Duke Research Blog

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

Category: Lecture Page 1 of 15

Understanding and Addressing Vaccine Hesitancy

In the midst of increasing outbreaks of vaccine-preventable disease, Duke global health researcher Lavanya Vasudevan (PhD, MPH, LPH) is investigating the reasons for vaccine hesitancy with focus on America and Tanzania.

Vaccine hesitancy refers to the refusal of or delay in accepting vaccinations, despite their availability. Vasudevan hopes to figure out what interventions will change the minds of target populations on such a heated topic.

She presented at Duke’s Global Health Institute on November 15th about her “big 5 research areas:” identification of sub-optimal vaccine uptake, contextualization of barriers to uptake, measuring parental concern, debunking misinformation, and developing and testing strategies aimed at addressing vaccine hesitancy.

Lavanya Vasudevan presenting at Duke’s Global Health Institute.

Globally, Vasudevan says that there are too many kids playing catch-up with their vaccines, meaning that even when children are getting vaccinated, the vaccinations they receive are not on time with the scheduled progression of immunizations, putting them at risk for contracting disease. Different countries measure vaccination coverage in different ways and on different timelines, which makes it harder to understand where sub-optimal vaccine uptake is happening. A better standard for assessing timeliness of vaccines is crucial. Vasudevan is working to confront this issue to gain better understanding of who and where hesitancy is coming from.

Identification of specific regions of vaccine hesitancy is crucial to navigating interventions, she added. Vasudevan wants to be able to pinpoint areas and understand the context-specific issues that vary across time, place, and vaccine type in order to be most effective.

She said that her work in Tanzania has provided insight to the problem of geographic accessibility and lack of proper supplies in the country, prompting delayed and missed vaccinations among 72% of children, according to self-reporting by their mothers. Tanzanian mothers expressed their frustrations during interviews. They frequently arrange to go to a clinic where vaccinations are offered on specific dates and travel long distances to get there. However, if there are not enough kids who come to be vaccinated, the facilities just won’t vaccinate those who did manage to show up for immunizations.  

Though the qualitative data gained through extensive interviewing and group discussions has been extremely useful and rich, Vasudevan says there is a need for quantitative tools that can rapidly screen for parent’s concerns when it comes to the vaccination of their children. Qualitative data is simply not informative on a large scale.

A review of pre-existing measures evaluated 159 studies, but the quantitative scales found were often complex and context-specific, as well as designed and validated for high-income settings. On this basis, Vasudevan and her larger research team decided to design a scale for use in Tanzania because of its specificity in addressing the contexts of the region. Tailored counseling is also being used to address the local concerns and issues.

Another parallel research project that Vasudevan is involved with aims to identify common vaccine myths, creating a taxonomy to tag these myths and developing and testing an intervention that will highlight and debunk misinformation found on the internet. The current end-goal for the work being done is a “vaccine fact-checker” that could be used on web browsers to identify the myths in vaccine-related information found online.

A common example of needles and vials containing immunization products (Creative Commons).

In closing, Vasudevan identified three main areas for developing and testing intervention strategies. She says these are behavioral nudges, educational strategies, and vaccination policy and legislation.

There is a need for parent-focused strategies that recognize parental concern for their child’s safety on all sides of the vaccination issue, she said. Stringent policies are likely to alienate hesitant parents rather than increasing vaccine uptake. This is why Vasudevan is so focused on understanding and contextualizing issues specific to hesitancy among parents. It seems that increase of vaccinations and improvement of immunization timeliness lies in hearing and reconciling with parental apprehensions and underlying root causes of these hesitations.

One area of focus that Vasudevan feels is underutilized is pre-natal care. Reduction of the divide between obstetrician/gynecologists (OBGYNs) and pediatric care may be a crucial component to educate parents and enrich their understanding about vaccinations following the birth of the child.

Beyond everything else, she said, building trust is essential; simply providing information to parents is not enough. It takes time and empathy to be enable parents to make healthy vaccination choices. Providing credible resources in a safe environment while tuning in to the causes of hesitancy may be the next step to the reduction of vaccine-preventable disease, a current top ten threat to global health.

Post by Cydney Livingston

The Anthropology of “Porkopolis”

Alex Blanchette, cultural anthropologist and lecturer in anthropology and environmental studies at Tufts University, is a scholar of pork production.

As America’s pork industry is continually pushed to ever greater production, so are the human beings who labor to breed, care for, and slaughter these animals.

Blanchette, who gave a talk hosted by the Ethnography Workshop at Duke on November 4th, said there is an intimate relationship between pig and person. The quality of the factory farm worker’s life is tied to that of the porcine species.

Alex Blanchette of Tufts University

Blanchette’s current work will be published in the 2020 ethnographic book – Porkopolis: American Animality, Standardized Life, and the “Factory” Farm. The book is focused on the consequences of human labor and identity that are bound to the pig – an animal which has become more industrialized over time due to corporations’ goal of a mass produced, standardized pig predictable in nature, uniform in existence, and easy to slaughter.

A common practice in factory farming is the ‘runting’ of litters, genetically making piglets smaller to increase the number each sow produces. But this practice has propelled a fundamental shift in the need for human workers to act as neonatal nurses, what Blanchette calls “external prosthetics,” to care for the newborns. Blanchette described one extraordinary worker responsible for taking care of piglet litters, saving the weak and deformed after birth. She has taken measures so drastic as to give a piglet mouth-to-mouth, incubate them in her pockets, and quickly form body-casts out of duct-tape for the small creatures. This worker has had the chance to study over 400,000 piglets in her seven-year career, encountering conditions of the pig body that no scientist has seen in real life.

Blanchette explained the active engagement required in any portion of the factory production. For example, people working with pregnant sows have to be extremely conscious of the way that the pigs are perceiving them to keep the sensory state of the mother pigs balanced. This means avoiding touching them unless work requires it, not wearing perfumes on the job, and taking overall care and precision in every motion throughout the workday. The danger is the risk of causing mass miscarriages and spontaneous abortions within a barn of sows because of their genetically engineered weakness and inability to handle stresses.

Piglets nursing in a device known as a farrowing crate.

Blanchette said one worker could be seen standing in the exact same place over the course of 1,000 compiled picture frames. He developed this habit to prevent large hogs in open pens from knocking him down and biting his legs while he was working. This is something that Blanchette said he couldn’t manage for more than a few minutes even though he too has worked within the pork industry before.

Workers on slaughter and “disassembly” lines are responsible for making the same exact cut or slice 9,500 times a day.

And finally, the conformation of human labor to the precisions of the factory pig often does not stop at the end of the work shift. In rural factory farming areas, corporations try to re-engineer the human communities in which their workers live to further regulate the human body outside of work because of potential impacts on the pigs. For example, workers’ socialization has been monitored by companies in some cases due to the threat of communicable disease reaching the hogs through human kinship.

No worker knows the pig from birth to death, but for the individual portion of the pig’s life for which they are responsible, they are bound intimately and intricately to the hog, Blanchette said. These people are also disproportionately people of color and immigrant workers who are underpaid for how strenuous, demanding, and encapsulating this labor is. Workers in factory farms often have little protections, and Blanchette’s work gives new life to the consequences of industrial capitalism in America as the pig has become a product of vertical integration in rural communities.

We have long been moving at the speed limits of human physiology in the pork industry,  Blanchette said. In 2011, one company’s annual effort to improve their corporation was to build a new human clinic on the jobsite to treat cuts and injuries acquired on the slaughter lines. This clinic was also responsible for assessing new hires in order to match the strongest part of their body to a place on the line where they would be most productive.

The interior of a typical confined animal feeding operation (CAFO).

Factory farms are actively searching for new money to be found in the pig and to have a closed-loop system which uses every aspect of its life and death for profit. This has caused a deep integration of the “capital swine” into everyday human life for the laborers and communities sustained by these economic ventures.

The Trump administration recently removed standards for pork slaughter line speeds and ultimately reduced overall regulations. People like Blanchette are already considering something you too might be wondering, What happens next? Where does pork and the human labor behind it go from here?

Post by Cydney Livingston

Does aging make our brains less efficient?

We are an aging population. Demographic projections predict the largest population growth will be in the oldest age group – one study predicted a doubling of people age 65 and over between 2012 and 2050. Understanding aging and prolonging healthy years is thus becoming increasingly important.

Michele Diaz and her team explore the effects of aging on cognition.

For Michele Diaz, PhD, of Pennsylvania State University, understanding aging is most important in the context of cognition. She’s a former Duke faculty member who visited campus recently to update us on her work.

Diaz said the relationship between aging and how we think is much more nuanced than the usual stereotype of a steady cognitive decline with age.

Research has found that change in cognition with age cannot be explained as a simple decline: while older people tend to decline with fluid intelligence, or information processing, they maintain crystallized intelligence, or knowledge.

Diaz’s work explores the relationship between aging and language. Aging in the context of language shows an interesting phenomenon: older people have more diverse vocabularies, but may take longer to produce these words. In other words, as people age, they continue to learn more words but have a more difficult time retrieving them, leading to a more frequent tip-of-the-tongue experience.

In order to understand the brain activation patterns associated with such changes, Diaz conducted a study where participants of varying ages were asked to name objects depicted in images while undergoing fMRI scanning. As expected, both groups showed less accuracy in naming of less common objects, and the older adult group showed a slightly lower naming accuracy than the younger.

Additionally, Diaz found that the approach older adults take to solving more difficult tasks may be different from younger adults: in younger adults, less common objects elicited an increase in activation, while older adults showed less activation for these more difficult tasks.

Additionally, an increase in activation was associated with a decrease in accuracy. Taken together, these results show that younger and older adults rely on different regions of the brain when presented with difficult tasks, and that the approach younger adults take is more efficient.

In another study, Diaz and her team explored picture recognition of objects of varying semantic and phonological neighborhood density. Rather than manipulation of how common the objects presented in the images are, this approach looks at networks of words based on whether they sound similar or have similar meanings. Words that have denser networks, or more similar sounding or meaning words, should be easier to recognize.

An example of a dense (left) and sparse (right) phonological neighborhood. Words with a greater number of similar sounding or meaning words should be more easily recognized. Image courtesy of Vitevitch, Ercal, and Adagarla, Frontiers in Psychology, 2011.

With this framework, Diaz found no age effect on recognition ability for differences in semantic or phonological neighborhood density. These results suggest that adults may experience stability in their ability to process phonological and semantic characteristics as they age.

Teasing out these patterns of decline and stability in cognitive function is just one part of understanding aging. Research like Diaz’s will only prove to be more important to improve care of such a growing demographic group as our population ages.

Post by undergraduate blogger Sarah Haurin

Post by undergraduate blogger Sarah Haurin

Legendary Paleontologist Richard Leakey Visits Duke

Hoping to catch up with an old friend who is a professor at Duke, Richard Leakey accepted an invitation to speak at the university on Oct. 22, though he “gave up public speaking to a large extent many years ago.”

Richard E. Leakey visited Duke on Oct. 22, 2019.

Leakey, age 74, is a world-renowned pioneer in Paleoanthropology – the study of the human fossil record – and is also well-known for his involvement in Kenyan politics and lifelong efforts towards conservation and wildlife protection. Once, he famously burned twelve tons of elephant tusks that were confiscated from poachers, which gathered international attention and helped usher in a global ban on the ivory trade.

Leakey came to paleontology by heredity. He is one of an entire family of Paleo-pioneers. His mother, Mary, discovered a skull in Africa that was dated to 1.75 million years ago (MYA) in 1960. Leakey said that this “electrified interest in the origin story” – that is, the human origin story. When his father, Louis, showed that the “quite clever” ancient tools he had discovered were made around 1.75 MYA, the original idea that human origins began outside of Africa began to change.

Leakey said the British people were hoping that “if we had evolved … let it happen in England” and if not England, then Asia, but this was not to be the case. At first, Louis Leakey was ostracized because of his work and discoveries of human origins in Africa. This helped steer Richard away from academics because of the fights that he saw his father endure.

Leakey’s famous 1984 Kenyan discovery, “Turkana Boy,” a 1.5 million-year-old, nearly-complete specimen of Homo erectus. (Wikipedia)

Successfully achieving his self-described ambition to not finish high school, Richard Leakey was thrown out of school at age 16. Yet today he is accredited with many awards, has written at least eight books, and has advanced the Leakey family legacy of discovery. From 1968 to the present day, he and fellow workers have discovered enormous numbers of fossils of our ancestors along the East and West shores of Lake Turkana in Kenya, which have an age span from 4.5 MYA to our very recent ancestors, which Leakey calls “fossil us.”

Leakey described for the Duke audience in an overflowing auditorium at the Nasher Museum a scenario he facilitated with colleagues and students.

He had taken a group to a camp site to talk about evolution and asked them to perform some tasks. First, they were charged to make tools from stone. The following day, they were led to a freshly slaughtered goat. Leakey told his pupils to butcher the goat and remove the flesh from its carcass.

After several hours watching the individuals try to pull at the goat with their hands to no avail, Leakey suggested that they might use their new stone tools. So they did, but they still could not get through the animal’s tough hide, even with a blade.

He said that during human evolution, our imagination was turned on genetically and this gave early humans the “capability to think of things that weren’t.” There is lots of work to be done studying an ancient period over 3.5 million years that Leakey says lends itself to “early ancestry of speech, imagination, [and] cooperation.” He is hopeful for the knowledge and new understandings that will come from investigation of this period. 

“Why not ask someone to help you?” Leakey prompted again, and within an hour, nothing was left of the goat. The exercise demonstrated that though other monkeys and apes use stone, it is the human’s vocal communication and sense of working together that sets us apart, says Leakey.     

Leakey’s current project is a “mega-museum” to “cerebrate and celebrate the story of the African origin.” The origin story which his parents first provided crucial evidence for is hugely important to the African continent and to the people of Africa and because we have “desecrated our motherland,” he said. Leakey wants the museum to highlight stages of evolution, genetics, climate, ecology, other species, and extinctions.

An architectural rendering of Ngaren: The Museum of Humankind to be built near Nairobi. (Studio Libeskind )

Before moving into the panel and Q&A portion of his talk, which was moderated by Duke professors Steven Churchill and Anne Yoder, Leakey prompted the audience to think about climate change, asking why we do not think we need to save ourselves. If we die, then other species go with us.

“Don’t for a minute think that climate change isn’t a real crisis that we’re in together,” Leakey said, earning a round of applause.

Post by Cydney Livingston

How the Flu Vaccine Fails

Influenza is ubiquitous. Every fall, we line up to get our flu shots with the hope that we will be protected from the virus that infects 10 to 20 percent of people worldwide each year. But some years, the vaccine is less effective than others.

Every year, CDC scientists engineer a new flu virus. By examining phylogenetic relationships, which are based on shared common ancestry and relatedness, researchers identify virus strains to target with a vaccine for the following flu season.

Sometimes, they do a good job predicting which strains will flourish in the upcoming flu season; other times, they pick wrong.

Pekosz’s work has identified why certain flu seasons saw less effective vaccines.

Andrew Pekosz, PhD, is a researcher at Johns Hopkins who examines why we fail to predict strains to target with vaccines. In particular, he examines years when the vaccine was ineffective and the viruses that were most prevalent to identify properties of these strains.

A virus consists of RNA enclosed in a membrane. Vaccines function by targeting membrane proteins that facilitate movement of the viral genome into host cells that it is infecting. For the flu virus, this protein is hemagglutinin (HA). An additional membrane protein called neuraminidase (NA) allows the virus to release itself from a cell it has infected and prevents it from returning to infected cells.  

The flu vaccine targets proteins on the membrane of the RNA virus. Image courtesy of scienceanimations.com.

Studying the viruses that flourished in the 2014-2015 and 2016-2017 flu seasons, Pekosz and his team have identified mutations to these surface proteins that allowed certain strains to evade the vaccine.

In the 2014-2015 season, a mutation in the HA receptor conferred an advantage to the virus, but only in the presence of the antibodies present in the vaccine. In the absence of these antibodies, this mutation was actually detrimental to the virus’s fitness. The strain was present in low numbers in the beginning of the flu season, but the selective pressure of the vaccine pushed it to become the dominant strain by the end.

The 2016-2017 flu season saw a similar pattern of mutation, but in the NA protein. The part of the virus membrane where the antibody binds, or the epitope, was covered in the mutated viral strain. Since the antibodies produced in response to the vaccine could not effectively identify the virus, the vaccine was ineffective for these mutated strains.

With the speed at which the flu virus evolves, and the fact that numerous strains can be active in any given flu season, engineering an effective vaccine is daunting. Pekosz’s findings on how these vaccines have previously failed will likely prove invaluable at combating such a persistent and common public health concern.

Post by undergraduate blogger Sarah Haurin
Post by undergraduate blogger Sarah Haurin


The Costs of Mental Effort

Every day, we are faced with countless decisions regarding cognitive control, or the process of inhibiting automatic or habitual responses in order to perform better at a task.

Amitai Shenhav, PhD, of Brown University, and his lab are working on understanding the factors that influence this decision making process. Having a higher level cognitive control is what allows us to complete hard tasks like a math problem or a dense reading, so we may expect that the optimal practice is to exert a high level of control at all times.

Shenhav’s lab explores motivation and decision making related to cognitive control.

Experimental performance shows this is not the case: people tend to choose easier over hard tasks, require more money to complete harder tasks, and exert more mental effort as the reward value increases. These behaviors all suggest that the subjects’ automatic state is not to be at the highest possible level of control.

Shenhav’s research has centered around why we see variation in level of control. Because cognitive control is a costly process, there must be a limit to how much we can exert. These costs can be understood as tradeoffs between level of control and other brain functions and consequences of negative affective changes related to difficult tasks, like stress.

To understand how people make decisions about cognitive control in real time, Shenhav has developed an algorithm called the Expected Value of Control (EVC) model, which focuses on how individuals weigh the costs and benefits of increasing control.

Employing this model has helped Shenhav and his colleagues identify situations in which people are likely to choose to invest a lot of cognitive control. In one study, by varying whether the reward was paired only with a correct response or was given randomly, Shenhav simulated variability in efficacy of control. They found that people learn fairly quickly whether increasing their efforts will increase the likelihood of earning the reward and adjust their control accordingly: people are more likely to invest more effort when they learn that there is a correlation between their own effort and the likelihood of reward than when rewards are distributed independent of performance.

Another study explored how we adjust our strategies following difficult tasks. Experiments with cognitive control often rely on paradigms like the Stroop task, where subjects are asked to identify a target cue (color) while being presented with a distractor (incongruency of the word with its text color). Shenhav found that when subjects face a difficult trial or make a mistake, they adjust by decreasing attention to the distractor.

The Stroop task is a classic experimental design for understanding cognitive control. Successful completion of Stroop task 3 requires overriding your reflex to read the word in cases where the text and its color are mismatched.

A final interesting finding from Shenhav’s work tells us that part of the value of hard work may be in the work itself: people value rewards following a task in a way that scales to the effort they put into the task.

Bias in Brain Research

Despite apparent progress in achieving gender equality, sexism continues to be pervasive — and scientists aren’t immune.  

In a cyber talk delivered to the Duke Institute for Brain Sciences, professor Cordelia Fine of the University of Melbourne highlighted compelling evidence that neuroscientific research is yet another culprit of gender bias.

Fine says the persistent idea of gender essentialism contributes to this stagnation. Gender essentialism describes the idea that men and women are fundamentally different, specifically at a neurological level. This “men are from Mars, women are from Venus” attitude has spread from pop culture into experimental design and interpretation.

However, studies that look for sex differences in male and female behavior tend to show more similarities than differences. One study looked at 106 meta-analyses about psychological differences between men and women. The researchers found that in areas as diverse as temperament, communication styles, and interests, gender had a small effect, representing statistically small differences between the sexes.

Looking at fMRI data casts further doubt on how pronounced gender differences really are. A meta-analysis of fMRI studies investigating functional differences between men and women found a large reporting bias. Studies finding brain differences across genders were overrepresented compared to those finding similarities.

Of those small sex differences found in the central nervous system, Fine points out how difficult it is to determine their functional significance. One study found no difference between men and women in self-reported emotional experience, but found via fMRI that men exhibited more processing in the prefrontal cortex, or the executive center of the brain, than women. Although subjective experience of emotion was the same between men and women, the researchers reported that men are more cognitive, while women are more emotional.

Fine argues that conclusions like this are biased by gender essentialism. In a study she co-authored, Fine found that gender essentialism correlates with stronger belief in gender stereotypes, that gender roles are fixed, and that the current understanding of gender does not need to change.

When scientists allow preconceived notions about gender to bias their interpretation of results, our collective understanding suffers. The best way to overcome these biases is to ensure we are continuing to bring more and more diverse voices to the table, Fine said.

Fine spoke last month as part of the Society for Neuroscience Virtual Conference, “Mitigating Implicit Bias: Tools for the Neuroscientist.” The Duke Institute for Brain Sciences (@DukeBrain) made the conference available to the Duke community.  

Post by undergraduate blogger Sarah Haurin
Post by undergraduate blogger Sarah Haurin

The Importance of Moms

Emily Bray, Ph.D., might have the best job ever. Since earning her bachelor’s at Duke in 2012, she has been researching cognitive development in puppies, which basically means she’s spent the last seven years playing with dogs. If that’s not success, I don’t know what is.

Last Friday marked the 10th birthday of Duke’s Canine Cognition Center, and the 210th birthday of Charles Darwin. To celebrate, Brian Hare, Ph.D., invited former student Bray back to campus to share her latest research with a new generation of Duke undergraduates. The room was riveted — both by her compelling findings and by the darling photos of labs and golden retrievers that accompanied each slide.

Dr. Emily Bray shows photos of her study participants

During her Ph.D. program at the University of Pennsylvania, Bray worked with Robert Seyfarth, Dorothy Cheney, and James Serpell to investigate the effects of mothering on puppy development. For her dissertation, she studied a population of dog moms and their puppies at The Seeing Eye, Inc. The Seeing Eye is one of the oldest and largest guide dog schools in the U.S. They have been successfully raising and training service dogs for the blind since 1929, but like most things, it is still an imperfect science. Approximately half of the puppies bred at The Seeing Eye fail out of program. A dog that completes service training at The Seeing Eye represents two years of intensive training and care, and investing so much time and money into a dog that might eventually fail is problematic. Being able to predict the outcomes of puppies would save a lot of wasted time and energy, and Emily Bray has been doing just this.

What makes a good dog mom? (Photo from Dirk Vorderstraße, from Wikimedia Commons)

Through her work at The Seeing Eye, Bray found that, similar to humans, dogs have several types of mothering styles. She discovered that dog moms tend to fall somewhere on the spectrum from low to high maternal involvement. Some of the moms were very involved with their puppies, and seldom left their side. These hovering moms had high levels of cortisol, and became quite stressed when separated briefly from a puppy. They coddled their children, and often nursed from a laying down position, doing everything they could to make life easy for their babies. On the other side of the spectrum, Bray also observed moms that displayed much more relaxed mothering. They often took personal time, and let their puppies fend for themselves. They were more likely to nurse while sitting or standing up, which made their children work harder to feed. They were less stressed when separated from a puppy, and also just had generally lower levels of cortisol. Sound like bad parenting? Believe it or not, this tough love actually resulted in more successful puppies.

Duke’s very own assistance dogs in training!

As the puppies matured, Bray conducted a series of cognitive and temperament tests to determine if maternal style was associated with a certain way of thinking in the puppies. Turns out, dogs who experienced high maternal care actually performed much worse on the tests than dogs who were shown tough love when they were young. At The Seeing Eye graduation, it was also determined that high maternal care and ventral nursing was associated with failure. Puppies that were over-mothered were more likely to fail as service dogs.

Her theory is that tough love raises more resilient puppies. When mom is always around, the puppies don’t get the chance to experience small stressors and learn how to deal with challenge. The more relaxed moms actually did their kids a favor by not being so overbearing, and allowed for much more independent development.

Bray is now doing post-doctoral research at the University of Arizona, where she is working with Canine Companions for Independence (CCI) to determine if maternal style has similar effects on the outcomes of dogs that will be trained to assist people with a wide range of disabilities. She is also now doing cognition and temperament tests on moms pre-pregnancy to determine if maternal behavior can be predicted before the dogs have puppies. Knowing this could be a game changer, as this information could be used for selective breeding of better moms.

Me snuggling Ashton, one of the Puppy Kindergarten dogs

If you got the chance to hang out with puppies Ashton, Aiden, or Dune last semester, you have an idea of how awesome Bray’s day-to-day work is. These pups were bred at CCI, and sent to Duke to be enrolled in Duke Puppy Kindergarten, a new program on campus run through Duke’s Canine Cognition Center. Which of these three will make it to graduation? I’ve got money on Ashton, but I guess we’ll have to wait and see.

The bottom line according to Bray? “Mothering matters, but in moderation.”

Nature vs. Nurture and Addiction

Epigenetics involves modifications to DNA that do not change its sequence but only affect which genes are active, or expressed. Photo courtesy of whatisepigenetics.com

The progressive understanding of addiction as a disease rather than a choice has opened the door to better treatment and research, but there are aspects of addiction that make it uniquely difficult to treat.

One exceptional characteristic of addiction is its persistence even in the absence of drug use: during periods of abstinence, symptoms get worse over time, and response to the drug increases.

Researcher Elizabeth Heller, PhD, of the University of Pennsylvania Epigenetics Institute, is interested in understanding why we observe this persistence in symptoms even after drug use, the initial cause of the addiction, is stopped. Heller, who spoke at a Jan. 18 biochemistry seminar, believes the answer lies in epigenetic regulation.

Elizabeth Heller is interested in how changes in gene expression can explain the chronic nature of addiction.

Epigenetic regulation represents the nurture part of “nature vs. nurture.” Without changing the actual sequence of DNA, we have mechanisms in our body to control how and when cells express certain genes. These mechanisms are influenced by changes in our environment, and the process of influencing gene expression without altering the basic genetic code is called epigenetics.

Heller believes that we can understand the persistent nature of the symptoms of drugs of abuse even during abstinence by considering epigenetic changes caused by the drugs themselves.

To investigate the role of epigenetics in addiction, specifically cocaine addiction, Heller and her team have developed a series of tools to bind to DNA and influence expression of the molecules that play a role in epigenetic regulation, which are called transcription factors. They identified the FosB gene, which has been previously implicated as a regulator of drug addiction, as a site for these changes.

Increased expression of the FosB gene has been shown to increase sensitivity to cocaine, meaning individuals expressing this gene respond more than those not expressing it. Heller found that cocaine users show decreased levels of the protein responsible for inhibiting expression of FosB. This suggests cocaine use itself is depleting the protein that could help regulate and attenuate response to cocaine, making it more addictive.

Another gene, Nr4a1, is important in dopamine signaling, the reward pathway that is “hijacked” by drugs of abuse.  This gene has been shown to attenuate reward response to cocaine in mice. Mice who underwent epigenetic changes to suppress Nr4a1 showed increased reward response to cocaine. A drug that is currently used in cancer treatment has been shown to suppress Nr4a1 and, consequently, Heller has shown it can reduce cocaine reward behavior in mice.

The identification of genes like FosB and Nr4a1 and evidence that changes in gene expression are even greater in periods of abstinence than during drug use. These may be exciting leaps in our understanding of addiction, and ultimately finding treatments best-suited to such a unique and devastating disease.   

Post by undergraduate blogger Sarah Haurin

Post by undergraduate blogger Sarah Haurin

Sean Carroll on the Evolution of Snake Venom

What’s in a snake bite?

According to University of Wisconsin-Madison evolutionary biologist Sean Carroll who visited Duke and Durham last week, a snake bite contains a full index of clues.

In his recent research, Carroll has been studying the adaptations of novelties in animal form, such as snake venom. Rattlesnakes, he explains, are the picture of novelty. With traits such as a limbless body, fangs, infrared pits, patterned skin, venom, and the iconic rattle, they represent an amazing incarnation of evolution at work.

Rattlesnakes: the picture of novelty (Photo from USGS)

Snake venoms contain a complex mixture of proteins. This mixture can differ in several ways, but the most interesting difference to Carroll is the presence or absence of neurotoxins. Neurotoxic venom has proven to be a very useful trait, because neurotoxins destroy the nervous tissue of prey, effectively paralyzing the animal’s respiratory system.

Some of today’s rattlesnake species have neurotoxic venom, but some don’t. So how did this happen? That’s what Carroll was wondering too.

Some genes within genomes, such as HOX genes, evolve very slowly from their original position among the chromosomes, and see very few changes in the sequence in millions of years.

But snake venom Pla2 genes are quite the opposite. In recent history, there has been a massive expansion of these genes in the snake genome, Carroll said. When animals evolve new functions or forms, the question always arises: are these changes the result of brand new genes or old genes taking on new functions?

Another important consideration is the concept of regulatory versus structural genes. Regulatory genes control the activity of other genes, such as structural genes, and because of this, duplicates of regulatory genes are generally not going to be a favorable adaptation. In contrast, structural gene activity doesn’t affect other genes, and duplicates are often a positive change. This means it is easier for a new structural gene to evolve than a regulatory one. Carroll explained.

Evolutionary Biologist Sean Carroll (Photo from seanbcarroll.com)

Carroll examined neurotoxic and non-neurotoxic snakes living in overlapping environments. His research showed that the most recent common ancestor of these species was a snake with neurotoxic venom. When comparing the genetic code of neurotoxic snakes to non-neurotoxic ones, he found that the two differed by the presence or absence of 16 genes in the metalloproteinase gene complex. He said this meant that non-neurotoxic venom could not evolve from neurotoxic venom.

So what is the mechanism behind this change? What could be the evolutionary explanation?

When Carroll’s lab compared another pair of neurotoxic and non-neurotoxic species in a different region of the US, they found that the two species differed in exactly the same way, with the same set of genes deleted as had been observed in the first discovery. With this new information, Carroll realized that the differences must have occurred through the mechanism of hybridization, or the interbreeding of neurotoxic and non-neurotoxic species.

Carroll’s lab is now doing the structural work to study if the genes that result in neurotoxic and  non-neurotoxic protein complexes are old genes carrying out new functions or entirely new genes. They are using venom gland organoids to look into the regulatory processes of these genes.

In addition to his research studying the evolution of novelties, Carroll teaches molecular biology and genetics at Madison and has devoted a large portion of his career to  storytelling and science education.

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