Fall 2021-- Re-Shaping Our Understanding of RNA

Carolina Scientific

Carolina

scıentıfic FALL 2021 | Volume 14 | Issue 1

—RE-SHAPEING OUR UNDERSTANDING OF RNA— full story on page 10 1

PAST EDITIONS OF CAROLINA SCIENTIFIC

Check out all of our previous issues at issuu.com/uncsci.

As the organization continues to grow, we would like to thank our Faculty Advisor, Dr. Lillian Zwemer, for her continued support and mentorship.

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Carolina Scientific

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

Letter from the Editors: The past two years have revealed the importance of scientific research to the general public like never before. At UNC, we are lucky to have investigators at the forefronts of their fields – from public health to cosmology, and even science education. We hope this semester’s magazine gives you a diverse and accessible snapshot of the exciting research happening on campus.

Whether it is how targeting a lesser-known molecule, RNA, could save lives (p. 10), why space travel advances aging (p. 24), or how Black men receive less preventative testing for HIV (p. 28), we want the magazine to inspire you to not only learn more about research at UNC, but to ask the difficult questions and seek the evidence for answers in your everyday life. We hope you enjoy!

- Divya Narayanan and Megan Butler

on the cover

“Rather than fixating on proteins, why not exploit RNA to develop drugs and therapeutics?” Dr. Kevin Weeks’ lab developed a technology called SHAPE, that in conjunction with mutational profiling, create what Dr. Weeks describes as a “chemical microscope.”

Full story on page 10.

Photo courtesy of Creative Commons.

carolina_scientific@unc.edu carolinascientific.org instagram: @carolinascientific facebook.com/CarolinaScientific

Executive Board Editors-in-Chief Divya Narayanan

Megan Butler Design Editor Sarah (Yeajin) Kim Copy Editor Gargi Dixit Web Editor Heidi Cao & Publicity Chair Associate Editors Maia Sichitiu Megan Bishop Robert Rampani Faculty Advisor Dr. Lillian Zwemer Contributors Staff Writers Copy Staff Kayla Blades Kruti Bhargav Kylie Brown Ambika Bhatt Henry Bryant Nicholas Boyer Ellen Han Ash Chen Xiaolong Huang Gargi Dixit Isaac Hwang Aastha Dubal Lasya Kambhampati

AJ Ferido Sprihaa Kolanukuduru

Isaac Hwang Sophia Palmieri Nisha Lingam Neha Saggi Divya Narayanan Kanishka Shah Claire Nolan Neil Sud Stephen Thomas Maya Ticku Sreya Upputuri Ashley Villaneuva

Alexandra Yarashevich Jadan Zawierucha Kelly Yun Designers Julia Bay Siona Benjamin Tanisha Choudhury Emma Craver Sarah (Yeajin) Kim Ridhi Yarlagadda Kelly Yun Cassie Wan

Illustrator(s) Tanisha Choudhury

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Carolina Scientific

Life Sciences the truth behind Tau Pro6 Unraveling tein Ashley Villaneuva

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contents

Medicine & Health Therapy Interventions: 20 Endocrine Helping Women Accesss the Care they 22

Neil Sud

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Re-SHAPEing our understanding of RNA Kayla Blades

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the Cell Code: Cellular 12 Hacking Reprogramming for Cardiac Diseases

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Henry Bryant

Environmental Science in the Air: How Birds Use the 14 Life Environment to Fly More Efficiently 16

Need Endometrial Cancer and Obesity

The Discovery of "RiboSNitches" and its Relation to RNA Structure

Ellen Han

Captain, we shrunk the sharks!

Sophia Palmieri

Physical Science interaction's impact on 18 Cannibal the Early Universe

Lasya Kambhampati

The Shield of Our Hearts: Exploring How and Why Our Defenses Fall in Space Isaac Hwang

Phototherapetutic Technology Lightens the Load on Rheumatoid Arthritis Kanishka Shah

Never Tested: A Community-Based Investigation into the Lack of HIV Testing Maya Ticku

Psychology & Neuroscience the Gender Gap in 30 Narrowing STEM Through Changing Attitudes 32 34

Xiaolong Huang

Kylie Brown

How much do we truly know about the brain?

Jadan Zawierucha

The Maze of Substance Use Disorders Sprihaa Kolanukuduru

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Life Sciences

Unraveling the truth behind Tau Protein Compounds to minimize the tangling of tau proteins

By Ashley Villanueva

Photo of beta-amyloid protein clump disrupting neuron function in the brain.

Image courtesy of National Institute on Aging.

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or most, memories serve to ground and orient, allowing humans to form meaningful attachments and make crucial associations between ourselves and our surroundings. From problem solving to spatial awareness, memory is the basis of people's productive daily lives. However, many over the age of 65 begin to worry about the gradually debilitating effects of Alzheimer’s disease (AD), where the progressive loss of neurons and shrinking of brain regions cause familiar tasks to become confusing and difficult. For years, scientists have explored options to alleviate the effects of Alzheimer’s or slow its progression.

The first step of prevention against this

widespread and devastating disease begins with determining its pathological mechanism.

In 2017, Dr. Todd Cohen and his team made groundbreaking discoveries regarding the mechanism behind acetylation of tau proteins.

The twofold mechanism begins with the disengagement of the tau protein from microtubules, which are parts of a neuron that transport substances to other parts of the cell. In the second step, tau proteins aggregate. Acetylation is a post-translational modification PTM) involving the attachment of an acetyl group to a protein. PTM is a process that happens after proteins are synthesized and is important to their

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development. Dr. Cohen and his team discovered that the acetylation of tau

Figure 1. Photo of tau proteins in neurons of a tissue culture. Image by Gerry Shaw.

Life Sciences

Carolina Scientific proteins can cause protein clumps or techniques from a variety of different tangles in the brain that are associated fields to answer his research questions. with the neurodegenerative symptoms For instance, although he was initially in Alzheimer’s disease.1 These protein inexperienced in electrophysiology, he clumps form due to the presence of now applies the technique to assess amyloid-beta proteins, which normally how neurons fire. With skills relating restore and repair neurons, but can to biochemistry, he is able to purify also transform into plaques outside of proteins and understand how tinkering neurons that send signals to provoke with them can change their behaviors. the tangling. Amyloid-beta plaques Other methods of research to and tau tangles form the basis of most study Alzheimer’s disease include Alzheimer’s research.2 cell cultures. In culture, scientists can In the past few years, Dr. observe how neurons die, and animal Cohen’s lab has shifted its laboratory behavior observations to learn more approach from investigation of the about how humans could react to dual-mechanism to its potential clinical Alzheimer’s without using humans for applications. Substantial evidence testing. Animal models are useful for supports that the acetylation of tau researchers to understand how a disease proteins cause tangles in the brain can manifest in the entire organism. andkill neurons. As a result, researchers Mice modeling the progression can now develop drugs or antibodies of Alzheimer’s Disease are closely that target the proteins in an effort to monitored to track how their cognition alleviate or stop the progression of the slowly fades over time.2 Using a hiddendisease. Dr. Cohen says that his team platform water maze, Dr. Cohen can now focuses on assess the mouse’s brain “g e n e r a t i n g function specifically in “If we can do a small the actual the hippocampal brain part to advance the compounds” region. Essential to with “more of understanding of how learning and memory, a translational the hippocampus is you treat a patient approach, so especially vulnerable or whether there’s a we can advance to degeneration in the things in the biomarker that can tell early stages of AD. This clinic”.1 experimental technique you if someone is going demonstrates However, the scientific mouse’s propensity for to get Alzheimer’s research is never spatial learning, which is disease, we can work an easy task. something that typically towards stopping Many researchers declines in Alzheimer’s face challenges disease. Exploration in progression... for me, across the the field of neurobiology that’s the ultimate board, ranging guides Dr. Cohen and his from scientific, team to understanding goal. ” psychological, where proteins are and financial going in a neuron. The problems. It can even be difficult to lab observes postmortem brain tissue decide where to begin and which to study what the brain looks like after questions to start answering. “It’s very severe Alzheimer’s and to discover challenging and not very rewarding which pathological mechanisms are because you’re spending more time appropriate to occur in humans. From optimizing and troubleshooting than neuroscience to biochemistry, Dr. Cohen you are figuring stuff out. But when you synthesizes a variety of techniques do figure things out, it’s one of the most achieve his scientific goals. rewarding things in the world”,1 shares Although Dr. Cohen and his team Dr. Cohen. have contributed greatly in the field of Although Dr. Cohen has Alzheimer’s research, there is still great formal education in microbiology room for growth and more to be learned and pharmacology, he has utilized about the acetylation of tau proteins

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and the types of compounds that could be developed to alleviate their clumping in neurons. “It comes in bits and pieces,” says Dr. Cohen. “If we can do a small part to advance the understanding of how you treat a patient or whether there’s a biomarker that can tell you if someone is going to get Alzheimer’s disease, we can work towards stopping progression... for me, that’s the ultimate goal.”1

Dr. Todd Cohen

References

1. Interview with Todd Cohen, Ph.D. 9/17/21 2. Hanna Trzeciakiewicz, Jui-Heng Tseng, Connor M. Wander, Victoria Madden, Ashutosh Tripathy, ChaoXing Yuan & Todd J. Cohen. Scientific Reports. 2017, 44102.

Illustration

by Tanisha Choudhury

Life Sciences

The Discovery of “RiboSNitches” and its Relation to RNA Structure

By Neil Sud

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veryone’s deoxyribonucleic acid (DNA) genetic makeup is 99% identical—it’s the 1% difference in DNA that makes everyone unique. Changes in the DNA are called mutations and can lead to a variety of appearances biologists call phenotypes. Genetic mutations can even cause diseases such as cystic fibrosis and color-blindness. To understand the mechanisms behind genetic mutations and how they lead to different phenotypes, it is important to understand a lesser known but just as important molecule called ribonucleic acid (RNA). Before DNA is converted to a protein to perform specific functions, DNA is first converted into RNA. Dr. Alain Laederach, a professor in the department of biology at the University of North Carolina at Chapel Hill, does extensive research on this topic. He aims to understand the relationship between human genetics, what makes all of us different from each other, and RNA by studying the central dogma of biology.

The central dogma of biology consists of three steps: replication, where existing DNA is copied to make new DNA; transcription, when segments of DNA are transcribed into messenger RNA (mRNA) molecules; and translation, during which the mRNA molecules are translated to produce a sequence of amino acids. Amino acid sequences eventually make up the proteins that perform various functions for the human body. RNA plays a very important role in this process and determines what makes all of us different from one another. Since DNA gets transcribed into RNA, any mutations in DNA also appear in the RNA. Dr. Laederach described his research, more specifically, as “the interface of how mutations affect the way that the RNAs our cells produce ultimately control gene regulation and, at the end of the day, phenotype.”1 Genotypes refer to the combination of alleles that code for a specific phenotype. Dr. Laederach’s lab at UNC is interested in all aspects of RNA structure and folding, examining RNA both computationally and experimentally. The way that RNA folds can affect the proteins that are produced leading to different phenotypes. This idea of RNA structure affecting gene expression is especially important in Dr. Laederach’s research.

Figure 1. Dr. Laederach (middle) and his lab team. Photo by the Laederach Lab Every living organism must be able to sense and respond to environmental stimuli on the cellular level, meaning that genes need to be able to get “switched” on and off based on the environment.2 When studying this concept, Dr. Laederach developed the term “RiboSNitches”, a word he created that is based on well-studied elements in the RNA of bacteria called riboswitches. Notice the difference in the spelling--the idea of a riboswitch is that the RNA can fold into this complex structure to bind a small molecule, and the molecule “switches” genes on and off. It is a way for bacteria to control gene expression.

An example of a riboswitch is the glycine riboswitch, which binds an amino acid called glycine. In the bacteria Bacillus subtilus, the glycine riboswitch “turns on” a gene called gcvT, which controls glycine degradation. When the RNA detects an excess of glycine, turning on the gene, gcvT, will facilitate glycine degradation. Given the right trigger, RNA can control its own transcription with the use of riboswitches. A recurring theme with gene expression is structure. Different structures lead to different gene expressions. The riboswitch makes the RNA fold into a certain structure, which allows it to “switch” on

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Life Sciences

and off genes.1 However, eukaryotes, more complex organisms that include humans, contain genetic variations which often come in the form of singlenucleotide polymorphisms (SNP). SNPs are a substitution of a single nucleotide at a specific position in the genome and can cause structural change in the RNA. A gene sequence could contain the nucleotides ATCGAT, but if the third nucleotide was changed from a C to an A, that would be classified as an SNP. So, a “RiboSNitch” is an SNP that changes the structure of RNA leading to different regulation of a certain gene, adopting multiple structures. Dr. Laederach describes riboSNitches as “structured elements in RNA that undergo a conformational change if a functional mutation (or SNP) is present.”1 He contributed to a paper published in 2015 titled “The potential of the riboSNitch in personalized medicine”, which discusses SNP-induced structure change in the human transcriptome and the importance of riboSNitch discovery in interpreting GWAS results Figure 3. GWAS classifies SNPs into disease-specific and nonand massive sequencing projects.3 GWAS refers to the Genome-Wide Association Studies, an approach used in specific. Photo by Wasana Sukhumsirichart 2018 genetics research to associate specific genetic variations with new technology, he is now able to study RNA in living cells. particular diseases. It involves scanning the genomes from a Being able to study RNA in living cells is especially promising number of different people and looking for genetic markers because he can now study how proteins and other parts of the (like SNPs) that can be used to predict the presence of a disease.⁴ cells interact with RNA. Although RNA is not as well-known Laederach and his co-authors conclude that riboSNitches can be as DNA, it is recently becoming very important in the world used to interpret GWAS data and predict certain diseases and of science. Dr. Laederach says, “all of a sudden, in the last two phenotypes. As medicine becomes more individualized, RNA years, my field and the techniques used in my lab became really structure and riboSNitches will become increasingly important. relevant to an issue of global importance in terms of biomedical health and science.”1 Overall, the mechanisms of riboswitches in bacteria and riboSNitches in humans show the importance of the structure of RNA. Going forward, RNA structures will start to become an integral part of RNA related research projects and understanding human disease.

“All of a sudden, in the last two years, my field and the techniques used in my lab became really relevant to an issue of global importance in terms of biomedical health and science” References Figure 2. An example of a riboswitch adopting two different structures based on whether it binds to metabolite (+M) or if it doesn’t bind to (-M). Each of the two structures lead to different gene expression. Photo by Nature Education, 20102

1. Interview with Alain Laederach, Ph.D. 09/15/21 2. Edwards, A.; Batey R. T. Riboswitches: A Common RNA Regulatory Element. https://www.nature.com/scitable/ topicpage/riboswitches-a-common-rna-regulatory-element-14262702/ (accessed September 24th, 2021) 3. Laederach, A.; Solem, A.C; Halvorsen, M.; Ramos, S.B.V; Wiley Interdiscip Rev RNA. 2015, 6, 517-532.

4. Collins, F.S; Genome-Wide Association Studies (GWAS). https://www.genome.gov/genetics-glossary/GenomeWide-Association-Studies (accessed September 24th, 2021)

Using the knowledge from riboSNitches and RNA structures in addition to the development of new technology, the Laederach Lab is currently working on two main projects: studying neurodegenerative diseases such as frontotemporal dementia, and studying chronic obstructive pulmonary diseases (COPD). RNA structure plays a major role in both of these diseases types. Dr. Laederach described that with the development of

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“RNA Polymerase II." Photo courtesty of National Institutes of Health (NIH) [CC

Life Sciences

Re-SHAPEing our understanding of RNA

By Kayla Blades

M

ost people understand the terms “deoxyribonucleic acid (DNA)” and “protein” when it comes to the subject of biology. But what about the importance of another biological molecule, ribonucleic acid, or RNA? RNA is a fundamental molecule of biochemistry with numerous different functions including carrying genetic information, regulation and gene expression, and catalyzing biological reactions. The “Central Dogma of Biology” connects all these biological molecules as DNA, which contains essential genetic information and, is transcribed into mRNA, which is then translated to a protein encoded by the genetic information.

There is also a wide variety of various types of RNA including messenger RNA (mRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA), that all have different functions in the cell. Fields such as molecular biology and biochemistry have often emphasized research surrounding the study of proteins. However, RNA is a perplexing molecule that is seldom understood, but is essential to the proper function of the cell. Like many other biological molecules, the structure

of RNA assists in regulating its function, as both structure and function are interconnected. Working towards an understanding of RNA structure and function further informs future possibilities, research, and applications of RNA – and UNC professor Dr. Kevin Weeks and his team aim to do exactly that.1 Dr. Kevin Weeks, a distinguished professor in the Department of Chemistry at the University of North Carolina Chapel-Hill, researches RNA as a key to fully understanding cell biology. Dr. Weeks’ lab underlines the importance of RNA molecules in STEM research and seeks to further explore the vast capabilities of this essential unit of life. His research has also led to the creation of a local biotech company, Ribometrix, which he co-founded with UNC undergraduate alum, Katie Warner.

Figure 1. An overview of the mechanism of SHAPE

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Carolina Scientific There is a diverse array of strategies currently in use in the field of therapeutic medicine and pharmacology.

Therapeutic molecules predominately function by binding to proteins. Dr. Weeks advocates for a different perspective— Dr. Kevin Weeks rather than fixating on proteins, why not exploit RNA to develop drugs and therapeutics? The first step in implementing RNA knowledge in drug discovery is to gain a better understanding of RNA structure and function. Targeting RNA, opens up a whole new world of conceivable solutions to the intricate complications that arise in therapeutic discovery. This concept was initially seen as a radical idea in the scientific community, but as Dr. Weeks, his lab, and other groups, have continued research into this subject, it has become a more plausible and realistic solution to creating drugs and expanding the applications of RNA in a variety of academic fields.

Figure 2. SHAPE Reactivity Dr. Weeks’ lab developed a technology called Selective 2’-Hydroxyl Acylation analyzed by Primer Extension (SHAPE) technology that it uses in conjunction with mutational profiling (MaP) to create what Dr. Weeks describes as a “chemical microscope.”1,2 This allows us to gain a more detailed look into the world of RNA. This advancement in chemical probing technique has allowed for a more precise measurement and characterization of RNA structure for large and complex molecules in a more quantitative way and with higher accuracy than previously possible. These technologies have been widely adopted across multiple biological disciplines.1 Often times, scientists try to replicate the cellular

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Life Sciences

environment when conducting laboratory experiments, but mimicking the conditions inside a cell can be very challenging.

A vital advantage of SHAPE chemical probing is that the strategy functions well in a cellular environment, not just in a test tube, indicating the practicality of this methodology in RNA research.

SHAPE chemical probing uses a reagent that reacts with the 2’-hydroxyl of RNA, a chemical group unique to RNA, to assess the trends and patterns of chemical modifications. The differences in reactivity of the individual nucleotide building blocks in RNA can provide precise information regarding the structure of RNA.2 SHAPE reagents are composed of small aromatic compounds with a half-life capable of allowing for a real time snapshot RNA structure and that are soluble enough to react in a cellular environment. The quantitative component of SHAPE technology reflects local nucleotide flexibility in RNA. SHAPE provides a quantitative understanding of structure by efficiently conducting a large number of measurements of local nucleotide flexibility.

After establishing an effective technique for measuring RNA structure, Dr. Weeks’ lab hit a major roadblock on, how to most efficiently then analyze these data. The solution to this challenge came through the invention of the Mutational Profiling (MaP) readout approach, which is a method of visualizing produced by SHAPE technology using modern high-throughput sequencing methods.2 The use of sequencing is adept because the technology is cost effective and widely available. This technology is able to handle a significant amount of RNA structure information. For example, Dr. Weeks’ laboratory has an instrument that can sequence 30 million pieces of DNA in about two days.1 Dr. Weeks’ lab celebrates the accomplishments of SHAPE technology, its influences in the scientific field, and advances it has enabled in the pursuit of RNA knowledge.

Although his research on SHAPE technology is coming to a close, there are still numerous things to learn about the vast world of RNA. Dr. Weeks emphasizes that, “the reason SHAPE is so powerful is that it’s not used just by highly trained chemists, but it is used by all kinds of people, biologists, molecular biologists, virologists.” SHAPE is a technology that can be easily implemented in a variety of academic fields.1 RNA genomes and studying RNA viruses have become a priority in research efforts due to the spread of RNA viruses,’ including COVID-19. As Dr. Weeks’ lab shifts their focus into RNA-targeted therapeutics, SHAPE continues to provide new insight and discoveries into the unknown corners of the world of RNA.

References 1. Interview with Weeks, Ph.D. 09/17/21 2. Weeks, K. M. SHAPE Directed Discovery of New Functions in Large RNAs. Acc. Chem. Res. 2021, 54 (10), 2502– 2517. https://doi.org/10.1021/acs.accounts.1c00118.

Image courtesy of ZEISS Microscopy from Germany, CC BY 2.0

Life Sciences

The Fountain of Youth… for Cells Treating Cardiac Diseases by Reprogramming Fibroblasts

By Henry Bryant

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ods, a type of cell in the eye, detect light and send signals to the optic nerve to be processed by the brain.

Pacemaker cells, a type of heart cell, have the ability to produce a heartbeat through electrical signals.

While different cell types look and behave differently from each other, every cell in a person’s body contains the same underlying code called DNA, which contains instructions for making everything inside one’s cells.

DNA is divided into units called genes, which provide code to make specific proteins. Each type of cell turns on and off different genes to produce different proteins needed for that specific cell type. The differences in gene expression lead to the functional and structural difference between different types of cells.

At conception, one cell subsequently divides to make every type of cell in the body. This type of cell, known as a stem cell, has the ability to differentiate into many different cell types. While this stem cell is able to differentiate into any type of cell, tissuespecific stem cells are more limited and can only differentiate into a few specific

types of cells found in the same tissue (such as blood cells). A cell’s final form is typically permanent and is controlled by a complex interaction of signaling molecules, mostly transcription

the University of North Carolina at Chapel Hill, and the Associate Director of McAllister Heart Institute, is a pioneer in the field of cellular reprograming.

Dr. Qian’s lab investigates causes of cardiac diseases including myocardial infarction (MI), chronic heart failure, and cardiac heart disease. He and his team use mouse models to parallel the disease progressions in humans. In addition, Dr. Qian’s lab works to uncover cellular reprogramming mechanisms in order to change cells’ function and help fight the mentioned cardiac diseases.

One example of cellular reprogramming done in Dr. Qian’s lab is the conversion of fibroblasts, which are connective tissues, into cardiomyocytes, the muscle cells of the heart that generate the squeeze of a heartbeat. The conversion of fibroblasts to cardiomyocytes is accomplished by the addition of three transcription factors to fibroblast cells: Gata4, Mef2c, and Tbx5. Dr. Qian’s lab demonstrated that the levels of each transcription factor is important in improving the conversion efficiency of the fibroblasts.1

“The Qian lab is pushing cellular reprogramming from the realm of science fiction to reality” factors, that ultimately determine the cell type. Transcription factors help to turn genes “on and off” by changing, promoting, or blocking proteins that make RNA from DNA, which is later translated into the final protein.

Researchers have been learning about the function of transcription factors’ intertwined chemical signals, not only to understand what causes stem cell differentiation, but also to understand how to reverse the differentiation process: to turn differentiated cells back into undifferentiated stem cells.

Li Qian, an Associate Professor in the department of Pathology and Laboratory Medicine Department at

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Life Sciences

Carolina Scientific

Dr. Li Qian, PhD

By continuing to help understand and improve cellular reprogramming techniques, the Qian lab is pushing cellular reprogramming from the realm of science fiction to reality, manifesting Dr. Qian’s statement that cellular “reprogramming is the future” of medicine.2 Cellular reprogramming provides a promising future in clinical treatments. The method uses a patient’s own cells to treat diseases rather than organ transplants or prescription drugs. Organs for transplant are in short supply and patients could wait over a year to find a transplant match.3 Additionally, a patient must be on immunosuppressants for a long time after the transplant to avoid rejection of the new organ. Immunosuppressants put the patient at an increased risk of contracting diseases as the body’s immune system is weakened. Even with immunosuppressants and other tests

physicians perform to ensure organ acceptance, there is still no guarantee that the organ will be accepted by the patient. Finally, organ transplant is a very physically demanding procedure and requires months to recover from.

Prescription drugs can also have disadvantages, such as unwanted side-effects. By using one’s own cells, cellular reprogramming avoids the long waiting process and risks of rejection of traditional organ transplants. While cellular reprogramming delivery methods are still being researched, the proposed solutions are much less invasive than organ transplants and do not have negative side effects like some prescription drugs.

Cellular reprogramming is a promising field, however there are still limitations that are being researched.

Firstly, as mentioned earlier, is the problem of transcription factor delivery to the cells. While introducing the transcription factors are done fairly easily in vitro, adding transcription factors to specific cells in the body proves a much more difficult task. One solution is to use mRNA injections to introduce the transcription factors to the body, similar to how the COVID-19 vaccines work. In this method, mRNA (the template used to turn DNA codes into proteins) is inserted into cells to produce the protein of interest. In the case of COVID-19 vaccines, these are non-harmful spike proteins that the virus contains so that your body can recognize the disease if you get infected later. Another major hurdle for the field is the narrow context

Figure 1. Image of a fibroblast cell (left) is converted into a cardiomyocyte (right).

Images courtesy Qian Lab.

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in which cellular reprogramming is currently being researched. Most cellular reprogramming is for fresh and sudden injuries (such as heart attacks) that are easier to treat than long-term degenerative diseases. In addition, reprogramming done in one cell type is unlikely to work in another type of cell. Dr. Qian’s lab is working to broaden the scope of the field by looking at fundamental similarities between cardiomyocytes, hepatocytes (liver cells), and neurons to find commonalities between different cell types.

Dr. Qian, in addition to her own research, has taken on other roles including Animal Cores Facilities Advocacy Committee Chair, Faculty Director of UNC Human Pluripotent Stem Cell Core, and Department of Pathology and Laboratory Medicine Research Advisor. Dr. Qian was also named one of the best reviewers for Cell Press, one of the most prestigious biology journals in the world. Her philosophy is to give each article one reviews the same time and respect that one would for a close colleague or one’s own student. By doing this, the conversation becomes much more constructive and researchers tend to be more responsive to criticism.4 Dr. Qian carries the same respect for her own students as she uses her own experiences and failures to “share knowledge,” with and inspire her students2, not only to advance the field of biology, but to foster the next generation of curious explorers.

References

1. Wang, Li, et al. “Stoichiometry of Gata4, Mef2c, and Tbx5 Influences the Efficiency and Quality of Induced Cardiac MYOCYTE Reprogramming.”

Circulation Research, vol. 116, no.

2, 2015, pp. 237–244., https://doi. org/10.1161/circresaha.116.305547.

2. Interview with Li Qian, Ph.D. 09/07/21 3. “Sign up to Save Lives.” Information about Organ, Eye, and Tissue Donation, https://www.organdonor.gov/.

4. Qian, Li. “Advice from Cell Press Reviewers.” Cell, vol. 179, no. 1, 2019, pp. 40–45., https://doi.org/10.1016/j. cell.2019.08.044.

Environmental

Life in the Air: Examining How Birds Use Environmental Energy

By Ellen Han

H

umans have spent centuries trying to solve the puzzle of flight, but even the most advanced aerial technologies stand no chance when compared to the natural world. With a millennia’s worth of evolution working to their advantage, flying animals are uniquely adapted to life in the air and serve as the ultimate resource for the continuation of technological innovation. From birds to insects, the hidden mechanics that govern animal flight have captured the interest of scientists and engineers alike for centuries.

Among these scientists is Dr. Ty Hedrick, a professor and researcher at UNC-Chapel Hill who specializes in biomechanics and aerodynamics. In other words, he’s interested in how animals fly. Dr. Hedrick first cultivated this interest as an undergraduate researcher at Brown University training starlings to fly in wind tunnels. After a brief stint at a software company, he went on to Dr. Ty Hedrick complete his thesis, centered around avian flight, and earn his Ph.D. in Biology at Harvard University. Since then, Dr. Hedrick has completed numerous experiments aimed to advance our understanding of aerial motion by studying various types of birds, insects, and even gliding animals like lizards.

Part of Dr. Hedrick’s current research focuses on the ways in which birds are able to use environmental energy to reduce their energy expenditure in flight. One of his recent studies shows that shorebird flocks, while they may appear disorganized, actually contain miniature V-formations similar to the larger, simpler V-formations found in large migratory birds, like Canadian geese. Representing an intermediate between the cluster flocks of starlings and these large V-formations, Dr. Hedrick’s research suggests that these miniature V-formations could be an adaptation for increased aerodynamics and reduced energy needs.

Another of Dr. Hedrick’s studies focused on common swifts, a species recognized due to their highly aerial tendencies, even for birds. Able to sleep in the air, these birds remain in flight for 10 months at a time and only return to land to mate and rear chicks. “If they ever evolved some sort of live reproduction in the air, ” Dr. Hedrick jokes, “we’ll probably never see them land again.” Using a special form of videography, the study found that common swifts, are able to glide using various environmental conditions—gusts, thermals, and air columns—to keep their energy balance at essentially zero.

In other words, much of the common swift’s continuous 10 months in the air is spent gliding, a form of locomotion that reduces their energy expenditure to nothing.

Now, Dr. Hedrick and his team have shifted focus to starlings, which they hypothesize to be able to take advantage of certain wakes to reduce the energy costs required by flight.

To observe these birds, Dr. Hedrick’s team uses a large animal flight wind tunnel facility designed by Dr. Kenny Breuer, a collaborator on the study and fluid-dynamic system engineer from Brown University. Located in Rhode Island, this facility allows Dr. Hedrick’s team to record and observe multiple birds

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Carolina Scientific flying, analyzing the behavior and interactions of up to five birds at a time. Additionally, Dr. Hedrick’s team makes use of an actuated wing in their observations to simulate various environmental conditions in the wind tunnel—upwashes,

Environmental

adapt to constantly changing environmental conditions could form a basis for the ways scientists engineer and design aerial

Figure 1. Graph showing the average angle between neighboring birds over an extended shorebird flock. Aaron J. Corcoran; Tyson L. Hedrick. Compound-V formations in shorebird flocks. Elife. 2019, 8, e45071. downwashes, and even the wake of another bird flying ahead.

Another collaborator on this study is Dr. Alex Gerson from UMass Amherst, a “migratory physiologist” studying how animals use energy on a longer timescale. Specializing in metabolic measurements, Dr. Gerson tracks precisely how much energy birds use by measuring their rate of respiration —how much oxygen they inhale and carbon dioxide they exhale. This is tracked via radio-labelled sodium bicarbonate microinjections, which get incorporated into exhaled carbon dioxide and are tracked to calculate energy expenditure.

After spending the summer shuttling back-and-forth from the Rhode Island flight facility to North Carolina amid new, pandemic-related challenges, Dr. Hedrick is now taking the time to sort through the data set. So far, it seems too early to tell whether the data supports the initial hypothesis.

However, there is some evidence that one of the wake configurations used, called the tip vortex, is beneficial to the starlings. Linking back to the V-formations observed in migratory birds, a tip vortex is created in flight by a leading bird, and can reduce energy expenditure for the trailing bird.

Dr. Hedrick’s team is finding that starlings seem to gravitate towards the area where a tip vortex should be present, and they don’t flap as much when they do encounter a vortex.

Looking forward, Dr. Hedrick plans to continue conducting live bird experiments. Up next, he hopes to study eagles, which are larger in size and more easily comparable to human technologies, but are also more difficult to acquire.

He hopes to specifically examine flight stability, which could contribute to developing drone stabilization techniques;— while a drone might find itself completely destabilized after a large gust of wind, large birds are able to maintain their balance and easily recover. Examining the ways that birds can

Figure 2. A sample common swift flight path.

The thick color-coded lines denote flight speed, while the thin black lines show the amount of time spent flapping. Tyson L. Hedrick; Cécile Pichot; Emmanuel de Margerie. Gliding for a free lunch: biomechanics of foraging flight in common swifts (Apus apus). J. Exp. Biol. 2018, 221 (22), jeb186270. speed, while the thin black lines show the amount of time spent flapping. technology in the future.

But above all, Dr. Hedrick is genuinely passionate about his research. “I like watching animals move,” he explains, “I think it’s beautiful and amazing, and I could sit and look at high-speed videos of birds flying for hours and never get bored with it.”

References 1. Interview with Tyson L. Hedrick, Ph.D. 9/22/21.

2. Aaron J. Corcoran; Tyson L. Hedrick. Compound-V formations in shorebird flocks. Elife. 2019, 8, e45071.

3. Tyson L. Hedrick; Cécile Pichot; Emmanuel de Margerie.

Gliding for a free lunch: biomechanics of foraging flight in common swifts (Apus apus). J. Exp. Biol. 2018, 221 (22), jeb186270.

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Environmental

Captain We Shrunk the Sharks!

By Sophia Palmieri

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ifty years ago, the release of Jaws painted sharks as man-eating machines. Now, the first thing anyone thinks about when they go to the beach is, “are there sharks in this water?” You want there to be as few sharks as possible, but what if that was a reality? People killed sharks because they were afraid, without considering how eliminating apex predators can affect the ecosystem. Luckily, passionate scientists at the UNC Institute of Marine Sciences (UNCIMS) are contributing to a global movement for shark conservation and rehabilitation.

Dr. Joel Fodrie, the lead biologist on the UNC Institute of Marine Sciences’ shark survey.

In 2009, upon joining the faculty at the University of North Carolina, Dr. Joel Fodrie and his team at UNC’s Institute of Marine Sciences were given the opportunity to undertake a survey of shark populations in coastal North Carolina that began in 1972 – now spanning 50 years of data. Each year, biweekly survey trips are conducted between April and November, where researchers catch, collect measurements, and tag 15+ species of sharks common to the area. Their goal is to monitor the population dynamics of sharks over many decades to understand how these species change in response to human-induced and natural drivers. The extensive data collected is a powerful tool to view long-term changes that may help predict the future of shark populations and contribute to relevant studies.

Years of research suggest that fishing negatively affects marine ecosystems. Characteristically, fishermen target the largest fish which disturbs the ecosystem’s balance. There are two schools of thought regarding how overfish-

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ing affects the physical size of the remaining individuals. A geneticist might argue that selective pressure would evolutionarily favor fish that grow slower or to a smaller size at adulthood over those that mature

Characteristically, fishermen target the largest fish which disturbs the ecosystem’s balance.

quickly. In contrast, researchers focused on environmental influences might argue that depleting the populations may reduce competition, allowing other individuals to thrive and grow larger. The UNC-IMS shark study has recently been exploring the trends in species-by-species shark sizes over the past several decades. Emerging patterns in the data show sharks across all studied species experiencing a significant reduction in average size. This suggests that natural selection of smaller sharks is present, and does not appear to be fully counterbalanced by environmental

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Environmental forces that would allow the fewer, remaining sharks to grow faster.

Dr. Fodrie conducted another project, during his first years at UNC, surveying shark sizes recorded in local fishing tournaments across the northern Gulf of Mexico. This study displayed a similar decrease in the size of tiger sharks - from the largest, at 900 pounds in the 1970s-1980s, to only 250-pounds in the 1990s-onwards.3 “A 250-pound shark will scare anyone, even me”, Dr. Fodrie admits, “but a 900-pound shark will bite a 250-pound shark in half. So what does that mean in terms of changing the landscape of fear and predation impacts in the ocean as we’ve lost those really big fish?”1 It’s an important concept to consider when determining the application of UNC-IMS’ research.

Figure 1: Research technician Phil Herbst during a shark survey field trip safely restraining tiger shark to obtain size measurements and identification

Another signal of change in these long-term data, as Dr. Fodrie noted, shows Bonnethead sharks, or “blue crab consumption factories,”1 relocating north along the Southeastern coast of the United States – potentially in response to regional warming. However, blue crab currently happens to be North Carolina’s most important commercial fishery. The balance between fishing and natural predation is tricky, but the blue crab is

in a particularly salty situation. The UNC-IMS shark survey is essential for documenting the size and population changes of these sharks to provide the requisite data to assist future research. An ecosystem is like a livi n g

Figure 2: The UNC-Institute of Marine Sciences’ recently designed shark survey logo.

thing, with different connections and intricacies, studying one part of it can help you gather information about the whole system.

Whether scientists investigate the effects of overfishing on sharks, blue crab populations, or any other part of the ecosystem, it’s all connected. As Dr. Fodrie says, “I kind of come at them sort of gloriously, like yeah, we want to understand more about sharks, but in our best form, what can we do to understand how they fit in the ecosystem, eating blue crabs and other things we care about? A requisite for that is simply understanding what the community of sharks is, like how abundant are they seasonally and over longer time scales?”1 It’s in that context that the UNC shark survey is a unique asset.

The challenge when researching shark populations is the lengthy maturation and reproduction periods. Researchers can tag a shark and it will still be alive twenty years later. It requires consistent work over a long period of time to understand the impact of shark population decline. For sharks, it’s an incredibly lengthy

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task to replace lost population, and the rest of the ecosystem suffers as a result. Because of this, one of the main difficulties Dr. Fodrie faces is maintaining people’s motivation to support the survey. Due to its longterm nature, one may not see the survey’s results for another three decades. “Finding sources of suppor for such an extended effort”, Dr. Fodrie explains, “is a really interesting challenge that they don’t teach you in ecology 101, but you try to pick up those skills.”1 There may be a whisper in the data that suggests populations are rising after 20 to 30 years of more intense motivation for shark conservation. Without finding a single tiger shark from 1990 to 2010, they now find 2 to 3 per year, and quite large, between 7 to 10 feet long, roughly 250 to 400 pounds.2 With additional time and data, researchers will be better equipped to understand recent changes and make further conclusions about shark population trends. Thanks to Dr. Fodrie and scientists at the UNCIMS, we can monitor shark populations and sizes to ensure the health of shark populations and their ecosystem.

References

1. Interview with Joel Fodrie, Ph.D. 09/14/21 2. Benavides, M.T; Fodrie, J.F; Fegley, S.R; Bargione, G; Marine and Coastal Fisheries 2021, 13, 228-239 3. Powers, S.P; Fodrie, F.J; Scyphers, S.B; Drymon, J.M; Shipp, R.L; Stunz, G.W; Marine and Coastal Fisheries: Dynamics, Management, and Ecosystem Science 2013, 5, 93–102

Image courtesy of ESO/S. Brunier, CC BY 4.0

Physical

Cannibalistic Particles’ Impact on Early Universe Cannibalistic particles changes theory on Universe

By Xiaolong Huang

I

t all begins with a singularity. Within 10-32 seconds, the Universe surges to at least 1078 times its previous volume in a phase named inflation. After inflation, the Universe enters a radiation-dominated era (RDE), when the radiation - particles moving at lightspeed - permeate the cosmos. But the transition between inflation and RDE remains a mystery, which has sparked considerable interest among cosmologists, including Dr. Adrienne Erickcek, a theoretical cosmologist in the UNC-Chapel Hill physics and astronomy department. In her most recent research, she explores how the current physics theories on dark matter can enhance our understanding of the structures in the early Universe.

The difficulties in researching the interval between inflation and RDE come from a lack of knowledge in the matter that forms our Universe. The standard model, the contemporary model of particle physics, only applies to five percent of the Universe’s mass, and we know little about the remaining ninetyfive percent. With ninety-five percent of the Universe’s mass being unknown, it is impossible to understand thoroughly the events near the beginning of time.4 A significant portion of the unknown mass, roughly twenty-six percent, consists of dark matter. Dark matter does not interact with normal matter via the strong force and the

electromagnetic force. In other words, dark matter is intangible - cannot be seen, cannot be touched, cannot be detected by any device. The only observable imprint from dark matter comes from its gravitational impacts.

For example, using gravity to estimate galaxies’ mass always leads to higher mass than other methods – this clearly results from dark matter.4 To Dr. Erickcek and her team, dark matter can lead to great breakthroughs in cosmology and

physics. “Dark matter is pristine; it only feels gravity. Dark matter is a more clean record of what the Universe has been doing gravitationally. Normal matter can never tell us about the early Universe,” said Dr. Erickcek.1 To explain the mysterious behavior of dark matter, cosmologists have proposed many theories on the origin of dark matter. Among the many hypotheses, the “hidden sector dark matter” theory draws much attention.

Figure 1. Mass ranges for dark matter and mediator particle candidates, experimental anomalies, and search techniques. Figure from US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

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Physical

Carolina Scientific According to this theory, the dark matter belongs to a hidden sector in which different fundamental laws govern. The hidden sector has no direct interaction with the normal sector, but several “portal” interactions may exist between these two sectors.4 Using an analogy, the hidden sector is like a world of ghosts, which we do not interact with.

Under certain conditions, interactions between people and ghosts will happen in some haunted house – the portal interactions. One such portal interaction is the cannibalistic particles in the hidden sector. The cannibal particles perform self-annihilation, which causes them to decay into normal matter.2 This property intrigues Dr. Erickcek and her team, whose research later reveals cannibalistic particles’ profound implications on the composition and structural formation of the early Universe.

The cosmologists categorize the Universe’s history into different stages based on what dominates the Universe - matter, radiation, or cannibalistic particles. The conventional chronology of the Universe does not take into account the existence of cannibalistic particles, but these particles may have once dominated the Universe because of their self-annihilation property of these particles. In her most recent publications, Dr. Erickcek and her team has shown that this self-annihilation property can give rise to a cannibalistic-particle domination era. This modification towards the original chronology of the Universe alters the previous assumptions on the distribution of matter in the Universe.3

Dr. Adrienne Erickcek

Figure 2. A figure illustrating two possible relationships between dark matter and cannibalistic particles. Figure from article by Adrienne L. Erickcek et al.

The changes in the matter power spectrum from cannibalistic particles convey much information about the formation of dark matter microhalos, the cosmological structures formed by dark matter. Dr. Erickcek and her team have shown that an ECDE will lead to the generation of much more dark matter microhalos than the previous assumption.

In addition, in the presence of an ECDE, the generation of dark matter microhalos will occur much earlier than the prediction of the conventional cosmology. Dr. Erickcek has also provided estimates for the masses of the earliest-forming halos and their formation times in terms of the properties, such as the characteristic mass and the formation time, of the cannibal particles field. In addition, Dr. Erickcek and her team have identified which regions of cannibal parameter space enhance the microhalo abundance. Although the current results cannot set robust observational constraints, the microhalos can be detected and researched by pulsar timing array and the isotropic gamma-ray background.2,3 In conclusion, Dr. Erickcek and her team’s research uses the latest theory of dark matter as a tool to explore the history of the early Universe. They establish that the cannibalistic particles, an intrinsic property of the hidden sector, can leave a distinctive peak in the matter power spectrum and affect the formation of dark matter microhalos. In addition, the cannibalistic particles may lead to a cannibal-dominated era, which can generate distinctive observational signatures. The research of Dr. Erickcek

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and her team in the cannibalistic particles provides a new window into the evolution and composition of the early Universe. In the future, Dr. Erickcek plans to continue her current path of using dark matter as a probe to investigate the first second of the Universe. With the efforts of Dr. Erickcek and additional developments in fundamental physics, humanities may one day reach the singularity.

References

1. Interview with Adrienne Erickcek, PhD. 09/09/2021.

2. Erickcek, Adrienne L., et al.

“Cannibal Domination and the Matter Power Spectrum.” Physical Review D, vol. 103, no. 10, 2021, https://doi. org/10.1103/physrevd.103.103508.

3. Erickcek, Adrienne L., Pranjal Ralegankar, and Jessie Shelton.

“Cannibalism’s lingering imprint on the matter power spectrum.” arXiv preprint arXiv:2106.09041 (2021).

4. Feng, J., Fox, P., Dawson, W. A., Ammons, M., Axelrod, T., Chapline, G., Drlica-Wagner, A., Golovich, N., & Schneider, M. (2017). US Cosmic Visions: New ideas in dark matter 2017 : Community report. https://doi. org/10.2172/1389964

Image “B0006421 Breast cancer cells” [CC BY-NC-ND 2.0]

Health & Medicine

Endocrine Therapy Interventions: Helping women access necessary care

By Neha Saggi

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urgery, chemotherapy, radiation, and other methods of primary cancer treatment are only a first step in medication for 70% of women with breast cancer. A common form of further medication is endocrine therapy, which is prescribed to women anywhere from five to ten years after they have completed their primary cancer treatment.

Estrogen therapy to reduce cancer occurrence could take two possible avenues: estrogen targeting and estrogen reduction.

Estrogen is a hormone important for the normal regulation of female sexual and reproduction. A large portion of breast cancer cells have receptors for hormones like estrogen, allowing estrogen to stimulate growth of breast tumors. By targeting estrogen, endocrine therapy prevents it from binding to receptors on cancer cells, thus preventing cancer recurrence. The other main form of endocrine therapy reduces the amount of estrogen that the body makes. Rather than preventing estrogen from binding to cancer cells, this form of therapy prevents estrogen’s creation. It thereby also reduces the risk of cancer recurrence. Through these two pathways, endocrine therapy effectively prevents estrogen from stimulating cancerous breast cells and tumors, and it has been found to reduce the risk of breast cancer recurrence by 50%.

However, endocrine therapy’s poor adherence rate presents a clear challenge. Many patients do not correctly follow their treatment plans. A primary reason is the long-term nature of endocrine therapy. A variety of other factors also contribute to low endocrine therapy adherence, including any side effects, cost of medication, the need for regular refills, lack of motivation, lack of tangible benefits, and simply forgetting to medicate.

Dr. Stephanie Wheeler and her team, based in the Gillings School of Global Public Health, determined that these reasons are multifaceted enough for research and

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intervention. Two years ago, they obtained a 5-year grant from the National Cancer Institute for their project, titled the “Guiding Endocrine Therapy Success through Empowerment and Technology” study. A national, multi-site randomized trial, the GET SET Study recruits women with breast cancer who have hormone receptor-positive diseases. In this case, their breast tumors have hormone receptors that are responsive to endocrine therapies. Importantly, black women and young women are oversampled in the study; based on current data, these two groups have shown more struggles with this particular medication over time, and medical research has not robustly represented these groups in the past.

The study designed and piloted two major interventions.

First, they developed a virtual counseling system that functions through motivational interviewing, an evidencebased behavioral technique. Dr. Wheeler summarizes that the goal of this counseling system is to “meet women where they are and help them articulate their goals of care, addressing their person-specific barriers” to taking this medication. The second intervention is a text Dr. Stephanie Wheeler message reminder alert sent to women’s phones on a daily basis. The trial randomizes the women to receive the counseling, text message, both, or neither. Broadly, the researchers aim to determine the longterm efficacy and feasibility of the interventions to help women take their medication. Some considerations include whether the interventions are culturally appropriate and cost-

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Health & Medicine

Figure 1. Sequencing of Endocrine Therapy in Postmenopausal Women with Advanced Breast Cancer. James N. Ingle. Clin Cancer Res January 1 2004 (10) (1) 362s-367s; DOI: 10.1158/1078-0432.CCR-031200 effective.

Dr. Wheeler is excited about the implications of this project. Recognizing the underlying social determinants that affect health, many of which are caused by structural inequality, she foresees applications of this research in improving healthcare accessibility. Historically marginalized populations, such as racial and ethnic minority groups, rural populations, lower-income communities, and uninsured populations are disproportionately affected by many health issues, and they are at higher risk for many non-communicable diseases. Improving healthcare delivery through interventions like counseling and regular reminders should, by extension, improve outcomes of cancer care. Dr. Wheeler hopes to prompt further thinking about “creative ways to redesign the systems of care in which people are operating” with a focus on policy, changing the ways in which hospitals caring for patients and “making it structurally easier for patients to receive the care that they deserve. Health policymakers need to better understand the social determinants of people’s cancer treatment experiences so that all of the medical advancements and treatments that we have can actually be realized.”

As the study progresses, the researchers must carefully consider how to implement the interventions beyond the study sample. Beyond North Carolina, what are the best ways to implement the intervention? Can large hospitals and small clinics both manage the work and staff required? Do different populations of women require slightly different interventions?

As Dr. Wheeler puts it, “we need to consider how the patient populations are different, how the contexts are different, and how we can think about implementing and translating these evidence-based practices into new settings where they can be shifted or adapted a little bit to meet the needs of patients in those populations.” Beyond the specific adaptations, researchers are also thinking about how to incorporate similar interventions into routine practice, so that they are

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commonplace among healthcare centers. Accessibility and adherence to secondary cancer treatment are necessary areas of investigation, and Dr. Wheeler’s team is paving the way to improving treatment for countless survivors of breast cancer.

Figure 2. Carlson, Robert W. and I. Craig Henderson.

“Sequential Hormonal Therapy for Metastatic Breast Cancer after Adjuvant Tamoxifen or Anastrozole.” Breast Cancer Research and Treatment 80 (2004): 19-26.

References 1. Interview with Stephanie B. Wheeler, PhD, MPH, 9/14/21 2. “What Is Get Set?” Homepage | Get Set, https://getsetstudy.org/.

Endometrial Cancer and Obesity Linking endometrial cancer and the worst of all maladies

By Lasya Kambhampti

CC BY 2.0

E

ndometrial cancer is the fourth most common cancer for women in the U.S. with over 70,000 new cases every year.1,2,3 In contrast to other cancers, the incidence and mortality rates for endometrial cancer are increasing, especially in black women.

UNC Chapel Hill’s Dr. Bae-Jump is on a mission to help change that by exploring the impact of obesity on endometrial cancer in order to develop better treatments.

Dr. Bae-Jump has always been interested in gynecological oncology.

She “really wanted to take care of women” but “wanted to expand beyond breast cancer.”1 Although breast cancer research is vital, it is also one of the most studied cancers whereas other gynecological cancers, like endometrial cancer, are neglected and underfunded.

“For every life lost to breast or prostate cancer, we’re spending thirty times more research dollars than every life lost to endometrial cancer,” she says.1 Unlike other cancers, endometrial cancer has only recently had new drugs approved by the FDA for the first time in decades.

Figure 1. A depiction of how mouse models are created. Image courtesy of the National Human Genome Research Institute.

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As she learned more about endometrial cancer in graduate school, she recognized that there was a significant connection between obesity and endometrial cancer but there simply wasn’t enough research out there that explained that connection.1 After graduating and receiving her Ph.D., Dr. Bae-Jump decided to go back to medical school and become a translational scientist. A translational scientist works in research that will directly apply to the clinical or medical field, such as the development of new therapies or procedures. She felt that while she learned the details behind specific molecular pathways in graduate school, “[she] wasn’t learning the big picture or the big questions about what was going to move treatment forward.”1 She wanted to be in the clinic seeing patients and learning what was needed and then working to create those treatments in her lab. “Observations that I make as a physician then go back to my research questions,” she says.1 Currently, Dr. Bae-Jump’s lab is working on understanding obesity’s impact on endometrial cancer and how different therapies can alleviate those impacts. She believes that the increasing frequency and mortality

Carolina Scientific for endometrial cancer is linked to the obesity epidemic, which is why it is so important to discover therapies that deal specifically with obesity-driven endometrial cancer.1 In order to study this, the lab has created a variety of mouse models that can develop endometrial cancer.

The mice were fed a variety of diets, such as high-fat or low-fat. In mice with stimulated obesity from the high-fat diet, the tumors tend to grow bigger and faster. There are also genetic and metabolic differences between the tumors from the low-fat and highfat diet mice.

More specifically, here is increased activity in lipid pathways, p r o t e i n biosynthesis, and glucose pathways in obese mice.

Now that the lab understands the specific impacts that obesity can have on endometrial tumor growth, they are trying to find different therapies to mitigate these effects.1 The lab has looked at different drugs that affect metabolism, such as metformin and statins. It is also looking at how changes in diet and exercise can impact tumors. Changing from a high-fat diet to intermittent fasting seems to have

the greatest effect on reversing the detrimental effects of obesity on tumor growth although some aspects remain the same. Switching to a low-fat diet can also reverse some negative effects but has proven to be less effective in the mice models. When the mice switched from a high-fat diet to intermittent fasting, they found that tumor growth and tumor take were reduced. Tumor take refers to the likelihood that tumors develop in the mice after being injected with cancer- causing agents. Normally, eighty percent of mice will develop tumors after having specific genes deleted but only sixty percent of mice who switched to intermittent fasting developed tumors. Although the results are not as great as those seen in mice who have been on a lowfat diet the entire time, it is still highly promising. The lab is also looking at metabolic changes within the tumors after switching diets.

Not only has the lab discovered therapies in mice models, but they are also now running clinical trials in order to prove treatment effectiveness in humans.1 Currently, Dr. Bae-Jump’s lab has clinical trials looking at the impacts of exercise, immunotherapy and different drugs that have proven to be effective in mouse models. They also have a trial that teaches women highintensity interval training and measures the impact of this intervention on their tumors.

The lab is also focusing on disparities between black and white women and how that impacts outcomes.1 Specifically, the lab is looking at genomic and microbiome differences that could help point to new therapies. They’ve found that the mutations in the tumors in black women lead to worse prognoses and different microbial patterns in the tumors. Now, they’re running a population study

“For every life lost to breast or prostate cancer, we’re spending thirty times more research dollars than every life lost to endometrial cancer”

Dr. Bae-Jump

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Figure 2. A depiction of stage II endometrial cancer. Image courtesy of Terese Winslow LLC.

called the Carolina Endometrial Study.

The study will hopefully enroll 1,000 women across North Carolina and take a deeper dive into the disparity between black and white women. Ideally, the results of the study will provide clinics with essential intervention points that help improve outcomes. Dr. Bae-Jung hopes to continue working on the Carolina Endometrial Study and get to the root of the disparities between different races.

References

1. Interview with Victoria L. Bae-Jump, M.D./Ph.D. 9/27/21.

2. Uterine Cancer: Statistics, https:// www.cancer.net/cancer-types/uterinecancer/statistics (accessed September 28, 2021) 3. Henley SJ, Miller JW, Dowling NF, Benard VB, Richardson LC. Uterine Cancer Incidence and Mortality — United States, 1999–2016. MMWR Morb Mortal Wkly Rep 2018;67:1333–1338.

DOI: http://dx.doi.org/10.15585/mmwr. mm6748a1

Health & Medicine

The Shield of Our Hearts: Exploring How and Why Our Defenses Fail in Space

By Isaac Hwang

Image by fleskw [CC BY 2.0].

T

he human heart has a shield protecting it from illness. Identified first in elderly patients suffering from coronary artery disease (CAD), CXCL5 is an a protective inflammatory agent in the blood that protects everyoneagainst this disease, identified first in the elderly suffering from coronary artery disease.1 CAD causes plaque buildup in the arteries, reducing blood flow to the heart.2 NASA’s Gene Lab found that CXCL5 levels increased dramatically while astronauts were in space and then promptly decreased to normal levels once they were back on Earth. After exposure to higher levels of CXCL5 while in space, astronauts experienced aging and increased susceptibility to conditions such as osteoporosis, — a disease of weakened bones, — and coronary artery disease once they were back on the ground.1,3 After hearing about the parallels in the NASA research and his CXCL5 research, UNCChapel Hill researcher Dr. Jonathan Schisler decided to contact NASA to work together, believing that: “collaboration is the best way for me to expand the research program.”1 Dr. Schisler’s open attitude on collaboration enabled the McAllister Heart Dr. Jonathan Schisler — PI at Institute at UNC-Chapel the McAllister Heart Institute. Photo courtesy of Alyssa Hill to work with NASA to Lefaro determine what was the

Figure 1. Photograph of the team visiting NASA Space Radiation Laboratory. Photo courtesy of Afshin Beheshti

cause of increased CXCL5 levels in space. They further investigated the compound as a cardioprotective factor OR cause of the advanced aging seen in returned astronauts.

Dr. Jonathan Schisler and his team traveled to the Brookhaven National Laboratory, NY to test factors that could be responsible for the increased levels of CXCL5 in astronauts in space: microgravity and deep-space radiation. With Brookhaven’s resources, the team tested whether microgravity or deep-space radiation has a greater effect on CXCL5 expression.1 To specifically understand the effects of microgravity on CXCL5 levels, suspending the mice by their tails mimicked the effects of microgravity on astronauts’ bodies, To test the radiation levels found in space, they exposed the mice to Galactic Cosmic Radiation (GCR) and Solar Particle Event Simulation (SPE sim), radiation commonly experienced by astronauts while in space.⁴

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Carolina Scientific GCR is present in all parts of the galaxy and is a form of background radiation.⁵ SPE radiation originates from the sun’s activity, such as magnetic storms on the sun’s surface.⁶ Both types are commonly experienced by astronauts and could be responsible for the increased expression of CXCL5 during space travel. Ongoing data analysis could yield vital information on the deep-space factors responsible for elevated CXCL5 levels.

Health & Medicine

of cardiovascular diseases such as coronary artery disease. Furthermore, the analysis done by

Figure 3. Photo of the radiation room where the mice were irradiated. Courtesy of Leah Oswald

Figure 2. Photograph of the team working on dissecting mice. Photo by Alyssa LaFaro, UNC Research

Dr. Schisler next wanted to determine the specific cardioprotective or aging effects of CXCL5 during space travel. To test the effect of CXCL5 on the aging process, Dr. Schisler and his team used micro -RNA suppressors to control the amount of CXCL5 present in the bloodstream of the mice. By testing the relative effects of CXCL5 levels on protection against microgravity and radiation, NASA researchers can determine the best countermeasure for astronauts going to space.

After completing the study’s data collection processd, the lab is currently collaborating with other universities around the world to study histology, perform genetic analysis, and determine the results of their investigation. The results could provide a better insight into the mechanism behind CXCL5 expression and how its concentration in the blood could be increased for patients on Earth. As CXCL5 is known to be a cardio protector for geriatric patients, the ability to artificially increase levels would revolutionize fighting cardiovascular disease.1 The collaboration between the Schisler Lab and NASA has led to ground-breaking developments in the field of cardiovascular health and space biology in that the results from this study could prove key to understanding the genetic mechanism behind CXCL5 expression and allow for better prevention

collaborating universities could help the future of space biology by understanding the purpose of CXCL5 and the ways to counter the negative effects of space travel on the physiology of astronauts. These amazing developments can be aptly summarized by Dr. Schisler: “Science is awesome.”1

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References 1. Interview with Jonathan C. Schisler, Ph.D. 09/17/21.

2. Coronary artery disease. https://www.mayoclinic.org/ diseases-conditions/coronary-artery-disease/symptomscauses/syc-20350613 (accessed September 25th, 2021).

3. Osteoporosis. https://my.clevelandclinic.org/health/ diseases/4443-osteoporosis (accessed September 25th, 2021).

4. Schisler, Jonathan C.; UNC Chapel Hill, Chapel Hill, NC. Federal grant application, 2021.

5. Galactic Cosmic Ray Simulation. https://www.bnl.gov/ nsrl/userguide/GCRSim.php (accessed September 25th, 2021).

6. Solar Particle Event Simulation. https://www.bnl.gov/ nsrl/userguide/SPE-simulation.php (accessed September 25th, 2021).

Health & Medicine

Phototherapeutic Technology Lightens the Load on Rheumatoid Arthritis

By Kanishka Shah

Figure 1: Red Blood Cells Rheumatoid Arthritis (RA) is an incurable disease light that penetrates through body tissue and breaks the that affects over 1% of the US population. Not only did this B12-phototherapeutic bond2. “Due to the 3-month lifechronic disease constitute up to $40 billion of societal costs span of RBCs, patients only need a monthly dose of the in 2010 alone, current treatment for RA is low in efficacy phototherapeutic: this significantly reduces side-effects and highly stressful for the patients involved. But what if associated with toxins in the drug, such as diabetes there was an approach to RA treatment that reduced the and osteoporosis,” stated Ms. Zywot3. Phototherapeutic burden on both patients and resources? Ms. Emilia M. technology therefore provides a solution to the anxiety, Zywot and her fellow researchers at the Tarrant/Lawrence complications, and risks associated with traditional RA Collaboration have addressed these problems head-on by treatment. blending the principles of physics and medicine into an The reduction in glucocorticoid exposure brought alternative treatment option for RA. about by phototherapeutic technology is reflected in A central flaw in traditional RA treatment is the animal trials conducted by the Tarrant/Lawrence team. physical and emotional stress inflicted upon the patients’ Mice affected by lab-induced arthritis were randomly bodies. Systemic glucocorticoids – injection of a steroid placed into three groups. The positive control group that suppresses the immune system into the joints – is the was treated by systemic glucocorticoids, the negative primary method of RA treatment currently administered, control group did not receive any RA treatment, and the and is known to produce inadequate phototherapeutic group was or adverse side effects in up to 20% treated using the Tarrant/ “...investing in phototherapeutic drugs lessof patients. Ms. Zywot’s work with Lawrence technology. Level RA revolves around reducing the ens the amount of toxic steriod introduced of arthritis in the laboratory into the joins of RA patients, thus limiting body’s exposure to glucocorticoids. mice was measured using a harm inflicted upon their bodies as a result Phototherapeutics – a branch of clinical disease score index of of treatment.” medicine that employs the curative 0-4. The positive control group uses of light rays – lies at the core received daily injections of of Tarrant/Lawrence’s research. A phototherapeutic drug glucocorticoids until arthritis was suppressed (clinical developed by the research team is attached to vitamin score = 0), whilst the phototherapeutic group only received B-12; this complex is unable to diffuse through the a single drug dose at the start of the experiment. At the membrane after being loaded into a red blood cell (RBC) end of the trial, it was discovered that phototherapeutic (Figure 31). Consequently, after the RBC carrier transports technology effectively suppressed acute inflammatory the phototherapeutic around the body, physicians can arthritis in lab mice with 78% less exposure to steroids control the drug’s release by using long wavelength than in traditional systemic treatment (Figure 1)2.

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Health & Medicine

Figure 2: Phototherapy Treatment Results

Therefore, investing in phototherapeutic drugs lessens the amount of toxic steroid introduced into the joints of RA patients, thus limiting harm inflicted upon their bodies as a result of treatment.

In addition to reducing steroid exposure, phototherapeutic treatment grants physicians and patients more control over RA. Different phototherapeutic drugs are each assigned unique activation wavelengths: this adds an aspect of orthogonal control to RA treatment2. “Physicians are able to manage drug release both spatially and temporally – they can control exactly where and when the drug is released,” commented Ms. Zywot3. Furthermore, phototherapeutic technology does not require a special light source – drug release

transported by the RBCs, and triggered by light-sensitive queues,” stated Ms. Zywot3. Therefore, practically any disease that requires localized drug delivery can be treated using phototherapeutic technology. One such disease is cancer: cancer treatment kills cells in the body, including non-cancerous species, and therefore takes a toll on the patient’s body. Phototherapeutic technology can potentially reduce the number of chemotherapies a patient has to endure, thus alleviating the strains placed on their health3.

Overall, Ms. Zywot has worked with the Tarrant/ Lawrence Collaboration to develop an ingenious alternative for otherwise painful and tedious RA treatment.

Phototherapeutic technology is a standout example of how principles from seemingly opposing fields of science can be combined to produce tangible solutions for realworld problems. The application of phototherapeutic technology to rheumatoid arthritis provides a safer and more efficient line of treatment for patients, which can be extended to an array of other chronic diseases and conditions. Phototherapeutic technology hence represents a major stride in the direction of providing accessible and effective medical treatment for millions of patients around the world.

Figure 3: Adminitering light therapy

can be triggered using an ordinary laser pointer (Figure 2). Therefore, similar to how diabetics inject their own insulin, RA patients can potentially initiate drug release in their joints whenever pain is felt, and are hence less dependent on hospital visits. Phototherapeutic drugs therefore significantly minimize the time and difficulties associated with managing RA. Whilst tackling the array of problems associated with RA, phototherapeutic technology has the potential to be applied to a broad selection of diseases. “Our technology was created such that any drug can be attached to B-12,

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References

1. Sant-Rayn Pasrciha. The Conversation. https://theconversation.com/how-our-red-blood-cells-keep-evolvingtofight-malaria-96117 2. Victoria Wickenheisser, Emilia M. Zywot, Emily Rabjohns, Natalia Orlova, Christina M. Marvin, Song Ding, David S. Lawrence, Teresa R. Tarrant, Photonic Diagnosis, Monitoring, Prevention, and Treatment of Infections and Inflammatory Diseases ,2020, 11223, 112230R-8.

3. Interview with Emilia M. Zywot, 02/20/2021

Health & Medicine

Image “"Wearing a red ribbon for World AIDS Day" [CC BY-NC-ND 2.0]

Never Tested: A Community-based Investigation into a Lack of HIV Testing

By Maya Ticku

H

ealthcare has progressed significantly since the 1980s HIV/AIDS epidemic. However, there is still attention given to HIV prevalence among Black men who have sex with men (Black MSM). Black MSM have a 1 in 2 lifetime risk in becoming HIV-positive, and Although HIV testing is becoming increasingly popular, a gap remains in the Black MSM population.1 Investigating and identifying the factors explaining the lack of HIV testing among population groups begins with those who have had no prior history of HIV testing.

Dr. Derrick Matthews, an Associate Professor from the Gillings School of Public Health at UNC-Chapel Hill, has dedicated career to researching how certain social determinants contribute to the health disparities among HIV prevention, particularly within the scope of Black MSM. Dr. Matthews’s interest in HIV/AIDS prevention kickstarted an interest in the public health field. He noticed the research being done on HIV/AIDS prevention was about people who looked like him, but not a lot of it being conducted by people who looked like him.2 Dr. Matthews received his PhD in Health Behavior from UNC in 2013 and went on to complete his postdoctoral work at the University of Pittsburg. Though he has been at UNC since 2018, his work as a co-investigator on the study of Black MSM and HIV testing began at the University of Pittsburgh.

At its core, Dr. Matthews’ investigation into the causes and consequences of inadequate HIV testing among Black MSM was a surveillance study.

Dr. Matthews and his team believed that “the best public health strategies for this study were not going

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to come out of the brains of researchers; instead, they would come out of what was already happening on the ground for individuals and in communities.” 2 The investigation utilized a survey with a range of questions covering HIV testing history. Dr. Matthews and his team partnered with an organization called the Center for Black Equity, an organization dedicated to improving health and wellness opportunities for Black LGBTQ+ communities. The organization helped Matthews and his team coordinate with Black Pride events happening across the country, as well as HIV organizations in each city.2 While on the ground, Dr. Matthews and his team’s daily routine of data collection began by partnering with the local Black Pride organizers in each city before arrival to identify which events would have a substantial population of Black MSM, whether gay clubs or bars.2

“the best public health strategies for this study were not going to come out of the brains of researchers; instead, they would come out of what was already happening on the ground for individuals and in communities.”

With over 5,000 responses to the survey, Dr. Matthews and his team were able to elucidate patterns among those who had never received an HIV test.

Carolina Scientific Lower income or educated individuals had a lower likelihood of testing for HIV. Although the percentages of those who had never received an HIV test were small – around 10% – Dr. Matthews explains that small percentages still matter, especially for an infectious disease epidemic in which small populations can sustain.2 The survey also revealed the two primary reasons why the Black MSM population has such a high instance of never testing for HIV: (1) individuals did not perceive themselves as being at risk of being HIV-positive and (2) some individuals already believed themselves to be HIV-positive. In fact, the survey responses and optional HIV test results suggested that if an individual guessed they were HIV-positive, they were more likely to actually test positive. Additionally, the survey responses revealed that among those that were never tested, about a third tested positive, which is a higher percent than self-identified HIV-negative men who had tested at least once.

Health & Medicine

community focus. When asked about the importance

Figure 2. A rainbow flag which has been used to represent LGBT pride. Photo by Wikimedia Commons.

Dr. Derrick Matthews Dr. Matthews admits that he “used to be more interested in the psychological factors of why someone didn’t get a test” and instead reveals that the root of why Black MSM populations have demonstrated these trends lies in the structure of healthcare systems, rather than individual reasons.2 The average age of individuals who had never received an HIV test was 31, which Dr. Matthews says, “shows us that the healthcare system is failing these men.” 2 A survey approach makes for an accessible design in investigating a health disparity such as HIV, that is present in LGBTQ communities across the country. However, Dr. Matthew’s study is unique in its

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of a community-engaged study, Dr. Matthews names building respect and forming meaningful relationships as prominent advantages of his methodology.2 He admits that during “the first year we didn’t collect a single piece of data, it was only about visiting these cities and talking with these organizations.” 2 A sense of community has allowed Dr. Matthews and his team to stay in touch with the organizations and participants that they partnered with throughout the study, and even help other organizations like local health departments to utilize the data the team collected for their own cities.

In terms of the future of this study, Dr. Matthews is broadening his research scope to be more inclusive of Black queer people in general, extending it to cover other inequities and patterns of health concerns. With the community-based component of his study, COVID-19 has made it difficult to navigate the future of this study.

Rather than a continuation of the study, Dr. Matthews notes that this study has served as an impetus for other researchers. Despite the challenges of navigating the minutia of continuing the study through the pandemic, Dr. Matthews and his team’s findings live on through the work of other researchers who took inspiration from the clear demonstration of health disparities among Black MSM.

References 1. Hess, K. L.; Hu, X.; Lansky, A.; Mermin, J.; Hall, H. I. Annals of Epidemiology. 2017, 27(4), 238–243.

2. Interview with Dr. Derrick Matthews, Ph.D. 9/15/21.

Psychology & Neuroscience

Narrowing the STEM Gender Gap by Shaping Attitudes

By Kylie Brown Image sourced from: Pixabay

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icture what you would draw if asked to draw a scientist. The most common sketches allude to an older, white male with crazy hair and glasses. Unfortunately, this stereotype is eerily similar to the STEM workforce: only 8% of STEM jobs in the US are occupied by women who are also ethnic minorities.¹

Nicole Else-Quest, Ph.D.

Dr. Nicole Else-Quest, an associate professor in the Department of Women’s and Gender Studies, runs the Learning and Identity lab. With her team, she investigates gender disparities in STEM participation and achievement. Specifically, the lab focuses on understanding the motivations behind students’ interest in STEM, as well as developing interventions to change the culture of STEM to better represent marginalized groups. Dr. ElseQuest’s work is fundamental to “change science and change science education so that it is more inclusive and more representative of the diversity of our country.”² In her paper Math and Science Attitudes and Achievement at the Intersection of Gender and Ethnicity, Dr. Else-Quest examines how perception of STEM and success in math and science courses vary at the intersection of gender and ethnicity.

While a considerable gender gap exists regarding who pursues a STEM career, evidence does not support the conclusion that women fail to pursue STEM careers due to lower ability or aptitude than men. Therefore, the disparity may be explained in part by a difference in attitudes towards STEM; individuals pursue tasks in which they believe they will be successful. Dr. Else-Quest’s paper provides strong support for this alternative explanation.

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Carolina Scientific Despite similar end-of-year grades in math and science, male adolescents reported higher math selfconcept and expectations of success than female adolescents, while girls reported higher science value.² Additionally, gender differences were fairly consistent across ethnic groups. Therefore, STEM attitudes are a strong predictor of achievement in math and science courses, but the intersection of gender and ethnicity does not mitigate the effect.¹ Research of this nature is significant because it allows researchers to go “beyond describing those patterns to explaining them and changing them” by providing an understanding as to why diverse minority groups are underrepresented in STEM.2 In order to reach their conclusions, the ElseQuest team conducted a study in which 367 tenth grade students were recruited from five ethnically diverse public high schools in Philadelphia. The participants completed surveys that inquired about their self-concept of ability, task value, and expectations of success. Examples of questions asked include “Compared to most of your other school subjects, how good at math are you?” and “How important do you think math will be to you in the future?” Students ranked themselves on a scale to indicate self-perceived ability/task value/ expectation of success.¹ Using the scale values, the researchers conducted statistical analyses to determine the strength of the relationships between ethnicity, gender, and overall science attitudes.

Notably, the paper reveals that female adolescents placed a greater value on science than male adolescents, contradicting the low percentage of women in the STEM workforce. Dr. Else-Quest and her team describe two possible explanations for this paradox. First, girls’ more negative attitudes with respect to success in science could overshadow its perceived greater value; therefore, they are dissuaded from pursuing science despite recognizing its value. Second, the survey responses could reflect the type of science course students were enrolled in at the time of this study: nearly 60% of participants were enrolled in a biology course.

Since women tend to prefer biology over other areas of science, this could explain the surprising pattern in the data that female adolescents value science more than their male counterparts, despite being underrepresented in STEM.¹

Psychology & Neuroscience

The most recent development associated with this project involves reforming the asymmetrical patterns of representation in STEM. Dr. Else-Quest currently conducts research that focuses on understanding the climate in STEM and leveraging students’ values in STEM education, in hopes of determining how best to support students from underrepresented groups and keep them on track to attain fruitful scientific careers.

“STEM attitudes are a strong predictor of achievement in math and science courses, but the intersection of gender and ethnicity does not mitigate the effect” Dr. Else-Quest hopes her research will help more students continue in science by “helping to capture their interests and helping them see connections, to see how science is relevant to their goals.”² In order to narrow the gender gap in STEM, it is crucial to start with the next generation of scientists, understand the barriers they face, and subsequently remove these obstacles to clear a pathway to persist in STEM.

References

1. Else-Quest, N.M.; Mineo, C.C.; Higgins, A. Psychol.

Women Quart. 2013, 293-309.

2. Interview with Nicole Else-Quest, Ph.D. 9/16/21.

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Neurocience & Psychology

How Much Do We Truly Know About the Brain?

By Jadan Zawierucha Figure 1. A rat astrocyte in culture expressing mutant hepaCAM protein (green) makes branches onto itself and is surrounded by other non-mutant astrocytes (magenta). Courtesy Dr. Baldwin.

W

hen it comes to research of the brain, scientists have struggled to get the whole picture. To fully understand how the brain is functioning, one needs to understand the function of glial cells. Glial cells are cells in the brain that are key regulators of brain development and function. Astrocytes, a major glial cell type in the mammalian brain, play an important role in balancing connections with neurons and other brain cell types to orchestrate proper brain development. Through this network of interactions, astrocytes control a wide variety of processes that are important for proper brain development and function. Despite the many important functions of astrocytes, the mechanisms that drive the development and interactions of astrocytes remain poorly understood. Furthermore, astrocyte disfunction has been implicated in many neurological disorders, but how this happens is currently unknown. To address critical knowledge gaps and better understand the role of astrocytes in the human brain, Dr. Katie Baldwin’s laboratory studies the fundamental aspects of astrocyte cell biology. She investigates how defects of astrocyte development facilitate the pathogenesis of neurological disorders.1 In the brain, astrocytes form non-overlapping territories to regulate critical aspects of synaptic development and function. “This process is regulated by interactions between astrocytes and neurons via cell adhesion molecules”, which are cell-surface proteins that are involved in the binding of cells with other cells, Baldwin explains. “How astrocytes coordinate developmental processes among one another to parse out the synaptic neuropil [the space between neuronal and glial cell

bodies] and form non-overlapping territories is unknown.”1 In a recent study, Dr. Baldwin’s team discovered that astrocytes establish and maintain certain territories with the help of a cell adhesion molecule called hepaCAM. When hepaCAM is lost from one astrocyte, the neighboring astrocytes invade its territory. When hepaCAM is removed from all astrocytes, many problems arise. Mutations in hepaCAM are known to cause brain disorders in humans, affecting brain development and function.1 In the team’s study, they show that “hepaCAM, a disease-linked, astrocyte-enriched cell adhesion molecule, regulates astrocyte competition for territory and [structure] in the developing mouse cortex. Furthermore, conditional deletion of HepaCAM from developing astrocytes significantly impairs gap junction coupling”, or intercellular connections, “between astrocytes, and disrupts the balance between synaptic excitation [the firing of electrical nerve impulses] and inhibition [the prevention of the transmission of a nerve signal].”1 Mutations in hepaCAM are known to cause megalencephalic leukoencephalopathy with subcortical cysts, a rare brain disorder in humans.

Therefore, findings suggest that disruption of the selforganization methods of astrocytes could be an Dr. Katherine Baldwin, PhD. underlying cause of neural

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Figure 2. Two astrocyte neighbors in the mouse cortex, expressing different fluorescent proteins. diseases.1 Dr. Katie Baldwin originally became interested in brain biology when her sister developed spina bifida, a condition where the spine and spinal cord do not form properly. She was intrigued by the nervous system and wanted to study the regeneration of brain cells, so she pursued her PhD in this field.

During her graduate work, Dr. Baldwin became fascinated by how the immune system can influence the regeneration of neurons, leading her to research the importance of other cells in the brain that are not neurons, and how they work. As she began to think about what she wanted to do after graduate school, she began to read more into glial cells, including astrocytes, and became fascinated. “I realized, wow, these cells are amazing, and there’s so much we don’t know about them,” Baldwin explained, “It seemed like an area where there was a lot more questions than there were answers, and that was really fascinating to me … that there are all these disorders impacting people’s lives and then, to realize we’ve pretty much been ignoring half of the brain ... because only half the brain is neurons, and the other half is other cells including glial cells.”2 In the fall of 2015, Dr. Baldwin joined Dr. Cagla Eroglu’s laboratory at Duke University for her postdoctoral fellowship, where she began to study astrocyte biology in the context of brain development. Her work led to collaborations with researchers in Spain and Austria, and they worked together to understand the function of hepaCAM in astrocytes.

In April 2021, Dr. Baldwin established her own lab at UNC, the Baldwin lab, and is building her research program to follow up on the studies that she’s done in her post-doc with hepaCAM. Dr. Baldwin is excited by “making a new discovery” and “seeing something new with her own eyes” regarding her research. “The complex shapes of the astrocytes are so beautiful,” stated Baldwin.2 She feels that “the importance is to fully understand how the brain functions, and to do so, we need to understand the function of glial cells, including astrocytes. This is very important because with the technology nowadays, it turns out that a lot of gene-dissociated genes are

Neuroscience & Pyschology

expressed much more strongly in the astrocytes than in the neurons, meaning that these cells are playing an important role in many brain disorders.”2 With the new lab at hand, she expects to encounter several new obstacles along the way. “A new lab takes time to get up and running,” recalled Baldwin, “and there’s the possibility that there will be experiments that will fail, and hypotheses that will be proven wrong.”2 Moving forward, Dr. Baldwin feels that this research has the potential to change the way we think about neurological disorders.2 She plans to build her lab and continue studying hepaCAM in astrocytes. She says that “there is still so much we don’t know about astrocyte biology. Studying the function of hepaCAM in astrocytes will help address this important gap in our understanding.” She wonders, “if hepaCAM is completely deleted, can it cause neurodevelopmental disorders?”2 Even more long-term, she desires to one day understand how the different environments that astrocytes are in, whether it be “gray matter” or “white matter”, influence the function of astrocytes. Dr. Baldwin is going to continue to recruit members for her team and build her lab to one day work out these questions. She is very excited to be at UNC and for the new, different things going on in neuroscience research. She has already had interesting discussions with other faculty at UNC about how they can collaborate in the future. Her research goes to show that there may be a better explanation for neurological disorders. Not only that, but maybe even one day, this can be a target for better treatments. As Baldwin proclaims, “It’s really fascinating to realize how much we truly don’t know about the brain!”2

Figure 3. A fluorescently labeled astrocyte in the mouse cortex.

References 1. Baldwin, Katherine T.; Tan, Christabel X.; Strader, Samuel T.; Estévez, Raúl; Ji, Ru-Rong; Eroglu, Cagla; HepaCAM controls astrocyte self-organization and coupling. 2021, 109, 2427-2442.

2. Interview with Katherine Baldwin, PhD. 9/17/21.

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Psychology & Neuroscience

Unraveling the Maze of Matching Substances with Treatments By: Sprihaa Kolanukuduru

D

rugs are a prevalent part of society with immense repercussions, yet the amount of knowledge and effectiveness of treatments are lacking. Substances’ classes and subclasses abound, with their various effects permeating through society. From prescription opiates to the extracurricular use of other drugs, multiple sources are contributing to the same problem: Substance Use Disorders (SUDs). Dr. Charlotte Boettiger, the principal investigator of the CAB Lab, hopes to change how substances directly affect function and behavior. Dr. Boettiger focuses on the mechanisms in the brain and the intermediate phenotypes that engage in these disorders. Intermediate phenotypes are measurable traits viewed through the lens of neuroscience as opposed to focusing on clinical treatment.1, ⁴ Through her research, she hopes to break the umbrella term of “Substance use disorders” down by identifying the specifics to effectively treat each malfunction.2 SUDs have continued to be an undertreated spectrum of disorders, which serves as an underlying motivation for the CAB Lab

to pursue their research questions. Dr. Boettiger discusses, “ It’s clear that there’s not really enough treatment options available, which was the case 30 years ago, but it continues to be an underlying problem.” As a graduate student, Dr. Boettiger studied songbirds and the neural circuits associated with learning, later transitioning to research motivated behaviors and addiction. To answer questions and identify the methods of malfunction, the CAB Lab uses a variety of methodology, such as neuroimaging such as MRI scans (Figure 1), surveys, and observing human subjects. Dr. Boettiger collaborates with Dr. Donita Robinson to study dysfunction caused by alcohol and use or substance abuse using rat models.2,⁴ Various animal models are used to better understand disorders and neural mechanisms, with certain models being better aligned to certain research questions as shown in Figure 2.

Most current studies at the CAB Lab involve human subjects and survey alcohol history and cognitive function.⁴ A focus of interest for the lab is behavioral flexibility as affected by alcohol use during the

Figure 1: MRI image of the brain. Photo by Dr. Charlotte A. Boettiger

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Carolina Scientific adolescent period, alongside studying how previous alcohol use

Figure 2: Various Animal Models and Their Subsequent Research Topics Used in Neuroscience Research. Photo from Harvard Neuro Blog by Alex Chen. can impact the risk of later substance use. The CAB Laby isare using multiple different methods to assess humans and working with Dr. Robinson’s lab to understand the mechanisms and circuitry behind the behavioral flexibility correlated withto substance use.

A recent study conducted in collaboration with Dr. Robison’s lab focuseds on ethanol exposure at the adolescent age specifically to see how long-term the effects are. Titled, “Adolescent Intermittent Ethanol Impairs Behavioral Flexibility in a Rat Foraging Task in Adulthood,” the researchers hypothesized that alcohol exposure during a critical period would lead to a decrease in behavioral flexibility. The study concluded that the rat brain at that younger age is sensitive to injury from substance abuse at that younger age in the hippocampus and the frontal cortex. Additionally, the hypothesis of reduced flexibility was confirmed.3 Rats were taught associations in foraging tasks, which involve odor sensing. While the ability to differentiate between various odors was unaffected in the ratsremained the same, alcohol impairment led to a wide difference in the amount of time it took the control group and the alcohol-exposed groups to complete certain foraging tasks.

Rats exposed to alcohol during the critical period were more likely to make errors multiple times before reaching the correct response during a reversal of the conditions learned by the rat.

In comparison, the control group made errors after completing a correct response. Similar studies have been conducted regarding the ability of rat models to adapt to spatial tasks. It is feasible to view the effects of a substance on behavior when conducting a

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Psychology & Neuroscience

present study with animal models, compared to retrospectively survey adults, which can dictate the methodology chosen.2 Overall, the rat brain is sensitive to injury or harm from alcohol exposure during adolescence, which can imply that a similar sensitivity exists in the human brain.

There is an extensive amount of work conducted on the sensitivity of the brain to alcohol in animal brains, but a significantly smaller amount of work is done to confirm the same effects in humans. Primarily, the CAB Lab aims to translate findings found in animal brains to humans. In May, the lab published an article titled, ”High Trait Attention Promotes Resilience and Reduces Binge Drinking Among College Students With a Family History of Alcohol Use Disorder.” In contrast to prior research, this study involved humans, who wereare the main subjects of the lab. By surveying around 500 college students with or without a history of alcohol use disorders, the lab tested how attentional ability, which refers to an individual choosing to pay attention to a certain stimulus or not, can affect a possible alcohol use disorder in college students with a family history. The main findings of this study were that a higher attentional ability is negatively correlated to binge drinking.

As a result, it can be concluded that individuals who have more problems with attention and a family history of alcohol use are more likely to binge drink.⁵ The results of this publication, among the other studies fromof the lab, serve to identify possible targets for therapies. From identifying correlations between substance use disorders, traits, and other mechanisms, the Dr. Boettiger’s research is very translatable.

Dr. Boettiger’s research has far-reaching implications for further studies. The projects all serve to answer a question that can keep building on itself. With the large-scale idea of identifying the specific disordered paths to the same malignant effect, the work done at the CAB lab serves to identify ways to differentiate and better treat SUDs. As the lab isolates mechanisms and traits that lie at the root of these disorders, their findings can serve as a starting point for further research into the mechanisms themselves.

Furthermore, the results from the topics of study at the CAB lab can be used in a clinical research setting to investigate potential treatment options. Dr. Boettiger describes the work at her lab as translational, saying “We hope our work help and improve the field’s chances of identifying effective interventions."2 Hopefully, as Dr. Boettiger continues to conduct research motivated by clinical questions revolving around substance use and addiction, the path to effective treatment of these disorders will stand out in the maze.

References

1. Flint, J., Timpson, N., & Munafò, M. (2014). Assessing the utility of intermediate phenotypes for genetic mapping of psychiatric disease. Trends in neurosciences, 37(12), 733–741. https://doi.org/10.1016/j. tins.2014.08.007 2. Interview with Charlotte A. Boettiger, Ph.D. 09/09/2021 3. Sey, N., Gómez-A, A., Madayag, A. C., Boettiger, C. A., & Robinson, D. L. (2019). Adolescent intermittent ethanol impairs behavioral flexibility in a rat foraging task in adulthood. Behavioural brain research, 373, 112085. https://doi.org/10.1016/j.bbr.2019.112085 4. Boettiger, C. (n.d.). Cognition & Addiction Behavioral Neuroscience Lab. cablab.web.unc.edu 5. Elton A, Allen JH, Yorke M, Khan F, Lin Q and Boettiger CA (2021) High Trait Attention Promotes Resilience and Reduces Binge Drinking Among College Students With a Family History of Alcohol Use Disorder. Front. Psychiatry 12:672863. doi: 10.3389/fpsyt.2021.672863

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“The whole of science is nothing more than a refinement of everyday thinking.”

- Rosalind Franklin

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

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Spring 2021 Volume 13 | Issue 2

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

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