Duke Research Blog

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

Category: Genetics/Genomics Page 1 of 8

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

Malaria Hides In People Without Symptoms

It seems like the never-ending battle against Malaria just keeps getting tougher. In regions where Malaria is hyper-prevalent, anti-mosquito measures can only work so well due to the reservoir that has built up of infected humans who do not even know they carry the infection.

In high-transmission areas, asymptomatic malaria is more prevalent than symptomatic malaria. Twenty-four percent of the people in sub-Saharan Africa are estimated to harbor an asymptomatic infection, including 38 to 50 percent of the school-aged children in western Kenya. Out of the 219 million malaria cases in 2017 worldwide, over 90%  were in sub-Saharan Africa.  

Using a special vacuum-like tool, Kelsey Sumner, a former Duke undergraduate now completing her Ph.D. at UNC-Chapel Hill, collected mosquitoes in households located in rural western Kenya. These weekly mosquito collections were a part of her pre-dissertation study on asymptomatic, or invisible, malaria. She visited Duke in September to catch us up on her work in Data Dialogue event sponsored by the mathematics department.

Sumner and colleague Verona Liao, in front of a sticky trap for mosquitoes

People with asymptomatic malaria carry the infection but have no idea they do because they do not have any indicators. This is incredibly dangerous because without symptoms, they will not get treated and can then infect countless others with the disease. As a result, people with an asymptomatic infection or infections have become a reservoir for malaria — a place for it to hide. Reservoirs are a group that is contributing to transmission at a higher rate or proportion than others.

Sumner’s study focused on examining the effect of asymptomatic malaria on malaria transmission as well as whether asymptomatic malaria infections would protect a person against future symptomatic infections from the same or different malaria infections. They were particularly looking into Plasmodium falciparum malaria. In Kenya, more than 70% of the population lives in an area with a high transmission of this potentially lethal parasite.

“P. falciparum malaria is very diverse in the region,” she said. “It’s constantly mutating, which is why it’s so hard to treat. But because of that, we’re able to actually measure how many infections people have at once.” 

The researchers discovered that many study participants were infected with multiple, genetically-distinct malaria infections. Some carried up to fourteen strains of the parasite.

Participants in the study began by filling out an enrollment questionnaire followed by monthly questionnaires and dried blood spot collections. The project has collected over nearly 3,000 dried blood spots from participants. These blood spots were then sent to a lab where DNA was extracted and tested for P. falciparum malaria using qPCR

“We used the fact that we have this really diverse falciparum species in the area and sequenced the DNA from falciparum to actually determine how many infections people have,” Sumner said. “And then, if there’s a shared infection between humans and mosquitoes.”

Sumner and her team also visited symptomatic participants who would fill out a behavioral questionnaire and undergo a rapid diagnostic test. Infected participants were able to receive treatment. 

While people in the region have tried to prevent infection through means like sleeping under insecticide-treated nets, malaria has persisted. 

One of the Kenyan staff members hanging a CDC light trap for mosquitoes

Sumner is continuing to analyze the collected DNA to better understand asymptomatic malaria, malarial reservoirs and how to best intervene to help stop this epidemic. 

“We’re basically looking at how the number of shared infections differ between those that have asymptomatic malaria versus those that have symptomatic malaria.”

She and her team hypothesize that there are more asymptomatic infections that would result in and explain the rapid transmission of malaria in the region.

Post by Anna Gotskind

Love at First Whiff

Many people turn to the Internet to find a Mr. or Ms. Right. But lemurs don’t have to cyberstalk potential love interests to find a good match — they just give them a sniff.

A study of lemur scents finds that an individual’s distinctive body odor reflects genetic differences in their immune system, and that other lemurs can detect these differences by smell.

Smell check: Fritz the ring-tailed lemur sniffs a tree for traces of other lemurs’ scents at the Duke Lemur Center.
Smell check: Fritz the ring-tailed lemur sniffs a tree for traces of other lemurs’ scents. Photo by David Haring, Duke Lemur Center.

From just one whiff, these primates are able to tell which prospective partners have immune genes different from their own. The ability to sniff out mates with different immune genes could make their offspring’s immune systems more diverse and able to fight more pathogens, said first author Kathleen Grogan, who did the research while working on her Ph.D. with professor Christine Drea at Duke University.

The results appeared online August 22 in the journal BMC Evolutionary Biology.

Lemurs advertise their presence by scent marking — rubbing stinky glands against trees to broadcast information about their sex, kin, and whether they are ready to mate.

Lemurs can tell whether a mate’s immune genes are a good genetic match by the scents they leave behind.
Lemurs can tell whether a mate’s immune genes are a good genetic match by the scents they leave behind. Photo by David Haring, Duke Lemur Center

For the study, Grogan, Drea and colleagues collected scent secretions from roughly 60 lemurs at the Duke Lemur Center, the Indianapolis Zoo, and the Cincinnati Zoo. The team used a technique called gas chromatography-mass spectrometry to tease out the hundreds of compounds that make up each animal’s signature scent.

They also analyzed the lemurs’ DNA, looking for differences within a cluster of genes called MHC that help trigger the body’s defenses against foreign invaders such as bacteria and viruses.

Their tests reveal that the chemical cocktail lemurs emit varies depending on which MHC types they carry.

To see if potential mates can smell the difference, the researchers presented lemurs with pairs of wooden rods smeared with the bodily secretions of two unfamiliar mates and observed their responses. Within seconds, the animals were drawn to the smells wafting from the rods, engaging in a frenzy of licking, sniffing, or rubbing their own scents on top.

In 300 trials, the team found that females paid more attention to the scents of males whose immune genes differed from their own.

MHC genes code for proteins that help the immune system recognize foreign invaders and distinguish “friend” from “foe.” Since different genetic versions respond to different sets of foreign substances, Grogan said, sniffing out genetically dissimilar mates produces offspring more capable of fighting a broad range of pathogens.

Just because females spent more time checking out the scents of dissimilar males doesn’t necessarily make them more likely to have kids together, Grogan said. Moving forward, she and her colleagues plan to use maternity and paternity DNA test results from wild lemurs living in Beza Mahafaly Reserve in Madagascar to see if lemur couples are more different in their MHC type than would be expected by chance.

Similar results have been found in humans, but this is the first time the ability to sniff out partners based on their immune genes has been shown in such distant primate kin, said Grogan, who is currently a postdoctoral fellow at Pennsylvania State University.

“Growing evidence suggests that primates rely on olfactory cues way more than we thought they did,” Grogan said. “It’s possible that all primates can do this.”

This research was supported by the National Science Foundation (BCS #0409367, IOS #0719003), the National Institutes of Health (F32 GM123634–01), and the Duke University Center for Science Education.

CITATION: “Genetic Variation at MHC class II Loci Influences Both Olfactory Signals and Scent Discrimination in Ring-Tailed Lemurs,” Kathleen E. Grogan, Rachel L. Harris, Marylène Boulet, and Christine M. Drea. BMC Evolutionary Biology, August 22, 2019. DOI: 10.1186/s12862-019-1486-0

Post by Robin A. Smith

Do DNA Tests Sell Rosy Ideas About Race for Profit?

Earlier this year,  the online DNA testing company Ancestry.com faced a media firestorm and social media backlash after posting a controversial ad on its YouTube page.

The DNA testing company Ancestry.com took down its ad, “Inseparable,” in April 2019 in response to criticism that it romanticized slavery.

Titled “Inseparable,” the 30-second ad depicted a white man in the antebellum South asking an African-American woman to flee to the North with him. Before the woman can answer, the piece cuts to a tagline: “Only you can keep the story going. Uncover the lost chapters of your family history with Ancestry.” Many criticized the ad’s historical inaccuracy, showcasing a rosier portrayal of a complicated past. To extinguish flames, Ancestry completely pulled the ad from its platforms.

A recent Duke study of dozens of other ads across multiple DNA testing companies shows that this isn’t the only example of mixed messaging about race and identity from the world of genetic ancestry tests.

The tests are quite simple: order a kit, send off a saliva sample and receive an ethnicity estimate within weeks. A test taker’s ethnicity is broken down into percentages based off their DNA matches compared to a globally referenced DNA database. Kits can range in price from $79 to$400. Sales of DNA testing kits had reached 12 million people by 2017, as reported by ScienceLine.

As part of the six-week summer research program Story+, Duke students Dakota Douglas, Mona Tong and Madelyn Winchester analyzed the messaging in 90 video ads from the companies 23andMe, AncestryDNA and MyHeritageDNA to see what they promise consumers.

Many of the ads lured customers with promises of a newfound identity and possible family members, the team found. One Ancestry.com ad, entitled “Kyle,” depicts a customer whose childhood was steeped in German culture, but discovers as an adult that he is also part Scottish and Irish. He happily “traded in his lederhosen for a kilt,” completely forgoing his previous heritage and reducing a newly discovered culture to stereotypes.

“There were a lot of advertisements similar to that one,” said team member Mona Tong. “Many found a new identity embracing it fully despite a lack of any cultural connections.”

“Kyle” illustrates a phenomenon described in a 2018 study from the University of British Columbia, which found that people tended to “cherry-pick” the results, identifying more with certain ethnicities and cultures to appear different. Whites were more likely to see their results as “transformational” than their nonwhite counterparts.

“It’s not a bad idea to test your genes for medical reasons,” said Patricia Bass, the team’s project mentor. “However, these ads can be misleading by assuming that someone’s cultural and racial heritage are determined by genes.”

While the majority of subjects featured within the ads were white, the few ads that featured people of color often glossed over the complicated history of someone’s lineage or conveniently left out difficult topics. Ancestry’s “Anthem” ad detailed historical reenactments of an African tribal women, prohibition gangsters, a man fleeing England for America and Native Americans somberly heading to a new land. A voiceover speaks with inspiration ending with a shot of a biracial woman.

In marketing the idea that we are all one, the ads fetishized mixed-race subjects, while ignoring the genocide and displacement of people, the team found.

The team hopes future research will further examine the impact of these ads on people’s view of identity. Importantly, one could note if there were any focus groups to test these ads before release.

“It furthers the idea of colorblindness,” Tong said. “It assumes that relationships are contingent upon common ancestry and genes.”

“In a way, companies are trying to help by focusing on the interconnectivity and commonalities between people,” Tong said. “But it hurts more than it helps.”

Story+ is a six-week undergraduate research program offered through the John Hope Franklin Humanities Institute and Bass Connections, with support from the Duke University Libraries and Versatile Humanists at Duke.

By Deja Finch

Overdiagnosis and the Future of Cancer Medicine

For many years, the standard strategy for fighting against cancer has been to find it early with screening when the person is still healthy, then hit it with a merciless treatment regimen to make it go away.

But not all tumors will become life-threatening cancers. Many, in fact, would have caused no issues for the rest of the patients’ lives had they not been found by screening. These cases belong to the category of overdiagnosis, one of the chief complaints against population-level screening programs.

Scientists are reconsidering the way to treat tumors because the traditional hit-it-hard approach has often caused the cancer to seemingly go away, only to have a few cells survive and the entire tumor roar back later with resistance to previously effective medicine.

Dr. Marc Ryser, the professor who gave this meaty talk

In his May 23 talk to Duke Population Health, “Cancer Overdiagnosis: A Discourse on Population Health, Biologic Mechanism and Statistics,” Marc Ryser, an assistant professor at Duke’s Departments of Population Health Sciences and Mathematics, walked us through how parallel developments across different disciplines have been reshaping our cancer battle plan. He said the effort to understand the true prevalence of overdiagnosis is a point of focus in this shift.

Past to Future: the changing cancer battle plan
Credit: Marc Ryser, edit: Brian Du

Ryser started with the longstanding biological theory behind how tumors develop. Under the theory of clonal sweeps, a relatively linear progression of successive key mutations sweeps through the tumor, giving it increasing versatility until it is clinically diagnosed by a doctor as cancer.

Clonal sweeps model, each shade is a new clone that introduces a mutation credit: Sievers et al. 2016

With this as the underpinning model, the battle plan of screen early, treat hard (point A) makes sense because it would be better to break the chain of progression early rather than later when the disease is more developed and much more aggressive. So employing screening extensively across the population for the various types of cancer is the sure choice, right?

But the data at the population level for many different categories of cancers doesn’t support this view (point B). Excluding the cases of cervical cancer and colorectal cancer, which have benefited greatly from screening interventions, the incidence of advanced cases of breast cancer and other cancers have stayed at similar levels or actually continued to increase during the years of screening interventions. This has raised the question of when screening is truly the best option.

Scientists are thinking now in terms of a “benefit-harm balance” when mass-screening public health interventions are carried out. Overdiagnosis would pile up on the harms side, because it introduces unnecessary procedures that are associated with adverse effects.

Thinking this way would be a major adjustment, and it has brought with it major confusion.

Paralleling this recent development on the population level, new biological understanding of how tumors develop has also introduced confusion. Scientists have discovered that tumors are more heterogeneous than the clonal sweeps model would make it appear. Within one tumor, there may be many different subpopulations of cancer cells, of varying characteristics and dangerousness, competing and coexisting.

Additional research has since suggested a more complex, evolutionary and ecological based model known as the Big Bang-mutual evolution model. Instead of the “stepwise progression from normal to increasingly malignant cells with the acquisition of successive driver mutations, some cancers appear to evolve more like a Big Bang, where the malignant ability is already concentrated in the founder cell,” Ryser said.

As the first cell starts to replicate, its descendants evolve in parallel into different subpopulations expressing different characteristics. While more research has been published in favor of this model, some scientists remain skeptical.

Ryser’s research contributes to this ongoing discussion. In comparing the patterns by which mutations are present or absent in cancerous and benign tumors, he obtained results favoring the Big Bang-mutual evolution model. Rather than seeing a neat region of mutation within the tumor, which would align with the clonal sweeps model, he saw mutations dispersed throughout the tumor, like the spreading of newborn stars in the wake of the Big Bang.

How to think about mutations within a tumor
credit: NASA

The more-complicated Big Bang-mutual evolution model justifies an increasingly nuanced approach to cancer treatment that has been developing in the past few years. Known as precision medicine (point C), its goal is to provide the best treatment available to a person based on their unique set of characteristics: genetics, lifestyle, and environment. As cancer medicine evolves with this new paradigm, when to screen will remain a key question, as will the benefit-harm balance.

There’s another problem, though: Overdiagnosis is incredibly hard to quantify. In fact, it’s by nature not possible to directly measure it. That’s where another area of Ryser’s research seeks to find the answers. He is working to accurately model overdiagnosis to estimate its extent and impact.

Going forward, his research goal is to try to understand how to bring together different scales to best understand overdiagnosis. Considering it in the context of the multiscale developments he mentioned in his talk may be the key to better understand it.

Post by Brian Du

We Can’t Regrow Limbs Like Deadpool, But This Creature Can

Try as we might, humans can’t regrow limbs. But losing your left leg isn’t such a problem for axolotls.

Image result for axolotl

Last Wednesday, Dr. Jessica Whited gave a fascinating talk about the importance of studying these strange little salamanders. Axolotls are capable of regenerating lost limbs so well that once a limb has fully grown back, you can’t tell the difference. No scars, no deformities. This genetic phenomenon serves as a powerful model for uncovering what mechanisms might be required for stimulating regeneration in humans.

The limb regeneration process goes through a few stages. Within hours after amputation, a wound epidermis forms around the injury. Next, a blastema grows – a big clump of cells that will be the basis for future growth. After that, a new limb just kind of sprouts out as you might imagine.

Image result for axolotl limb regeneration

So what gives the axolotl this seemingly magical ability? In attempt to answer that question, Whited’s lab looked at how the process starts – specifically at the creation of the blastema, something mammals do not form post-injury. They found that a single amputation causes an activation of progenitor cells throughout the axolotl’s body. Cells in the heart, liver, spinal cord, and contralateral limb all reenter circulation. Essentially an activation signal is sent throughout the whole body, indicating a systemic response to the injury rather than a local one.

Another question Whited sought to answer was if the same limb could regenerate multiple times. She had her student Donald Bryant carry out an experiment on a group of axolotls. Bryant would repeatedly amputate the same limb, letting it fully regrow for ten weeks between amputations. The results of the experiment show that after five amputations only 60 percent of the limb would regenerate. This percentage decreased with the number of amputations. So while axolotls may seem like they have super powers, they aren’t exactly invincible. They decline in their regenerative capabilities after repeated amputation.

Protein EYA2 PDB 3GEB.png

A key finding in this experiment was that repeated amputation led to a decrease in the EYA2 gene (Eyes Absent 2). This particular gene was deemed necessary for the blastema cells to progress through different growth checkpoints. It is required during the cell cycle “to execute decisions about whether the cells will continue to proliferate or not.” So while we don’t exactly know why, we do know that EYA2 plays an important role in the axolotl’s regenerative powers.

Although Whited and her team were able to uncover some important findings, several questions still linger. How is the activation of EYA2 induced following amputation? Why is repeated amputation linked to less EYA2 genes? If cells are poised to anticipate injury / DNA damage, why is it that repeated amputation leads to less regeneration?

Image result for deadpool baby hand

Humans and other mammals are not quite as lucky as the axolotl. Amputation is a relevant and serious issue, yet no biological solution has been devised. Thankfully, the research conducted around axolotl regenerative properties could provide us with knowledge on natural cellular reprogramming. Maybe one day we’ll be able to regrow limbs just like Deadpool.

Will Sheehan
Post by Will Sheehan

Using Genetic Clues to Reform Cardiac Care

Experiencing cardiac arrest can be compared to being in a hot air balloon in a room that is rapidly filling with water. You are trapped, desperately aware of the danger you are in, and running out of time.

Andrew Landstrom, PHD, MD, shared this metaphor with his audience in the Duke Medicine Pavilion last Thursday, and a wave of empathy flooded through his listeners. He works as an Assistant Professor of Pediatrics in Duke University’s School of Medicine, and devotes his time and energy to studying the genetic and molecular causes of sudden cardiac death in the young.

Andrew Landstrom, PHD, MD (Photo from Duke Center for Applied Genomics and Precision Medicine)

For families of children who have died suddenly and unexpectedly, the worst thing of all is hearing their doctors say, “we have no idea why.” A third of sudden death cases in children have negative autopsies, which means these children die with no explanation.

When faced with an inconclusive autopsy, everyone wants answers. Why did these children die? How do we know it’s a problem with the heart? What can be done about it? What does it mean for the siblings of the child who died?

It has since been discovered that many of these unexplained deaths are actually the result of cardiac channelopathies, which are DNA mutations that cause ion channel defects in heart cell proteins. These mutations can mess up the electrical activity of the heart and cause a heart to beat in an irregular rhythm, which can have fatal consequences. Since this is a molecular problem, and not a structural one, it cannot be identified with a conventional autopsy, and requires a deeper level of genetic and molecular analysis.

One type of channelopathy is a condition known as CPVT, which is short for catecholaminergic polymorphic ventricular tachycardia. This potentially life-threatening genetic disorder is the result of a point mutation in the genome, which means that one tiny nucleotide being changed in the DNA can lead to the single most fatal arrhythmia (irregular heart rhythm) known.

Sixty percent of children suffering from CPVT have a mutation in their RYR2 gene. This gene encodes for a protein that is found in cardiac muscle, and is a key player in how calcium is processed in heart cells. The mutated version of this gene results in proteins that let way too much calcium flood the cell, which can cause fatal changes in heart rhythm.

Dr. Landstrom has been using genome research to identify and explain sudden cardiac death in children, but the human genome doesn’t always provide straightforward answers. The problem is, a mutation in the RYR2 gene doesn’t always mean a person will have CPVT, and having an incidental RYR2 gene is much more common than being diagnosed with CPVT. Dr. Landstrom is studying this gene to try to figure out which variants are pathologic, and which are physiological.

“The human genome is a lot more confusing than I think I gave it credit for, and we’re just learning to deal with that confusion now,” he admitted to his audience Feb. 14.

The Components of the Human Genome (photo from NHS National Genetics and Genomics Education Centre)

If a variant is falsely identified as pathologic, a patient will be given incorrect therapies, and suffer through unnecessary procedures. However, if a variant is falsely identified as physiological, and the patient isn’t given the necessary treatment, there will be no mitigation of the patient’s life threatening disease. Neither of these are good outcomes, so it’s very important to get it right. The current models for predicting pathogenicity are poor, and Dr. Landstrom is looking to design new model that will be able to avoid the personal, subjective opinions of human doctors and determine if a variant is pathologic or not.

Could serotonin levels be used to predict an infant’s vulnerability to SIDS? (photo from Elmedir, Wikimedia Commons)

Another area that is of interest to Dr. Landstrom is the problem of Sudden Infant Death Syndrome (SIDS), which affects about six in every 10,000 infants, and cannot be diagnosed before death. He is on the search for a biomarker that would be able to predict an infant’s vulnerability to SIDS, and thinks that these deaths may be related to elevated levels of serotonin. Finding a marker like this would allow doctors to save many healthy infants from unexplained death. Dr. Landstrom knows its not easy research and admitted “we have to fail — we are meant to fail,” on the path to success. He is very aware of both the ethical complexity and the exciting implications of genome research at Duke, and committed to converting his research into patient care.

Post by Anne Littlewood

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

Pursuing Smell as a Path Into the Brain

Although the mystery of how the brain works and grows is a massive puzzle to figure out, the hope is that piece by piece, we can start to work towards a better understanding.

A person’s (or fly’s) sense of smell, or their olfactory system, is one of these pieces.

Though olfaction may not be the first part of the nervous system to cross someone’s mind when it comes to how we understand the brain, it is actually one of the most complex and diverse systems of an organism, and there’s a lot to understand within it, says Pelin Volkan, an assistant professor of biology and neurobiology and investigator in the Duke Institute for Brain Sciences.

Pelin Volkan in her lab.

Volkan and her lab have been working with fruit flies to try to unfold the many layers of the olfactory system, or the, “giant hairball,” as Volkan calls it.

Though she has been doing this work for years, she didn’t begin with an interest in neuroscience. Volkan was more interested in genetics in college and didn’t really start exploring neurobiology and development until her master’s degree at a Turkish university, when she worked with rats.

Not keen on working with rodents as model organisms but sticking with them anyway, she moved from Turkey to UNC to get her PhD, where she strayed away from neuroscience into molecular biology and development. Eventually, she realized she had a stronger passion for neuroscience, and ended up doing a postdoc at a Howard Hughes Medical Institute lab at UCLA for six years.

There, she became interested in receptors and neuronal wiring in the brain, propelling her to come to Duke and continue research on the brain’s connections and development.

One of the main reasons she loves working with the olfactory system is the many different scientific approaches that can be used to study it. Bouncing between using genetics, evolution, development, molecular biology,and other areas of study to understand the brain, her work is never static and she can take a more interdisciplinary approach to neuroscience where she is able to explore all the topics that interest her.

 Volkan says she has never had to settle on just one topic, and new questions are always arising that take her in directions she didn’t expect, which is what makes her current work particularly enjoyable for her.

“You have your stories, you close your stories, but then new questions come into play,” Volkan says. “And you have no choice but to follow those questions, so you just keep on going.”

And isn’t that what science is all about?

Guest Post by Angelina Katsanis, NCSSM 2019

Gene-Editing Human Embryos: What, How, Why?

Every seat full. Students perched on the aisle stairs and lining the back walls.

What topic could possibly pull so many away from their final exams? Not “How to Stop Procrastinating” nor “How to Pass Life After Failing Your Exams” but rather “Gene-Editing Human Embryos: Unpacking the Current Controversy” on the Duke campus.

Since Chinese researcher He Jiankui announced at the Second International Summit on Human Genome Editing in Hong Kong that he made the world’s first genetically engineered babies, a debate on the ethical implications has raged on social media.

On December 6, the University Program in Genetics and Genomics and the Molecular Genetics and Microbiology department co-hosted a panel responding to He’s claims. Charles A. Gersbach from the Biomedical Engineering department lead the discussion of what exactly happened and then joined the panel which also contained Misha Angrist, a senior fellow in the Science & Society initiative;  Heidi Cope, a genetic counselor; Giny Fouda, an assistant professor in pediatrics; and Vandana Shashi, a genetic counselor.

Dr. He Jiankui announced he had used CRISPR to edit genes in twin embryos that were then born at full term.

But what exactly has He potentially done to these twin girls? Can they fly? Breathe underwater? Photosynthesize? Not exactly. He said he deleted a gene called CCR5 to increase their HIV resistance. Two percent of Northern Europeans naturally have a mutation that removes the CCR5 gene from their DNA and as a result do not display any traits other than increased HIV resistance.

Many researchers have explored blocking CCR5 activity as a potential HIV treatment. Using CRISPR-Cas9, a genetic engineering technology that can cut and paste specific sequences in the DNA, He targeted CCR5 during in vitro fertilization. According to his tests, he successfully removed both copies of the CCR5 gene in one of the girls. However, in the other girl, the CCR5 remained normal on one chromosome and on the other, CRISPR had deleted more than intended.  The effects of that additional deletion are unknown. 
Both the girls are mosaics, meaning the genetic change occurred in some of their cells and not in others, leading to still more uncertainties.

Researchers have conducted genetic engineering experiments on both somatic cells and human embryo cells that were never brought to term. (Somatic cells constitute all parts of the body other than the eggs and sperm.) But because He altered the twin girls as embryos and then they grew to full term, their children could inherit these changes. This alters their family line, not just a single individual, increasing the ethical implications.

According to Shashi, He’s experiment becomes difficult to justify. Additionally, embryos have not consented to these changes in their genetics, unlike a patient undergoing genetic therapy.

Many doctors, scientists, and journalists have also questioned He’s lack of transparency because he hid this work until his grand announcement, which caused China to arrest him. In addition, as Cope explained, “it is not typically the PI who does the informed consent process” as He did with these parents.

While He defends his work by saying that the girls’ father carries HIV and wished to increase the girls’ safety, the twins were not actually at great risk for HIV. Their father’s medical history does not increase their chances of contracting the virus, and the overall risk for HIV in China is low. As Fouda emphasized in the panel, “there was no justification for this experiment.” While He discussed the potential for genetic engineering to help society, for these two individuals, no medical need existed, and that increases the ethical dilemma.

A final concern of researchers is the current inability to ensure technical competency and accuracy. As seen by the additional deletion in one of the girls,  CRISPR-Cas9 still makes errors. Thus using it to alter not only a human being but all of that individual’s progeny would demand a much higher standard, something close to a life-or-death scenario.

But, the panelists also noted, if it hadn’t been He, it would have been somebody else. Perhaps somebody else may have done it more ethically with more transparency and a more traditional consent process, Angrist said.

While He’s claims have yet to be proven, the fact that they could reasonably be true has many concerned. The World Health Organization has announced that they will begin greater oversight of genetic engineering of the human germline.

On campus over the last weeks, I’ve heard mixed reviews on He’s work with some joking about future superhero babies while others have reacted with fear. The technology does live among us; however, the world is working on writing the guidebook and unrolling the yellow tape.

Post by Lydia Goff

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