. Surratt, and Joel A. Thornton. Environmental Science & Technology 2014, 2014 48 (19), 11178-11186.
4. Surratt, J. Welcome to the Surratt Group. https://jasonsurratt.web.unc. edu/ (accessed March 23, 2022.)
34
The research team
Although oyster reefs are mainly thought of as producers of appetizers on the half shell, they also hold great importance on the coast as they help reduce erosion and improve water quality. The intertidal oyster grows rapidly every year, but only on the sides of the reef. It is easy to see how fast oyster reefs grow over the years, but the question is why are they growing so rapidly? This is because there is a sweet spot that enhances oyster reef growth, and this is on the sides of the sloping reefs.
The Sweet Spot of Intertidal Oysters Rapid Growth of Oysters on Slopes By Breanna Hux Image courtesy of Mathieu Landretti, CC BY-SA 4.0, via Wikimedia Commonsenvironmental science
Dr. Antonio Rodriguez, Earth, Marine, and Environmental Sciences Department Professor who works out of the Institute of Marine Sciences (IMS), participated in a hands-on project involving these oyster reefs along the southeast coast of North Carolina with his faculty colleagues and students.Rodriguez and the accompanying team initially examined the growth of experimental oyster reefs created by a graduate student in 1996. Although Rodriguez has only been looking into these reefs for a little over 10 years, some of the IMS faculty have been studying these oysters for over 40 years.1 Looking into the growth patterns of oyster reefs holds importance for restoring oysters in a manner that returns coastal benefits to North Carolina.According to a journal article written by Molly Bost, a Ph.D. student within Rodriguez lab, the study looked at the growth of “12 natural intertidal reefs in coastal North Carolina that range between 1395 and 62 years old” through coring and laser scanning. 2 The first thing that Rodriguez and the team did was use a jackhammer to pound a metal pipe into the reefs to get vertical cores of the reefs. They then carbon-dated the first oyster to colonize each reef to determine the age. Next, the team used laser scanners to image the reefs and map elevations at a fine scale. These were impressive results as they showed the reef was not growing rapidly on top at all! However, the reef Figure 1. Coring in the oyster reef. Image courtesy of Antonio Rodriguez.
The biggest factor about this research to Rodriguez is that he can make a difference in the world, as oysters are used to protect the coasts and maintain the balance of ocean ecosystems.Overall, the research conducted by Rodriguez and his colleagues has illustrated where and how oysters grow best, which can lead to humans effectively using them to their benefit in the future. Oyster reefs allowed Rodriguez to get into a science that he never thought he would be a part of. The science behind the growth of oyster reefs can help make a difference in the real world, which is why Rodriguez plans to continue looking into oyster reefs that are thousands of years old and over 2 meters thick!
Dr. Antonio Rodriguez environmental science
According to Rodriguez, he and the team encountered various obstacles while coring these oyster reefs.1 In general, the reefs are difficult to work with because they are very sharp and jagged, as Rodriguez compares them to walking on little razors. Another problem was that the reefs needed to be entirely exposed so that they could be studied, and low tide commonly did not correspond with predictions. There would be times, Rodriguez explained, where they would bring all their equipment out to the reef, and the tide would never end up falling low enough.Other places, such as the New England coast, have higher relief shorelines and rock outcrops that prevent erosion. However, the only natural hard substrates off the coast of North Carolina are oyster reefs, which is why the research of these reefs has become so important. Rodriguez states that this project is important to him because he has been able to conduct research that “has a practical aspect to it and that other people also care about.”1
2. Bost, M.; Rodriguez, A.; Ridge, J.; Miller, C.; Fegley, S. Natural Intertidal Oyster Reef Growth Across Two Landscape Settings and Tidal Ranges. Estuaries and Coasts, 2021, 1-14. Figure 2. Oyster reef on the coast of North Carolina. Image courtesy of Antonio Rodriguez.
35 Carolina Scientific was increasing rapidly on the sides at approximately 4 cm per year. After looking at the results, they found that whenever an oyster is too high on the reef, they get dried out very quickly from the sun. On the other hand, whenever an oyster is too low on the reef, there is too much competition with the other marine organisms in the water. Therefore, the perfect place for an oyster to thrive is on the sides of the reefs, where they are neither too high nor too low. The overall results were that “restored oyster reefs thrive across a narrow range of elevations but have the potential to grow above mean sea-level.”2 The oysters’ growth depending on the elevation shows that all the work done to look at the sides compared to the top and the bottom of the reefs paid off! These results effectively represent the best way the reefs grow, which can be used to help make sure coasts are protected effectively.
References 1. Interview with Antonio Rodriguez, *title*. 2/11/22
ByPlantsinResearchCellArabidopsisCharismaDaniel
36
Growing Tall:
Figure 1. Flowering Arabidopsis Thaliana plant, (C) WUS is produced to regulate stem cell proliferation and is repressed by CLV1. The CLV3 peptide interacts with the CLV2/CRN receptor complex to repress WUS. Image courtesy of Amala John and Daniel S. Jones . Dr. Zachary Nimchuk
begins its life as a minuscule seed, which ultimately becomes a differentiated and complex organism through a series of cell divisions and signaling pathways. Studying diverse signaling pathways across a wide range of plant species is often challenging, so a common model species is needed. Within the plant biology department of the University of North Carolina at Chapel Hill (UNC), principal investigator Dr. Zachary Nimchuk and his team have been using Arabidopsis thaliana to make advancements in the understanding of plant stem cell regulation. The model organism Arabidopsis thaliana is as essential to plant biology as Mus Musculus, the common mouse, is to mammalian laboratory research. Dr. Nimchuk comments on the importance of the model organism, stating “along came this model plant Arabidopsis, where you could map and clone the genes…you could look at all the classical things that a plant did and try to identify the genes that underlie this process.”
life sciencesEveryplant
Dr. Nimchuk describes himself as a science-minded man who has always been interested in the natural world around him. In his childhood, he loved being out in nature and remembers going down to the river to lift rocks to discover what could be hiding beneath them. During his undergraduate career at the University of Toronto in Canada, Dr. Nimchuk took courses on plant biology. These courses and the professors who taught them helped ignite Dr. Nimchuk’s interest in plant research. He obtained his Ph.D. from UNC while studying cellular signaling responses to plant pathogens in the Jeff Dangl Laboratory. After receiving his Ph.D., Dr. Nimchuk did his postdoctoral research at the California Institute of Technology, where he began many of the research projects that he continues to lead today at UNC. The Nimchuk laboratory is interested in understanding how plant stem cells communicate with each other during the process of development and differentiation. During the early development of Arabidopsis, the plant’s stem cells communicate with each other through signaling pathways, coordinate with neighboring cells, exchange information, and then decide what to become and when to divide. In Arabidopsis, there is a shoot apical meristem (SAM) located at the plant’s growing tip. The SAM holds a reservoir of stem cells which inflorescence, which produces the plants’ essential
Illustration by Tanisha Choudhury
Stem
3. Arabidopsis Thaliana plants in Nimchuk laboratory
Figure 2. Arabidopsis Thaliana plants in Nimchuk labo ratory.
“Understanding how plants can tolerate differences in temperature to main tain their growth, I think is something that’s going to be increasingly impor tant, if not critical to un derstanding how we can address the effects of crop production in the face of climate change.”Figure
1.Interview with Dr. Nimchuk, Ph.D. 02/16/22
In the 2020 paper, “CLAVATA Signaling Ensures Reproductive Development in Plants Across Thermal Environments,” the Nimchuk laboratory made the discovery that in colder or ambient temperatures, CLV2/CRN is necessary for continuous flower growth. Dr. Nimchuk commented, “When we grow a plant [Arabidopsis] and it doesn’t grow as well… it’s missing flowers under certain environmental conditions, that makes us curious and want to know why… there’s this kind of natural interest in understanding this process that I think drives a lot of what we do for everybody in the lab.”
37 Carolina Scientific life sciences reproductive flowering organs. The Nimchuk lab is currently researching several signaling pathways and essential genes whose mutations can influence the growth of the SAM and the stem cells within it. Several key players help regulate stem cell proliferation in the SAM. The WUSHEL (WUS) gene encodes a protein that promotes the formation and maintenance of stem cells. The CLAVATA3 (CLV3) gene codes for a protein that represses WUS expression. Mutations to CLV3 causes plants to have abnormally large SAMs. The receptor complex CLAVATA2/CORYNE (CLV2/ CRN) is necessary for continuous flower development in the growing Arabidopsis plant. CLV2 is a receptor-like protein, and CRN is a transmembrane pseudokinase, or an enzyme that spans across the plasma membrane. CLV2/CRN work together to regulate stem cell proliferation (fig. 1C). CLV3 interacts with the CLV2/CRN receptor complex to repress WUS. Mutations of CLV3 also lead to abnormal SAMs. Mutations of these critical players in stem cell communication often produce deficiencies observed in the Arabidopsis plant’s phenotypes. In addition to observing mutant phenotypes, further steps must be taken to investigate these effects at the cellular level. Confocal microscopy is an imaging technique that allows scientists to see the inside of plant tissues. Before imaging, Arabidopsis genes are often tagged with GFP, Green Fluorescence Protein, which allows scientists to visually mark the location of the gene’s expression. Additionally, propidium iodide (PI) is used as a magenta dye that magenta dye that binds to the plants’ cell walls so that the outline of the plant’s cell walls can be observed. And lastly, scanning electron microscopy, or SEM, is another form of microscopy that is used to generate detailed images of the SAM. Applications of these techniques allow researchers at the Nimchuk laboratory to visualize various aspects of plant stem cell development.
2.Jones, D. S., John, A., VanDerMolen, K. R., & Nim chuk, Z. L. (2020, November 5). Clavata signaling ensures reproductive development in plants across thermal environments. Cur rent Biology. Retrieved February 22, 2022, 2.Soyars, C. L., James, S. R., & Nimchuk, Z. L. (2016, January 22). Ready, aim, shoot: Stem cell regulation of the shoot apical meristem. Current Opinion in Plant Biology. Retrieved February 22, 2022, from com/4.Nimchukpii/S1369526615300042?via%3Dihubhttps://www.sciencedirect.com/science/article/Lab.Availableonline:https://freeman-lab.(lastcited:02/19/22)
Not only does understanding the impact temperature has on these signaling pathways in Arabidopsis help deepen our understanding of this model organism, but the genetic discoveries made in Arabidopsis can also help us understand similar pathways in other species of plants such as the ones used in agriculture. The Nimchuk laboratory is currently exploring similar signaling pathways and genes in crop species such as lettuce and sunflowers. Dr. Nimchuk states that “understanding how plants can… tolerate differences in temperature to maintain their growth, I think is something that’s going to be increasingly important, if not critical to understanding how we can address the effects of crop production in the face of climate change.” Looking forward, the Nimchuk laboratory will continue their research in Arabidopsis, deepening their understanding of this organism and applying their findings to make more advances in plant science. Dr. Nimchuk states that “One of the fun things about science is that it’s constantly moving.” Understanding stem cell signaling pathways opens the door to exploring and answering more questions in plant biology.
References
Image Courtesy of the National Cancer Institute
The human body contain thousands of genes in our DNA that make us who we are. From eye color to hair color, all parts of the body are encoded by genes. The level of DNA condensation also contributes to what genes are expressed." The condensed sections of the DNA are harder for the body to decipher, while the looser sections can be read easily. DNA methylation is another way in which certain genes can be ‘turned off’. Through this process, a methyl group (CH3, two carbon atoms and three hydrogen atoms) are added to DNA, which stop it from being expressed. The body does not always need the tremendous amount of genetic information that it codes for and as a result, DNA methylation silences certain parts. While this is an exceptional function allowing our bodies to perform efficiently, certain genes need to be always working such as tumor-suppressor genes; these genes allow our bodies to naturally fight against tumor growth and potentially even cancer development. When methylation turns them off, there is nothing stopping a normal and healthy cell from dividing uncontrollably, which in most cases results in cancer. The accidental inactivation of the tumor-suppressing genes is the root of various forms of cancer and by studying methylation mechanisms, a cure can be devised to deal with cancer. A possible way of addressing this problem is by turning on the gene again. To better understand this concept the following example can be considered: DNA methylation switches the type of hemoglobin being produced in a fetus ver sus after birth. Just by adding a methyl group to the DNA, the type of hemoglobin produced by the body can change. This example highlights how a small change can have a huge impact on the body overall. In addition to this, it is important to consider that the process of DNA methylation is not a negative one. It is an indispensable process for your body, however when it goes awry and methylates necessary genes, a plethora of disorders can form. These range from sickle cell anemia to cancer. This modification of the DNA is heritable and can be passed down through generations. However, a current cure is under development to help reverse this process2 in Dr. David William’s lab with a primary focus on cancer de velopment. Their lab initially started using methylation inhibitors that stop methylation from taking place, how By Prima Gurjar
38
life sciences
Figure 1. Visualization of the process of DNA Meth ylationlaboratory. Image by Priyom Bose.
Gene on, Cancer off; Gene off, Cancer on Turning on genes to stop cancer
References 1.Interview with David Williams, Jr., MD, Ph.D. 02/02/2022 2.Das M. Partha; Singal Rakesh; DNA Methylation and Cancer 2004, https://ascopubs.org/doi/10.1200/ jco.2004.07.151
Figure 2. The process of DNA Methylation is heri table and is passed down generation to generation.
While this process sounds straight-forward, there are many complexities present. The process of DNA meth ylation can only be reversed if the DNA is still unharmed and not mutated otherwise devising a treatment plan becomes increasingly complex since the lost DNA and gene need to be accounted for and replaced. In addition to this, another function of methyla tion is its impact on memory storage and developmen tal skills. If these processes are stopped, they can have unintended and dangerous consequences in the human body. Currently, Dr. William’s research is focused on the cellular level, analyzing potential negative implications before any experiments are performed on animals. Since this research topic addresses increasingly complex top ics, collaboration is vital to its success in producing a possible cure. Different researchers who have masteries in different topics, work together to progress the overall goal of devising a cure for rebooting DNA methylation for the tumor-suppressor gene. Some examples are the analysis of basic structure, attention to molecular detail, and constructing a peptide-drug treatment. Each one of these parts plays an important role in keeping the lab running with innovative ideas that fuel their goals of devising a cure for improper DNA methylation.Alllabs are destined to face some obstacles. In specific, Dr. William’s lab struggles to find a proper peptide-drug treatment that can be delivered to target improper DNA methylation. Even after the researchers were able to manually alter parts to obtain the desired results, the challenge comes in finding a pep tide-drug treatment that would attain the same re sults all on its own. For the treatment to be effective, it must work without any outside intervention. This means that the drug’s molecular structure, chemical properties, and many other qualities all must be exactly what the researchers are looking for. In addition to this, the lab is also studying protein to protein interactions, which are a lot harder to control with the input of a drug treatment. Once this discovery is made however, clinical trials can be run on animals to track the drug’s impacts. If all these steps go according to plan, the lab would progress to test the drug’s impact on humans. Currently the lab is working on finding a proper molecule to be delivered as a drug; if it passes all the necessary requirements, a successful cure for DNA methylation errors could be ad dressed.It becomes evident that a tremendous amount of effort goes into this experiment. Even after facing disheartening results, the cumulative passion and op timism shared for this project can be depicted through Dr. William’s words: “I’m hoping in the near future that we will figure out a way to deliver this peptide that inhibits this com plex in cells. This would be the basis to start testing in animals.”Through collaboration and an impeccable work ethic, Dr. William’s lab hopes on finding a drug that can stop the inactivation of important genes caused by methylation. They have faced many challenges along the way; however, they hope to be able to apply their re search to a wide variety of diseases: breast and epithelial cancer, leukemia, and even sickle cell anemia and other blood disorders.
Source: Image from Alamy. Dr. David Williams life sciences
39 Carolina Scientific ever these inhibitors stopped important genes from be ing turned off as well. It became evident that there were unforeseen side effects leading to undesired changes that harm the body and as a result shifted their focus to studying the protein readers of the methylation. Study ing these readers allow a more specific approach so just the desired area can be targeted, reducing the chances of negatively impacting the body. The lab studies the functions of these proteins in the hopes of being able to turn on indispensable genes to improve bodily function.
When it comes to cancer research, there are many unknowns. Beyond the surface-level knowledge of rapidly dividing cells and attempts to find a way to prevent and treat cancer, scientists have started to dig deeper. Currently, there are new genetic discoveries as to what may contribute to cancer. In order for DNA to fit in our cells, it loops and coils around tiny proteins forming a substance called chromatin. When cells replicate and divide, chromatin condenses into chromosomes, the tiny forms of DNA found in the nuclei of our cells. Within the nucleus, double-stranded DNA is transcribed, or coded, into single-stranded RNA that is then free to move out of the nucleus and into the rest of the cell. Once exiting the nucleus, RNA’s genetic code is translated into a protein through a process called gene expression. Gene expression is an essential process for organisms since it creates the proteins that our cells and bodies use for cellular identity and function. Altered regulation of gene expression is associated with many diseases, including cancer.1 Cohesin, a ring-shaped protein complex, is a molecule that mediates the spatial folding patterns of chromosomes- a process essential to gene expression. Sequencing techniques, methods that are used to determine the entire genetic makeup of a specific organism or cell type, have revealed that cohesin subunits are found in various types of cancer when used on cancer genomes. The Jill Dowen lab at UNC Chapel Hill seeks to understand how structure dictates function: how the spatial folding patterns of chromosomes caused by cohesin influences which genes are expressed and if it serves a role in cancer. “While it’s a beautifully, simple structure-function question, it turns out to be a pretty complicated answer,” explainsCohesin’sDowen.2 protein complex is composed of three core subunits along with components called accessory and regulatory factors. At sites of DNA transcription in the nucleus, when DNA is transcribed into RNA, cohesin appears to extrude chromatin, thus generating a loop of DNA. These DNA loops are the main spatial folding pattern of chromosomes that are essential to the process of gene expression. Recently, sequencing techniques used on cancer genomes have revealed that cohesin subunits are in various types of cancer. Mutations, deletions, and insertions in cohesin complex components are found in several types of tumors and blood cancers. This suggests that cohesin mutations may disrupt its role as a “spatial organizer of gene control” and cause misfunction.1 In order to investigate this, the Jill Dowen Lab utilized the CRISPR-Cas9, a genome editing system made of the Cas9 enzyme and a piece of “guide RNA”. The guide RNA binds to a chosen sequence in DNA and the Cas9 enzyme cuts the DNA at a specific location. This is done so that other sections of DNA can be added or removed. CRISPR-Cas9 was used to introduce a variety of mutated cohesin complexes into murine (mouse) embryonic stem cells. They sought to examine the stem cells’ molecular and cellular consequences. Some of the cohesin variants tested caused changes to transcription and increased the rate by which cancer cells divide in the embryonic stem cells. Additionally, some variants had effects on differentiation, the process by which immature
Cohesin: How to Catch a Culprit in Cancer
40
Dr. Jill Dowen
By Jadan Zawierucha
Image by Flickr. life sciences
Figure 1. Murine embryonic stem cells. Image courtesy of Dr. Jill Dowen
“Cohesin is one of the most mutated protein complexes, but there is still no clear answer as to whether or how it contributes to disease. If we can establish that link, then cohesin research can potentially have a broad reach to many different disease contexts, since it is frequently disrupted in many different types of cancers,” explains Dowen.2 Cohesin mutations are also found in a set of developmental disorders, which are human health problems that are usually recognized at birth, where children are affected with physical and mental issues. Thus, cohesin research does not only pose benefits for cancer in the future; there is a whole other set of human diseases that can possibly benefit from better molecular understanding of how cohesin works and is connected to disease processes.
Dr. Jill Dowen started working with cohesin during her post-doctoral fellowship at the Massachusetts Institute of Technology (MIT) in 2010. When she was still a graduate student and considering what she wanted to work on during her post-doctoral research, she was interested in stem cells and wanted to learn genomics techniques, which were both prominent subjects at the time. She decided to do her postdoctoral work in the Richard Young Lab, which had both of these components. Later in 2015, she established her own lab at UNC and has now built her research program to continue her work with genomic techniques and stem cells. Most of the work in her lab, to date, has been towards understanding the proteins and molecular mechanisms that form spatial folding patterns of chromosomes. This is important in regulating gene expression, “which is a basic question about how our cells function in normal context,” explains Dowen.2 In the future, her team hopes to investigate and understand changes in cell state. As an organism develops, its cells change their gene expression programs, and she wants to know the ways in which genome structure are helping or changing dynamically during that process. Yet, her team is interested in understanding the ways in which these cellular processes can go wrong in order to discover if there is potential to intervene and fix the molecular defects that underly human disease.
References 1. Rittenhouse N.L.; Carico Z.M.; Liu Y.F.; Stefan H.C.; Arruda N.L.; Zhou J; Dowen J.M.; Functional impact of cancer-associated cohesin variants on gene expression and cellular identity 2021, Apr 15;217(4):iyab025. doi: 10.1093/ge netics/iyab025. PMID: 33704438; PMCID: PMC8049558.
41 Carolina Scientific cells take on individual characteristics and reach their mature, or specialized, form and function. Thus, the results indicated that cancer-associated cohesin variants are enough to cause inappropriate gene expression. They also suggest that abnormal cohesin function may contribute to human disease by altering the expression of genes important for proper cellular identity and function.”1
Figure 2. Cohesin Protein Complex. Image courtesy of Dr. Jill Dowen life sciences
2. Interview with Jill Dowen, PhD. 2/16/22
When juggling a million things, sleep always takes a back seat. Sleep is refreshing, and most people are familiar with the effects of a single bad night of sleep. However, the implications of sleep disruption are much more drastic than the general assumption. Dr. Graham Diering, with his lab, studies the mystery of sleep; surprisingly, a process so ingrained in a person’s biological and societal routine still manages to be a topic with multiple doors unopened. After receiving both his B.S. and Ph.D. at the University of British Columbia in Biochemistry, he discovered his interest in neu roscience, and went on to complete a postdoctoral program at Johns Hopkins. At the University of North Carolina at Cha pel Hill, Dr. Diering began researching the molecular mecha nisms of cognition, specifically through the lens of synaptic plasticity. This term refers to the ability of the neural circuits in the brain to shift and remodel, specifically at the sites where neurons interact.1Sleep serves as a timeframe for remodeling the brain, specifically plasticity, which aligns with how sleep can benefit cognitive function. The Diering Lab explores two main avenues; they strive to understand the molecular basis of sleep and how sleep disruption presents itself in various neurological illnesses. The Diering Lab has made substantial progress on an swering their first question of what specific processes, at the molecular level, are ingrained in sleep. A hypothesis that the lab studies is the synaptic homeostasis hypothesis of sleep. This hypothesis refers to offsetting the strengthening of the synapses that occur during the day, when an individual is awake and actively taking in new information, by weakening synapses during sleep; in other words, synapses, or the junc tions between neurons, are weakened during sleep to balance how they are strengthened during the day. A recent review titled “Homer1a and mGluR1/5 Signaling in Homeostatic Sleep Drive and Output” published by the Diering Lab details recent findings regarding a neuronal protein, Homer1a, and its role in supporting the synaptic homeostasis hypothesis. It has been found that the activation of a receptor on neurons, mGluR1/5 by the Homer1a protein is a major driver of this synaptic plasticity in the brain during the sleep cycle. mGluR refers to a receptor on neurons that takes up an excitatory neurotransmitter, glutamate, through a specific method in volving proteins5. The protein Homer1a is important in regu lating synaptic plasticity in the context of sleep and weaken ing synapses, which holds significance for understanding how sleep affects cognition.2 To reach this conclusion, a method the lab employs is quantitative proteomics, which allows re searchers to view multiple proteins, and in this context, allows them to view the composition of an entire synapse. They also used western blots, as shown in Figure 1, where proteins can be visually quantified and used to compare a wake and sleep mouse model. Using mice models extends to answering the lab’s second focus. OF Fundamental Sleep
Figure 1. The Western Blotting Technique. Photo from the Diering Lab. life sciences Image by Pixabay [CDD20]
B Y: S P R I H A A K O L A N U K U D U R U THE DYNAMIC BENEFITS
42
References 1. Citri, A., Malenka, R. Synaptic Plasticity: Multiple Forms, Func tions, and Mechanisms. Neuropsychopharmacol 33, 18–41 (2008).
Figure 2. Photo from the Diering Lab. Artwork created by a member of the Diering Lab.
Dr. Diering studies sleep partly because of the medical implications. Dr. Diering says, “Sleep disruption is associ ated with every single neurodegenerative disease… By treating sleep we can probably benefit lots of different aspects of health and behavior.” 4 The widespread pres ence of sleep disruption in neurodevelopmental disorders led the lab to zoom in on two diseases. To study how sleep is intertwined with wellness, the lab works with two mice mod els: one is manipulated to represent the onset of Alzheimer’s disease, and the other is manipulated to represent the Autism Spectrum Disorder. Using these two models, the lab has been able to track that in the pathology of both illnesses, chronic sleep disruption is one of the first symptoms. Both these ill nesses also present with a decline in cognition and increase in neurodegeneration specifically in the Alzheimer’s model, yet sleep disruption precedes both, therefore indicating a sig nificance in studying sleep as it pertains to neurological dis orders.3As a continuation of this, the lab researches how sleep deprivation changes in its impacts through distinct stages of development. The effects of sleep disruption in children look different than in adults; the primary difference is that sleep disruption is less recoverable in children than adults. From studying the differences in younger mice as compared to older, there is evidence that sleep is required for brain devel opment, primarily in maturing synapses, meaning it is less re coverable earlier in life. However, with this research being con ducted on mice, there is a limitation as to the transferability of knowledge. With mice, the lab cannot account for psychiatric conditions, or accurately assess therapies.4 While these are drawbacks, this research still provides the basis for im pactful future avenues. With the research Dr. Diering has done on the molecular ba sis of sleep, the next step is to understand how this in teracts with other systems and what pharmacology can be used as a treatment.
Currently, pharmacology has lengths to treat sleep disruption, but with Dr. Diering’s research, there are clearer steps towards developing such a drug. Understanding sleep at the molecular level is medically significant and can help the health care industry craft therapies specific to illnesses. Fur thermore, Dr. Diering is interested in finding a way to rescue sleep before the point of neurodegeneration.4 With the ma lignant implications of sleep disruption, Dr. Diering’s research is crucial to maintaining health. It is quite easy to shrug off an hour or two of sleep, but with Dr. Diering’s work, hopefully we can better understand the importance of something as rou tine as a good night’s rest.
43 Carolina Scientific
3. Diering, G. H. (n.d.). The Diering Lab. https://dieringlab.web. unc.edu/ 4. Interview with Graham H. Diering 5. Martin, S. C., Monroe, S. K., & Diering, G. H. (2019). Homer1a and mGluR1/5 Signaling in Homeostatic Sleep Drive and Output. Yale Journal of Biology and Medicine, 92, 93–101.Dr. Graham H. Diering Illustration By Jun Cen life sciences
2.https://doi.org/10.1038/sj.npp.1301559Diering,G.H.,Nirujogi,R.S.,Roth, R. H., Worley, P.F., Pandey, A., Huganir, R.L. (2017). Homer1a drives homeostatic scaling of excitatory synapses during sleep. Science. 355: 511-515.
Genome Initiative, an international team, helped sequence the Arabidopsis genome. Dr. Copenhaver described his experience on the team as a lot of fun and elaborated that “there were sequencing groups from a lot of countries, the United States, Japan, Europe, all working together to try to get the genome done.”1 The genome contains only five chromosomes — threadlike structures of nucleic acids and proteins that carry genetic information — with 25,498 genes encoding proteins from 11,000 families3. The team’s findings “provides the foundations for more comprehensive comparison of conserved processes in all eukaryotes, identifying a wide range of plantspecific gene functions and establishing rapid systemic ways to identify genes for crop improvement”3 When sequencing the Arabidopsis genome, Dr. Copenhaver specifically worked on trying to figure out the location of the centromere in an Arabidopsis chromosome and of its composition. He described centromeres as “molecular handles that help the cell move chromosomes around during division.”1
Figure 1. A picture of the Arabidopsis flowering plant. Photo taken by BlueRidgeKitties/Flickr (CC BY-NC-SA 2.0). Arabidopsis flowering plant holds vast applications life sciences
One may be familiar with mustard, a common condiment eaten with burgers or hotdogs. Shockingly, this ingredient is related to flowering plants seen blooming around UNC Chapel Hill’s campus. These plants include vegetables like broccoli, cabbage, cauliflower, and a less commonly known plant called Arabidopsis thaliana.1 Despite its unfamiliarity, this unsuspecting plant is actually an essential model organism in plant genetic research. Dr. Gregory P. Copenhaver, a professor at UNC Chapel Hill, uses Arabidopsis thaliana as a model flowering plant to understand the complete set of genetic material present in an organism, also known as the genome. He describes the Arabidopsis as the “fruit fly of the plant world.”1 There are several reasons for why Arabidopsis is used as a “test organism” by many scientists involved in plant biology. First, the plant is small, so scientists can grow many plants in a small space. Second, Arabidopsis plants progress rapidly through their life cycles. It takes about seven weeks to go through a complete life cycle from seed to seed, which allows geneticists to go through many generations of plants per year. Third, Arabidopsis was the first plant to have its genome fully sequenced, which was found to be relatively small compared to similar plant species. A full genome sequence gave scientists the ability to experiment with “really powerful genetics and genomics much more attainable for research labs.”1 These characteristics of Arabidopsis made it a very favorable test organism for geneticsTheresearch.Arabidopsis
44
He discovered that the centromeres are composed of moderately repetitive DNA and a core of 180 base pair repeats. Furthermore, he found that DNA within the centromeres of Arabidopsis chromosomes not only serve a structural purpose but also encode several expressed genes.2 Currently, Dr. Copenhaver’s lab at UNC uses Arabidopsis to study a By Neil Sud
THE P OTENTIAL OF THE ARABIDOPSIS THALIANA IN GENETICS AND PLANT B IOLOGY R ESEARCH
Figure 2. A representation of the five Arabidopsis chromosomes. Each chro mosome is represented as a colored bar where the sequenced portions are red and centromeric regions are light blue.3 Dr. Gregory P. Copenhaver.
3. The Arabidopsis Genome Initiative. Analysis of the Genome Sequence of the Flowering Plant Arabidopsis Thali ana. Nature 2000, 408 (6814), 796–815.
References 1. Interview with Gregory P. Copen haver, 2022.
2. Copenhaver, G. P.; Nickel, K.; Kuromori, T.; Benito, M.-I.; Kaul, S.; Lin, X.; Bevan, M.; Murphy, G.; Harris, B.; Parnell, L. D.; McCombie, W. R.; Martienssen, R. A.; Marra, M.; Preuss, D. Genetic Definition and Sequence Analysis of Arabidopsis Centromeres. Science 1999, 286 (5449), 2468–2474.
Dr. Copenhaver specifically highlights the effect of changing temperature due to global climate change and how it affects plant reproductive potential.1 In the future, Dr. Copenhaver’s lab hopes to use Arabidopsis to focus on epigenetics. Epigenetic information is created by modifications to DNA and proteins that associate with DNA. They do not change the information within a gene itself, but instead change the way the cell expresses that gene by controlling how much of the gene is expressed in response to environmental conditions. This is similar to his current work of understanding how environmental factors affect meiotic recombination. Overall, Arabidopsis has become an essential model organism in the field of genetics and plant biology, and Dr. Copenhaver’s work demonstrates the vast applications of Arabidopsis ranging from understanding diseases such as Down Syndrome to biotechnology research.
Dr. Copenhaver’s main goal is to understand how the cell regulates the number and placement of meiotic recombination so that cells undergo segregationchromosomeproperly. life sciences
Syndrome,knownTrisomyconditioninexampleAimbalances.chromosomeinprimaryofthishumansisacalled21,alsoasDownwhere there are three copies of chromosome 21 instead of two. Therefore, it is important for meiotic recombination to happen at least once in every chromosome in order to prevent the mis segregation of chromosomes.1
Dr. Copenhaver’s main goal is to understand how the cell regulates the number and placement of meiotic recombination so that cells undergo chromosome segregation properly. He does this by thinking about it from a geneticist’s point of view, which means that he “breaks things in the genome and sees what happens.”1 For example, if there was a gene in the Arabidopsis genome that he suspects to play a role in meiotic recombination, he would use a gene-editing tool like CRISPR to mutate the gene and see if it alters alsorecombinationmeioticfactorshowUnderstandinginrecombinationmeioticthecell.externalaffectisimportant.
45 Carolina Scientific process called meiotic recombination, the physical interaction of chromosomal DNA between two parent chromosomes. This happens during meiosis in a process called crossing over, where genes transfer from paternal chromosomes onto maternal chromosomes and vice versa to enhance genetic diversity. A cell undergoes meiotic recombination to check if the chromosomes are paired correctly. However, mistakes can arise from this resulting
Crucial to this streamlined approach for genetic analysis is Hi-C technology, which captures the organizational structure of chromatin in 3-D. As Dr. Won
Image courtesy of Vincent Croset (Creative Commons) sciences
life
Invisible Ink: A Systematic Exploration of GenesNoncoding
Dr. Hyejung Won, PhD, Assistant Professor By Ashley Villanueva
An understanding of variants in these regions of DNA is crucial, since psychiatric diseases such as autism, schizophrenia, bipolar disorder, and attention-deficit/ hyperactivity disorder (ADHD), as well as degenerative brain disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer’s, and Parkinson’s, all originate from mutations located in the non-coding portions. However, it is challenging to identify the functions of the noncoding genome for targeted therapeutic outcomes because they are not expressed through proteins in the same way as coding genes are. “We know how to interpret variants located in protein-coding genes,” says Dr. Hyejung Won, a researcher at UNC. “But we don’t have this code or grammar when it comes to the non-coding region, so it’s very difficult to interpret their functional outcome even after we identify their region.”2
During Dr. Won’s doctoral work, she studied transgenic mouse models to characterize a particular gene associated with autism. She aimed to establish the mechanism of autism caused by a specific single gene through observations of the mouse’s phenotype, or its outwardly observable genetic traits. This scientific approach had proven to be unfruitful for many researchers, however, because an unlucky choice of gene to monitor could lead to unproductive examination for a phenotype that could not be easily distinguished. Rather than screening gene by gene, she needed to develop a systematic approach to effectively identify the variants causal to disorders of interest as well as the functions of the genes those variants affected.
46
Astruggle for researchers, as well as those with psychiatric or neurodegenerative disorders, is the difficulty of deciphering of the large network of non-coding regions of the DNA. These non-coding genes, comprising 98% of the human genome and previously understood to be the “junk” of genetic material, have been found to play an important role in the functions of cells and regulating gene activity.1
References 1. What is noncoding DNA? https://medlin eplus.gov/genetics/understanding/basics/
Neurosci.Rajarajan,3.2.known%20purposepercent%20of,%2C%E2%80%9D%20with%20no%20noncodingdna/#:~:text=Only%20about%201%20(accessedFebruary25th,2022).InterviewwithHyejungWon,Ph.D.2/25/22.Sey,N.Y.A.;Hu,B.;Mah,W.;FauniH.;McAfee,J.C.;P.;Brennand,K.J.;Akbarian,S.;WonH.Nat.2020,23,583–593.
Figure 1. Cell-type specificity is exhibited in the extent of overlap between neurons and glial cells in Dr. Won’s devel opment of H-MAGMA. Image courtesy of Dr. Won life sciences
47 Carolina Scientific completed her post-doctoral program at University of California at Los Angeles, she and her colleagues utilized this newly developed technology to study the two groups of non-coding genes associated with autism: synaptic and chromatin regulators. Mutations of chromatin genes, which are mainly expressed in fetuses, have long lasting developmental consequences. With the help of Hi-C, Dr. Won was able to develop a chromatin structure map of the fetal cortex, which she was driven to use to determine the functions of non-coding genetic variants.Through these findings, Dr. Won has developed a systematic approach for pinpointing functional variants, the genes they will affect, and what they will do for her current and future research endeavors. First, she utilizes Massively Parallel Reporter Assay (MPRA), a screening platform that simultaneously observes the activity of thousands of genetic variants in a single experiment, to determine which variants are causal to specific disorders. Next, she considers which gene specific variants are going to affect using the Hi-C technology she was able to utilize in her post-doc. In some of her more recent research, she has developed technology called Hi-C-coupled MAGMA, or H-MAGMA, which gathers brain tissues from chromatin interaction profiles across multiple developmental periods and brain cell types.3 Finally, in her last step, she is able to figure out what these genes are doing with the ultimate objective to better understand the mechanism of the gene. This is enabled through Clustered Regularly-Interspaced Short Palindromic Repeats (CRISPR), a tool that allows researchers to modify genomes. Every successful research career also has its challenges. One of Dr. Won’s greatest struggles, along with others in her field, is cell type specificity, or the measure of one gene compared to others in the data set. The brain is a heterogeneous organ, meaning it has variability in its cellular composition. For example, characteristics of postmortem ASD brains are upregulation of glial genes and downregulation of neuronal genes.3 When studying a specific gene, it can be challenging to regulate for the specific expression one is looking for, but in her study regarding the development of H-MAGMA, Dr. Won et.al. were able to detect 20-40% of cells in a cell-type specific manner (Figure 2). 3 A second major problem is variability in mechanisms causing neurogenerative or psychiatric disorders even within people diagnosed with the same problems. A single therapeutic approach is not possible for every person with a disorder or disease. With precision medicine, professionals examine the wholistic lifestyles of individuals so they are able to receive personalized care for their disorders. Alternatively, research like Dr. Won’s has allowed for researchers to examine convergence across mechanisms. If there is a great amount of convergence, larger groups of people would be effectively impacted by a single therapeutic approach.Asoverbearing as the attempt to understand unexpressed gene functions and variants is, researchers such as Dr. Won are making great strides for those with psychiatric and neurodegenerative disorders through utilizing current technologies to create a systematic approach.
Overcoming the Odds: How Early Childhood Adversity Influences Brain Development
48 psychology & neuroscience
Despite what a high school genetics teacher might say, not all of who we are is hereditary. While there is no clear answer to which force more powerfully influences human development, research has shown how environmental factors hold their ground in this fight.
Dr. Margaret Sheridan is an assistant professor at the University of North Carolina Chapel Hill’s Clinical Psychology Program and the director of the Child Imaging Research on Life Experience (CIRCLE) Lab on campus, where she conducts research on how early childhood experiences influence brain development. Before her interest in psychology began, Dr Sheridan was a theater major. She found herself captivated trying to understand the characters featured in plays and discovered her interest in psychology. In graduate school, Dr. Sheridan studied how socioeconomic status can influence brain function and continues to make advancements in these disciplines today. More recently, Dr. Sheridan published a series of papers using data from the Bucharest Early Intervention Project, a study that began in 2000, in which children who were abandoned at birth in Bucharest, Romania were randomly assigned to remain in institutional care or be placed in highquality foster homes.1 The goal of the study was to investigate the impact of early childhood caregiving on development, investigating if and how environmental factors during childhood influenced individuals. In her publication, Causal effects of early caregiving environment on development of stress response system in children, Dr. Sheridan uses the same sample from the Bucharest Early Intervention project to investigate the impact of institutionalization on physiology. The study found that children who remained in institutionalized care displayed
The ‘nature versus nurture’ debate has been ongoing among scientists for decades, in which the concept of “nature” alludes to how genetics influences human development, whereas the concept of “nurture” centers around the influence of environment factors on development.
Dr. Margaret Sheridan Figure 2. Dr. Sheridan is currently working on studiesneuroimagingusingfMRI to investigate how early life experiences impact neuronal development.
By Gillian Arleth
The Bucharest Early Intervention project is a longitudinal study that will continue to follow these children for years to come to see the long-term effects of childhood adversity on development. In the meantime, Dr. Sheridan and colleagues have numerous projects underway through the CIRCLE Lab.
49 Carolina Scientific psychology & neuroscience a blunted, or less reactive, response to stress.2 Interestingly, the children who were randomly assigned to foster care had responses to stress that were normal for developing children.
The ongoing Wellness Health and Life Experiences (WHALE) Study identified young children between 4 and 7 years old as facing early life adversity. Neuroimaging and interviews are being conducted to examine any differences between children who face a deprivation in caregiving vs children exposed to violence. Another study that is currently underway in the CIRCLE Lab is the Study of Toddler to Teenager Anxiety and Resiliency (STTAR) Study.
2 This suggests that family care has an impact on physiology, including stress responses. Due to the random assignment involved in the study, causal relationships can be drawn, which is quite remarkable. Dr. Sheridan further explains this and states, “What’s amazing about this study is one can see whether changes in physiology were caused by the family care. This is one of the first times that we can really show a causal relationship”.3Additionally, the time in which a child was placed into foster care had an impact on the physiological results.
References 1. Bucharest Early Intervention Project https://www.bucha restearlyinterventionproject.org/ (accessed February 19th, 2.2022).McLaughlin, K; Sheridan, A; Tibu F; Fox, N; Zeanah, C; Nelson, C. PNAS. 2015, 112, 5637-5642.
The study found that earlier placement into foster care was associated with more intense cortisol responses.2 The adrenal cortex, which sits on top of the kidneys, releases several hormones in response to stress, including cortisol, a primary stress hormone (Figure 1). The release of cortisol serves as a homeostatic response to stress where the body tries to restore a stable equilibrium. Dr. Sheridan and colleagues also found that when children were removed from institutionalized care and placed into foster homes before they were 24 months old, they displayed a significantly greater cortisol response than those placed into foster care after 24 months old.2
3. Interview with Margaret Sheridan, Ph.D. 02/10/22
In collaboration with Duke University, researchers are following up with adolescent individuals who faced early childhood adversity. Together these ongoing projects are enhancing our understanding of the long-term effects of early childhoodResearchadversity.is emerging that indicates how early childhood experiences can have significant impacts on neuronal development. Many of these studies are still ongoing since it takes years of commitment to fully investigate the longitudinal impacts of early life adversity. Dr. Sheridan and other researchers in the field are developing new and innovative ways to investigate these complex research questions and reexamine how we think about the unending nature vs nurture debate.
“The study found that children who remained in institutionalized care displayed a blunted, or less reactive response to stress.”
Figure 1. HPA axis and cortisol release is modulated by early childhood adversity. Children who were removed from institutionalized care and placed into high-quality foster homes showed more intense cortisol responses.
50
to COVID-19. iStock experts/)covid-19-stress-coping-healthy-habits-usc-social-science-(https://news.usc.edu/167512/ psychology & neuroscience
Figure 3. Individual Struggling
The study showed that counterfactual thinking can be an important part of processing stressors or major life changes.1 She believes that “immersing oneself in the counterfactual thought is actually more beneficial than letting it run through one’s brain over and over again” because the process allows individuals to learn from these experiences and move on.2 For example, instead of thinking “I wish I had studied more for this test,” it is more helpful to think “If I had spent an extra hour studying for this test, I would have understood the connection between the brain and hormones better and I could have gotten a better grade on the test and class.” Additionally, immersive counterfactual thinking can lead to better outcomes in the future when the same obstacle is presented again or when a stressor is persistent for an extended period of time (Figure 2).
Counterfactual Thinking: Turning What-ifs into Stress Busters
Dr. Natasha Parikh with Stressors Related
By Simran Bhatia
Many college students today consider themselves overthinkers. An exam may go unexpectedly poorly, and overthinkers often find themselves frantic, and begin to brainstorm ways they could have avoided the unfortunate predicament thinking “If only I had studied more for this test….” or “What if I had just stayed in last night...”. Many people fall victim to this phenomenon, known as counterfactual thinking. But they are not alone: almost everyone experiences counter-factual thinking on a regular basis.1 Dr. Natasha Parikh, a professor of psychology at UNC-Chapel Hill, is particularly interested in the mechanisms of counterfactual thinking. She studies how this pattern of thinking can be used to one’s advantage as a healthy way of managing stressors and coping with negative situations. During her time as a doctoral student at Duke University, Dr. Parikh noticed that while some of her peers thrived in stressful environments, others seemed to face more challenges in accomplishing their goals. She wondered why individuals react differently to stressors and how the persistence of these stressors can impact a population (Figure 1).2 These curiosities inspired Dr. Parikh to research counterfactual thinking. In a recent research study, she observed a group of participants that were tasked to ruminate on significant events that had taken place in their life over the past five years. The participants then generated counterfactual scenarios that may have led to better or worse outcomes during these events.1
psychology & neuroscience
The process also has extensive applications in helping individuals recover from trauma or manage their stressors in clinical therapy. Currently, therapeutic methods such as imaginal exposure or imagery rescripting employ remarkably similar mechanisms to counterfactual thinking.2 Patients may work through negative emotions while processing traumatic events. Although these methods are accepted by therapists and other mental health professionals, there is very little existing scientific evidence to support their claims. However, Dr. Parikh believes that her research can support professionals by providing the necessary evidence to confirm the benefits of counterfactual thinking while discovering ways to innovate existing treatments.2Dr.Parikh is currently working on applying her research on counterfactual thinking to a new study that monitors the emotional, social, and cognitive development of children and young adults navigating childhood and adolescence during the COVID-19 pandemic. According to Dr. Parikh, her project is, “one of the few that has data from before and will potentially have data from after the pandemic”.2 Due to the wide breadth of this data, she will be able to observe the pandemic’s impact on the normal trajectory of development for children of various ages. Additionally, she will study how children have managed the longterm stress associated with the pandemic. In her own words: “It’s caused so much change in their day-to-day lives, not having school for a while or being with family so much more—especially the teenage years when social life is so important. So, we are really interested in all the changes that have occurred because of the pandemic, largely in social and family relationships, and then how that is affecting their stress levels in dealing with the pandemic” (Figure 3).2
References 1. Stanley, M. L.; Parikh, N.; Stewart, G. W.; De Brigard, F. Conscious Cogn. 2017, 48, 283–291. 2. Interview with Natasha Parikh, Ph.D. 02/10/22. Figure 2. Young Adult Overwhelmed with Anxiety. Image Courtesy of VectorStock by Ma_Rish
Researchers have been highly susceptible to the challenges presented by the COVID-19 crisis. The pandemic’s unpredictability adds further difficulties to ongoing research, specifically when recruiting study participants. Dr. Parikh observes that people are less likely to participate in research studies due to health concerns. While this is certainly an obstacle, like most researchers and scientists working today, Dr. Parikh’s priority is to ensure that all participants are comfortable participating in research. She believes that it is of the utmost importance to remember that research participants are not numbers on a page and that it is crucial to respect their feelings and acknowledge that they may be managing major stressors.2 In the future, Dr. Parikh hopes to expand on her current research by exploring sibling relationships and how those dynamics have changed during the pandemic. She also hopes to continue researching counterfactual thinking related to COVID-19 directly to understand how this psychological process may change people’s perspective on the stressors they faced regarding the pandemic.
51 Carolina Scientific
52
Bilingualism, the mastery of two languages, connects people across the world in immeasurable ways. Even still, psychologists such as Dr. Carla Fernandez, strive to measure the impact of bilingualism through her research. Dr. Fernandez, and other psychologists who focus on language science, investigate the interaction between bilingualism and neurological processes and structures. One focus of Dr. Fernandez’s research is bilingualism’s impact on language acquisition, or the learning of new languages. Her research is personally significant because of her identity as a SpanishEnglish bilingual. Additionally, her native country, Paraguay, has two official languages: Spanish and indigenous Guaraní. The prevalence of people fluent in two languages during her upbringing also shaped her passion for studying bilingualism. Her most recent study, “Overlapping and distinct neural networks supporting novel word learning in bilinguals and monolinguals” investigated the relationship between integration of new words and the amount of languages known. In this experiment, twenty-four English monolinguals and twenty-four Spanish-English bilinguals learned two sets of Swahili words over the course of two days and then tested on the second day while in an fMRI. Swahili is not a common language in the U.S, and most language studies use Romance languages, which made this study unique. It also allowed the researchers to better evaluate if the participants were truly learning.Theresults of the memory tasks and recorded brain activity showed that there was not seemedmonolingualsbilingualsEssentially,norofateitheracquisitioninoutperformanceanlanguagefromgroupanystagethetestingtraining.andtohavesimilar capabilities of learning new words in an unfamiliar language like Swahili over a short period of time based on how their memory task performance. Additionally, the overall findings show that there is overlap for the areas of the brain in word retrieval and recognition for monolinguals and bilinguals. The study did find differences despite the observed overlap in neural structures, such as those with dual fluency had more brain activity in the overall IFG region of the brain. Monolinguals however, had greater right-side IFG activity, which is an area of the brain that recent studies show are a crossroads for abstract and concrete knowledge. Activation in different areas of the brain displays that mastering more than one language does impact learning. These findings represent the relationship between Dr. Carla Fernandez
Figure 1. A human brain. Photo by iStock.
Is Being AdvantageousBilingualforLearning New Languages?
Image courtesy of Raziakhatun12, CC BY-SA 4.0, via Wikimedia Commons psychology & neuroscience
© V. Yakobchuk/Fotolia
By Hannah Garner
discovers more about the properties of bilingualism and mental structures, it shows how language acquisition undoubtedly shapes social life. Connection to others is bilingualism’s greatest advantage. Dr. Fernandez’s research supports her personal belief that bilingualism is valuable because it connects us to our heritage.Dr. Fernandez has worked on studies that consider toddler’s brain structures while learning a new language and how identity affects dialect expectations. She also has presented at various conferences in her field, including a presentation at Cambridge University about code switching for Spanish and English. Currently, she is working on publishing literature on how the stereotyping of physical features leads to expectations of that person having an accent, while also investigating stigmas held towards people with accents. Her current work furthers our understanding of bilingualism’s involvement with socialization and social structures. Research that displays how bilingualism is an asset for life potentially will reduce the stigma that can be associated with being multilingual, such as having an accent, and increase appreciation for this skill.
53 Carolina Scientific language acquisition and languages spoken, however there are limitations. It could be difficult to generalize this study to the practicalities of learning a language in real life because of the study’s use of Swahili. Meaningfulness of a word influences its integration into memory, and using an unfamiliar language made the words less meaningful for the participants. Using Swahili equalized the evaluation of bilinguals and monolinguals, but potentially decreased the accuracy of how people learn languages in their daily lives. Another necessary consideration is that the experiment’s design used visual presentations, which possibly could have influenced the results. Recent research has shown bilinguals have an advantage in learning new languages when the information is presented audio-visually or through audio. This suggests that the same information might be encoded differently based on where the information comes from, and that retrieval of the information might also differ. Based on these findings, Dr. Fernandez wants to further analyze how a different design will impact the depth of learning observed. Researchers can alter this design by expanding the amount of time between learning the words from two days to a greater length of time, such as a week. By lengthening the learning period, researchers may observe different areas or levels of brain activity because it will provide participants with more time to encode and learn. The process of learning over an extended period of time may differ from short-term learning. This process could potentially differ between monolinguals and bilinguals, which would further highlight how multilingualism can alter brain mechanisms. Fernandez suggests that using an EEG could also be useful as prior research has shown seeing a word only once produces unconscious neural activity. Unconscious neural activity would display learning that is occurring implicitly and unknowingly, instead of declarative learning that is measured on memory tasks.
References
1. Interview with Carla Fernandez, PhD. 02/11/2022.
Figure 2. Activation differences between monolinguals and bilinguals in response to learned (recent and remote) Swahili words. Bakker-Marshall, I., Takashima, A., Fernandez, C., Janzen, G., McQueen, J., & Van Hell, J. (2021). Overlapping and distinct neural networks supporting novel word learning in bilinguals and monolinguals. Bilingualism: Language and Cognition, 24(3), 524-536. doi:10.1017/S1366728920000589
Figure 3. Words. Photo by iStock. psychology & neuroscience
2. Bakker-Marshall, I., Takashima, A., Fernandez, C., Janzen, G., McQueen, J., & Van Hell, J. J. Bilingualism: Lang. and Cogn. 2021, 24(3), 524-536.
3. Della Rosa PA, Catricalà E, Canini M, Vigliocco G, Cappa SF. J. Neuroimage. 2018, 175, 449-459.
4. Johnson JS, Newport EL. J. Cogn Psychol. 1989, 1, 60-99..
lifeconsidermultilingualismResearchingmustaspectsofsuchaseducation, socialization and connection, memory, problem solving, and more. Views on bilingualism are continuously changing. Dr. Fernandez commented on her own history; her grandmother believed being raised bilingual from a young age would confuse Dr. Fernandez and lessen her understanding of language when she was a child. Contrary to what Dr. age.languagebestshowsbelieved,grandmotherFernandez’sresearchthatthetimetolearnaisatayoungAsresearch
5. Fernandez, C., Campbell, E., Bachman, M., Woldorff, M., & Bergelson, E., ResearchGate 2021. 6. Walker, A., Fernandez, C., & van Hell, J., ResearchGate 2020.
Testing your knowledge solidifies your memory
Colorful image of generic brain with various highlighted. Pixabay, accessed through Stockvaultpsychology & neuroscience
Death by Review: Why Restudying is NOT the Best Strategy for Your Memory
Photo by
54
lobes
By: Meitra Kazemi
Think back to the last time you found your mind wandering. We have all experienced it. One minute you are hard at work and the next you are picturing yourself on vacation at the beach. It is commonly understood today that paying more attention to a subject can help you remember it. Dr. Neil Mulligan is a Professor of Psychology and Neuroscience at the University of North Carolina at Chapel Hill studying attention and memory, two vital functions in the lives of disciples of the arts, sciences, and many other fields. He worked on research describing Attention and the Testing Effect1 as well as The Testing Effect Under Divided Attention2, in 2016 and 2017 respectively. Dr. Mulligan describes the testing effect as “the idea that retrieving information from memory can help you learn that material more effectively, under some conditions, than if you were to restudy the material.”3 For example, if you complete a textbook reading for a class, you will better solidify the information in your memory by testing yourself on the material rather than restudying the material by rereading or highlighting your notes.3
This concept is expanded upon further in his articles, in which he describes the findings of his studies that providing divided attention while studying can have a large negative effect on the initial learning and storage of information, also Figure 1. Bar graph depicting information recall under 2 attention conditions and restudy vs. retrieval conditions.
Dr. Neil Mulligan
55 Carolina Scientific known as encoding. However, divided attention has little effect on one’s ability to recall the information, also known as memory retrieval.1,2 His work investigates the idea that retrieval is a learning experience itself, and despite the student and teacher perspective that tests only measure knowledge, they can also be learning experiences.3 Dr. Mulligan’s studies measured the role of attention in memory through use of three phases.1,2 In the first phase, participants studied a set of assigned word pairs.1,2 The second phase involved splitting the participants into groups that either restudy the word pairs or are tested on their knowledge to activate retrieval.1,2 Within the second phase, participants were also split into groups where some were allowed to focus on the material fully. Other participants were asked to do another task, like identifying odd numbers, while working on their assigned function for phase two.2 Lastly, the third phase administers a memory test for the material to see whether the retrieval groups or restudy groups remember more of the information.1,2Dr.Mulligan’s results showed that participants from the restudy group of phase two performed worse on the test from phase three than individuals from the retrieval group.1,2 However, when participants are distracted during their retrieval periods, there is no decrease in memory on the final test.1,2 The lack of memory decrease presented indicates that distraction can harm one’s restudying but not their ability to recall the initially learned information. This unusual outcome indicates that retrieval-based learning may have different characteristics than other kinds of learning, such as its relative immunity to distraction.3 Dr. Mulligan proposed the observed resilience to interference may contribute to the benefits of testing for memory retrieval.3 It may be that when you take a test, it insulates you from the omnipresent negative effects of distraction in one’s environment or through internal thoughts.3Despite these results, it’s important to keep in mind that intentionally adding in distractions may not be the wisest studying technique.3 As Dr. Mulligan says, “distraction didn’t help learning with the retrieval-based learning. It just didn’t harm it the way it harms other sorts of learning. The idea is that adding distraction on purpose wouldn’t help anybody, it just might not hurt the effectiveness of retrieval-based learning like self-quizzing and self-testing compared to what might happen if you’re trying to study by re-reading sections that you highlighted previously.”3 Therefore, rereading or highlighting texts is much more susceptible to negative impact from distractions than self-quizzing.3 Mulligan added that there is evidence that doing retrieval-based learning actually makes it easier to stay on task and less likely for your mind toThewander.3outcomes of these two studies expressed some unexpected findings as we see that distraction does not seem to impact how well we recall information, but it can be extremely detrimental to our ability to learn the information initially.1,2 The studies also displayed that reviewing and restudying material have a higher susceptibility to distraction when compared with self-testing methods.1,2 Overall, these results can help guide one’s choice of which study strategies to employ when learning new material and suggest that our understanding of how we learn new information continues to have room for further exploration. Remember — if you catch your mind wandering back to those sheep, it may be time to change up your study methods.
psychology
& neuroscience
3. Interview with Neil Mulligan, PhD. 2/18/2022. 4. Pixabay. (2016). Graphical Brain. Stockvault. Retrieved February 18, 2022, from https://www.stockvault.net/pho to/199820/graphical-brain.
Figure 2. Bar graph depicting conditional (on retrieval in phase 2) information recall across 2 attention conditions and restudy vs. retrieval groups.
References 1. Mulligan, N. W., & Picklesimer, M. (2016). Attention and the testing effect. Journal of Experimental Psychology: Learning, Memory, and Cognition, 42(6), 938–950. https:// 2.doi.org/10.1037/xlm0000227Buchin,Z.L.,&Mulligan, N. W. (2017, May 15). The Test ing Effect Under Divided Attention. Journal of Experimen tal Psychology: Learning, Memory, and Cognition. Advance online publication. http://dx.doi.org/10.1037/xlm0000427
Figure 3. Bar graph depicting unconditional information recall across 2 attention conditions and restudy vs. retrieval groups.
56 Heidi Cao WebTreasurerEditor/ Carolina Scientific Executive Board Isaac Hwang Associate FundraisingEditor/Chair Divya Narayanan Editor-in-Chief Megan Butler Editor-in-Chief Gargi Dixit Copy Editor Sarah (Yeajin) Kim Design Editor Megan Bishop Managing Editor Robert Rampani Associate EditorMaddy Stratton Associate Editor
57 Carolina Scientific Work for Carolina Scientific! Carolina Scientific is always looking for staff writers, designers, and illustrators! If you are interested, please contact carolina.scientific@gmail.comFindusonfacebookfacebook.com/CarolinaScientificFollowusontwitter@UNCSciCheckoutourwebsitecarolinascientific.orgFollowusoninstagram@carolinascientific Are you interested in communicating science to a broad audience? Do you want to engage in thought-provoking investigations? Does your passion for the sciences extend into the world of research? Do you want to combine your creative talents with your fasincation with the science?
58 “The more clearly we can focus our attention on the wonders and realities of the universe about us, the less taste we shall have for destruction” - Rachel Carson 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. Image by Ildar Sagdejev, [CC-BY-SA-3.0]. SpringCarolinascıentıfic2021Volume13|Issue2
