Carolina
Carolina Scientific
sc覺ent覺fic Spring 2014 | Volume 6 | Issue 2
THE GALAXY INSIDE YOUR MIND new research uncovers functions of star-shaped neural cells full story on page 18 1
Carolina
scıentific Mission Statement:
Executive Board
Founded in Spring 2008, Carolina Scientific serves to educate undergraduates by focusing on the exciting innovations in science and current research that are taking place at UNC-Chapel Hill. Carolina Scientific strives to provide a way for students to discover and express their knowledge of new scientific advances, to encourage students to explore and report on the latest scientific research at UNC-Chapel Hill, and to educate and inform readers while promoting interest in science and research.
Letter from the Editor: Sometimes research answers questions we didn’t know we should be asking. Researchers didn’t expect to learn they could create methanol from formic acid (page 10), or that changes in insulin level could affect cancer risk (page 30). Other times research provides solutions for long-standing problems such as how to safely treat hemophilia (page 28) or how to reduce harmful side effects of powerful drugs (page 20). Research can also help us understand complicated processes, such as the sinking of marine “snow” and its role in carbon sequestration (page 26) or the way addiction affects immune response even after recovery (page 42). We hope you find in these pages the joy of discovery, the excitement of the unexpected, and the thrill of the unknown. -Kati Moore
on the cover
Editor-in-Chief Managing Editor Associate/Design Editor Associate Editor Copy Editor Treasurer
Kati Moore Hannah Aichelman Erin Moore Josh Sheetz Matthew Leming Linran Zhou
Advisors Faculty Advisor Gidi Shemer, Ph.D. Graduate Advisor Courtni Kopietz Graduate Advisor Dan Lane Contributors Staff Writers
Copy Staff
Sean Anderson Aisha Anwar Corey Buhay Guy Cecelski Dana Corbett Brian Davis Rukmini Deva Varun Gulati Tracie Hayes Karthika Kandala Kensey Katz Laura Kim Congcong Li Daniel Liauw Parth Majmudar Travis Murphy Taylor Nelsen Ian Rahn Jenna Sawafta Brook Teffera
Aisha Anwar Glynis L. Coyne Brian Davis Alex Dugom Suzahn Ebert Wylder Fondaw Kimberly Hii Naveen Iqbal Justin Pack Cody Phen Emily Smith
Design Staff Kristine Chambers Tracie Hayes Kimberly Hii Stephanie Liffland Meghan McFarland Matt Morrow Taylor Nelsen Rosa Park Ying Zhou
carolina_scientific@unc.edu carolinascientific.web.unc.edu facebook.com/CarolinaScientific issuu.com/uncsci @uncsci
Image by Josh Sheetz
UNC researchers use advanced imaging and genetic tools to investigate the structure and function of astrocyte cells in neural networks. See page 18 for the full story.
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contents
Biology
Chemistry
4
The Solar Guillotine
28
Treating Hemophilia
8
Self-Healing Materials
29
The Protein Network
Clean Energy
30
An Unexpected Role for Insulin
32
Understanding Disease
33
Through the Looking Glass
34
A Vector to Cure
10
Splitting water creates effective solar fuels Sean Anderson Toughness and self-repair of biomaterials Daniel Liauw Methanol: a potential game changer Parth Majmudar
Health & Medicine
12 14
Doctors to Storytellers
Purpose and impact of narrative medicine Aisha Anwar
The Dish on DHA
Fatty acids affect cognitive function Rukmini Deva
Pharmacology
16
18 20
Policing DNA Damage
Cellular response to damaged DNA Karthika Kandala
26
Predicting antibiotic resistance Travis Murphy Insulin impacts cell growth and cancer Laura Kim G-protein regulation of pathogens Ian Rahn Zebrafish model heart formation Dana Corbett
Drug delivery via lipid calcium phosphate Congcong Li
Linguistics & Psychology
Shooting for the Stars
Astrocyte regulation of neural activity Brook Teffera
A New Brain Disorder Treatment Sodium’s newfound role in cell signaling Kensey Katz
Environmental Science
22
Researchers find safer treatment Varun Gulati
36
Giving Back More Than Smiles
38
Happiness Manifested
40
Neural Bridges of a Baby’s Brain
42
How Your Brain Can Make You Sick
Nutrient Overload
Global warming encourages toxic algae growth Corey Buhay
Underwater Snow
Modeling marine aggregates Taylor Nelsen
3
Cleft lip and palate repair Jenna Sawafta
Positive emotions impact overall health Brian Davis Understanding brain development Tracie Hayes
Understanding heroin dependency Guy Cecelski
Figure 1. In a breakthrough from the UNC Energy Frontier Research Center (EFRC), the sun’s energy is harnessed in order to split water into its component parts, which produces hydrogen fuel. Hydrogen is stored while the byproduct, oxygen, is released into the air. Images courtesy of UNC EFRC. Graphic art by Yan Liang.
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The Solar Guillotine how splitting water leads to containable fuels by Sean Anderson
I
t turns out that a potential secret to the preservation of the planet, and ultimately the human race, is found within the grass we step on and the trees that shade us. Dr. Thomas J. Meyer and his team at the UNC-Chapel Hill Energy Frontier Research Center (EFRC) have used a method similar to that used in photosynthesis in plants to produce solar fuels that could one day diminish our need for fossil-based fuels. By designing a new and faster way of splitting water molecules into their basic components of hydrogen and oxygen, Dr. Meyer and his team believe they have found the missing piece in one promising solution. They are making solar fuels more usable because hydrogen production from water splitting has become Dr. Thomas J. Meyer easier. With more than 82 percent of the world’s energy needs being met by fossil fuels in 2011, the need for alternative fuel sources is at an all-time high.1 The goals for fuel production in artificial photosynthesis are similar to plant photosynthesis. The targets are either hydrogen production from water split-
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Figure 2. UNC Energy Frontier Research Center (EFRC) Director Thomas J. Meyer discussing research progress at a center meeting. The EFRC aims to use dye sensitized photoelectric cells to drive solar reactions. Image courtesy of UNC EFRC.
ting or reduction of carbon dioxide to a carbon-based fuel such as gasoline.2 Fuel cells are already in use today, generating electricity by way of an electrochemical reaction where oxygen and a stored hydrogen-rich fuel combine to form water that can be used to power your car’s headlights or charge a battery.3 As Dr. Meyer explains, the problem with solar as a predominant energy source is that “you have to face up to the fact that the sun goes down at night.” This is where his team’s use of DSPEC comes in. DSPEC, or dye sensitized photoelectrosynthesis cell, is a molecular assembly that consists of a light-absorbing chemical called a chromophore that speeds up reactions. That molecule is then bound to the surface of a nanoparticle of a transparent conducting oxide (Figure 1). These nanoparticles are part of film, which is then coated with a microscopic layer of titanium oxide (TiO2). When sunlight comes in, the chromophore molecule gets excited and transfers an electron to the nanoparticle followed by electron transfer from the catalyst, which begins the process of water oxidation. Electrons in the
nanoscopically thin TiO2 layer — the key players in energy transfer — are able to rapidly travel through the nanoparticle to a second site, an electrode, where hydrogen is produced.2 Before the use of thin-layer TiO2, the electrons moved at speeds far too slow to efficiently produce hydrogen. Using the thin-layer TiO2 reduces the speed to around a nanosecond, allowing the electron to escape and for hydrogen to be made. Thus, the production of hydrogen instead of electricity allows the energy to be stored within the bonds of the hydrogen molecule for storage and extraction at a later time. Dr. Meyer explains that he doesn’t “have to build a better battery or construct a hydro-dam — just make the molecules and burn them.”4 He described a future where, in 20 or 30 years, large multi-acre solar panel farms provide energy in rural areas. The system would require two types of solar panels — one panel used to make electricity while the other utilizes Meyer’s water splitting technology to produce hydrogen gas. Gas would then be transported or stored on site for use when needed. By
“You take this dreaded greenhouse gas and keep cycling it back and forth with no net loss to the atmosphere.” -Dr. Thomas Meyer
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is being used to reduce greenhouse gases to carbon fuels to be stored for later use. As Dr. Meyer explains, “You take this dreaded greenhouse gas and keep cycling it back and forth with no net loss to the atmosphere.”3 This work in conjunction with advances in hydrogen storage could change the way that the world meets its energy needs. The big picture of Dr. Meyer and his team’s research is to work out a closed system based on the use of solar energy. This system will use naturally abundant carbon dioxide and water splitting to make mixtures of hydrogen and carbon monoxide as a precursor to methanol, gasoline and other carbon-based fuels for transportation and power production. As it stands, Dr. Meyer and his team have succeeded in bringing us one step closer to tackling the world’s energy issue.
References
1. Fossil Fuels. Retrieved from http://www.globalization101. org/fossil-fuels/. 2. Alibaei, L., Brennaman, M.K., Norris, M.R., Kalanyan, B., Song, W., Losego, M.D., Concepcion, J.J., Brinstead, R.A., Parsons, G.N., Meyer, T.J. “Solar water splitting in a molecular photoelectrochemical cell.” Proceedings of the National Academy of Sciences of the United States of America 110, 20008. 2013. 3. Introduction, Fuel Cell Today. Retrieved from http:// www.fuelcelltoday.com/about-fuel-cells/introduction. 4. Interview with Thomas J. Meyer, Ph.D. 01/30/2014.
Figure 3. UNC EFRC small center graduate students conduct experiments in the UNC EFRC Laser Facility. Image courtesy of UNC EFRC. burning the gas in a nearby power plant, energy stored in the hydrogen would be utilized in gas turbines to generate electricity on demand, as needed. Dr. Meyer describes this construct as the “integrated energy factory of the future.”4 The key to making solar fuels a viable option for meeting the future energy needs of the world comes down to efficiency. Even with a device that was 10 percent efficient, meeting the energy needs of the United States with solar energy alone would require a collection area about the size of North Carolina.4 Meyer and his team, on the heels of this breakthrough, are now focused on maximizing efficiency and stability, so that these new technologies are able to last as long as possible. As scientists reach the goals of increased efficiency and stability of solar energy, the possibilities for economic viability will increase, and the green approach will appear more appealing to the public. Dr. Meyer and the faculty, staff and students in the US Department of Energy-funded UNC EFRC for Solar Fuels are now working on completing the cycle of this remarkable system. They will accomplish this by tackling the increasing amounts of greenhouse gases in the atmosphere. Along with water splitting and production of hydrogen gas, the DSPEC
The key to making solar fuels a viable option for meeting the future energy needs of the world comes down to efficiency.
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chemistry
the science of
SELF-HEALING MATERIALS By Daniel Liauw
O
ver 20 years after the release of “Terminator 2,” Spanish scientists have developed a rival to the notorious liquid metal robot who had the ability to repair himself. Nicknamed the “Terminator” polymer, this self-healing material has several profound uses.1 On a small scale, it can provide a child with protection such as an artificial skin graft that will both keep up with the child’s growth and provide a barrier against germs. On a larger scale, it is being applied to the engineering of aircrafts, allowing for spontaneous repair of damages that are unseen by the human eye. Self-healing materials (Figure 1) are a smart breed of biomaterials designed to respond to and repair mechanical damage while maintaining structural integrity and mechanical performance. Sara Turner, a third-year graduate student in the UNC-Chapel Hill chemistry department and a member of Dr. Valerie Ashby’s research group, has decided to pursue the enormous project of creating a new, strong, self-healing material. One recurring goal of material development has been to emulate the materials of nature, a process known as biomimicry. Perhaps the most elusive of these goals is that of self repair. In hindsight, all Dr. Ashby and her strategies to improve the reliability and strength of research group aim materials developed over to synthesize a new the course of human innovation are ultimately spontaneous self- based on the paradigm of damage prevention, more healing material. specifically designing and preparing materials so that formation and extent of damage as a function of time is postponed as much as possible. In recent years, however, an alternative approach to damage prevention has surfaced. This type of prevention is called damage management, and involves building materials with the capability to repair damage incurred during use.
While mechanical properties of skin and bone are far inferior to those of man-made polymers today, their ability to repair or heal damage given the right healing conditions allows for lifelong regeneration.2 Of course, the mechanisms of healing found in natural materials cannot be copied exactly, but since human and animal skins are polymeric in nature, Dr. Ashby and her research group wonder why we do not try extending self-healing behavior Dr. Valerie Ashby to man-made polymers. Although several self-healing materials have already been synthesized, even stronger materials are in demand for larger-scale applications, such as the engineering of aircrafts. Spontaneous repair of damages that are unseen by the human eye requires that materials are not only strong and selfreparable, but also quickly reparable to near-original strength. “However, there is typically a trade-off between reparability and mechanical properties, with a high degree of self-reparability being achieved mainly with materials having low mechanical strength and stiffness,” says Turner.3 The weaker a material tends to be, the better it will self-heal to its original strength. Herein lies perhaps the biggest question chemists have yet to solve.4 There exists a spectrum of difficulty in synthesizing selfhealing materials ranging from the stimuli-responsive materials (which require a stimulus such as heat, light or pressure) to the spontaneous materials. Stimuli-responsive self-healing materials are easier to synthesize and are helpful for a user’s control of healing. However, many applications demand selfhealing without human intervention, simply because minimal damage that is difficult to identify often has immense ramifications. Dr. Ashby and her research group aim to synthesize a
force Figure 1. Self-healing materials can spontaneously repair in response to an applied force. Image by Daniel Liauw.
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Figure 2. The brush polymer, which can be a self-healing system, exhibits reversibility through the fracture and repair of bonds. It self-heals via bonding as “molecular Velcro.” Image by Sara Turner. new spontaneous self-healing material. Over the past decade, several methods for spontaneous self-healing have been identified. Capsule-based self-healing materials isolate a liquid healing agent in capsules throughout the matrix of a material.5 Turner explains that if this material were applied to an airplane’s wing, an “impact would rupture these capsules, triggering self-healing mechanisms as the healing agent quickly fills the cavities in the region of damage and hardens with the other material.”3 On the other hand, vascular self-healing materials place healing agents in a network of interconnected hollow channels. When the channel, or vasculature, is damaged, a first round of healing agent at the location is released and depleted, hardening at the site of impact. However, other connected channels or even an external source may refill this network, allowing for multiple local healing events.5 This process is similar to that when a capillary network in the dermis layer of skin supplies blood to heal a cut in the epidermis layer (Figure 3). Dr. Ashby and Turner have been working to create intrinsically self-healing materials that do not require sequestered pockets of healing agent. These materials rely heavily on the chemistry of the materials, particularly the reversibility of reactions and the entanglement of chains, which occurs when polymer chains are simply wrapped around one another. Sara Turner explains, “When I talk about polymers, I like to explain them as hair. It is a lot easier to pull apart a few strands of untangled hair than tangled, matted hair. Polymers get their strength in a similar way: from entanglements between chains. However, when a polymer material is damaged, entanglements are broken, and the only way for the material to repair itself is by re-entangling.”3 In other words, after the entanglements are broken, the reversibility of the damage process is key to self-healing. For example, self-healing brush polymers (Figure 2) gain strength from hydrogen bonding, a sort of molecular Velcro. When under stress, the polymer chains (“hairs” or “brushes”) that are bonded together separate with minimal destruction into individual chains. However, after the damage is applied, the brushes naturally desire to reform the molecular Velcro.2 The more polymer chain entanglements exist in the material (i.e. matted hair), the stronger the material gets. Self-healing properties are primarily left to the chemistry of the individual polymer chains. The chemical synthesis and design of these smart materials to exhibit self-repair biomimicry with both strength and elasticity has placed self-healing materials research at the crux of advancements in biology, chemistry, engineering and medicine. What has driven Dr. Ashby and Turner towards the
Figure 3. A self-healing material spontaneously repairs with a series of interconnected channels, known as a microvascular network, after cracks are formed in the coating. Image courtesy of Sara Turner. development and design of spontaneous, self-healing materials has been the hope for improved safety, energy, lifetime and environmental impact of man-made materials. As Turner explains, “strong self-healing materials will be really important looking towards a greener future. If a material can heal itself, you will not have to replace it!”3 Scientists in this field are both learning from and giving back to nature. By mimicking the self-healing capabilities of natural materials, the Ashby group hopes to preserve the planet and provide a brighter, greener future.
References
1. Wilson, P. Polymer regenerates all by itself. (2013, September 13). Retrieved from www.rsc.org/chemistryworld/2013/09/polymer-regenerates-elastomer-heals-independently. 2. Chen, Y., Kushner, A., Williams, G., Guan, Z. “Multiphase design of autonomic self-healing thermoplastic elastomers.” Nature Chemistry 4, 467–472. 2012. 3. Interview with Sara Turner. 02/07/2014. 4. Herbst, F., Seiffert, S., Binder, W.H. “Dynamic supramolecular poly(isobutylenes)s for self-healing materials.” Polymer Chemistry 3, 3084–3092. 2012. 5. Herbst, F., Döhler, D., Michael, P., Binder, W.H. “SelfHealing Polymers via Supramolecular Forces.” Macromolecular Rapid Communications 34, 203–220. 2013. 6. Interview with Valerie Ashby, Ph.D. 01/25/2014.
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chemistry
METHANOL:
a game changer in clean energy By Parth Majmudar The energy crisis is among the most important issues facing the world today and is at the forefront of economics, politics and the sciences. It is also at the crux of Dr. Alexander Miller’s synthetic chemistry research at UNC-Chapel Hill. Dr. Miller’s research focuses on the synthesis of alternative fuels from sustainable resources such as methanol.
I
f perfected, the synthesis of methanol would be a game changer in the world of green energy. For many years, methanol has been seen as a potential green energy source, but it was not economically or scientifically feasible to synthesize on a massive scale. Methanol could provide a low-pollution, less flammable and higherperformance alternative to gasoline for cars. In fact, methanol is such an effective and safe fuel that, from 1965 to 2006, pure methanol was the required fuel for racecars in the IndyCar series until it was replaced by ethanol.1 However, methanol formation is not an environmentally friendly process. The synthesis begins with coal or natural gas and requires a great deal of energy to proceed to completion. Dr. Miller suggests a more eco-friendly In Dr. Miller’s process: using formic attempt to create acid as an intermediate to synthesize methanol methanol from from biomass. Dr. Miller biomass, he found also believes that it is possible to use carbon that methanol dioxide in the creation formed instead of formic acid, which would both consume when formic acid carbon dioxide and was passed over a cleanly create formic acid.2 unique catalyst. Creating methanol from formic acid was not originally Dr. Miller’s goal. Instead, as a postdoctoral student with Dr. Karen Goldberg at the University of Washington, he stumbled across the reaction in what he calls a “moment of serendipity.” In his attempt to create methanol from biomass, he found that methanol
formed instead when formic acid was passed over a unique catalyst. A catalyst is a material which drives a reaction forward without being consumed. After discovering this reaction, Dr. Miller saw its potential merits and made perfecting it his own focus.3 In 1911, a reaction similar to that studied by Dr. Miller was indirectly discovered. It had not been Dr. Alexander Miller given a second look until Miller re4 discovered it a couple of years ago. This is likely due to the recent need for easily synthesized methanol. Only now is converting carbon dioxide to liquid fuels becoming a relevant field of study, and Dr. Miller is excited to be at its forefront.2 The reaction of formic acid discovered by Dr. Miller is dictated by the following equation: 3 HCO2H (aq) formic acid
CH3OH (aq) + H2O (aq) + 2CO2 methanol
water
carbon dioxide
This reaction competes with the inherent reactivity of formic acid, which is to release hydrogen and carbon dioxide gas. As it is, the reaction that produces no methanol dominates the one that produces only water and carbon dioxide. One of the major goals of Dr. Miller’s research is to find the optimal conditions that would force the methanol-producing reaction to occur and have no hydrogen form. One key to this is the catalyst that Dr. Miller helped develop, which contains a
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transportation fuel and precursor to plastics, drugs, and more
CO2
HCO2H
CH3OH
formic acid
iridium catalyzed
Figure 1. Schematic describing the creation of methanol from carbon dioxide and formic acid, a reaction that could potentially benefit the environment. Dr. Miller’s research aims to find optimal conditions to form methanol without hydrogen byproducts. Concept by Dr. Miller, figure by Erin Moore.
precious metal called iridium and is stable in the atmosphere.2 ready in place.2 When Dr. Miller first discovered the reaction, it exhibDr. Miller’s research has gained nationwide attention. ited limited preference for the In 2012, he was named one of formation of methanol, instead Forbes magazine’s prestigious “30 producing copious amounts Under 30” in the energy category.5 “Serendipity in research is of hydrogen gas, an undesired But he partially credits his success underrated. A lot of times, the byproduct. However, by mein discovering this alternative ticulously tweaking the condienergy method to good fortune most interesting things are the tions of the reaction, Dr. Miller and sound science. “Serendipity ones that come out of nowhere has increased the selectivity of in research is underrated. A lot of the reaction for methanol to 12 times, the most interesting things and surprise you.” percent. While this selectivity are the ones that come out of no-Dr. Alexander Miller is far from where he would like where and surprise you, and by it to be, this still demonstrates noticing those things and finding substantial progress. 2,4 out what they are, you can actuMany challenges remain for the research teams of Dr. ally change the game,”2 Dr. Miller said. Miller and Dr. Goldberg. In addition to the necessity of increasing the selectivity of the reaction, the iridium catalyst is References rare and expensive. “For new reaction discovery, starting with 1. Methanol Basics. (1994, August). Retrieved from http:// heavy metals is a little bit easier in terms of your chances of www.methanol.org/Methanol-Basics/Resources/MethanolBasics/EPA-Methanol-Fact-Sheet.aspx. successfully finding a new reaction.” Dr. Miller sees two potential solutions to this problem, 2. Interview with Alexander J.M. Miller, Ph.D. 02/04/2014. both of which he is exploring. Either the reaction would have 3. Mitchell, C. University Gazette: Classic tale lands chemto be made incredibly efficient with the iridium catalyst, or a ist on Forbes’ ‘30 under 30’. (2013, February 26). Retrieved working catalyst would have to be developed from a more from http://gazette.unc.edu/2013/02/26/classic-tale-landschemist-on-forbes-30-under-30/. abundant metal such as iron, nickel or cobalt.2 Despite these hurdles, the reaction shows significant 4. Miller, A.J.M., Heinekey, D.M., Mayer, J.M., Goldberg, progress and potential. Of the possible forms of alternative K.I. “Catalytic Disproportionation of Formic Acid to Generenergy, methanol could be the easiest and most economical ate Methanol.” Angewandte Chemie International Edition to implement. As a start, methanol could be blended into gas- 52, 3981–3984. 2013. oline, in a manner similar to ethanol. Gas stations could eas- 5. Helman, C. Forbes 30 Under 30: Energy. (2012, December ily be repurposed to become methanol stations. Since both 17). Retrieved from http://www.forbes.com/pictures/megasoline and methanol are liquid fuel, the infrastructure is al- f45jdde/alexander-miller-29/.
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medicine
DOCTORS to STORYTELLERS Narrative-based medicine allows doctors to treat patients holistically BY AISHA ANWAR
P
opular culture has produced a dichotomy in the image of doctors — between the caring, heroic doctor clad in a white coat and the oblivious, unfeeling doctor that makes snap clinical decisions. An image that eludes us, though, is one of the doctor as a witness. While treating the sick, doctors are witnesses to the indignities of illness and recovery, to life and death. This means they must learn to closely listen to their patients in order to better understand and help them. Though the concept is not new, the term “Narrative Medicine” is largely attributed to Rita Charon, physician and literary scholar at Columbia University. She has published many papers on the topic, outlining the importance of narrative in shaping more empathetic and able doctors. Narrative has been and remains a vital aspect of medicine, but the presumed existence of two estranged cultures — the humanities and the natural sciences — has given birth to a system of education in which these disciplines are taught separately. Dr. Matthew Taylor, assistant professor of English at UNC-Chapel Hill, suggests that this is beginning to change.1 “There is a real attempt to allow doctors to express themselves in ways that haven’t traditionally been accepted in the medical profession, ways that are not just reducible to numbers but rather allow a certain amount of feeling and subjectivity to come across,” Dr. Taylor said. Of course, Narrative Medicine is also a move towards more patient-centered care and allows patients to tell their own stories without interruptions. As people are allowed to describe the story of their illness within the larger frame of their lives, doctors can deal with patients in a more holistic manner — treating the patient rather than the illness. Thus,
narrative-based medicine has come to occupy two interconnected arenas of storytelling: patient narratives and doctor narratives.2 In an essay titled “Narrative Medicine, Negative Capability, and Me,” physician and writer Terrence Holt explores the attractions and pitfalls of narrative-based medicine. While he addresses the potential harm of such doctor narratives (namely, lack of trust from patients), Dr. Holt argues that there is an alDr. Terrence Holt ready existing fascination with medical narrative amongst audiences. Medical dramas, such as Grey’s Anatomy, have penetrated the entertainment industry and display this fascination. For Dr. Holt, these shows “address a deeply-held wish and allay (or at least entertain) an abiding fear: that doctors might care for them; that anybody, in the enormous machine that is a hospital, might be personally concerned with their mortality.” More importantly he argues that a good doctor is analogous to a good reader — someone that is able to engage with the text on multiple levels by interpreting, reacting, translating and analyzing simultaneously.2 To test the impact of narrative on patients, Dr. Holt conducted a pilot research study in which he asked cancer patients at UNC Hospitals to write their own personal stories. Questionnaires were subsequently used to assess the patients’
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ligations of agency than a doctor is. And a doctor is certainly not exempt from answering questions of meaning,” Dr. Holt said. Medical Humanities is a growing field that has produced several multidisciplinary courses and studies at UNC. Recognizing the necessity of reexamining the medical culture, Dr. Holt constructed the syllabus for a course titled “Medicine, Literature, and Culture.”4 A compilation of novels, critiques and essays in this course offers not only new reading material but emphasizes new ways of reading. Dr. Matthew Taylor, one of the professors now teaching this course, agrees that it allows students to sit side by side in a dialogue on how to improve the practice of medicine by studying the culture born out of it.1 Since it was first approved, the course has been taught by Dr. Matthew Taylor Dr. Jane Thrailkill Dr. Jane Thrailkill. “Folks working in science and medicine are starting to acknowledge the ways in which they need the humoods before and after the exercise. He found that people manities,” Dr. Thailkill said. who wrote about their experience had lower self-esteem than Honors Carolina expanded on the course and introthose that were a part of a control group. Thus, Dr. Holt’s study duced a Medicine, Literature, and Culture interdisciplinary provided a glimpse of the potential benefits and harms of Nar- minor. The minor includes a variety of courses that examine rative Medicine.3 medicine through the lens of culture as “A humanities scholar it relates to medical ethics and practices Dr. Holt will be conducting a similar study in the spring. As part of a team is no more exempt from as well as shifting understandings of disthat recently received a grant from the ease and doctor-patient relationships.6 Mellon Foundation, he will replicate the obligations of agency Additionally, the English and Comparahis study with groups of retirees who than a doctor is. And a tive Literature Department announced will take part in writing and discussion a new Masters Degree track for Medical doctor is certainly not Humanities. sessions concerning the challenges of aging. This study will aim to observe exempt from answering Dr. Thrailkill argues that we need whether there is a meaningful difference to stop framing medicine as resistance to questions of meaning.” death because it “lacks insight into what between those who are given a chance to write about their experience versus the ancients called ars moriendi, ‘the art -Dr. Terrence Holt those who simply come in and talk about of dying well’.” She notes that while “modit. Dr. Holt believes that studying changes in mood will reflect ern medicine’s alliance with science has given us extraordithe impacts of narrative because narrative affects cognition in nary means for tending to the sick and wounded and for exnumerous ways. He predicts that those who write about their tending life, [it] has little wisdom for families grappling with experience will have less difficulty adjusting to old age.4 who will care for a disabled loved one.”5 Narrative Medicine While Dr. Holt’s assessment is primarily qualitative, bio- aims to change that. medicine has become increasingly dependent on empirical data, favoring facts over individual experiences.1,4 Moreover, References the move to statistical analysis has been mirrored by a veiling 1. Interview with Matthew Taylor, Ph.D. 01/31/2014. of medical practice behind technical jargon, creating an issue 2. Holt, T. “Narrative Medicine and Negative Capability.” of communication across the doctor-patient boundary. This Literature and Medicine 23, 318–333. 2004. problem highlights the importance of Narrative Medicine as 3. Derewitcz, M. The Doctor’s Writing. (2010, May 1). a means of achieving mutual understanding between patient Retrieved from http://endeavors.unc.edu/spr2010/docand doctor. Between consulting colleagues and jotting down tors_writing.php. patient histories, doctors speak a language that entirely ex- 4. Interview with Terrence Holt, Ph.D. 02/05/2014. cludes the patient. While the patient waits for a translation, a 5. Interview with Jane Thrailkill, Ph.D. 02/03/2014. divide occurs, ultimately isolating the patient. Narrative Medi- 6. Interdisciplinary Minor in Medicine, Literature, and cine aims to bridge that gap by allowing more fluid dialogue Culture. Retrieved from http://honorscarolina.unc.edu/ on the patient’s level. This is important because the medicine current-students/curriculum/interdisciplinary-minor-inraises questions of meaning and agency in connection to ill- medicine-literature-and-culture/. ness and death and attempts to intervene in those processes. 7. Announcing a New MA Degree Track at UNC. Retrieved Dr. Holt compares narrative-based medicine to two patholo- from http://englishcomplit.unc.edu/litmed. gists examining a slide of tissue specimen. In order to answer 8. Medicine, the Humanities, and the Human Sciences — a the question “Is this cancer?” they have to observe it and form two-day conference. Retrieved from http://heymancenter. org/events/medicine-the-humanities-and-the-humanan interpretation.4 “A humanities scholar is no more exempt from the ob- sciences/.
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nutrition
the dish on
DHA
By Rukmini Deva
maternal diet lacking DHA may harm prenatal cognitive development
W
alking down an aisle at Whole Foods, “DHA” and “omega-3” labels adorn various food items including milk, eggs, nuts, flaxseeds and oils. What is this mystery substance, and why are grocery stores promoting it? Docosahexaenoic acid (DHA) is an omega-3 fatty acid critical for optimal brain health and function at the prenatal stage of development as well as later in life.1 Despite its importance as a key hormone in brain function, DHA levels are low in America. This national deficiency has led to the production of DHA-fortified baby formulas and prenatal vitamins. Dr. Carol Cheatham, a developmental cognitive neuroscientist at UNC-Chapel Hill’s Nutrition Research Institute, is working to understand the implications of this nationwide DHA deficiency. Specifically, her research focuses on the process and efficacy of DHA transfer from mother to child via both the placenta and breast milk.3 Although physicians have long touted the advantages of breastfeeding, Dr. Cheatham’s research shows how, without proper maternal diet, breastfeeding may not always provide some important nutrients. The explanation lies in the genotype of the mother. Seven percent of US women are genetically unable to synthesize DHA.3 Consequently, these women have less DHA in their blood plasma during pregnancy, resulting in a lower amount of DHA supplied to the fetus during its
brain development phase and after birth. “I don’t want women to think that breast milk is bad; I want to encourage breastfeeding. But if certain women are part of this seven percent, then they will have to eat plenty of DHA,” Dr. Cheatham said. DHA-fortified formula is commercially available, but clinical trials have not been able to prove that supplemental DHA has the same benefits as natural DHA; Dr. Carol Cheatham in fact, fewer than 40 percent of trials have found that it does. Moreover, physicians in the United States do not commonly test for reduced DHA levels in their patients.3 As a result, it is unlikely that a woman in America will know if she is part of the seven percent of females who cannot synthesize DHA. One way to correct a DHA deficiency is by reducing omega-6 intake and increasing omega-3 intake. Dr. Cheatham recommends that all pregnant women, regardless of their genotype, obtain exogenous sources of DHA and other omega-3 acids Figure 1. In one of Dr. Cheatham’s labs, a six month old named Lincoln participates in a unique study. His scalp covered in 128 electrically sensitive sponge cups, Lincoln sits quietly on his mother’s lap, watching a screen of blinking images. As Lincoln observes each passing image of a toy, the sensors create a graphical representation of his brain activity. Upon seeing new toys, Lincoln’s brain activity increases. When a familiar toy appears, however, the brain does not expend its energy to process the familiar toy again. Photo by Jon Lakey, Salisbury Post.
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nutrition
Figure 2. Yvonne Perkins and her 6-month-old son Lincoln take part in Dr. Cheatham’s nutrition study, which analyzes cognitive effects of reduced maternal DHA intake. Photo by Jon Lakey, Salisbury Post. through foods such as eggs, nuts, oils, fish, flaxseeds and dairy products.5 The positive correlation between DHA intake and increased cognitive function has been determined in various research findings, including a study in which Dr. Cheatham measured the memory and cognition of babies that were not of speaking age (Figure 1). The babies in this study were six months old and exclusively breastfed. “We were able to show that the breast milk of the moms who were in this seven percent had lower DHA, and their babies were delayed in their development,” Dr. Cheatham said. Certain ethnic groups, including the Inuit, have consumed a diet rich in DHA for generations, but no longer have the gene for synthesizing DHA. This trend is presumably due to the evolutionary effects of fetal programming, a life-long alteration of tissue functions and structures as a result of fetal environment. The Inuit population has fed on whale blubber for generations, which is rich in omega-3 fatty acids.3 “Now that the Inuit have adopted a more Westernized diet, they need to make sure they are getting enough DHA because they can no longer make their own,” Dr. Cheatham said. Similar effects of fetal programming can also occur in other populations. “Because women are supplementing during pregnancy and during breastfeeding, they may be setting their children up to expect the same from the outside world. I am afraid they are setting up an entire generation to require exogenous DHA,” says Dr. Cheatham. In future studies, Dr. Cheatham plans to investigate
whether mothers who cannot synthesize DHA naturally crave foods with more DHA during their pregnancies because their fetuses require it. “It could be what we call ‘eating to their genes’,” Dr. Cheatham said. Dr. Cheatham hopes that with increased DHA research, a genetic test screening for the DHA-synthesizing gene will eventually become more common during check-ups. “My ultimate goal would be to say, yes, moms are now able to find this out, and [DHA deficiency] is not a problem anymore,” Dr. Cheatham said.
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References
1. Horrocks, L.A., Yeo, Y.K. “Health benefits of Docosahexaenoic acid (DHA).” Pharmacological Research 40(3), 211–225. 1999. 2. McNamara, R.K. “DHA Deficiency and Prefrontal Cortex Neuropathology in Recurrent Affective Disorders.” The Journal of Nutrition 140(4), 864–868. 2010. 3. Interview with Carol Cheatham, Ph.D. 02/01/2014. 4. Simmer, K., Patole, S.K., Rao, S.C. “Long-chain polyunsaturated fatty acid supplementation in infants born at term.” Cochrane Database of Systematic Reviews. CD000376. 2011. 5. Sacks, F. Omega-3 Fatty Acids. Retrieved from http:// www.hsph.harvard.edu/nutritionsource/omega-3/. 6. Godfrey, K.M., Barker, D.J. “Fetal programming and adult health.” Public health nutrition 4(2B), 611–624. 2011.
pharmacology
policing DNA damage a proteomic approach to cancer research By Karthika Kandala
C
entrosomes, lysosomes, ribosomes, endoplasmic reticulum, mitochondria and many other structures compose the smallest system of the human body: the cell. While cells may be tiny, they are incredibly chaotic and complex. The human cell is being studied by many researchers around the world, including Dr. Michael Emanuele, an assistant professor in the Department of Pharmacology in the UNC-Chapel Hill School of Medicine and the Lineberger Comprehensive Cancer Center. Dr. Emanuele studies cell growth and cell communication in hopes of finding cures for many diseases, including cancer. More specifically, he focuses on the way proteins are organized within a cell, or the cell’s proteome. Dr. Emanuele is currently exploring protein degradation, a key regulator of cellular physiology and disease in individuals. One of the main aspects of protein degradation is how it changes in response to cell growth DNA damage. “Most of the cells in and DNA damage can my body and your be caused by many body are relaxing, factors, such as UV while cells in a cancer rays from the sun or from a cigapatient are spreading smoke rette (Figure 1). Allike wildfire.” though these factors -Dr. Michael Emanuele can cause damage to DNA, cells are very good at repairing this “broken DNA.” One way cells respond to and repair damaged DNA is by degrading proteins that would prevent repair while also preventing the destruction of the enzymes that aid in the restoration process (Figure 2).1 However, when the damage is not fixed, diseases such as cancer can result. Cancer, the second highest cause of death in the United States,4 is characterized by unregulated cell growth. “Most of the cells in my body and your body are relaxing, while cells in a cancer patient are spreading like wildfire,” Dr. Emanuele explains.1 The questions that the Emanuele Lab is primarily concerned with are “What triggers the cells to spread like wildfire?” and “What can be done about it?” Dr. Emanuele is attempting to answer these questions by analyzing the cell cycle. Dr. Emanuele’s lab studies pro-
tein degradation because it is a key indicator of cell health. Protein degradation acts as a regulator in the progression of the cell cycle, and this process is severely perturbed in many cancers. The cell cycle and protein degradation machinery are crucial aspects of cancer research because it is now known that defects in the Dr. Michael Emanuele protein degradation process are one of the causes of cancer. Mapping the signals that control protein degradation is essential, and Dr. Emanuele compares the focus of these questions to turning on a light switch at home. Similar to cancer, a light is connected by various signaling networks; when one of those networks is not functioning properly, the output (light) is not achieved. Whereas a failure in a wire results in the light not being turned on, a signaling failure in the cell cycle can result in the development of cancer.1 The goal in both cases is to find the exact wire or signal that is causing the negative result. It is with this goal in mind that Dr. Michael Emanuele utilizes two proteome analysis techniques, which have become revo-
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Before
After
Incoming UV Photon
Figure 1. UV rays can contribute to DNA damage and potentially cause cancer. Image created by NASA.
Carolina Scientific lutionary in his field of study. Global Protein Stability (GPS) and Quantitative Ubiquitylation Interrogation (QUAINT) are two emerging technologies that assess different aspects of protein degradation. Dr. Emanuele was first introduced to these techniques while at Harvard Medical School, and over the years he has contributed significantly to the advancement of both methods. GPS is unique because it allows researchers to study approximately 15,000 proteins simultaneously. Furthermore, researchers can study the degradation process of this vast number of proteins in live cells. QUAINT provides a more quantitative analysis of protein degradation by measuring the amount of ubiquitylation on many thousands of cellular proteins. Ubiquitin is a regulatory protein which targets proteins for degradation (Figure 3). Additionally, QUAINT can identify sites where protein degradation is prominent, allowing for more research in that specific area. This connection between the activation of ubiquitin and DNA damage due to environmental factors is also an important aspect of cell communication and Dr. Emanuele’s work. One of the advances Dr. Emanuele’s work was able to establish was the relationship between UV rays and levels of the protein NUSAP1, which has been proven to provide cells with more resistance to the toxic effect of cancer treatments. Dr. Emanuele and a team of researchers proved that after UV treatment, there was degradation of the NUSAP1 protein.3 The implications of this research are incredible because UV rays are a significant source of DNA damage, and Dr. Emanuele’s work shows a direct connection between the environmental factor of UV damage and therapeutic cancer treatments. Although Dr. Emanuele’s research impacts all types of cancer research, his primary focus is on breast cancer. As stated by Dr. Emanuele, “UNC is one of the best places in the world for breast cancer research.” UNC is one of 11 institutions in the United States to receive a Specialized Programs of Research Excellence (SPORE) grant.1 Each recipient of the SPORE grant is asked to focus on a specific human organ. The grant that UNC received allows the university to focus its research on the breast.3 With this grant already being given to the Lineberger Comprehensive Cancer Center, it was only natural for Dr. Emanuele to focus on this aspect of cancer. Dr. Emanuele’s research has been highlighted in various publications for its advancement in the study of one of the most complex entities in the world: the human cell. However, he has always emphasized that one’s working environment has a great effect on his or her research. Dr. Emanuele was not hesitant to state that “coming to UNC was a great decision because it is a fantastic place for science.” He believes that one of the greatest aspects of the institution is that there are “a variety of people studying different aspects of cell function and disease.” This characteristic of UNC has allowed for a “collegial” environment in the workplace, which has allowed him and his research to fit right in.1 Although Dr. Emanuele has only been at UNC for one year, his efforts in the field of cancer cell biology have already been recognized by many of his peers. Hopefully, these efforts continue to advance the study and understanding of cancer and other diseases.
pharmacology
Figure 2. DNA repair is crucial to preventing diseases such as cancer. DNA ligase is a key enzyme in the repair process. Image public domain.
Figure 3. Ubiquitin is a regulatory protein found in human cells. Image by Rogerdodd [CC-BY-SA-3.0].
References
1. Interview with Michael Emanuele, Ph.D. 01/03/2014. 2. Emanuele, M.J., Elia, A.E., Xu, Q., Thoma, C.R., Izhar, L., Leng, Y., Guo, A., Chen, Y.N., Rush, J., Hsu, P.W., Yen, H.C., Elledge, S.J. “Global Identification of Modular Cullin-RING Ligase Substrates.” Cell 147(2), 459–474. 2011. 3. Translation Research Program. Retrieved from http://trp. cancer.gov. 4. Leading Causes of Death. (2013, December 30). Retrieved from http://www.cdc.gov/nchs/fastats/lcod.htm
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pharmacology
A stained astrocyte, with blue indicating DNA in the nucleus and yellow indicating a combination of two proteins in the cell filaments. Dr. Ken McCarthy studies the role of astrocytes in modulating neuronal activity. Image by Gerry Shaw.
SHOOTING FOR THE STARS a look at the galaxy inside your head
R
eading this article will transform your mind. As you process and memorize this information, neurons strengthen synapses in your brain in order to help your recollection of the words you see.1 This process is performed by glial cells, the most prominent cells in the brain.1 The subset of glial cells involved in this process are called astrocytes, named after the Latin and Greek roots for “star cells.”2,3 Ironically, we know more about the stars peering down at us than we do about the “stars” in our heads, but the gap is rapidly closing. Dr. Ken McCarthy, a professor in the Department of Pharmacology at UNC-Chapel Hill, is one of the leading scientists in this field of study. Research has been fruitful for him and his research group, whose investigations into the functions of astrocytes have uncovered a myriad of speculation and potential.
“When research is going well, all your experiments open up new experiments and new questions,” he said.4 The fact of the matter is, the brain is made up of more than just neurons. While most research on the brain focuses on neurons because they are relatively easy to observe, the structure and function of astrocytes remain a mystery. These star cells each surround about 100,000 synapses, the structures involved in communication between neurons, and are activated by intercepting some of the neurotransmissions between these neurons.4,5 Upon activation, the astrocytes modulate neuronal activity in some unknown way. The crux of Dr. McCarthy’s research revolves around the desire to understand how astrocytes regulate neuronal activity, but research on these cells has been confined by the limitations of neuroscience. Astrocytes share their responses
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By Brook Teffera
and chemistry with other cells in the brain, making it tremendously difficult to study the functions of these particular cells.1 However, scientists have recently found two ways to overcome these obstacles, by using both imaging and genetic tools. The former method allows researchers to observe changes in the brain’s structure and electrical activity. The latter method involves the manipulation of genetic structures that relate to astrocytes in order to observe the consequences. One technique that uses genetic tools, known as “conditional knockout,” destroys astrocyte-related genes and observes the effects.1 This method determines some of the functions of astrocytes, such as regulation of the brain’s levels of calcium and potassium ions that neurons use to communicate to each other. If the astrocytes fail to perform such regulation, the organism will
pharmacology
Carolina Scientific suffer from seizures.1 Consequently, sci- Carthy’s research project by being entists can confirm that astrocytes buf- biologically inert.6 In other words, no lifer positive ion levels in the brain. This gand-gated ion channels respond to the method of study also led to the conclu- addition of CNO, nor do the unmodified sion that astrocytes provide nutrients GPCRs present in the mice under obserto neurons and remove waste, allowing vation. The only receptor that responds synapses to repolarize and receive new to injection of CNO is a mutated GPCR information.1 expressed in the transgenic mice. This Dr. McCarthy and his research receptor, in turn, only influences astroteam’s latest mechanism of research cytes. Mutated GPCRs such as these are uses a different type of genetic method called DREADD receptors and experito study astrocytes. Rather than elimi- ence activation solely by some artificial nating genetic expression of astrocytes, ligand. The acronym DREADD stands for they add mutated receptors to the end “designer receptor exclusively activated of DNA promoters that selectively acti- by designer drug.”1 The “designer drug” vate astrocytes. referenced in this research setting is They achieve this activation by CNO. injecting a drug called a ligand, speEvery cell has GPCRs, and glial cifically clozapine-N-oxide, or CNO, into cells are no different. What makes Dr. genetically modified mice.1,6 Ligands McCarthy’s research so compelling is are compounds, such as neurotransmit- that his DREADD receptors activate ters, that activate two major receptor glial cells without stimulating other proteins in the body, ligand-gated ion cells in the brain, such as neurons.1 The channels and G-protein coupled recep- research team breeds mice that have tors (GPCRs).1 a DREADD receptor downstream of a The former describes a group of promoter, and this receptor only plays proteins that form a pore through a cell a role in astrocyte functions. Thanks to membrane; the this advancement, Rapid movement, such it is now posligand acts like a key that opens the to observe as playing “Flight of the sible ion channel and the phenotypic Bumblebees” on the fluxes a wave of consequences of positive ions, such stimulapiano, uses ligand gated astrocyte as calcium, to the tion in live mice, ion channels and ion and the McCarthy cell.1 Rapid movement, such as does just that. cascades to give the cells lab playing “Flight of These genetically the action potential the Bumblebees” altered mice exon the piano, uses a DREADD necessary to complete press ligand-gated ion receptor develthese tasks. channels and ion oped from a Gqcascades to give GPCR receptor the cells the action potential necessary and are observed for changes in their to complete these tasks. phenotype following the injection of GPCRs, on the other hand, take CNO.6 longer than ligand-gated ion channels The transgenic mice injected with to work. Once activated by a ligand, CNO underwent changes in heart rate, these protein receptors undergo an en- body temperature and motor coordinazymatic process that includes a struc- tion, among other behaviors.6 “We were tural change of the receptor, a change stunned,” Dr. McCarthy said. “We’d have in the G-protein, and a signal for second never guessed that activating astrocytes messengers, such as calcium ions, to would influence these different physiinfluence the cell’s phenotype. These ological behaviors.”1 receptors typically contribute to cell Dr. McCarthy and his team recorddivision, size, and metabolism and are ed a wide range of phenotypic responsalso the focus of most pharmaceutical es to astrocyte stimulation. Members of drugs.1,4,7 the central and autonomic nervous sysThe ligand CNO furthers Dr. Mc- tems responded to the injection of the
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Dr. Ken D. McCarthy ligand CNO much differently than from the injection of the saline control compound. While Dr. McCarthy is excited about his work, he acknowledges the need for more research. “The frustrating part is that we don’t know how it’s working. Now our efforts are trying to understand how [that is] working,” Dr. McCarthy said. Still, there is no doubt that he would not have it any other way. “It’s almost never that you come to the end of the pathway and say ‘My career is over!’” he said, laughing. “You want to know why or how and what’s the next step.”4
References
1. Interview with Ken D. McCarthy, Ph.D. 01/17/2014. 2. astro-. Retrieved from http://dictionary.reference.com/browse/astro-. 3. -cyte. Retrieved from http://dictionary.reference.com/browse/-cyte. 4. Interview with Ken D. McCarthy, Ph. D. 02/7/2014. 5. Sufflebeam, R. Neurons, Synapses, Action Potentials, and Neurotransmission. (2008). Retrieved from http:// www.mind.ilstu.edu/curriculum/neurons_intro/neurons_intro.php. 6. Agulhon, C., Boyt, K.M., Xie, A.X., Friocourt, F., Bryan L. Roth, B.L., McCarthy, K.D. “Modulation of the autonomic nervous system and behaviour by acute glial cell Gq protein-coupled receptor activation in vivo.” The Journal of Physiology 591(22), 5599–5609. 2013. 7. Email with Ken D. McCarthy, Ph.D. 02/11/2014.
pharmacology
REVOLUTIONIZING
Brain Disorder Treatment
New research on sodium’s interaction with a brain cell receptor can lead to targeted therapies for Parkinson’s, depression and mood disorders.
BY KENSEY KATZ
I
mproved methods of brain disorder treatment may be on the horizon, thanks to researchers’ new understanding of the role of sodium ions in cell signaling. Through an emerging field which Dr. Patrick Giguere of the UNC-Chapel Hill Department of Pharmacology calls “functional selectivity,”1 pharmaceutical companies will have the potential to both magnify the desired effects of drugs like morphine, codeine and oxycodone and to reduce these drugs’ harmful side effects.1 “For the future, [functional selectivity] will be important because this is what we want to do eventually — to make a drug that will activate one pathway but not every pathway,” said Dr. Giguere.1 Dr. Giguere, a postdoctoral researcher in the laboratory of Dr. Bryan Roth, conducts research that focuses on sodium ion interactions with a G-protein coupled receptor (GPCR) called the opioid receptor. GPCRs are a large family of cellular proteins that receive external signals on the cell surface and help regulate a variety of physiological functions. Many marketed drugs act by binding to these receptors; specifically, the opioid receptor is a common pathway for many drugs that treat brain disorders.2 Dr. Giguere and other members of Dr. Roth’s research group collaborated with Dr. Raymond Stevens at The Scripps Research Institute (TSRI) in California to explore the opioid receptor’s function, most importantly its interac-
“We want to make a drug that will activate one pathway but not every pathway.” -Dr. Patrick Giguere
tion with sodium. Dr. Giguere noted that this collaboration with the Stevens lab in California was essential to the success of the study. “The science is like that now. . . We need collaboration because it requires so many skills, so much equipment, so many different resources,” Dr. Giguere said.1 Because it is “inherently Dr. Patrick Giguere flimsy and fragile when produced in isolation,” the mechanism of the opioid receptor’s function has eluded scientists in the past.2 In the 1970s, researchers at Johns Hopkins University observed that sodium is present in the middle of the receptor to regulate signals, but they could not decipher the molecular basis of their findings.3 In 2012, however, the Stevens lab successfully created a high-resolution crystal structure of the opioid receptor, the highest generated so far for a GPCR (Figure 1). This two-year process enabled researchers to better understand the receptor’s anatomy. The Roth lab then used this structure to test and analyze the function of sodium. The researchers discovered a specific site on the receptor where sodium “sits” and controls receptor activity.2 By tweaking certain amino acids essential to the interaction with the sodium ion, they found that they could drastically change signaling properties of the receptor. “Now we know exactly where in the receptor we need this selectivity,” Dr. Giguere said.1 Understanding this mechanism of regulation at the
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pharmacology
an interest in applying this research to synthesize a new drug. Trevena was created in 2007 for the sole purpose of using new GPCR research to create new medications.5 “There’s a really big potential for this receptor for therapeutics, but it’s going to take a long time before we get a drug in the pharmacy,” Dr. Giguere said.1 By illuminating the details of sodium’s interaction with the opioid receptor, researchers may be able to extend the results to a variety of pharmaceutical settings. “In this case we focus on brain disorders, but [the research] can be applied to many other receptors that would be
By illuminating the details of sodium’s interaction with the opioid receptor, researchers may be abe to extend the results to a variety of pharmaceutical settings. involved in many other systems and many other diseases,” said Dr. Giguere.1 According to Dr. Giguere, nearly 50 percent of prescribed drugs target this family of receptors. “This is the most ‘drug-able’ family of receptors, and one of the reasons is because it controls almost every physiological process in the body. So it could be the immune system, the heart, almost everything you could think of — it can control those processes,”1 he said. Only after considerable testing will researchers know the extent to which they can reduce side effects of common drugs, but pharmacy goers may find more “functionally selective” drugs on the market soon.1 “This kind of study is really interesting,” Dr. Giguere said. “You start from something that’s a mystery, and you already know that it will be an important discovery. You know it’s going to be useful for anyone who’s working on GPCR.”1
Figure 1. The high resolution crystal structure of the delta opioid receptor, which was used to test and analyze the function of sodium. Sodium sits in the center of the receptor and regulates function. Image courtesy of Dr. Patrick Giguere. atomic level is crucial for improving therapeutic treatment for neurological disorders. Parkinson’s, depression and mood disorders are currently treated using drugs that target the opioid receptor. Many of these drugs cause serious side effects including seizures, tolerance, dependence and immunosuppression (debilitation of the immune system).1 With a better understanding of the opioid receptor, drug manufacturers can design drugs that only target the specific pathways that will treat the brain disorder, without triggering the side-effects.1 The Roth lab is working to create a “skeleton-drug” to test on the receptor. This is a very basic model of a drug that the lab can use for testing and later provide to drug companies for fine-tuning and improvement.1 The timeline for getting these drugs on the market is uncertain, according to Dr. Giguere, because it depends on drug companies’ interest in the research. Creating and testing new drugs requires money and resources. The company Trevena, however, has already expressed
References
1. Interview with Patrick M. Giguere, Ph.D. 01/31/2014. 2. Scientists Solve 40-year Mystery of How Sodium Controls Opioid Brain Signaling. (2014, January 20). Retrieved from http://www.scripps.edu/newsandviews/e_20140120/stevens.html. 3. Fenalti, G., Gigueru, P.M., Katritck, V., Huang, X.P., Thompson, A.A., Cherezov, V., Roth, B.L., Stevens, R.C. “Molecular control of δ-opioid receptor signaling.” Nature 506, 191–196. 2014. 4. Understanding Seizures — the Basics. (2013, April 3). Retrieved from http://www.webmd.com/epilepsy/understanding-seizures-basics. 5. About Trevena. Retrieved from http://www.trevenainc. com/about.php.
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Figure 1. Lake Taihu in China hosts a sizable algal bloom which renders the water green, opaque and toxic to both human health and the 22 health of the local ecosystem. Photo courtesy of Dr. Paerl.
Carolina Scientific
nutrient OVERLOAD toxic algae dye lakes green
by Corey Buhay
T
he poison was in the shellfish. It took the lives of 21 California sea otters in Monterey Bay in
2007.1
The source of the poison was a distant lake with a film over the water like green paint. That lake, Lake Pinto, was saturated with cyanobacteria, a toxinproducing microalgae better known as blue-green algae.2 Under the right Dr. Hans Paerl conditions, cyanobacteria multiply explosively. When they accumulate, they can blanket the water’s surface in a massive area called a “bloom.” The bloom dyes water so dense a green that light fails to penetrate a plastic bottle of the stuff. Dr. Hans Paerl, a professor of marine and environmental sciences at UNC-Chapel Hill’s Institute of Marine Science, studies cyanobacteria from his lab in Morehead City on the North Carolina coast. He works to explain the causes and consequences of toxic blue-green algal infestations, which are blooming all over the world in lakes, streams, rivers, estuaries and some coastal marine waters.3 Toxic algal blooms are a serious problem, but not just because their poisonous byproducts seep downstream and into the shellfish that otters love to eat.2 They are hazardous to domestic animals and to human health as well. Water filled with cyanobacteria is almost completely opaque (Figure 2). Blooms on the surface prevent light from penetrating into the depths of the body of water, to the detriment of any plant or animal that depends on sunlight. The hordes of algae do not last forever, and, as they begin dying, the bloom starts to shrivel, or decay. A decaying bloom can suck all the oxygen out of the water, leading to a mass extermination of fish and other marine wildlife.2 When the bloom finally crashes it can release immense quantities of nutrients. The sudden glut can be just as dangerous to water-dwelling species as a sudden disappearance of nutrients.2 “There are lots of economics at stake here, too, not just ecological impacts,” Paerl said.3 Blooms disrupt food chains, destroy the water quality for
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environmental science
Figure 2. Top: Dr. Paerl’s hands are bright green after being dipped in Lake Taihu, China. Extreme concentrations of cyanobacteria give the lake water its bright green hue. Bottom: Plastic containers are used to collect and test water samples as part of a bioassay experiment. Photos courtesy of Dr. Paerl. fishing and recreational uses, and reduce property values for waterfront real estate. What’s more, toxin-producing algae put the affected water completely off limits for drinking and irrigation use, said Dr. Paerl.3 Cyanobacterial blooms are not a new phenomenon, but they are becoming more intense and widespread. According to Paerl, humans are to blame. Cyanobacteria are most common where eutrophication, or an overabundance of nutrients, occurs.6 This usually includes nitrogen and phosphorous, nutrients commonly found in crop fertilizers and agricultural waste. The nutrients run off the farmland and into the water supply, where cyanobacteria thrive.4 Fertilizers are not the only cause of nutrient runoff, however. “There are both point sources and non-point sources of runoff,” Paerl explained. The point sources are farms, factories and waste treatment plants2 that scientists can look to as a definite cause of nutrient pollution.3 “Point sources are easier to deal with,” said Paerl. Nonpoint sources are tough to home in on and therefore difficult
to manage. Chesapeake Bay is one example of an estuary suffering from nutrient overloads and other conditions that can foster the growth of algal blooms. According to Dr. Paerl, nearly half of the nutrients flowing into the Bay come from non-point sources.3 One significant non-point source is the atmosphere. Rain can wash car exhaust, airborne manufacturing byproducts and other gaseous nutrients out of the air and into lakes, rivers and other bodies of water. Paerl said legal disputes have sprung up where nutrients have entered the atmosphere in one country’s territory and come down elsewhere, causing blooms or other complications.3 Cyanobacteria do occur naturally in waters unaffected by excess nutrients. Under these conditions, however, they exist in a balanced state with competing species like green algae and other types of phytoplankton. Cyanobacteria have become more prevalent recently because of warming temperatures, in which they thrive.4 Global warming increases the likelihood of droughts, which cause pure water to evaporate without being replenished. This concentrates the nutrients that already pollute bodies of water. With freshwater escaping and ever-increasing amounts of fertilizer flowing in, our natural reservoirs are becoming less water and more pollutant, a situation that fosters algal growth. Instances of erratic weather due to climate change can also encourage algal blooms.4 “Big storms and climatic events can overwhelm these kind of systems,” said Paerl.3 Extreme weather can flood a system with polluted runoff, pushing sensitive waters to a nutrient level in which blooms are likely to form. Fast-reproducing, less-established, often toxic species seize their chance to grow when the normal ecosystem is disrupted.6 Slower-growing forms of algae are the ones that have evolved to exist peacefully in a balanced, undisrupted environment.3 “Hydrology [the study of the movement of water] is important in determining the type of algae we get and whether they are the good guys or the bad guys,” said Paerl.3 Paerl’s most recent work addresses the extent to which nutrient overload is responsible for algal blooms. The scientists in his lab gather dozens of water samples from the lake, river or estuary they are studying (Figure 3). One sample goes untouched as a control group. To the others, the scientists add different quantities of various nutrients to see which nutrient causes blooms. Results from these experiments will help determine the nutrient input reduction necessary for controlling blooms.3 Until recently, water quality management was concerned mainly with phosphorous when treating water for excess nutrients.4 Paerl says overloads of nitrogen can be just as dangerous, particularly for species of algae that cannot get their nitrogen fix from the air alone.2 Paerl has been working at the very green Lake Taihu in China (Figure 1). A grant from the National Science Foundation (NSF) has funded his work there for several years because it is an extreme example of what could happen elsewhere if nutrient runoff is not controlled.3
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environmental science
Figure 3. What looks like a grid of partially submerged barrels is a bioassay setup in Lake Taihu, China. Scientists add various combinations of nutrients to the lake water in the containers to determine what nutrient levels caused algal blooms. Photo courtesy of Dr. Paerl. “It’s like a looking glass for how the situation could become if things continue that way here in the US,” he said.3 In Lake Taihu, both nitrogen and phosphorous are problematic.3 Chinese farmers are notorious for over-fertilizing their crops in an attempt to produce enough to feed their massive population. “There are more and more nutrients coming in all the time,” said Paerl. His recommendation: cutting inputs of both nitrogen and phosphorous by as much as 50 percent. Phosphorous filtration is established and relatively cheap. Getting the nitrogen out of water can be very expensive, though.3 Even so, it is less expensive than trying to get rid of cyanobacteria that have already established themselves in a lake. Filtering out the algae has been nearly impossible because of their tiny size.3 Some municipalities have resorted to dredging up organic matter and nutrients from the bottom of the lake. This method has had limited success.5 Releasing extra freshwater can help flush a bloom out of the system, but few places can spare this extra drinking water.2 Bubblers and mixers have been installed in some bodies of water to circulate the water and spread nutrients throughout.5 In theory this would keep cyanobacteria from crowding the surface and absorbing all the light and nutrients before they get to the sub-surface species of algae. However, Paerl cautions that mixers are usually only successful in small bodies of water and do little to solve the long-term problem
of over-fertilization.3 “The bottom line is that it’s cheaper to deal with algae blooms by stopping the nutrient runoff from happening in the first place,” said Paerl.3 We need to change the way we fertilize our crops and handle our industrial waste, suggests Paerl.4 “In the long run these strategies will save a lot of money.”3 Not to mention they will save a lot of otters.
References
1. Stephens, T. Sea otter deaths linked to toxin from freshwater bacteria. (2010, September 10). Retrieved from http:// news.ucsc.edu/2010/09/otter-toxin.html. 2. Paerl, H.W., Otten, T.G. “Harmful Cyanobacterial Blooms: Causes, Consequences and Controls.” Microbial Ecology 65(4), 995–1010. 2013. 3. Interview with Hans Paerl, Ph.D. 01/29/2014. 4. Paerl, H.W. “CyanoHABS and Climate Change.” Lake Line 8(2), 29–33. 2008. 5. Paerl, H.W., Hall, N.S., Calandrino, E.S. “Controlling harmful cyanobacterial blooms in a world experiencing anthropogenic and climate-induced change.” Science in the Total Environment 409(10), 1739–1745. 6. Paerl, H.W., Otten, T.G. “Blooms bite the hand that feeds them.” Science 342(6157), 433–444. 2013.
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environmental science
Shown here are particles of sediment and organic matter, which sink as aggregates in the ocean. Dr. Shilpa Khatri is investigating the dynamics of this “marine snow” in order to develop a mathematical model of the sinking. Photo by Zephyris.
UNDERWATER SNOW models of sinking marine aggregates lend insight into carbon cycle By Taylor Nelsen
B
eneath the breaking waves and sunlit ocean surface, a shower of snow begins to fall. This snow is not made of crystalline frozen flakes. Instead, it contains only phytoplankton cells, dead bits of once-living things, pieces of fecal matter and sediment that might be forming one of the largest carbon sinks ever found.1 Increasing carbon dioxide (CO2) levels are wreaking havoc in the Earth’s atmosphere, creating a warming world and acidified oceans. For now, CO2 levels in the atmosphere and ocean are in equilibrium. That is, when CO2 is released into the atmosphere, it finds its way into the ocean. But this is a delicate balance. The marine carbon cycle is a vital process in determining how much CO2 the ocean will absorb and where the
Figure 1. Organic marine aggregates formed in the laboratory look like those found in the ocean. Photo by M. Maille Lyons.
CO2 will go once it enters the ocean. In the marine carbon cycle phytoplankton play the fundamental role. These microscopic organisms take up and fix carbon just like any plant and then become temporary carbon sinks. If the phytoplankton are eaten by larger animals up the food chain or are dissolved by bacDr. Shilpa Khatri teria, the carbon they carry returns to the system.2 However, if the phytoplankton become incorporated into marine snow particles, they sink along with the carbon they carry. Dr. Shilpa Khatri works as a a researcher at UNC-Chapel Hill’s Joint Applied Mathematics and Marine Sciences Fluids Lab studying marine aggregates. “Understanding how [marine aggregates] sink in the ocean is really important to understanding how the carbon is going from the surface ocean to the deep ocean,” Dr. Khatri said. Usually when material sinks into the deep ocean, it remains there for very long timescales, making the deep ocean one of largest carbon sinks in the world. Understanding how the marine aggregates sink is more complicated than one might think. Ocean gradients caused by salt and temperature differences create layers of varying densities in the water column. This stratification not only affects the diffusion of salt into the porous spheres of marine snow, but also creates an unusual phenomenon known as entrainment (see “The Entrainment Effect,” top right).3 Scientists have long known that particles slow between layers of different salt concentrations. They know that diffusion of salt plays a large role in the continued settling of the particles. But their modeling and their observations were not
26
Carolina Scientific
environmental science The Entrainment Effect
The experiment pictured shows the drag freshwater creates on a solid sphere. Models such as this one can potentially approximate the sinking of marine particles settling in the deep ocean. Photo by Richard Parker.
matching up. When observed, the particles stayed at the strata the first model does not accurately predict the real phenommuch longer than expected given just diffusion. This is where enon exactly, it is reevaluated. the “effect of entrainment,” as Dr. Khatri puts it, comes in. In the work with the porous spheres used to imitate Researchers in the fluids lab noticed that in experi- marine aggregates, the first model failed to capture how long ments, solid spheres, heavier than both layers of stratified wa- the particles were resting at the interface but accurately capter, tended to come to a stop at the interface between the two tured how fast they settled before and after stopping at the inlayers of water.2 As the spheres sank they had a tendency to terface. By including entrainment in the model, however, the drag the less dense fresh water from the top layers down with researchers successfully captured how long a porous sphere them. Since the fresh water was less dense it tended to return rests at the interface between two strata of water and how fast to the top. Thus, the fresh wasinks. Even so, Dr. Khatri says ter pulled the spheres up just more work is needed to fully enough to stop them between understand how entrainment “Understanding how [marine strata. affects the settling of marine aggregates] sink in the ocean How exactly this phesnow and how thick its “shell” is important to understanding nomenon affects the settling can be. of marine aggregates is where In some places, aggrehow the carbon is going from the the applied mathematics gate layers can form in the surface ocean to the deep ocean.” ocean in which there are very work of Dr. Khatri, along with Dr. Richard M. McLaughlin and high abundances of these Dr. Roberto Camassa, is essenmarine snow particles in a tial. Through applied maththin vertical region. In these ematics, the scientists wish to accurately capture and then layers, bacterial activity and zooplankton foraging may be sigmodel how long each porous sphere stays between the layers nificantly enhanced. Oceanographers are interested in where of water.3 Dr. Khatri emphasizes that, in complex model build- these are occurring and predicting where they will form. ing, experts tend to start from simple and build up.2 “Under“[We] want to use this modeling of these single partistanding how these porous spheres are settling is . . . a first ap- cles to understand the group dynamics and be able to make proximation to these more complicated marine aggregate(s) predictions of where these layers form, how long they will perand how they are settling,” she said. sist and to answer some of these bigger questions,” Dr. Khatri It is important to start simple in making the mathemati- said. Even though the model is starting small, “the goal is to cal model so the equation derived from complex real world eventually build up and be able to make predictions” on globobservations can actually be solved. To do this, the research- al scales.2 ers use equations from basic physics principles to understand the forces acting on the sphere. Then they make assumptions, simplifications and reductions. Eventually, they acquire a sinReferences gle question to tackle, such as finding how much salt diffuses into the sphere. Then one by one the scientists add mass, 1. What is Marine Snow? (2014, January 23). Retrieved from http://oceanservice.noaa.gov/facts/marinesnow.html. acceleration, pressure, viscosity, buoyancy, weight and drag 2. Interview with Shilpa Khatri, Ph.D. 01/28/2014. back into the equation.2 3. Camassa, R., Khatri, S., McLaughlin, R.M., Prairie, J.C., The model is then compared to small scale experiments White, B.L., Yu, S. “Retention and entrainment effects: Exin the lab by taking pictures and video of the settling particle periments and theory for porous spheres settling in sharpand measuring the density gradients of the strata. Then they plug their known values back into their derived equation. If ly stratified fluids.” Physics of Fluids 25(8). 2013.
-Dr. Shilpa Khatri
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biology
a safer treatment for
HEMOPHILIA R
esearchers have been searching for a safe treatment for hemophilia for decades without finding a solution. An approved, yet controversial, treatment for this disorder is a clotting drug called NovoSeven, which binds to a protein called tissue factor (TF) that marks the outside of a cell.1 While it effectively stops uncontrolled bleeding, NovoSeven has been shown to form potentially fatal clots in major veins, a condition called thrombosis (Figure 1).1 Dr. Darrel Stafford of the UNCChapel Hill biology department has been a pioneer in the search for an alternative to NovoSeven to safely treat hemophilia and other instances of uncontrolled bleeding. Dr. Stafford’s research questions the current belief in the medical field that NovoSeven requires TF for proper clot formation. Dr. Douglas Monroe of UNC-Chapel Hill and Dr. Maureen Hoffman of Duke University proposed that NovoSeven could function properly
Figure 1. Deep Vein Thrombosis, a dangerous side effect of TFmediated blood clotting. Image by Bruce Blaus [CC-BY-3.0].
without the proposed “necessary” interactions with tissue factors. Dr. Stafford’s laboratory used this work as a springboard to design a more effective drug. By manipulating NovoSeven, Dr. Stafford’s molecular biology team has synthesized a modified version of the drug. NovoSeven is a complex, multi-domain protein, but the newly synthesized molecule has two segments replaced by an entirely different clotting protein. The result of the newly engineered protein allows for less specific interactions—reducing the drug’s tendency to form undesired clots.1 To test the modified version of NovoSeven, Dr. Stafford’s lab examined the clotting activity of both NovoSeven and its altered version. The original NovoSeven exhibited high activity levels of clotting when TF was present, while the modified version had no measurable activity. But when the modified drug was tested without TF, it exhibited high levels of activity, confirming that it functions properly without binding TF, unlike the original version of NovoSeven.1 Further experiments supported their results, showing that their new molecule acts without TF interactions. Next, Dr. Stafford’s team needed to confirm that it was as effective as the original gene in stopping bleeding.2 Researchers injected the clotting factor and the modified drug into different mice and recorded the clotting time for each mouse. Results showed that the difference in clotting time between both treatments was statistically insig-
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BY VARUN GULATI
nificant — the new protein was equally effective at forming clots. Thus, the synthesized molecule is able to treat hemophilia as well as NovoSeven without Dr. Darrel Stafford the risk of deep vein thrombosis.1 The implications of this study are far-reaching. According to Dr. Stafford, “Not only can this molecule replace [the original gene] in hemophilia treatment, but it also has many off-label uses.” Dr. Stafford described how immediate clotting is required for soldiers in battle who have massive bleeding or have lost a limb.2 By utilizing the modified drug instead of NovoSeven, soldiers would be able to initiate rapid blood clotting, saving lives without the risk of thrombosis. Dr. Stafford remains optimistic that this new drug will be commonly used in the coming years to safely treat hemophilia.
References
1. Feng, D., Whinna, H., Monroe, D., Stafford, D.W. “FVIIa as used pharmacologically is not TF dependent in hemophilia B mice.” The American Society of Hematology 123(11), 1764–1766. 2014. 2. Interview with Darrel W. Stafford, Ph.D. 01/24/2014.
Carolina Scientific
the PROTEIN
NETWORK Predicting antibiotic resistance with metabolic pathways
By Travis Murphy
W
ith constantly evolving bacteria on the rise, drug-resistant tuberculosis or cholera could be a plausible threat in the future. According to the Centers for Disease Control and Prevention, at least two million people become infected with antibioticresistant bacteria each year and at least 23,000 people die as a result.1 Artur Romanchuk, a graduate student in Dr. Corbin Jones’ laboratory in the department of biology at UNCChapel Hill, looks at the numerous metabolic pathways of bacteria and how they change over time to gain antibiotic resistance.2 All cells have their own metabolism, the process of taking up nutrients from the environment and transforming them into new cell materials and waste products.3 The energy harvested from the environment allows the cell to create new structures that will help it grow. A metabolic pathway describes a series of chemical reactions occurring inside a cell that converts one molecule into another. In most of these pathways, proteins called enzymes facilitate the reactions, and a different protein is often required for each step in the process.4 Bacteria can gain antibiotic resistance when there is a change in how they build and break down chemicals, or alter their metabolism.5 Bacteria can acquire antibiotic resistance in a number of ways, including the intake of resistance genes from other bacteria and the mutation of genes for antibiotic targets. For example, the antibiotic penicillin prevents bacteria from growing a cell wall, which is important for protection and structural support of the cell. A single mutation in the cell wall protein
in these bacteria can prevent penicillin from targeting the cell, rendering the bacteria resistant to penicillin. The concept of evolution, in which genetic variants are selected based on their reproductive fitness in their current environment, is one of the most central themes in all of biology.4 In microbial organisms, evolution occurs on a very short time scale due to the short reproduction cycle of bacteria. Romanchuk’s research on the changing metabolic pathways of bacteria can be used to help understand and even predict the evolution of bacteria. Romanchuk models the metabolic pathways of bacteria into a network of proteins with “each protein acting as a node in the network.” These models can help predict what will happen when the gene for one protein in the network is mutated, removed or increased. Romanchuk uses his models to classify proteins, based on previous research, as either “party” proteins or “date” proteins.6 A protein that interacts with many other proteins in a metabolic pathway would be considered a party protein, because without its function the pathway is ruined. On the other hand, a date protein is characterized as a protein that is not as integral in the metabolic pathway. Romanchuk will mutate both of these types of proteins in order to observe the effect on the cell’s metabolic network. When the defective protein ruins the cell’s metabolic network, one could observe evolution if the cell survives without the normal protein. By experimenting with these proteins in the pathway, one can also observe how one mutation in the pathway can confer resistance.
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biology The ability of bacteria to gain antibiotic resistance through the transfer of resistance genes from foreign bacteria was also considered Artur Romanchuk when developing Romanchuk’s model. In a recent experiment, he tested the protein network model with E. coli, cholera and MRSA by “switching” proteins between each bacterium. Romanchuk swapped “date” and “party” protein genes from one organism of E. coli with both cholera and MRSA genes and observed their survivability and antibiotic resistance. By observing which genes function in providing antibiotic resistance to surrounding bacteria, Romanchuk will further understand the role of metabolic changes in the development of antibiotic resistance.
References
1. Antibiotic/Antimicrobial Resistance. (2013, September 16). Retrieved from http://www.cdc.gov/drugresistance/threat-report-2013/. 2. Interview with Artur Romanchuk. 01/27/2014. 3. Madigan, M.T., Martinko, J.M., Stahl, D., Clark, D.P. Brock biology of microorganisms. (13th ed., p. 5–10). San Francisco, CA: Pearson Education, Inc. 2012. 4. Schmidt, S., Sunyaey, S., Bork, P., Dandekar, T. “Metabolites: a helping hand for pathway evolution?” Trends in Biochemical Sciences 28(6), 336–41. 2003. 5. Franke, C., Siezen, R.J., Teusink B. “Reconstructing the metabolic network of a bacterium from its genome.” Trends in Microbiology 13(11), 550–558. 2005. 6. Han, J.J., Bertin, N., Hao, T., Goldberg, D.S., Berriz, G.F., Zhang, L.V., Dupuy, D., Walhout, A.B.J., Cusick, M.E., Roth, F.P., Vidal, M. “Evidence for dynamically organized modularity in the yeast protein–protein interaction network.” Nature 430, 88–93. 2004.
biology
an unexpected role for
INSULIN
changes in insulin levels may increase cancer risk
By Laura Kim
T
he gastrointestinal (GI) tract of the digestive system in humans replaces itself every three days. This constantly changing system has fascinated Dr. P. Kay Lund of the Department of Cell Biology and Physiology at UNC-Chapel Hill, and she wants to know what happens when this replacement process goes wrong. Insulin is a hormone that travels through the blood and binds to insulin receptors, which are landing sites throughout the body specific for insulin that can trigger several different pathways that cause changes throughout the body. The most well known function of the insulin receptor is to control short term sugar levels throughout the body. Dr. Lund’s lab believes, however, that “insulin may be doing some things that we didn’t expect.”1 Recently, researchers have found that when insulin levels are high, the body may regulate growth and proliferation of cells rather than sugar levels. Initially, scientists believed growth was mainly controlled by another type of
receptor called the insulin-like growth factor receptor, which binds substances that are similar to insulin. However, researchers have found clues that perhaps the insulin receptor may play a larger role in growth than previously expected. The Lund lab has found that the original insulin receptor itself does not regulate growth, but an alternate form of the insulin receptor.2 They call the previously known insulin receptor the “metabolic receptor” isoform and the newly found receptor the “growth promoting” isoform. In order to understand how insulin may regulate normal or abnormal growth, the Lund lab has focused on the stem cells of the GI tract — constantly dividing, growing and developing into the other types of cells to perform specific functions of the system. The most recent publication from the Lund lab describes the differences between stem cells and fully differentiated or developed cells in the GI tract.2 They found that the newly discovered growth promoting isoform is expressed at much higher levels in stem
Figure 1. Left: Model showing the structure of insulin. Image courtesy of Roman Becker [CC-BY-SA-3.0]. Right: Intestinal stem cells can be grown in cultures to produce “mini” guts. Image courtesy of Dr. Lund.
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“Insulin may be doing some things that we didn’t expect.” -Dr. P. Kay Lund cells than in differentiated cells. In differentiated cells, however, the metabolic insulin receptor predominated. To determine direct changes to cells caused by the presence of the two insulin receptors, researchers increased expression of the metabolic insulin receptor on a colorectal cancer cell line. They found that the forced expression reduced proliferation of the cancer cells showing a direct association with the presence of the metabolic insulin receptor and reduced growth or specialization of even cancer cells.2 Scientists are using this data to further support the idea that insulin plays a role in growth and proliferation. This discovery has many clinical implications that have interested Dr. Lund. Type II diabetic, obese and elderly patients have all shown high levels of insulin. Another characteristic that these patients have in common is that they all have higher risks of cancer. Cancer consists of another growth of cells that do not stop proliferating and do not cor-
Carolina Scientific
biology
“This is the first, as far as I know, direct evidence that a situation of obesity and elevated insulin allows survival of genetically damaged cells.” -Dr. P. Kay Lund rectly differentiate. This association has prompted researchers to look further into a possible connection between the insulin system and cancer. Dr. Lund’s next step is to understand how changes in insulin caused by disease may increase cancer risks or resistance to cancer treatment, particularly in stem cells. An ongoing project in the Lund lab has attempted to make this connection. It was previously known that obesity increases the risk of colorectal cancer, and patients with type 2 diabetes do not respond as well to cancer treatment like radiation or chemotherapy. To test the connection between these diseases and efficacy of cancer treatment, a graduate student in the Lund lab has made diet-induced obese and insulin resistant mice to test the effects of radiation on these animals. Radiation works as a cancer treatment by damaging the DNA of proliferating cancer cells, which kills the cells and prevents additional replication of the cancer cells. The Lund lab subjected both healthy mice and obese and insulin-resistant mice to radiation therapy. Then, differences in the damage of the GI tract cells were compared. When the obese and insulin-resistant animals were challenged with radiation, their cells survived at a much higher rate than those of normal animals. This trend was particularly visible in the stem cells of these animals. “This is the first, as far as I know, direct evidence that a situation of obesity and elevated insulin allows survival of genetically damaged cells,” explains Dr. Lund.1 This finding is particularly alarming for cancer patients, since obesity and elevated insulin may now have a direct connection to survival of cancer
Figure 2. Top: Non-irradiated cells in the GI tract. Bottom: Damaged cells of the GI tract after irradiation. Images courtesy of Dr. Lund. cells. These experiments were done in non-cancer models, so she hopes to confirm these results in cancer models as well. Dr. Lund’s fascination with the ability of the GI tract to replace itself so quickly and so often has led her to her ultimate question — “Why doesn’t it go wrong more often?”1 While it may seem counterintuitive, the simplest way to go about answering this question was to first investigate what happens when a typically error-free system does go wrong. In trying to solve this problem, Dr. Lund’s lab has found an unexpected role for insulin and consequently opened many more opportunities for research. Insulin seems to be the new key in understanding the connection between the seemingly unrelated fields of diabetes, obe-
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sity, cancer and even aging. What was previously believed to be a hormone that played the simple role of regulating sugar has now been found to impact many more areas in physiology, and it is Dr. Lund’s goal to figure out exactly how it works.
References 1. Interview with P. Kay Lund, Ph.D. 02/03/2014. 2. Andres, S.F., Simmons, J.G., Mah, A.T., Santoro, M.A., Landeghern, L.V., Lund, P.K. “Insulin receptor isoform switching in intestinal stem cells, progenitors, differentiated lineages and tumors: evidence that IR-B limits proliferation.” Journal of Cell Science 126(24), 5645–5656. 2013.
biology
understanding disease through G-protein regulation of pathogens
By Ian Rahn
W
hile the general population may be unaware of the important roles G-proteins participate in regulating the human body, their roles in regulating sexually transmitted diseases should catch the public’s attention. Gproteins have taken the spotlight in a recent investigation of Trichomonas vaginalis, a pathogen leading to trichomoniasis, the most common curable human sexually transmitted disease (STD).2 By investigating G-protein functions, researchers have elucidated the inner workings of pathogens such as Trichomonas.2 Dr. Daisuke Urano, a UNC-Chapel Hill postdoctoral biochemist in Dr. Alan M. Jones’ laboratory, hopes to discover how Trichomonas regulates and sends signals throughout cells. By researching G-protein regulation in Trichomonas, Dr. Urano hopes to apply his understanding of this common STD to much more deadly pathogens. When a cell is stimulated in a particular way, a cascade of protein-protein interactions gives rise to a protein “pathway,” which leads to the desired response. G-proteins, a family of proteins involved in transmitting signals throughout the cell, have the unique ability to regulate multiple protein pathways.1 G-protein pathways are culprits in many aliments such as diabetes, blindness, allergies and certain forms of cancer, making them a hot topic in biochemistry. As a result of their diverse function in humans, most G-protein research focuses on mammalian rather than plant and pathogen models. Due to a lack of attention, scientists have little to no understanding of pathogen G-protein pathways.1 While it is relatively simple for scientists to sequence an organism’s full genome, it is difficult to understand functional protein pathways directly from a simple sequence.1 A genome offers little help to understand protein regulation — the physical representation of genes. Biochemical approaches in protein research create options to quantitatively track protein function and regulation. Understanding protein regulation is necessary to determine essential protein pathways for an organism’s survival. In the past two decades, pharmaceutical companies have capitalized on G-protein targeting drugs, which act by inhibiting entire protein pathways. As a result, more than half of drugs on the market target G-proteins as their receptors.1 “G-proteins are physiologically the most important signal pathway in the human body,” Dr. Urano said. Proteins, unlike DNA, do not have unlimited possibilities for sequencing. A
protein’s three-dimensional structure depends both on the properties of its building blocks, amino acids, and the environment required Dr. Daisuke Urano for a protein to function. Due to this, eukaryotes have similarities in their G-protein pathways. Understanding similarities between organisms helps scientists discover G-protein properties in other organisms. Similarities also allow researchers to apply knowledge from one pathogen to others. The Trichomonas parasite is closely related to brain-eating amoeba, and Trichomonas G-protein research is therefore helpful in understanding protein regulation in much more dangerous parasites. Trichomonas, a model organism part of the evolutionary group of eukaryotes known as Excavata, is a useful asset to research G-protein signaling in pathogens.2 As a biochemist, Dr. Urano researches protein function and regulation to learn more about the Trichomonas G-protein network. Testing protein regulation through protein interactions in this pathway will aid in the quest to discover how pathogens regulate their cells. Scientists do not currently understand how pathogen G-proteins send signals to other proteins in their G-protein network. G-proteins are present in pathogen cells, but the manner that they transduce signals, or convert a message to other proteins, is completely altered from the mammalian pathway. Dr. Urano hopes he can discover the method by which Trichomonas sends signals from G-proteins to the rest of the pathway. Discovering how the G-protein pathway regulates pathogen cells will allow clinical scientists to create methods to target and eliminate disease.
“G-proteins are physiologically the most important signal pathway in the human body.” -Dr. Daisuke Urano
References
1. Interview with Daisuke Urano, Ph.D. 01/31/2014. 2. Trichomoniasis- CDC Fact Sheet. (2012, August 3). Retrieved from http://www.cdc.gov/std/trichomonas/stdfacttrichomoniasis.htm. 3. Urano, D., Jones, J.C., Wang, H., Matthews, M., Bradford, W., Bennetzen, J.L., Jones, A.M. “Protein Activation without a GEF in the Plant Kingdom.” Plos Genetics. DOI: 10.1371. 2012.
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Carolina Scientific
through the
By Dana Corbett
P
eering through transparent zebrafish embryos can provide researchers with a lens to study heart formation and development.1 Dr. Jiandong Liu uses these unique transparent embryos to study cardiac function with the goal of applying his findings to the development of treatments for heart defects in humans. Dr. Liu’s research in the Department of Pathology and Laboratory Medicine within the UNC-Chapel Hill School of Medicine aims to understand the underlying mechanical processes involved in heart formation. Through collaborations, Dr. Liu hopes to eventually contribute to the advancement of human health. “It’s not just my lab,” Liu said. “It is the entire field [of cardiac development] that is interested in answering these questions.”1 The Liu lab is primarily interested in cardiac mechanotransduction — the conversion of mechanical forces into chemical signals. During a phase of cardiac development identified as linear heart tube stage, the heart begins to contract. Immediately after, the heart tube Figure 1. An adult female zebrafish. begins morphogenesis, developing its Image by Azul. shape through a series of complex processes that transform it into a functional pumping organ. Dr. Liu studies how these mechanical forces, generated by cardiac contraction, are transduced into the chemical signals that orchestrate the morphogenetic events occurring after the heart starts beating.1 Dr. Liu also studies the differentiation of the muscle cells of cardiac tissue known as cardiomyocytes. Primarily, he focuses on the progenitors of these cells — the cells from which cardiomyocytes originate — and how they interact with DNA and other regulatory systems to differentiate into cardiomyocytes.1 “If you know how the mechanical forces [of heart development] arise, then you can tweak and manipulate those forces to improve the functioning of the heart,” Dr. Liu said.1 Though the heart of a zebrafish only has two chambers, in contrast to a human’s four-chambered heart,1 zebrafish have several advantages over a mammalian counterpart as an animal model of cardiac development. Morphogenetic processes involved in the cardiac chamber formation occur in a similar fashion in both species.1
biology
This similarity is useful when studying the causes of heart defects in humans, because disruption of such developmental processes can cause structural and functional defects underlying congenital heart disease — a malformation of the heart present at birth.3 Moreover, both zebrafish and humans contract the heart using muscle fibers called sarcomeres. Understanding how bioDr. Jiandong Liu logical processes such as these occur in zebrafish can lend insight into the molecular mechanisms that regulate chamber formation and lead to congenital heart disease in humans.3 Perhaps the most significant advantage of the zebrafish model arises from its transparent embryo (Figure 2). This unique characteristic enables examination of cardiac development through a microscope, which yields observations impossible to obtain in the embryo of any mammal.1 Researchers can obtain hundreds of these embryos upon conception and observe the animal’s complete development in less than three days, eliminating the time constraints associated with many research studies.1 Zebrafish embryos Figure 2. The transparency can also survive with a dys- of the zebrafish embryo is functional heart through shown here. The right side many stages of prenatal of the image is where the tail development.2 This embryo begins, and the head is atvitality allows researchers tached to the yolk. Image by to study mutations causing Dietzel65 [CC-BY-2.5]. these dysfunctions in detail. Once the effects of these mutations are noted, scientists can better understand the genes that must be active and the molecular processes that must take place in order for a functional heart to develop.2 Dr. Liu’s research may have long-term implications for congenital heart disease, the number-one cause of death in infants due to inherited structural abnormalities in the United States.2 Zebrafish embryos continue to provide scientists with a unique research tool for obtaining critical knowledge of the biomolecular processes involved in heart formation.
References
1. Interview with Jiandong Liu, Ph.D. 02/06/2014. 2. Blue, G.M., Sholler, G.F., Harvey, R.P., Winlaw, D.S. “Congenital heart disease: current knowledge about causes and inheritance.” Medical Journal of Australia 197, 155–159. 2012. 3. Samsa, L.A., Yang, B., Liu, J. “Embryonic cardiac chamber maturation: Trabeculation, conduction, and cardiomyocyte proliferation.” American Journal of Medical Genetics Part C: Seminars in Medical Genetics 163, 157–168. 2013.
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biology
a vector to
CURE
drug delivery via lipid calcium phosphate A microscopy image of lipid calcium phosphates (LCPs). Dr. Leaf Huang’s lab develops uses for LCPs in drug delivery for cancer treatment.
By Congcong Li
I
t is pointless to write a letter that would never be received. Similarly, it would be futile to design a drug without a way to deliver it to target cells. Vectors, which are responsible for carrying drugs to their appropriate destination, are just as important in treating disease as the drugs they transport. Dr. Leaf Huang, Fred Eschelman Distinguished Professor at the UNC-Chapel Hill Eshelman School of Pharmacy, designed a novel vector that has safely and effectively delivered several types of drugs to target cells. The vector is named according to its three main components — lipid calcium phos-
Figure 1. The structure of lipid calcium phosphate (LCP) vector. Drugs, in this case siRNA, are trapped in the calcium phosphate core enclosed by the lipid membrane. Image courtesy of Dr. Leaf Huang.
phate, or LCP. It is structured as a double-layered lipid membrane enclosing a calcium phosphate core. Drugs embed in the calcium phosphate core to be carried in LCPs (Figure 1).1 A working vector must be able to not only carry a drug safely to its destination, but also release it readily Dr. Leaf Huang upon arrival. Dr. Huang and his team used calcium phosphate to achieve this goal. LCP enters a cell by endocytosis, a process in which cells engulf foreign particles. This mechanism leaves LCP in a compartment derived from the cell membrane called the endosome. “The pH inside an endosome is slightly acidic. We already know this,” Dr. Huang said. “That’s the reason why we chose calcium phosphate, because it is sensitive to acidity.”2 The acidity inside the endosome causes the calcium phosphate core to dissolve and LCP to disassemble. Consequently, the osmotic pressure, which is the tendency of water to flow inward, inside the endosome increases and causes the endosome to burst. Drugs are thus released from the endosome, ready to do their job (Figure 2).1 “It is a very rapid process. From the moment it enters a cell to its contents being released from the endosome, the time span is less than one minute,” Dr. Huang said.2 Dr. Huang and his lab are interested in using LCPs to deliver drugs for cancer treatment. They have already delivered several types of anti-cancer drugs using LCPs and successfully reduced tumor sizes in mice.1 One of the anti-cancer drugs already delivered is called small interfering RNA, or siRNA. It is a RNA molecule that can silence genes. One example of siRNA is vascular endothelial growth factor (VEGF) siRNA, which silences the gene that controls blood vessel formation. Without nutrient supply from the
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Carolina Scientific Figure 2. Efficient disassembly of LCP and release of drugs in a cell. Concept by Dr. Leaf Huang, image by Erin Moore.
biology
+
H
+
H +
H
Nanoparticles dissolve at low pH and disassemble
+
H
+
H
Osmotic pressure increase causes endosome swelling
Rapid, efficient drug release
blood, the cancer cells eventually starve to death.1 Gemcitabine monophosphate is another anti-cancer drug that works by inhibiting DNA synthesis. The drawback of gemcitabine monophosphate is that it cannot enter a cell by itself because it cannot penetrate the cell membrane. LCPs are able to do the ferry job and give gemcitabine monophosphate access to the interior where it can inhibit DNA synthesis and cause the cancer cell to die.1 Dr. Huang and his research team have used the combination of VEGF siRNA and gemcitabine monophosphate, both delivered by LCPs, to reduce the size of lung tumors in mice.1 Dr. Huang and his lab have also used LCPs for gene therapy, which treats disease by delivering certain genes for expression in diseased cells. Yunxia Hu, a former researcher in Dr. Huang’s lab, first proposed her ambition of delivering plasmid DNA, also as known as pDNA, to the human liver cells via LCPs.2 Dr. Huang responded to Hu’s proposal with enthusiasm. Dr. Huang and Hu’s focus is on Hepatitis B. “Our idea is to have pDNA express alpha interferon in the liver. Interferon is a very good drug to treat Hepatitis B, but it causes serious adverse reactions if you take it by intravenous injection. [It can cause] depression. What we are thinking is that we want the interferon to be expressed only in the liver,” Dr. Huang said.2 Because LCPs only release drugs inside cells, they can
help achieve this goal. Their small size, however, was a big challenge to Dr. Huang and his team. LCPs are nanoparticles with diameters of 25–30 nm, while a supercoiled pDNA is four times longer in length.1 To compact pDNA, Dr. Huang used a small protein molecule that has the ability to condense pDNA and bring it into the cell nucleus.2 This peptide’s efficiency was confirmed by Hu’s experiment in which fluorescently labeled pDNA strands were observed inside cell nuclei.3 Currently, Dr. Huang and his lab are working on how to rid the pDNA of the peptides once inside the nucleus so that its genes can be expressed more efficiently.2 Overcoming this hurdle would not only revolutionize the treatment for Hepatitis B, but also have the potential to cure many other diseases.
A working vector must be able to not only carry a drug safely to its destination, but also release it readily upon arrival. Dr. Huang and his team used calcium phosphate to achieve this goal.
References
1. Huang, L. Lipid-Calcium-Phosphate (LCP) Nanoparticles for Drug and Gene Delivery. Stanford University. 2013. 2. Interview with Lead Huang, Ph.D. 01/29/2014. 3. Hu, Y., Haynes, M.T., Wang, Y., Liu, F., Huang, L. “A highly efficient synthetic vector: nonhydrodynamic delivery of DNA to hepatocyte nuclei in vivo.” ACS Nano 7(6), 5376–5384. 2013.
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linguistics
Giving Back More Than Smiles BY JENNA SAWAFTA
I
n this age of communication the capability to express thoughts, needs and ideas is perhaps one of the most valuable abilities for not only normal livelihood but also innovation and change. Thousands of babies are born each year with cleft lip and cleft palate, leaving them without the ability to develop normal communication skills. If these defects are not treated in early childhood, they will likely have trouble breathing, eating, speaking, hearing and even smiling.1 Dr. David Zajac, a speech language pathologist and associate professor in the Craniofacial Center at the UNC School of Dentistry and the Division of Speech and Hearing Sciences, researches respiratory and speech complications associated with birth defects such as cleft lip and palate.2 A cleft lip occurs early in pregnancy when the tissues that form the upper lip do not physically join, leaving a slit in the upper lip. If the tissue of the palate, or roof of the mouth, fails to junction properly, babies are often left with a hole in this area. The occurrence of cleft lip and palate is much more common than cleft lip alone or cleft palate alone.1 The physical deformation of the smile is often what is correlated to these anomalies, though the complications go far beyond cosmetic. Chidren born with these defects have trouble feeding and talking, and often face hearing loss and/ or ear infections as well.2 Dr. Zajac’s recent research focused on the production of middorsum palatal stops, which occurs when the “t” sound
is pronounced as the “k” sound. For example, a child will pronounce the word “tap” as “cap” only differing in the first sound. In the English language, the “t” sound is produced with the tip of the tongue in the front of the mouth and the “k” is produced with the back of the tongue against the roof of the mouth.3 The significant difference in the place of articulation of these sounds along with the commonality of this speech probDr. David Zajac lem among children makes this error fascinating to many speech scientists. Some of them believe that this speech problem is due to the inability to prevent air from escaping through the nose.2,3 Zajac and his team, however, discovered that this articulation error occurs because the tongue does not have enough room to properly pronounce these sounds. 2 Zajac and his team conducted a study with three groups of children.3 The three groups consisted of children who produced middorsum palatal stops post cleft lip and palate (CLP) repair, children with CLP who did not produce these stops, and a control group of children without history of craniofacial anomalies who also did not produce these stops.3 These chil-
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Carolina Scientific
linguistics
Figure 1. Left: This mask is divided into two chambers: nasal and oral (along with a microphone). The chambers consist of fine mesh and wire screens that aid in identifying pressure changes associated with airflow. Right: This nasal mask allows measurement of nasal airflow lowers the level of cooperation required of children through simplification and elimination of flow tubes and pressure tabs that need to be inserted through the nose. Photos by Dr. David Zajac. dren were asked to pronounce words that included the “t” and solved prior to this age, the more likely it is that the child will “k” sounds using masks that measured oral and nasal pressure grow up with normal speech and language skills.2 Typically, and airflow while also recording sound. surgeries need to be done in a specifically timed manner. For Dr. Zajac and his team then measured the width of the instance, most cleft palate repairs are done around nine to children’s mouths at the ca12 months of age in order to nines and molars using dennot disrupt facial growth and tal impressions.3 The width teeth development, though “These children have very special, between the canines was cleft lips can be repaired very unique communication considerably smaller than in earlier months. 2 The rethe width between the mosearch that Dr. Zajac and his problems due to the clefting, but lars. Children with smaller team are doing is aimed at they also can have any of the other understanding the speech measurements at the front of their mouths, between the communication problems, and that is problem in order to find a canines, could not properly correct it. what made this area so challenging way toChildren produce the “t” sounds, causborn with and interesting to me.” ing the sound to be relayed cleft lip and cleft palates to the back of the mouth face more medical attention -Dr. David Zajac resulting in the pronounciawithin their first few years of tion of the “k”, resulting in the life than most people do in a production of “cap” instead of lifetime. Dr. Zajac and other “tap.”2,3 speech scientists are helping change the way these children As a result of the unique as well as common communi- live by providing research to help doctors improve children’s cation problems associated with these defects, many health ability to eat, hear, talk and simply smile. professionals and researchers from various disciplines are needed for treatment. The complexity of this field is amongst References the many factors that attracted Dr. Zajac. “These children have 1. Birth Defects: Facts about Cleft Lip and Cleft Palate. (2013, very special, very unique communication problems due to the July 15). Retrieved from http://www.cdc.gov/ncbddd/birthclefting, but they also can have any of the other communica- defects/cleftlip.html. tion problems, and that is what made this area so challenging 2. Interview with David Zajac, Ph.D. 01/31/2014. 3. Zajac, D.J., Cevidanes, L., Shah, S., Haley, K.L. “Maxillary and interesting to me.”2 Early interventions are the best route when dealing arch dimensions and spectral characteristics of children with not only craniofacial anomalies but most speech prob- with cleft lip and palate who produce middorsum palatal lems. The average person learns most of their speech and lan- stops.” Journal of speech, language, and hearing research guage by the age of three, and the more problems that can be 55(6), 1876–1886. 2012.
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psychology
Image by Camdiluv [CC-BY-SA-2.0].
HAPPINESS MANIFESTED
how positive emotions can reinforce healthy lifestyle changes
By Brian Davis
F
eeling good might not only be beneficial to the human psyche, but could also play an important role in our physical health. Dr. Barbara Fredrickson, the principal investigator of the Positive Emotions and Psychophysiology lab at UNC-Chapel Hill, studies how our thoughts and emotions influence our bodies biologically. Her most recent research identified the health benefits associated with psychological well-being.1 The consensus amongst psychologists is that feeling good translates to benefits in our physical health that transcend simply feeling well psychologically (e.g. reduced stress and depression). However, the reasoning behind this correlation is poorly understood.1 Through her research, Dr. Fredrickson was able to identify specific forms of happiness that predict how one’s genes are expressed within white blood cells. She found that our cells can differentiate the source of happiness, and they respond accordingly. “Our immune system, by being attuned to our emotional experience, readies us for the most likely biological threat,” she said.2 Dr. Fredrickson and her colleagues contrasted two forms of happiness: feelings of purpose, connection and meaning, known as eudaimonic well-being, and feelings of pleasure and satisfaction, known as hedonic well-being. When we are highly stressed, our cells increase the expression of genes
involved in inflammation and decrease the expression of genes involved in antibody synthesis in a process known as conserved transcriptional response to adversity (CRTA).1 Dr. Fredrickson and her colleagues found that the cells of people who predominantly experience a sense of eudaimonic well-being showed a reduction in CTRA, resulting in reduced inflammation and an increase in the production of antibodies. Conversely, Dr. Barbara Fredrickson the cells of people who predominantly experience a sense of hedonic well-being showed an increase of CTRA, resulting in increased inflammation and decreased antibody production.1 These findings support the idea that the cells in our body can detect the source of our happiness and change CRTA gene expression as a result. Hedonic and eudaimonic well-being are not mutually exclusive. It is difficult to imagine a scenario where you can experience purpose without pleasure, or pleasure completely devoid of meaning. Dr. Fredrickson’s message after analyzing the data is not that one should not pursue pleasurable expe-
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Carolina Scientific Produces more experiences of positive emotions, creating an upward spiral
psychology Enhanced health, survival, fulfillment
Building enduring personal resources (social support, resilience, skills, and knowledge)
Novel thoughts, activities, relationships
Figure 1. The Broadenand-Build Theory: Positive emotions serve to broaden awareness through thoughts, actions, and perceptions. Image adapted from Fredrickson and Cohn (2008, Fig. 48.1).
Broadening
Positive emotions
rience. She believes that pleasurable experiences do eventu- is going to influence who you are next season.”2 This idea that ally lead to eudaimonic well-being. “The data suggest that cultivating positive emotions leads to compounding effects the ‘feel good’ part on its own isn’t enough to drive health. that improves our life has led Dr. Fredrickson to theorize that It appears that health benefits emerge when feeling good experiencing positive emotions can contribute to an upward leads to doing good, or otherwise experiencing meaning and spiral in lifestyle changes. purpose.” The problem occurs when people are only focused The upward spiral theory of lifestyle change guides on their sensual pleasures in ways that are devoid of meaning new research in the Positive Emotions and Psychophysiand connectedness. Everyone has the potential to experience ology Laboratory. As a result of their previous findings in eudaimonic well-being. However, broaden-and-build research, the lab “It appears that health the positive emotion system can also has turned towards investigating easily lead to addiction.2 benefits emerge when feeling whether and how positive emotions Many experiences in our culalter a person’s bodily systems and good leads to doing good, ture are artificially created for us to nonconscious motives in ways that produce high amounts of pleasure, ultimately reinforce healthy lifestyle or otherwise experiencing such as the thrill of gambling or conchange. Members of the lab believe meaning and purpose.” suming, and do not allow for us to that positive emotions can both lead -Dr. Barbara Fredrickson reach deeper meaning. Dr. Fredrickpeople to new positive health beson explains, “Our culture has dissohaviors and also raise their overall ciated the most pleasurable part of experience and packaged psychological propensity for a suite of wellness behaviors.3 Dr. just that.” People frequently find themselves trapped in habits Fredrickson is adamant about the importance of understandwhere they become dependent on things that make them ing emotions in order to better grasp the effects they have feel good physically, says Fredrickson. This results in people on our overall health. “Without understanding emotions, [the feeling good for a short period of time due to satisfying their mind and body] are on separate realms. Understanding emosensual pleasures, but a void remains in the area of their lives tions helps us bridge mind and body.”2 that are associated with a sense of purpose and belonging. Dr. Fredrickson believes that we can “use our knowledge of positive emotion to build nonconscious habits to do the right References thing rather than being hijacked to do the wrong thing.”2 1. Fredrickson, B.L., Grewen, K. M., Coffey, K.A., Algoe, The core of Dr. Fredrickson’s research focuses on how S.B., Firestine, A.M. Arevalo, J.M.G., Ma, J., Cole, S.M. “A positive emotions affect us. Her broaden-and-build theory functional genomic perspective on human well-being.” Proof positive emotions (Figure 1) states that positive emotions ceedings of the National Academy of Sciences, PNAS Early expand one’s awareness through thoughts, actions and per- Edition. DOI:10.1073. 2013. ceptions, which leads to the eventual discovery of new re- 2. Interview with Barbara L. Fredrickson, Ph.D. 01/30/2014. sources such as knowledge, alliances and skills.3 “The bones 3. Fredrickson, B.L. “Positive Emotions Broaden and Build.” of the broaden-and-build theory are that what you feel today Advances in Experimental Social Psychology 47, 1–53. 2013.
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psychology
Bridges of a Baby’s Brain
understanding brain development through neural connections By Tracie Hayes
Image by Tracie Hayes.
E
arly in life, a baby’s brain is busy creating and organizing connections between bundles of neurons in order to set the foundation for higher thinking as the baby grows.1 A group of seven scientists at UNC came together to research the development of these functioning neural connections in the first two years of life.2 Dr. Kelly Giovanello, a neuroscientist in the Department of Psychology, works with healthy young and older adults to understand how neural regions support memory and change over time, primarily investigating how individual parts of the
Figure 1. Simplified diagrams of the networks of functional connections in the brain.6 Left: Primarily local connections, like the network of a neonate.1 Right: Both local and longdistance connections, like the network of a one year old. Images public domain.
brain contribute to different types of memory.1 A few years ago, Dr. Weili Lin, director of the Biomedical Research Imaging Center at UNC, asked Dr. Giovanello to consider the “other end of the developmental spectrum” – in other words, to study brain activity in babies to understand how the brain functionally develops.1 Dr. Wei Gao, in the Department of Radiology, carried out much of Dr. Kelly Giovanello the statistical work to create images to display their findings.1 “In neuroscience research it’s typically a team effort because not everyone is trained in every single aspect… and I think this paper is a great example of people with very different training coming together to do this exciting project,” explains Dr. Giovanello.1 The researchers hoped that discovering functional mechanisms of the brain at birth and how those mechanisms change over time would provide insight into the biological foundation of the developing brain.1 They were specifically interested in the brain network of a baby, and how this changes from neonate (less than two weeks old) to one year old, and from one year old to two years old.1,2
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Carolina Scientific To visualize the neural networks, babies of different ages were scanned with a functional MRI while sleeping.1,2 The network of the brain that is active during sleep is called the default mode.1 The default mode network has posterior and anterior hubs, which are high-activity regions where multiple functional connections pass through and are then sent elsewhere.1 The high activity of the default mode network allowed the researchers to obtain brain network data while the babies slept.1 “The brain is not a passive organ, it’s always active,” Dr. Giovanello said.1 Researchers used the functional MRI data to identify which structural connections in the brain are functioning at different ages.1 To do this, they measured the parts of the brain that consumed energy. Neurons need glucose and oxygen to respond to stimuli, and this is measured by the BOLD signal (blood oxygen level dependency), which Dr. Giovanello describes as a “correlate of neural activity.”1 The researchers analyzed two main types of functional connections: local and global.2 Local connections are between two regions of the brain that are near each other, and global connections are between distant regions of the brain.1 These connections are not single active neurons, but rather groups of active neurons that function together.1 The functional MRI data showed differences in the dominant connections among different age groups.1 The neonates demonstrated brain activity with primarily local connections.1,2 This indicated that the neonate brain is not heavily cross-connected; far-reaching parts of the brain do no correlate in activity.1 One year olds showed an abundance of functional connections, both local and global.1,2 Dr. Giovanello explains that long distance functional connections are “the foundation for higher order cognition . . . the ability to talk and move around, to perceive your world.”1 The increased proportion of long distance connections in one year olds therefore demonstrates why they are more social and interactive than neonates.1 The functional MRI scans of the two year olds showed a decrease in the number of functional connections compared to the one year olds, a trend which Dr. Giovanello describes as “a refinement of the system.”1,2 The decrease in functional connections is evidence of synaptic pruning, a process where weak and redundant connections are removed.3 After being refined, the connection network is similar to that of an adult.1 “There is likely a lot of redundancy in the amount of connections that [the one year olds have],” Dr. Giovanello said.1 “Although the total number [of connections] drops, there are more long-distance connections acting as ‘short-cuts’ bridging different local clusters, making the whole system more efficient in information transmission” for two year olds.4 These findings ultimately gave Dr. Giovanello and her colleagues an increased understanding of how a baby’s brain functionally develops (Figure 2). The baby is born with primar-
“The brain is not a passive organ. It’s always active.” -Dr. Kelly Giovanello
psychology
Figure 2. Red represents the anterior of the default mode network, and blue represents the posterior. The two parts become more locally specialized with age. The pink areas in the one and two year olds represent the network integration (correlation through long distance connections).2,5 Image courtesy of Dr. Wei Gao. Gao, W., Gilmore, J.H., Giovanello, K.S., Smith, J.K., Shen, D., Zhu, H., Lin, W. PLoS ONE 6, 1–13. 2011. ily local connections, and then in the first year adds multitudes of more connections, both local and global (Figure 1).1 Then, in the second year, the system becomes more efficient as some of the connections are dropped.1 Dr. Giovanello and her colleagues’ research characterizing brain network development in the early years of life will prove crucial to further research, including the study of neurodevelopmental disorders such as schizophrenia and autism.1 “If we can characterize what the ‘typical’ brain is as kids develop, we can then do comparisons between typically developing kids and individuals that are atypical because of some sort of neurodevelopmental disorder.”1
References
1. Interview with Kelly S. Giovanello, Ph.D. 01/31/2014. 2. Gao, W., Gilmore, J.H., Giovanello, K.S., Smith, J.K., Shen, D., Zhu, H., Lin, W. “Temporal and Spatial Evolution of Brain Network Topology during the First Two Years of Life.” PLoS ONE 6(9), 1–13. 2008. 3. Email with Kelly S. Giovanello, Ph.D. 02/19/2014. 4. Email with Wei Gao, Ph.D. 02/05/2014. 5. Bassett, D.S., Bullmore, E. “Small-World Brain Networks.” Neuroscientist 12(6), 512–513. 2006.
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psychology
how your brain can make you
SICK
BY GUY CECELSKI
Figure 1. Graduate student Lee Hutson studies signaling between neurons like this one to better understand interactions between the brain and the immune system. Image by Sevela P. [GPL].
C
harles just got out of rehab for severe heroin dependency. As he enters his home, he steps into the living room where he injected himself countless times before. In fact, there are still a couple of used needles laying on the coffee table. The smell of cheap air fresheners hits his nostrils. He takes off his shoes and his feet feel the shag rug that they know all too well. As these familiar stimuli welcome Charles, a curious thing is happening within his body. His immune system is weakening, just as it did before when he injected him-
Figure 2. This “connectome,” a map of the connections in the brain, shows the complexity of the organ that we are only beginning to understand. Image courtesy of V.J. Wedeen and L.L. Wald, Martinos Center for Biomedical Imaging at MGH.
self with heroin. Just by being in the same environment as when he was using drugs, Charles becomes more vulnerable to infections. While Charles is not a real person, his experiences are familiar to real heroin addicts. This strange phenomenon is part of what Lee Hutson, a fifth-year graduate student at UNC-Chapel Hill, is researching. Hutson is part of the behavioral Lee Hutson neuroscience program of the psychology department, under the supervision of Dr. Donald Lysle, and is researching neuroimmunology. Neuroimmunology is the study of how the immune system interacts with the brain. Robert Ader founded the field in the 1970s when he discovered that the immune system of rats was weakened simply by exposure to a solution that tasted like one that had previously made them sick.2 According to Hutson, the field “took off from there [because his research] showed the mind, cognitive perceptions of whatever you are experiencing are going to affect physiological function.”1 Another more recent development is the discovery of proteins called cytokines that respond to infection in the brain. This discovery provided evidence that the nervous system and the immune system interact biochemically. Hutson says that “pharmacologists who study drug abuse and study neurotransmitter function . . . will have to look at cytokines to fully understand these processes.”1
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Carolina Scientific Hutson’s latest research aims to explain Charles’s experience, also known as heroin-induced conditioned immunosuppression. Heroin causes the brain to release large amounts of dopamine, a chemical messenger, which can put stress on the body and thus suppress the immune system. The conditioned immunosuppression occurs when a certain response, such as a suppressed immune system due to drug use, is associated with an environmental stimulus, such as Charles’s living room. Repeated pairing of the stimulus and the response eventually causes the immunosuppression to occur in response to the environment of the drug use, even without the drug use itself. When asked about the severity of the conditioned response, Hutson replied, “The immune suppression from the drug is definitely something that’s significant for those currently using drugs . . . and just by being re-exposed to that environment in a drug-free state, they’ll be more susceptible to infection, just based on those cues that they are familiar with.”1 Due to the relatively recent discovery of the conditioned immune suppression effect, researchers are still trying to pinpoint its origin and how it works. Previous research has identified specific regions of the brain that are necessary for the conditioned response to occur.3 Hutson has added another piece of the puzzle by studying the role of the anterior ventral tegmental area (anterior VTA) in this immunosuppression.
Figure 3. Heroin use releases dopamine in the brain, which is crucial to the conditioned immunosuppression. Image by PublicDomainPictures [CCO 1.0]. The anterior VTA is involved in dopamine signaling to brain regions that are involved with heroin-induced conditioned immunosuppression. The results from his research show that the anterior VTA must be functional for the expression of the heroin-induced conditioned immune suppression to occur. Hutson provided evidence to support this theory by inactivating the anterior VTA in rats and infecting them after being exposed to the conditioned environment. The researchers then measured the response of the rats’ immune system compared to the control groups. Rats with an inactivated anterior VTA did not show the conditioned immunosuppression while those with an active anterior VTA did display a depressed immune system.
psychology
Previous research has shown the significance of other pathways, such as the stress pathway and fight-or-flight response, in the conditioned immune His immune system suppression. Hutson is weakening, just as it believes that his research fits into a largdid before he injected er picture of how the suppression occurs. himself with heroin . . . In “My hypothesis is the same environment that since [drugs] are as when he was using all stressors of some drugs, Charles becomes sort, [these pathways are] all working in more vulnerable to concert to produce infections. this immune suppres1 sion.” Hutson’s research is, as he puts it, is “very basic research just to try to figure out what’s going on.”1 He argues that, “you need to understand how a car works before you can fix it.”1 Hutson’s research is foundational in the field of neuroimmunology. His field is one with room for growth and expansion; therefore, the early research involves simply figuring out how different areas of the brain affect the immune system. Hutson’s research has expanded the scientific understanding of the connections and circuits involved in the conditioned immunosuppression and also provides support for further research in this area of the brain, particularly in relation to the immune system. Hutson plans to continue mapping out the regions of the brain involved in immunosuppression and to hopefully discover the source of cytokines in the brain. Hutson says he is not sure what the long-term significance of his research will be, but researchers will continue to lay this foundation and eventually build up toward real-world applications. Forty years ago, the scientific community had not seen evidence that the immune system was affected by neurological and psychological factors. Today, neuroimmunologists like Hutson are advancing their field to address factors in the nervous system so that scientists can reduce the risk of infection in people like Charles in the future.
References 1. Interview with Lee Hutson. 01/23/2014. 2. Pincock, S. Robert Ader. (2012). Retrieved from http:// www.thelancet.com/journals/lancet/article/PIIS01406736(12)60134-2/fulltext. 3. Szczytkowski, J.L., Lysle, D.T. “Conditioned effects of heroin on proinflammatory mediators require the basolateral amygdala.” European Journal of Neuroscience 28, 1867–1876. 2008. 4. Hutson, L., Szczytkowski, J.L., Saurer, T., Lebonville, C., Fuchs, R., Lysle, D.T. “Region-specific contribution of the ventral tegmental area to heroin-induced conditioned immunomodulation.” Brain, Behavior, and Immunity (pending publication). 2014.
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“Science, my lad, is made up of mistakes, but they are mistakes which it is useful to make, because they lead little by little to the truth.” - Jules Verne
Image by Ildar Sagdejev, [CC-BY-SA-3.0].
Carolina
scıentıfic
Spring 2014 | Volume 6 | Issue 2
This publication was funded at least in part by the Carolina Parents Council and by Student Fees which were appropriated and dispersed by the Student Government at UNC-Chapel Hill.
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