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Category: Genetics/Genomics Page 3 of 10

Duke’s Fundamental Research Can Turn Viruses Into Marvels

The COVID-19 epidemic has impacted the Duke research enterprise in profound ways. Nearly all laboratory-based research has been temporarily halted, except for research directly connected to the fight against COVID-19. It will take much time to return to normal, and that process of renewal will be gradual and will be implemented carefully.

Trying to put this situation into a broader perspective, I thought of the 1939 essay by Abraham Flexner published in Harper’s magazine, entitled “The Usefulness of Useless Knowledge.” Flexner was the founding Director of the Institute for Advanced Study at Princeton, and in that essay, he ruminated on much of the type of knowledge acquired at research universities —  knowledge motivated by no objective other than the basic human desire to understand. As Flexner said, the pursuit of this type of knowledge sometimes leads to surprises that transform the way we see that which was previously taken for granted, or for which we had previously given up hope. Such knowledge is sometimes very useful, in highly unintended ways.

Gregory Gray, MD MPH
Gregory Gray, MD MPH

The 1918 influenza pandemic led to 500 million confirmed cases, and 50 million deaths. In the Century since, consider how far we have come in our understanding of epidemics, and how that knowledge has impacted our ability to respond. People like Greg Gray, a professor of medicine and member of the Duke Global Health Institute (DGHI), have been quietly studying viruses for many years, including how viruses at domestic animal farms and food markets can leap from animals to humans. Many believe the COVID-19 virus started from a bat and was transferred to a human. Dr. Gray has been a global leader in studying this mechanism of a potential viral pandemic, doing much of his work in Asia, and that experience makes him uniquely positioned to provide understanding of our current predicament.

From the health-policy perspective, Mark McClellan, Director of the Duke Margolis Center for Health Policy, has been a leading voice in understanding viruses and the best policy responses to an epidemic. As a former FDA director, he has experience bringing policy to life, and his voice carries weight in the halls of Washington. Drawing on faculty from across Duke and its extensive applied policy research capacity, the Margolis Center has been at the forefront in guiding policymakers in responding to COVID-19.

Through knowledge accrued by academic leaders like Drs. Gray and McClellan, one notes with awe the difference in how the world has responded to a viral threat today, relative to 100 years ago. While there has been significant turmoil in many people’s lives today, as well as significant hardship, the number of global deaths caused by COVID-19 has been reduced substantially relative to 1918.

One of the seemingly unusual aspects of COVID-19 is that a substantial fraction of the population infected by the virus has no symptoms. However, those asymptomatic individuals shed the virus and infect others. While most people have no or mild symptoms, other people have very adverse effects to COVID-19, some dying quickly.

This heterogeneous response to COVID-19 is a characteristic of viruses studied by Chris Woods, a professor medicine in infectious diseases. Dr. Woods, and his colleagues in the Schools of Medicine and Engineering, have investigated this phenomenon for years, long before the current crisis, focusing their studies on the genomic response of the human host to a virus. This knowledge of viruses has made Dr. Woods and his colleagues leading voices in understanding COVID-19, and guiding the clinical response.

A team led by Greg Sempowski, a professor of pathology in the Human Vaccine Institute is working to isolate protective antibodies from SARS-CoV-2-infected individuals to see if they may be used as drugs to prevent or treat COVID-19. They’re seeking antibodies that can neutralize or kill the virus, which are called neutralizing antibodies.

Barton Haynes,MD
Barton Haynes, MD

Many believe that only a vaccine for COVID-19 can truly return life to normal. Human Vaccine Institute Director Barton Haynes, and his colleagues are at the forefront of developing that vaccine to provide human resistance to COVID-19. Dr. Haynes has been focusing on vaccine research for numerous years, and now that work is at the forefront in the fight against COVID-19.

Engineering and materials science have also advanced significantly since 1918. Ken Gall, a professor of mechanical engineering and materials science has led Duke’s novel application of 3D printing to develop methods for creatively designing personal protective equipment (PPE). These PPE are being used in the Duke hospital, and throughout the world to protect healthcare providers in the fight against COVID-19.

Much of the work discussed above, in addition to being motivated by the desire to understand and adapt to viruses, is motivated from the perspective that viruses must be fought to extend human life.

In contrast, several years ago Jennifer Doudna and Emmanuelle Charpentier, academics at Berkeley and the Max Planck Institute, respectively, asked a seemingly useless question. They wanted to understand how bacteria defended themselves against a virus. What may have made this work seem even more useless is that the specific class of viruses (called phage) that infect bacteria do not cause human disease. Useless stuff! The kind of work that can only take place at a university. That basic research led to the discovery of clustered regularly interspaced short palindromic repeats (CRISPR), a bacterial defense system against viruses, as a tool for manipulating genome sequences. Unexpectedly, CRISPR manifested an almost unbelievable ability to edit the genome, with the potential to cure previously incurable genetic diseases.

Charles Gersbach, a professor of Biomedical Engineering, and his colleagues at Duke are at the forefront of CRISPR research for gene and cell therapy. In fact, he is working with Duke surgery professor and gene therapy expert Aravind Asokan to engineer another class of viruses, recently approved by the FDA for other gene therapies, to deliver CRISPR to diseased tissues. Far from a killer, the modified virus is essential to getting CRISPR to the right tissues to perform gene editing in a manner that was previously thought impossible. There is hope that CRISPR technology can lead to cures for sickle cell and other genetic blood disorders. It is also being used to fight cancer and muscular dystrophy, among many other diseases and it is being used at Duke by Dr. Gersbach in the fight against COVID-19. 

David Ashley, Ph.D.
David Ashley, Ph.D.

In another seemingly bizarre use of a virus, a modified form of the polio virus is being used at Duke to fight glioblastoma, a brain tumor. That work is being pursued within the Preston Robert Tisch Brain Tumor Center, for which David Ashley is the Director. The use of modified polio virus excites the innate human immune system to fight glioblastoma, and extends life in ways that were previously unimaginable. But there are still many basic-science questions that must be overcome. The remarkable extension of life with polio-based immunotherapy occurs for only 20% of glioblastoma patients. Why? Recall from the work of Dr. Woods discussed above, and from our own observation of COVID-19, not all people respond to viruses in the same way. Could this explain the mixed effectiveness of immunotherapy for glioblastoma? It is not known at this time, although Dr. Ashley feels it is likely to be a key factor. Much research is required, to better understand the diversity in the host response to viruses, and to further improve immunotherapy.

The COVID-19 pandemic is a challenge that is disrupting all aspects of life. Through fundamental research being done at Duke, our understanding of such a pandemic has advanced markedly, speeding and improving our capacity to respond. By innovative partnerships between Duke engineers and clinicians, novel methods are being developed to protect frontline medical professionals. Further, via innovative technologies like CRISPR and immunotherapy — that could only seem like science fiction in 1918 (and as recently as 2010!) — viruses are being used to save lives for previously intractable diseases.

Viruses can be killers, but they are also scientific marvels. This is the promise of fundamental research; this is the impact of Duke research.

“We shall not cease from exploration
And the end of all our exploring
Will be to arrive where we started
And know the place for the first time.”

T.S. Eliot, Four Quartets

Post by Lawrence Carin, Vice President for Research

The evolution of a tumor

The results of evolution are often awe-inspiring — from the long neck of the giraffe to the majestic colors of a peacock — but evolution does not always create structures of function and beauty.

In the case of cancer, the growth of a population of malignant cells from a single cell reflects a process of evolution too, but with much more harrowing results.

Johannes Reiter uses mathematical models to understand the evolution of cancer

Researchers like Johannes Reiter, PhD, of Stanford University’s Translational Cancer Evolution Laboratory, are examining the path of cancer from a single sell to many metastatic tumors. By using this perspective and simple mathematical models, Reiter interrogates the current practices in cancer treatment. He spoke at Duke’s mathematical biology seminar on Jan. 17.

 The evolutionary process of cancer begins with a single cell. At each division, a cell acquires a few mutations to its genetic code, most of which are inconsequential. However, if the mutations occur in certain genes called driver genes, the cell lineage can follow a different path of rapid growth. If these mutations can survive, cells continue to divide at a rate faster than normal, and the result is a tumor.

As cells divide, they acquire mutations that can drive abnormal growth and form tumors. Tumors and their metastases can consist of diverse cell populations, complicating treatment plans out patient outcomes. Image courtesy of Reiter Lab

With each additional division, the cell continues to acquire mutations. The result is that a single tumor can consist of a variety of unique cell populations; this diversity is called intratumoral heterogeneity (ITH). As tumors metastasize, or spread to other locations throughout the body, the possibility for diversity grows.

Intratumoral heterogeneity can exist within primary tumors, within metastases, or between metastases. Vogelstein et al., Science, 2013

Reiter describes three flavors of ITH. Intra-primary heterogeneity describes the diversity of cell types within the initial tumor. Intrametastatic heterogeneity describes the diversity of cell types within a single metastasis. Finally, inter-metastatic heterogeneity describes diversity between metastases from the same primary tumor.

For Reiter, inter-metastatic heterogeneity presents a particularly compelling problem. If treatment plans are made based on biopsy of the primary tumor but the metastases differ from each other and from the primary tumor, the efficacy of treatment will be greatly limited.

With this in mind, Reiter developed a mathematical model to predict whether a cell sample collected by biopsy of just the primary tumor would provide adequate information for treatment.

Using genetic sequence data from patients who had at least two untreated metastases and a primary tumor, Reiter found that metastases and primary tumors overwhelmingly share a single driver gene. Reiter said this confirmed that a biopsy of the primary tumor should be sufficient to plan targeted therapies, because the risk of missing driver genes that are functional in the metastases proved to be negligible.

 In his next endeavors as a new member of the Canary Center for Cancer Early Detection, Reiter plans to use his knack for mathematical modeling to tackle problems of identifying cancer while still in its most treatable stage.  

Post by undergraduate blogger Sarah Haurin

Post by Sarah Haurin

First-Year Students Designing Real-World Solutions

In the first week of fall semester, four first-year engineering students, Sean Burrell, Teya Evans, Adam Kramer, and Eloise Sinwell, had a brainstorming session to determine how to create a set of physical therapy stairs designed for children with disabilities. Their goal was to construct something that provided motivation through reward, had variable step height, and could physically support the students. 

Evans explained, “The one they were using before did not have handrails and the kids were feeling really unstable.”

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Teya Evans is pictured stepping on the staircase her team designed and built. With each step, the lightbox displays different colors.

The team was extremely successful and the staircase they designed met all of the goals set out by their client, physical therapists. It provided motivation through the multi-colored lightbox, included an additional smaller step that could be pulled out to adjust step height, had a handrail to physically support the students and could even be taken apart for easy transportation.

This is a part of the Engineering 101 course all Pratt students are required to take. Teams are paired with a real client and work together throughout the semester to design and create a deliverable solution to the problem they are presented with. At the end of the semester, they present their products at a poster presentation that I attended. It was pretty incredible to see what first-year undergraduates were able to create in just a few months.

The next poster I visited focused on designing a device to stabilize hand tremors. The team’s client, Kate, has Ataxia, a neurological disorder that causes her to have uncontrollable tremors in her arms and hands. She wanted a device that would enable her to use her iPad independently, because she currently needs a caregiver to stabilize her arm to use it. This team, Mohanapriya Cumaran, Richard Sheng, Jolie Mason, and Tess Foote, needed to design something that would allow Kate to access the entire screen while stabilizing tremors, being comfortable, easy to set up and durable.

The team was able to accomplish its task by developing a device that allowed Kate to stabilize her tremors by gripping a 3D printed handlebar. The handlebar was then attached to two rods that rested on springs allowing for vertical motion and a drawer slide allowing for horizontal motion.

“We had her [Kate] touch apps in all areas of the iPad and she could do it.” Foote said. “Future plans are to make it comfier.”

The team plans to improve the product by adding a foam grip to the handlebar, attaching a ball and socket joint for index finger support, and adding a waterproof layer to the wooden pieces in their design. 

The last project I visited created a “Fly Flipping Device.” The team, C. Fischer, E. Song, L. Tarman, and S. Gorbaly, were paired with the Mohamed Noor Lab in the Duke Biology Department as their client. 

Tarman explained, “We were asked to design a device that would expedite the process of transferring fruit flies from one vial to another.”

The Noor lab frequently uses fruit flies to study genetics and currently fly flipping has to be done by hand, which can take a lot of time. The goal was to increase the efficiency of lab experiments by creating a device that would last for more than a year, avoid damaging the vials or flies, was portable and fit within a desk space. 

The team came up with over 50 ideas on how to accomplish this task that they narrowed down to one that they would build. The product they created comprised of two arms made of PVC pipe resting on a wooden base. Attached to the arms were “sleeves” 3D printed to hold the vials containing flies. In order to efficiently flip the flies, one of the arms moves about the axis allowing for multiple vials to be flipped that the time it would normally take to flip one vial. The team was very successful and their creation will contribute to important genetic research.

The Fly Flipping Device

It was mind-blowing to see what first-year students were able to create in their first few months at Duke and I think it is a great concept to begin student education in engineering through a hands-on design process that allows them to develop a solution to a problem and take it from idea to implementation. I am excited about what else other EGR 101 students will design in the future.

By Anna Gotskind


Working Through Frustrations to Understand Nature Better

This is the fifth of six posts written by students at the North Carolina School of Science and Math as part of an elective about science communication with Dean Amy Sheck.

Research is a journey full of uncertainty in which scientists have to construct their own path, even if they’re unsure of what the end of the journey actually is. Despite this unpredictability, researchers continue their journey because they believe their work will one day drive their fields forward. At least, that’s why Kate Meyer Ph.D. says she has investigated something called m6A for several years.

Kathryn Meyer, Ph.D.

“Virtually every study that I have ever been part of had some frustrations involved because everything can fall apart in just one night,” Meyer said. “Despite all the frustrations you might have, you are still in the research because you know that at the end of the day, you will get new knowledge that is worthy to your field, or perhaps to the world.”

N6-methyladenosine (or m6A) is a modification to one of the four main bases of RNA – adenosine. Because RNA plays a significant role as a bridge between genetic information and functional gene products, modifications in RNA can alter how much of a certain product will be produced, which then controls how our cells and eventually our whole body functions.

The idea of this tiny but powerful modification was first proposed in the 1970s. But scientists struggled to find where m6A was located in the cell before research Meyer made a major contribution to as a trainee was published in 2012. Combining a newly developed antibody that could recognize m6A and gene sequencing techniques that became more accessible to the researchers, Meyer’s work led to the first method that can detect and sequence all of the m6A regions in a cell.

m6A’s interaction with a neuron, as depicted on Dr. Meyer’s laboratory site.

Meyer’s work was transformative research. Her method allowed laboratories around the world to investigate what regulates m6A and what its consequences are. Meyer said this first study which ignited m6A field is one of her most prideful moments as a researcher. 

Significant progress has been made since 2012, but there are still lots of questions that need to be answered. Currently, Meyer’s research team is investigating the relationships between m6A and various neurological issues. She believes that regulation of m6A controls the expression, or activity level, of various genes in the brain. As such, m6A may play an important role in neurodegenerative diseases and memory.

Author Jun Hee Shin, left, and Kate Meyer in her lab.

As an assistant professor of both biochemistry and neurobiology at Duke, Meyer is definitely one of the most important figures in the m6A field. Despite her many accomplishments, she said she had experienced and overcome many frustrations and failures on her way to the results.

Guest Post by Jun Shin, NCSSM 2020

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

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