Duke Research Blog

Following the people and events that make up the research community at Duke.

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Drug Homing Method Helps Rethink Parkinson’s

The brain is the body’s most complex organ, and consequently the least understood. In fact, researchers like Michael Tadross, MD, PhD, wonder if the current research methods employed by neuroscientists are telling us as much as we think.

Michael Tadross is using novel approaches to tease out the causes of neuropsychiatric diseases at a cellular level.

Current methods such as gene editing and pharmacology can reveal how certain genes and drugs affect the cells in a given area of the brain, but they’re limited in that they don’t account for differences among different cell types. With his research, Tadross has tried to target specific cell types to better understand mechanisms that cause neuropsychiatric disorders.

To do this, Tadross developed a method to ensure a drug injected into a region of the brain will only affect specific cell types. Tadross genetically engineered the cell type of interest so that a special receptor protein, called HaloTag, is expressed at the cell membrane. Additionally, the drug of interest is altered so that it is tethered to the molecule that binds with the HaloTag receptor. By connecting the drug to the Halo-Tag ligand, and engineering only the cell type of interest to express the specific Halo-Tag receptor, Tadross effectively limited the cells affected by the drug to just one type. He calls this method “Drugs Acutely Restricted by Tethering,” or DART.

Tadross has been using the DART method to better understand the mechanisms underlying Parkinson’s disease. Parkinson’s is a neurological disease that affects a region of the brain called the striatum, causing tremors, slow movement, and rigid muscles, among other motor deficits.

Only cells expressing the HaloTag receptor can bind to the AMPA-repressing drug, ensuring virtually perfect cell-type specificity.

Patients with Parkinson’s show decreased levels of the neurotransmitter dopamine in the striatum. Consequently, treatments that involve restoring dopamine levels improve symptoms. For these reasons, Parkinson’s has long been regarded as a disease caused by a deficit in dopamine.

With his technique, Tadross is challenging this assumption. In addition to death of dopaminergic neurons, Parkinson’s is associated with an increase of the strength of synapses, or connections, between neurons that express AMPA receptors, which are the most common excitatory receptors in the brain.

In order to simulate the effects of Parkinson’s, Tadross and his team induced the death of dopaminergic neurons in the striatum of mice. As expected, the mice displayed significant motor impairments consistent with Parkinson’s. However, in addition to inducing the death of these neurons, Tadross engineered the AMPA-expressing cells to produce the Halo-Tag protein.

Tadross then treated the mice striatum with a common AMPA receptor blocker tethered to the Halo-Tag ligand. Amazingly, blocking the activity of these AMPA-expressing neurons, even in the absence of the dopaminergic neurons, reversed the effects of Parkinson’s so that the previously affected mice moved normally.

Tadross’s findings with the Parkinson’s mice exemplifies how little we know about cause and effect in the brain. The key to designing effective treatments for neuropsychiatric diseases, and possibly other diseases outside the nervous system, may be in teasing out the relationship of specific types of cells to symptoms and targeting the disease that way.

The ingenious work of researchers like Tadross will undoubtedly help bring us closer to understanding how the brain truly works.

Post by undergraduate blogger Sarah Haurin

Post by undergraduate blogger Sarah Haurin

 

Creating a Gender Inclusive Campus: Reflecting on “Becoming Johanna”

Following Duke’s Oct. 4 screening of the 2016 documentary, “Becoming Johanna,” students, faculty, staff and community members in the audience were eager to ask questions of the panel, which included the film’s director/producer, Jonathan Skurnik, and even the film’s transgender subject, Johanna Clearwater herself.

Johanna Clearwater pictured with the film’s director/producer Jonathan Skurnik

The film showcases the heart-wrenching and empowering story of a latina transgender teenager growing up in Los Angeles. After beginning her transition at age 16, Johanna faced the rejection of her mother and intense opposition from school authorities. Soon after, she was abandoned by her family and entered the foster care system, where she was lucky to find a much more supportive family environment. After changing schools, she connected on a personal level with her school principal, Deb, who helped Johanna find a community where she felt understood and supported. This success story of self-advocacy and resilience in the face of abandonment and exclusion highlights the daily struggles of many transgender teenagers. For these individuals, becoming comfortable in their own skin is the end of a long and demanding journey, often made even more difficult by the ignorance and cruelty of society. Finding and following the path to authentic expression takes a huge amount of courage, as this route is often layered with adversity.

Before the screening, Duke clinical social worker Kristin Russel put the film in context for the audience, inviting our reflection with her words: “A well told story… is really what can help us bridge the unfortunate distance that can remain uncrossed and misunderstood if such stories are silenced.” Chief Diversity Officer for the School of Medicine Judy Seidenstein then introduced the film and facilitated the panel discussion.

After the film, the audience was invited to join the conversation. Questions came from every demographic of the crowd, and provided a nice sampling of opinions. Many audience members pointed out how important these conversations are, especially in a conservative state like North Carolina that has so recently struggled with the protection of LGBTQ rights with last year’s ‘Bathroom Bill.’ Specifically, the questions and comments from hospital staff and faculty from the School of Medicine gave a nice insight into the direction of support on campus for sexual and gender diversity.

Audience members reflect on the film with those nearby

Cheryl Brewer, the Associate Vice President of Nursing, told the room about the inclusion work that she is leading in the School of Nursing. They have developed a new core curriculum to promote acceptance and support of gender and sexual diversity through situational trainings. She noted that there have been some people that struggle with implicit biases more than others, but that the program has been a success overall.

Russell spoke briefly about her work with transgender and gender diverse youth in the clinical setting and emphasized the importance of having family support. Legally and psychologically, maintaining family involvement and support of patients is essential for treatment.

Events like this one reflect ongoing efforts to support sexual and gender diversity within and beyond Duke, by promoting conversation and increasing empathy through storytelling. Duke is well on the way to becoming a much more inclusive community, where everyone can feel a sense of belonging.

Guest post by Anne Littlewood

Meet New Blogger Brian Du

Brian survives his week in the desert.

Hi! My name is Brian Du, and I’m a sophomore from Texas. I’m a pre-med majoring in computer science. I like vacations, hiking, and hiking on vacation. Besides these hobbies, I also love learning about science and hearing a good story. These latter two are exactly why I’m excited to be writing for the Duke Research Blog.

My first exposure to science happened in third grade because my goldfish kept getting sick and dying. This made me sad and I became invested in making them well again. I would measure pH levels regularly with my dad and keep notes on the fishes’ health. Eventually the process turned into a science fair project. I remember I loved presenting because I got to point out to the judges the ‘after’ pictures of my fish, which showed them alive, healthy, and happy (I think? it’s hard to tell with fish).

One happy fish!
Source: Reddit

My fish and I go way back.

After that third-grade experiment, I kept doing science projects — almost year after year actually — since I love the research process. From framing the right questions and setting up the experiment, to running the trials and writing up and sharing my work, my enthusiasm grew with each step. Come competition day, I noticed that in interviews that went well, my excitement was contagious, so that judges grew more eager too as they listened. And so I understood: a huge part to science is communication. Science, like food or a good story, is meant to be shared with others. The scientist is a storyteller, adjusting his presentation to captivate different audiences. With judges, I spoke jargon, but during public exhibition, where I chatted with anyone who came up to me, I got creative when asked about my research. Analogies helped me link strange concepts to everyday objects and experiences. An important protein channel became a pipe, and its inhibitor molecule a rock which would clog the pipe to make it unusable.

protein channel “pipe”
edited from CThompson02

Now that I’m at Duke, there’s so many stories to tell of the rich variety of research being done right on campus! I’ve written a few articles for the Chronicle covering some of the new medicine or proteins Duke professors have been involved in developing. As I keep an ear out for more stories, I hope to share a few of them in my upcoming posts, because I know they’ll be exciting!

Falling Out of Love With Science and Our Civic Duties

Last Friday, I attended Falling Out of Love with Science, a lunch function during which Milan Yager,executive director of the American Institute for Medical and Biological Engineering, discussed why those of us interested in scientific research should care about the actions of prominent politicians, especially those that relate to the underfunding of scientific research.

Milan Yager of AIMBE

Milan Yager is the executive director of the American Institute for Medical and Biological Engineering.

Before attending Yager’s talk, I guess I didn’t quite realize how much of innovation was enabled by government funding. Many revolutionary discoveries are made possible through the NIH (https://www.nih.gov) that we don’t even realize we use on a daily basis.

However, as I came to realize, public support for research funding is jeopardized by the propagation of fake news defeating the need for concrete scientific research, hence propelling research under-funding. Over time, funding for the NIH and other government research funding has declined, which has slowed American innovation.

What I enjoyed most about his talk however, was the unexpected motivational turn that it took at the end. He discussed how we, as young researchers invested in finding our personal truths through science, needed to use our voices to stand up against the proliferation of myths in politics in favor of concrete facts.

NIH funding trends

Here’s a curve we definitely want to bend: NIH research funding has flattened and fallen.

Though this can be done in different ways, Yager made sure to point out how essential it is for Americans to vote, citing a statistic that points out that 20 percent of Americans don’t vote because they are “simply too lazy.” (Learn how to register to vote in North Carolina.)

He also encouraged us to send letters to our senators, rally for what we believed in, and not give up on our goals in the face of adversity — something that he called “sitting at the table.” Yager points out that if you don’t “sit at the table,” then your issue won’t get the necessary exposure needed for it to be fixed.

What can we, as Duke students, take away from what Yager had to say? Mainly this: Duke is a research institution that is partially made capable by government funding; for our capacity for research to be continued to be fully realized, we must use our voices to make sure that the propagation of ‘fake news’ does not cut funding for factual research.

This is mainly achieved by voting– those who perpetuate false “facts” in order to remain in power must be replaced with those who realize the importance of scientific research.

Perhaps, for society to fall back in love with science, we need to fall out of love with the myths propagated by tribal politics.

Post by Rebecca Williamson

New Blogger Rebecca Williamson: The Moon and Some Stars

Hello! My name is Rebecca Williamson, and I am a freshman here at Duke University. Coming into college, I plan to major in economics, but that could very well change. As for my interests outside of the classroom, I enjoy singing and theater and am a member of Out of the Blue, one of the all-female a cappella groups here at Duke!

Rebecca Williamson, Duke 2022

Rebecca Williamson, Duke 2022

I fell in love with Duke the second I stepped on campus. I am excited to see what Duke has to offer me, but more importantly, what I can offer to Duke.

My interest in science, specifically astronomy, was piqued at a very young age. By age six, I had not one, but three,  Moon in my Room light up toys (remote controlled models of the Moon that scrolled through the waxing and waning phases of the Moon at the touch of a button) mounted in my bedroom. By nine, I had the entire planetary system (yes, including Pluto) hanging from my ceiling. Though I cannot say that my interests remain with astronomy, it is what first got me invested in science. I have since gained interest in the natural sciences and animal sciences, though every so often I do press some of the buttons on my Moon in my Room remote.

Some random boy imagines he's as cool as six-year-old Rebecca.

Some random boy imagines he’s as cool as six-year-old Rebecca.

My love of writing, however, was spawned by my love of theater. As an active member of my high school’s theater community, I was roped into being a part of, and eventually became the president, of my school’s Cappies Critics team. As a Cappie, I was expected to watch local high school plays and musicals and write critical, holistic reviews of them. This program jump-started my love for writing and helped me to develop my own unique journalistic voice.

solar system mobile. www.luxrysale.comI hope to combine my interest in the natural and animal sciences with my love for writing and chronicle some of the amazing research going on in these fields both on campus and around Durham! I also hope to incorporate my interests in music and theater into my inquiries and document scientific research surrounding music and the arts in the Duke community.

Duke University Research Blog, look out, because here I come!

Post by Rebecca Williamson

Aging and Decision-Making

Who makes riskier decisions, the young or the old? And what matters more in our decisions as we age — friends, health or money? The answers might surprise you.

Kendra Seaman works at the Center for the Study of Aging and Human Development and is interested in decision-making across the lifespan.

Duke postdoctoral fellow Kendra Seaman, Ph.D. uses mathematical models and brain imaging to understand how decision-making changes as we age. In a talk to a group of cognitive neuroscientists at Duke, Seamen explained that we have good reason to be concerned with how older people make decisions.

Statistically, older people in the U.S. have more money, and additionally more expenditures, specifically in healthcare. And by 2030, 20 percent of the US population will be over the age of 65.

One key component to decision-making is subjective value, which is a measure of the importance a reward or outcome has to a specific person at a specific point in time. Seaman used a reward of $20 as an example: it would have a much higher subjective value for a broke college student than for a wealthy retiree. Seaman discussed three factors that influence subjective value: reward, cost, and discount rate, or the determination of the value of future rewards.

Brain imaging research has found that subjective value is represented similarly in the medial prefrontal cortex (MPFC) across all ages. Despite this common network, Seaman and her colleagues have found significant differences in decision-making in older individuals.

The first difference comes in the form of reward. Older individuals are likely to be more invested in the outcome of a task if the reward is social or health-related rather than monetary. Consequently, they are more likely to want these health and social rewards  sooner and with higher certainty than younger individuals are. Understanding the salience of these rewards is crucial to designing future experiments to identify decision-making differences in older adults.

A preference for positive skew becomes more pronounced with age.

Older individuals also differ in their preferences for something called “skewed risks.” In these tasks, positive skew means a high probability of a small loss and a low probability of a large gain, such as buying a lottery ticket. Negative skew means a low probability of a large loss and a high probability of a small gain, such as undergoing a common medical procedure that has a low chance of harmful complications.

Older people tend to prefer positive skew to a greater degree than younger people, and this bias toward positive skew becomes more pronounced with age.

Understanding these tendencies could be vital in understanding why older people fall victim to fraud and decide to undergo risky medical procedures, and additionally be better equipped to motivate an aging population to remain involved in physical and mental activities.

Post by undergraduate blogger Sarah Haurin

Post by undergraduate blogger Sarah Haurin

The Complicated Balance of Predators and Prey

If you knew there was a grizzly bear sitting outside the door, you might wait a while before going to fill up your water bottle, or you might change the way you are communicating with their other people in the room based on your knowledge of the threat.

Ecologists call this “predation risk,” in which animals that could potentially fall prey to a carnivore know this risk is present, and alter their habits and actions accordingly.

A yellow slider turtle.

A yellow slider turtle.

One way in which animals do this is through habitat use, such as a pod of dolphins that changes where they spend most of their time depending on the presence or absence of predators. Animals might also change their feeding habits and diving behavior because of predation risk.

Animals do this all of the time in the wild, but when predators are removed from ecosystems by hunting or over-fishing, the effect of their absence is felt all the way down the food chain.

For example, large amounts of algae growth on coral reefs can be traced back to over-fishing of large ocean predators such as sharks, who then don’t hunt smaller marine mammals like seals. As seal numbers increase, there are more of them to hunt smaller fish that feed on vegetation, which means fewer smaller fish or plankton to keep algal growth in check, and algae begins to grow unchecked.

Meagan Dunphy-Daly

Meagan Dunphy-Daly

This is a “trophic cascade” and it has large effects on ecosystems, Duke Marine Lab instructor Meagan Dunphy-Daly  t0ld the Sustainable Oceans Alliance last Thursday. She has performed research both in labs and in the field to study the effects that removing large predators have on marine ecosystems.

Dunphy-Daly discussed one lab experiment where 10 yellow-bellied slider turtle hatchlings were kept in tanks where they couldn’t see people or anything else on the outside. In real life, blue herons and other large birds prey on these turtle hatchlings, so the researchers made a model skull of a blue heron that they painted and covered with feathers.

Turtles are air-breathing, so each hatchling was given the option to sit where they could be at the surface of their tank and breathe, but this spot was also where the turtle hatchlings thought the bird beak might shoot down at any time to try to “eat” them.

Their options were to get air and risk getting hit by the bird beak, or diving down to the bottom of the tank to get food. During this experiment, Dunphy-Daly found that turtle hatchlings actually decreased their dive time and spent more time at the surface. If the turtles are continuously diving, they are expending lots of energy swimming back and forth between the surface and the bottom, she said, which means if the predator were to actually attack, they would have less energy left to use for a rapid escape.

Even when there is food at the bottom, when a predator is present, these turtles alter their activity by taking deep dives less frequently so as to not max out their aerobic limit before they actually need to escape a predator.

This is one way in which animals alter their behavior due to predation risk.

But let’s say that predators were disappearing in their real habitats, so turtles didn’t feel the need to build up these emergency energy reserves to escape them. They might dive down and feed more frequently, which would then decrease the amount of the vegetation they eat.

This in turn could have an effect on oxygen levels in the water because there would be fewer plants photosynthesizing. Or another species that feeds on the same plant could be out-competed by turtles and run out of food for their own populations.

The absence of large or small predators can have large impacts on ocean ecosystems through these complicated trophic cascades.

Victoria PriesterPost by Victoria Priester

Smart Phones Are the New Windows to the Soul

It’s one of those things that seems so simple and elegant that you’re left asking yourself, “Geez, why didn’t I think of that?”

Say you were trying to help people lose weight, prep for a surgery or take their meds every day. They’re probably holding a smartphone in at least one of their hands — all you need to do is enlist that ever-present device they’re staring at to bug them!

So, for example, have the health app send a robo-text twice a day to check in: “Did you weigh yourself?” Set up a group chat where their friends all know what they’re trying to accomplish: “We’re running today at 5, right?”

This is a screenshot of a Pattern Health app for pre-operative patients.

It’s even possible to make them pinky-swear a promise to their phone that they will do something positive toward the goal, like walking or skipping desert that day. And if they don’t? The app has their permission to lock them out of all their apps for a period of time.

Seriously, people agree to this and it works.

Two app developers on this frontier of personalized, portable “mHealth” told a lunchtime session  sponsored by the Duke Mobile App Gateway on Thursday that patients not only willingly play along with these behavioral modification apps, their behaviors change for the better.

The idea of using phones for health behavior came to pediatric hematologist Nirmish Shah MD one day while he attempted to talk to a 16-year-old sickle cell disease patient as she snapped selfies of herself with the doctor. Her mom and toddler sister nearby both had their noses to screens as well. “I need to change how I do this,” Shah thought to himself.

Pediatric hematologist Nirmish Shah MD

Pediatric hematologist Nirmish Shah MD is director of Duke’s sickle cell transition program.

Twenty health apps later, he’s running phase II clinical trials of phone-based interventions for young sickle cell patients that encourage them to stay on their medication schedule and ask them often about their pain levels.

One tactic that seems to work pretty well is to ask his patients to send in selfie videos as they take their meds each day. The catch? The female patients send a minute or so of chatty footage a day. The teenage boys average 13 seconds, and they’re grumpy about it.

Clearly, different activities may be needed for different patient populations, Shah said.

While it’s still early days for these approaches, we do have a lot of behavioral science on what could help, said Aline Holzwarth, a principal of the Center for Advanced Hindsight and head of behavioral science for a Durham health app startup called Pattern Health.

Aline Gruneisen Holzwarth

Aline Holzwarth is a principal in the Center for Advanced Hindsight.

“It’s not enough to simply inform people to eat better,” Holzwarth said. The app has to secure a commitment from the user, make them set small goals and then ask how they did, enlist the help of social pressures, and then dole out rewards and punishments as needed.

Pattern Health’s app says “You need to do this, please pick a time when you will.” Followed by a reward or a consequence.

Thursday’s session, “Using Behavioral Science to Drive Digital Health Engagement and Outcomes, was the penultimate session of the annual Duke Digital Health Week. Except for the Hurricane Florence washout on Monday, the week  has been a tremendous success this year, said Katie McMillan, the associate director of the App Gateway.

New Blogger: Victoria Priester Loves Animals and Books

Hi! My name is Victoria Priester, and I’m a sophomore at Duke and one of this year’s new Duke Research bloggers.

Victoria meeting a very intelligent mammal.

I’m pre-vet, but I’ve always been a bookworm and have a love for expressing myself through writing that has given me a strained relationship with word counts. I’ll try to keep this intro post brief!

I’m majoring in English in addition to taking pre-veterinary classes, so my time in the library so far this year has been spent alternating between drawing resonance structures for organic chemistry and reading Jane Eyre in the Gothic Reading Room, which is my favorite study spot on campus.

Effective puppy medicine includes hugging and kissing.

I grew up in the suburbs of Washington, D.C. and now I work in the veterinary department at Duke Lemur Center. I’m also an editor and opinion columnist for The Chronicle. My favorite part of the academic scene at Duke is that pursuing such different interests at the same time is encouraged.

This year, I’m a part of the Bass Connections team that is studying how using expressive writing for resilience can help cancer patients process their experiences during treatment. I love finding new ways to connect my passion for writing with my interest in science, conservation and zoology.

One of the reasons I want to be a veterinarian is because I think veterinarians can and do play a crucial role in species conservation in zoos and animal sanctuaries. However, there is still a lot left to be learned about the animal species they care for.

For example, there is a species of lemur that consistently develops dental problems in captivity that lead to tooth loss, so there must be something about its diet in captivity compared to its diet in Madagascar that affects the health of its teeth. I care a lot about research concerning animals, conservation and pets, in addition to the health benefits of cathartic writing.

Victoria REALLY likes books.

I follow National Geographic on Twitter and read their articles as often as I can, but I usually end up just telling all of the cool facts I just learned to my parents, close friends or anyone else who is close enough to me to feel a slight obligation to listen and feign interest.

Through blogging, I hope to find a platform to synthesize new scientific findings surrounding animals, marine life or cathartic writing and post them to a place where people who care about and want to read about these topics can find them.

Post by Victoria Priester

Combatting the Opioid Epidemic

The opioid epidemic needs to be combatted in and out of the clinic.

In the U.S. 115 people die from opioids every day. The number of opioid overdoses increased fivefold from 1999 to 2016. While increased funding for resources like Narcan has helped — the opioid overdose-reversing drug now carried by emergency responders in cities throughout the country — changes to standard healthcare practices are still sorely needed.

Ashwin A Patkar, MD, medical director of the Duke Addictions Program, spoke to the Duke Center on Addiction and Behavior Change about how opioid addiction is treated.

The weaknesses of the current treatment standards first appear in diagnosis. Heroin and cocaine are currently being contaminated by distributors with fentanyl, an opioid that is 25 to 50 times more potent than heroin and cheaper than either of these drugs. Despite fentanyl’s prevalence in these street drugs, the standard form and interview for addiction patients does not include asking about or testing for the substance.

Patkar has found that 30 percent of opioid addiction patients have fentanyl in their urine and do not disclose it to the doctor. Rather than resulting from the patients’ dishonesty, Patkar believes, in most cases, patients are taking fentanyl without knowing that the drugs they are taking are contaminated.

Because of its potency, fentanyl causes overdoses that may require more Narcan than a standard heroin overdose. Understanding the prevalence of Narcan in patients is vital both for public health and educating patients so they can be adequately prepared.

Patkar also pointed out that, despite a lot of research supporting medication-assisted therapy, only 21 percent of addiction treatment facilities in the U.S. offer this type of treatment. Instead, most facilities rely on detoxification, which has high rates of relapse (greater than 85 percent within a year after detox) and comes with its own drawbacks. Detox lowers the patient’s tolerance to the drug, but care providers often neglect to tell the patients this, resulting in a rate of overdose that is three times higher than before detox.

Another common treatment for opioid addiction involves using methadone, a controlled substance that helps alleviate symptoms from opioid withdrawal. Because retention rate is high and cost of production is low, methadone poses a strong financial incentive. However, methadone itself is addictive, and overdose is possible.

Patkar points to a resource developed by Julie Bruneau as a reference for the Canadian standard of care for opioid abuse disorder. Rather than recommending detox or methadone as a first line of treatment, Bruneau and her team recommend buprenorphine , and naltrexone as a medication to support abstinence after treatment with buprenorphine.

Buprenorphine is a drug with a similar function as methadone, but with better and safer clinical outcomes. Buprenorphine does not create the same euphoric effect as methadone, and rates of overdose are six times less than in those prescribed methadone.

In addition to prescribing the right medicine, clinicians need to encourage patients to stick with treatment longer. Despite buprenorphine having good outcomes, patients who stop taking it after only 4 to 12 weeks, even with tapering directed by a doctor, exhibit only an 18 percent rate of successful abstinence.

Patkar closed his talk by reminding the audience that opioid addiction is a brain disease. In order to see a real change in the number of people dying from opioids, we need to focus on treating addiction as a disease; no one would question extended medication-based treatment of diseases like diabetes or heart disease, and the same should be said about addiction. Healthcare providers have a responsibility to treat addiction based on available research and best practices, and patients with opioid addiction deserve a standard of care the same as anyone else.

Post by undergraduate blogger Sarah Haurin

Post by undergraduate blogger Sarah Haurin

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