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

Category: Genetics/Genomics Page 1 of 10

Rewilding the Gut

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Processed foods and overuse of antibiotics can wreak havoc on the trillions of bacteria and other microbes that inhabit the gut. A new study of the gut microbiomes of lemurs looks at whether reconnecting with nature can help restore this internal ecosystem to a more natural state. Credit: Sally Bornbusch.

Modern life messes with the microbiome -– the trillions of bacteria and other microbes that live inside the body. Could reconnecting with nature bring this internal ecosystem back into balance?

A new study suggests it can, at least in lemurs. Led by Duke Ph.D. alumnus Sally Bornbusch and her graduate advisor Christine Drea, the research team collected fecal samples from more than 170 ring-tailed lemurs living in various conditions in Madagascar: some were living in the wild, some were kept as pets, and some were rescued from the pet and tourism industries and then relocated to a rescue center in southwestern Madagascar where they ate a more natural diet and had less exposure to people.

Collecting fecal samples in Madagascar

Then the researchers sequenced DNA from the fecal samples to identify their microbial makeup. They found that the longer lemurs lived at the rescue center, the more similar their gut microbes were to those of their wild counterparts. Former pet lemurs with more time at the rescue center also showed fewer signs of antibiotic resistance.

By “rewilding” the guts of captive animals, researchers say we may be able to better prime them for success, whether after rescue or before translocation or reintroduction into the wild.

This research was supported by grants from the National Science Foundation (1945776, 1749465), the Triangle Center for Evolutionary Medicine, Duke’s Kenan Institute for Ethics, the Margot Marsh Biodiversity Fund and Lemur Love.

CITATION: “Microbial Rewilding in the Gut Microbiomes of Captive Ring-Tailed Lemurs (Lemur catta) in Madagascar,” Sally L. Bornbusch, Tara A. Clarke, Sylvia Hobilalaina, Honore Soatata Reseva, Marni LaFleur & Christine M. Drea. Scientific Reports, Dec. 27, 2022. DOI: 10.1038/s41598-022-26861-0.

Robin Smith
By Robin Smith

Why Do Some Dogs Need High Chairs, and How Can Genetics Help?

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Jake, a German shepherd dog in a Bailey chair. Dogs with megaesophagus must eat in a vertical position to help food travel to their stomachs.
Photo credit: Beth Grant

Some dogs have to eat in a high chair—or, more specifically, a Bailey Chair. The chair keeps them in a vertical position while they eat so that gravity can do the work their bodies can’t: moving food from the mouth to the stomach.

These dogs have megaesophagus, an esophagus disorder that can prevent dogs from properly digesting food and absorbing nutrients. When you swallow a bite of food, it travels down a muscular tube, the esophagus, to the stomach. In humans, the esophagus is vertical, so our esophageal muscles don’t have to fight against gravity. But because dogs are quadrupeds, a dog’s esophagus is more horizontal, so “there is a greater burden on peristaltic contractions to transport the food into the stomach.” In dogs with megaesophagus, the esophagus is dilated, and those contractions are less effective. Instead of moving properly into the stomach, food can remain in the esophagus, exacerbating the problem and preventing proper digestion and nutrient absorption. 

Leigh Anne Clark, Ph.D., an associate professor at Clemson University, recently spoke at Duke about megaesophagus in dogs and its genetic underpinnings. She has authored dozens of publications on dog genetics, including five cover features. Her research primarily involves “[mapping] alleles and genes that underlie disease in dogs.” In complex diseases like megaesophagus, that’s easier said than done. “This disease has a spectrum,” Clark says, and “Spoiler: that makes it more complicated to map.”

Clinical signs of megaesophagus, or mega for short, include regurgitation, coughing, loss of appetite, and weight loss. (We might use the word “symptom” to talk about human conditions, but “a symptom is something someone describes—e.g., I feel nauseous. But dogs can’t talk, so we can only see ‘clinical signs.’”) Complications of mega can include aspiration pneumonia and, in severe cases, gastroesophageal intussusception, an emergency situation in which dogs “suck their stomach up into their esophagus.”

Leigh Anne Clarke of Clemson University

Sometimes megaesophagus resolves on its own with age, but when it doesn’t it requires lifelong management. Mega has no cure, but management can involve vertical feeding, smaller and more frequent meals, soft foods, and sometimes medication. Even liquid water can cause problems, so some dogs with mega receive “cubed water,” made by adding a “gelatinous material” to water, instead of a normal water bowl.

In dogs, mega can be either congenital, meaning present at birth, or acquired. In cases of acquired megaesophagus, the condition is “usually secondary to something else,” and the root cause is often never determined. (Humans can get mega, too, but as with acquired mega in dogs, mega in humans is usually caused by a preexisting condition. The best human comparison, according to Clark, might be achalasia, a rare disorder that causes difficulty swallowing.) Clark’s current research focuses on the congenital form of the disease in dogs.

Her laboratory recently published a paper investigating the genetic foundation of mega. Unlike some diseases, mega isn’t caused by just one genetic mutation, so determining what genes might be at play required some genetic detective work. “You see mega across breeds,” Clark says, which suggests an environmental component, but the disease is more prevalent in some breeds than others. For instance, 28 percent of all diagnoses are in German shepherds. That was a “red flag” indicating that genes were at least partly responsible.

Clark and her collaborators chose to limit their research study to German shepherds. Despite including a wide range of dogs in the study, they noticed that males were significantly overrepresented. Clark thinks that estrogen, a hormone more abundant in females, may have a protective effect against mega.

Clark and her team performed a genome-wide association study (GWAS) to look for alleles that are more common in dogs with mega. One allele that turned out to be a major risk factor was a variant of the MCHR2 gene, which plays a role in feeding behaviors. In breeds where mega is overrepresented, like German shepherds, “we have a situation where the predominant allele in the population is also the risk allele,” says Clark.

Using the results of the study, they developed a test that can identify which version of the gene a given dog has. The test, available at veterinary testing companies, is designed “to help breeders reduce the frequency of the risk allele and to plan matings that are less likely to produce affected puppies.”

Post by Sophie Cox, Class of 2025

What Are Lichens, and Why Does Duke Have 160,000 of Them?

Saxicolous lichens (lichens that grow on stones) from the Namib Desert, and finger lichen, Dactylina arctica (bottom left insert), common in the Arctic, on display in Dr. Jolanta Miadlikowska’s office. The orange color on some of the lichen comes from metabolites, or secondary chemicals produced by different lichen species. The finger lichen is hollow.

Lichens are everywhere—grayish-green patches on tree bark on the Duke campus, rough orange crusts on desert rocks, even in the Antarctic tundra. They are “pioneer species,” often the first living things to return to barren, desolate places after an extreme disturbance like a lava flow. They can withstand extreme conditions and survive where nearly nothing else can. But what exactly are lichens, and why does Duke have 160,000 of them in little envelopes? I reached out to Dr. Jolanta Miadlikowska and Dr. Scott LaGreca, two lichen researchers at Duke, to learn more.

Dr. Jolanta Miadlikowska looking at lichen specimens under a dissecting microscope. The pale, stringy lichen on the brown bag is whiteworm lichen (Thamnolia vermicularis), used to make “snow tea” in parts of China.

According to Miadlikowska, a senior researcher, lab manager, and lichenologist in the Lutzoni Lab (and one of the Instructors B for the Bio201 Gateway course) at Duke, lichens are “obligate symbiotic associations,” meaning they are composed of two or more organisms that need each other. All lichens represent a symbiotic relationship between a fungus (the “mycobiont”) and either an alga or a cyanobacterium or both (the “photobiont”). They aren’t just cohabiting; they rely on each other for survival. The mycobiont builds the thallus, which gives lichen its structure. The photobiont, on the other hand, isn’t visible—but it is important: it provides “food” for the lichen and can sometimes affect the lichen’s color. The name of a lichen species refers to its fungal partner, whereas the photobiont has its own name.

Lichen viewed through a dissecting microscope. The black speckles visible on some of the orange lichen lobes are a “lichenicolous” fungus that can grow on top of lichen. There are also “endolichenic fungi… very complex fungal communities that live inside lichen,” Miadlikowska says. “We don’t see them, but they are there. And they are very interesting.”

Unlike plants, fungi can’t perform photosynthesis, so they have to find other ways to feed themselves. Many fungi, like mushrooms and bread mold, are saprotrophs, meaning they get nutrients from organic matter in their environment. (The word “saprotroph” comes from Greek and literally means “rotten nourishment.”) But the fungi in lichens, Miadlikowska says, “found another way of getting the sugar—because it’s all about the sugar—by associating with an organism that can do photosynthesis.” More often than not, that organism is a type of green algae, but it can also be a photosynthetic bacterium (cyanobacteria, also called blue-green algae). It is still unclear how the mycobiont finds the matching photobiont if both partners are not dispersed together. Maybe the fungal spores (very small fungal reproductive unit) “will just sit and wait” until the right photobiont partner comes along. (How romantic.) Some mycobionts are specialists that “can only associate with a few or a single partner—a ‘species’ of Nostoc [a cyanobacterium; we still don’t know how many species of symbiotic and free-living Nostoc are out there and how to recognize them], for example,” but many are generalists with more flexible preferences. 

Two species of foliose (leaf-like) lichens from the genus Peltigera. In the species on the left (P. canina), the only photobiont is a cyanobacterium from the genus Nostoc, making it an example of bi-membered symbiosis. In the species on the right (P. aphthosa), on the other hand, the primary photobiont is a green alga (which is why the thallus is so green when wet). In this case, Nostoc is a secondary photobiont contained only in the cephalodia—the dark, wart-like structures on the surface. With two photobionts plus the mycobiont, this is an example of tri-membered symbiosis.

Lichens are classified based on their overall thallus shape. They can be foliose (leaf-like), fruticose (shrubby), or crustose (forming a crust on rocks or other surfaces). Lichens that grow on trees are epiphytic, while those that live on rocks are saxicolous; lichens that live on top of mosses are muscicolous, and ground-dwelling lichens are terricolous. Much of Miadlikowska’s research is on a group of cyanolichens (lichens with cyanobacteria partners) from the genus Peltigera. She works on the systematics and evolution of this group using morphology-, anatomy-, and chemistry-based methods and molecular phylogenetic tools. She is also part of a team exploring biodiversity, ecological rules, and biogeographical patterns in cryptic fungal communities associated with lichens and plants (endolichenic and endophytic fungi). She has been involved in multiple ongoing NSF-funded projects and also helping graduate students Ian, Carlos, Shannon, and Diego in their dissertation research. She spent last summer collecting lichens with Carlos and Shannon and collaborators in Alberta, Canada and Alaska. If you walk in the sub basement of the Bio Sciences building where Bio201 and Bio202 labs are located, check out the amazing photos of lichens (taken by Thomas Barlow, former Duke undergraduate) displayed along the walls! Notice Peltigera species, including some new to science, described by the Duke lichen team.

Lichens have value beyond the realm of research, too. “In traditional medicine, lichens have a lot of use,” Miadlikowska says. Aside from medicinal uses, they have also been used to dye fabric and kill wolves. Some are edible. Miadlikowska herself has eaten them several times. She had salad in China that was made with leafy lichens (the taste, she says, came mostly from soy sauce and rice vinegar, but “the texture was coming from the lichen.”). In Quebec, she drank tea made with native plants and lichens, and in Scandinavia, she tried candied Cetraria islandica lichen (she mostly tasted the sugar and a bit of bitterness, but once again, the lichen’s texture was apparent).

In today’s changing world, lichens have another use as well, as “bioindicators to monitor the quality of the air.” Most lichens can’t tolerate air pollution, which is why “in big cities… when you look at the trees, there are almost no lichens. The bark is just naked.” Lichen-covered trees, then, can be a very good sign, though the type of lichen matters, too. “The most sensitive lichens are the shrubby ones… like Usnea,” Miadlikowska says. Some lichens, on the other hand, “are able to survive in anthropogenic places, and they just take over.” Even on “artificial substrates like concrete, you often see lichens.” Along with being very sensitive to poor air quality, lichens also accumulate pollutants, which makes them useful for monitoring deposition of metals and radioactive materials in the environment.

Dr. Scott LaGreca with some of the 160,000 lichen specimens in Duke’s herbarium.

LaGreca, like Miadlikoska, is a lichenologist. His research primarily concerns systematics, evolution and chemistry of the genus Ramalina. He’s particularly interested in “species-level relationships.” While he specializes in lichens now, LaGreca was a botany major in college. He’d always been interested in plants, in part because they’re so different from animals—a whole different “way of being,” as he puts it. He used to take himself on botany walks in high school, and he never lost his passion for learning the names of different species. “Everything has a name,” he says. “Everything out there has a name.” Those names aren’t always well-known. “Some people are plant-blind, as they call it…. They don’t know maples from oaks.” In college he also became interested in other organisms traditionally studied by botanists—like fungi. When he took a class on fungi, he became intrigued by lichens he saw on field trips. His professor was more interested in mushrooms, but LaGreca wanted to learn more, so he specialized in lichens during grad school at Duke, and now lichens are central to his job. He researches them, offers help with identification to other scientists, and is the collections manager for the lichens in the W.L. and C.F. Culberson Lichen Herbarium—all 160,000 of them.

The Duke Herbarium was founded in 1921 by Dr. Hugo Blomquist. It contains more than 825,000 specimens of vascular and nonvascular plants, algae, fungi, and, of course, lichens. Some of those specimens are “type” specimens, meaning they represent species new to science. A type specimen essentially becomes the prototype for its species and “the ultimate arbiter of whether something is species X or not.” But how are lichens identified, anyway?

Lichenologists can consider morphology, habitat, and other traits, but thanks to Dr. Chicita Culberson, who was a chemist and adjunct professor at Duke before her retirement, they have another crucial tool available as well. Culbertson created a game-changing technique to identify lichens using their chemicals, or metabolites, which are often species-specific and thus diagnostic for identification purposes. That technique, still used over fifty years later, is a form of thin-layer chromatography. The process, as LaGreca explains, involves putting extracts from lichen specimens—both the specimens you’re trying to identify and “controls,” or known samples of probable species matches—on silica-backed glass plates. The plates are then immersed in solvents, and the chemicals in the lichens travel up the paper. After the plates have dried, you can look at them under UV light to see if any spots are fluorescing. Then you spray the plates with acid and “bake it for a couple hours.” By the end of the process, the spots of lichen chemicals should be visible even without UV light. If a lichen sample has traveled the same distance up the paper as the control specimen, and if it has a similar color, it’s a match. If not, you can repeat the process with other possible matches until you establish your specimen’s chemistry and, from there, its identity. Culberson’s method helped standardize lichen identification. Her husband also worked with lichens and was a director of the Duke Gardens.

Thin-layer chromatography plates in Dr. LaGreca’s office. The technique, created by Dr. Chicita Culberson, helps scientists identify lichens by comparing their chemical composition to samples of known identity. Each plate was spotted with extracts from different lichen specimens, and then each was immersed in a different solvent, after which the chemicals in the extracts travel up the plate . Each lichen chemical travels a characteristic distance (called the “Rf value”) in each solvent. Here, the sample in column 1 on the rightmost panel matches the control sample in column 2 in terms of distance traveled up the page, indicating that they’re the same species. The sample in column 4, on the other hand, didn’t travel as far as the one in column 5 and has a different color. Therefore, those chemicals (and species) do not match.

LaGreca shows me a workroom devoted to organisms that are cryptogamic, a word meaning “hidden gametes, or hidden sex.” It’s a catch-all term for non-flowering organisms that “zoologists didn’t want to study,” like non-flowering plants, algae, and fungi. It’s here that new lichen samples are processed. The walls of the workroom are adorned with brightly colored lichen posters, plus an ominous sign warning that “Unattended children will be given an espresso and a free puppy.” Tucked away on a shelf, hiding between binders of official-looking documents, is a thin science fiction novel called “Trouble with Lichen” by John Wyndham.

The Culberson Lichen Herbarium itself is a large room lined with rows of cabinets filled with stacks upon stacks of folders and boxes of meticulously organized lichen samples. A few shelves are devoted to lichen-themed books with titles like Lichens De France and Natural History of the Danish Lichens.

Each lichen specimen is stored in an archival (acid-free) paper packet, with a label that says who collected it, where, and on what date. (“They’re very forgiving,” says LaGreca. “You can put them in a paper bag in the field, and then prepare the specimen and its label years later.”) Each voucher is “a record of a particular species growing in a particular place at a particular time.” Information about each specimen is also uploaded to an online database, which makes Duke’s collection widely accessible. Sometimes, scientists from other institutions find themselves in need of physical specimens. They’re in luck, because Duke’s lichen collection is “like a library.” The herbarium fields loan requests and trades samples with herbaria at museums and universities across the globe. (“It’s kind of like exchanging Christmas presents,” says LaGreca. “The herbarium community is a very generous community.”)

Duke’s lichen collection functions like a library in some ways, loaning specimens to other scientists and trading specimens with institutions around the world.

Meticulous records of species, whether in databases of lichens or birds or “pickled fish,” are invaluable. They’re useful for investigating trends over time, like tracking the spread of invasive species or changes in species’ geographic distributions due to climate change. For example, some lichen species that were historically recorded on high peaks in North Carolina and elsewhere are “no longer there” thanks to global warming—mountain summits aren’t as cold as they used to be. Similarly, Henry David Thoreau collected flowering plants at Walden Pond more than 150 years ago, and his samples are still providing valuable information. By comparing them to present-day plants in the same location, scientists can see that flowering times have shifted earlier due to global warming. So why does Duke have tens of thousands of dried lichen samples? “It comes down to the reproducibility of science,” LaGreca says. “A big part of the scientific method is being able to reproduce another researcher’s results by following their methodology. By depositing voucher specimens generated from research projects in herbaria like ours, future workers can verify the results” of such research projects. For example, scientists at other institutions will sometimes borrow Duke’s herbarium specimens to verify that “the species identification is what the label says it is.” Online databases and physical species collections like the herbarium at Duke aren’t just useful for scientists today. They’re preserving data that will still be valuable hundreds of years from now.

Kinsie Huggins: the Future Doctor Who Could Shot-Put

From shot-putting, to helping conduct two research studies, to being selected for a cardiology conference, meet: Kinsie Huggins. She is from Houston, Texas, currently majoring in Biology and minoring in Psychology with a Pre-Med track here at Duke. With such a simple description, one can already see how bright her future is!

“I want to be a pediatrician and work with kids,” Huggins says. “When I was younger, I lived in Kansas, and in my area, there were no black pediatricians. My mother decided to go far to find one and I really bonded with my pediatrician. One day, I made a pact with her in that I would become a pediatrician too so that I can also inspire other little girls like me of my color and other minority groups.”

Having such a passion to let African-American and minority voices be heard, Huggins is also part of the United Black Athletes, using her shot-put platform to make sure these voices are heard in the athletics department.

And while she may be a top-notch sportswoman, she is also just as impressive when it comes to her studies and research. One of her projects focuses on the field of nephrology – the study of kidneys and kidney disease. She and a pediatric nephrologist are currently working on studying rare kidney diseases and the differences in DNA correlating to these diseases.

Kinsie is also a researcher at GRID (Genomics Race Identity Difference), which studies the sickle cell trait in the NCAA. With the sudden deaths of college athletes from periods of over-exhaustion during conditioning, there has been a rise in attention of sickle cell trait and its impact on athletes. At first, the NCAA implemented a policy that made it mandatory for college athletes to get tested for sickle cell in 2010, but some were wary about the lack of scientific validity in such claims. Now, the NCAA has funded GRID to conduct such research.

The difference of Normal red blood cell and sickle cell (CDC).

 “We are analyzing the policy (athletes need to be tested for sickle cell), interviewing athletes in check-ups, and looking at data to see if the policy is working out for athletes and their performance/health,” Huggins explains.

With such an impressive profile, it doesn’t go without saying that Huggins didn’t go unnoticed. The American College of Cardiology (ACC) select high school and college students interested in the field of medicine and have them attend a conference in Washington D.C. to hear about research presentations, groundbreaking results of late-breaking clinical trials, and lectures in the field. Having worked hard, Huggins was selected to be part of the Youth Scholars program from the ACC and was invited to the conference on April 2-4. 

Let’s wish Kinsie the best of luck at the conference and on her future research!

Post by Camila Cordero, Class of 2025

Quorum Sensing: The Social Network of Bacteria

Dr. Bonnie L. Bassler, the Chair of Molecular Biology at Princeton University, is an advocate for diversity in science.

Bonnie Bassler of Princeton University

Throughout her presentation of the Ingrid Daubechies Lecture on Jan. 31 during Research Week, she emphasized that the diversity of her scientific team allowed every lab member to contribute to different steps of the process of studying quorum sensing, a form of microbial communication. (Watch her talk.)

Bacteria are everywhere. They’re sitting at the tables you sit at, burrowing in the clothes you wear and unfortunately, also crawling around on your skin. For a long time, they’ve had a pretty bad reputation, and for good reason! They have caused plagues that have wiped out masses across the globe, driven up breath mint sales by thriving in your mouth and mutated into every biologist’s Boogeyman when you try to kill them with antibiotics – super bugs!

However, the bacterial redemption arc is also quite compelling. “Good guy” bacteria in the gut help us break down food, produce essential vitamins and also sometimes fight off their evil siblings.

So, good or bad, the impact of bacteria in our daily lives is undeniable. But how does a microscopic little being have the capacity to influence the macroscopic world so greatly?

It doesn’t. At least, not by itself.

Lactococcus lactis is one of the starter bacteria in a cheese culture!

A bacterium never works alone because its strength lies in its numbers! Groupwork and communication (as any Pratt star going through recruiting season will swear to their interviewers) are what make bacteria so powerful. A bacterium by its lonesome will act differently than a bacterium surrounded by its daughters, sisters and cousins (bacterial family tree dynamics can get a little unusual).

Knowing that bacteria optimize their behaviors to work efficiently in a group answers the question of how they are so powerful, but it raises another.

How do bacteria know when they have company?

In a world where social media helps us stay connected, it is easy to take rapid status updates for granted. But for tech-deprived microbial colony, how does one member gauge the population of their surroundings? This question is one that Bassler’s lab answered: with a special chemical compound called autoinducers.

Autoinducers are little chemical signaling molecules that each bacterium sends out into its immediate environment. These molecules allow for quorum sensing, or cell-to-cell communication, to take place among bacteria.

Basic quorum sensing: How bacteria know who’s around them. (Nidhi Srivaths)

Every bacterium senses changes in the concentration of these autoinducers in their surroundings. Sensing a sudden increase in autoinducer concentration will change a bacterium’s gene expression, protein synthesis, and consequently, behavior. It will adapt to group behavior, while a bacterium that senses a drop in autoinducers will adapt to individual behavior.

Bacteria not only sense how many others are around them but also who their neighbors are. Autoinducers are universal to both Gram positive and negative bacteria and are unique to the type of bacteria that produce them.

This provides the bacterium with qualitative information on the population of its surroundings. Are they friends or foes?

Quorum sensing also includes nametags so bacteria can tell friend from foe. (Nidhi Srivaths)

In marine vibrio (a genus of Gram-negative bacteria), Bassler’s lab found that quorum sensing could perform intra-species, intra-genus and inter-species identification. This additional information helps the microbes adjust their behavior – from being friendly and supportive towards their relatives to being aggressive and competitive with their enemies.

Bassler provided a real-world perspective on quorum sensing. One species of the vibrio genus, Vibrio cholerae, is responsible for causing Cholera a deadly food and water-borne disease that has plagued low- and middle-income countries for centuries.

When the cholera bacteria enter the host, they are highly virulent and create a sticky biofilm around themselves that helps them clump into aggregates. Their cell density increases with bacterial division until the bacteria sense a certain concentration of autoinducers. Then their gene expression is modified to reduce virulence and biofilm production and the bacterial gene expression patterns shift to escape mechanisms. The bacteria soon break out in large numbers in search of a new host. (Their human host has voluminous, watery diarrhea in response and that becomes the vector for infecting new hosts.)

While the sequence of events that occurred in a cholera infection was known, the discovery of quorum sensing in V. cholerae opens doors for possible treatments, Bassler said. As bacterial communication sets the cycle of infection and division in motion, interfering with the autoinducers produced or disrupting bacteria’s ability to sense them sets the stage for innovative therapies for several infectious diseases.

Quorum sensing is another step towards understanding the world of the tiny microorganisms that influence our world and Bassler and her team are another example of the incredible research that can come from diverse teams in science.

Post by Nidhi Srivaths, Class of 2024

Medicine Under a Microscope

Duke Research Week 2022 featured a range of speakers from across all disciplines. The Lefkowitz Distinguished Lecture on January 31st highlighted some of our favorite things here at Duke Research Blog: ingenuity and perspective. 

Dr. Huda Yahya Zoghbi’s career spans decades; her Wikipedia page sports an “Awards and Honors” section that takes up my entire computer screen. She is a geneticist, neuroscientist, pediatric neurologist, pharmaceutical executive, and literature lover. Her presentation kicked off 2022 Research Week with a discussion of her work on Rett Syndrome. (View the session)

Rett Syndrome is a rare genetic disorder. The gene that researchers identified as the driver of the syndrome is MeCP2, which is especially active in brain cells. Certain mutations of this one gene can be responsible for a loss of speech, development issues, and persistent fidgeting. 

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The MeCP2 protein. Image: Wikipedia Commons

Children with Rett Syndrome faced chronic misdiagnosis, and even with proper care were limited by a lack of research.

Duke’s Dr. Robert Lefkowitz introduced Zoghbi at the beginning of the seminar and explained how she came to become the leading expert on this relatively unknown disorder. After completing medical school in Beirut in the midst of the ravaging Lebanese Civil War, she came to Texas Children’s Hospital, where she was able to observe and diagnose her first case of the syndrome, a process spurred by a simple interest in a newly-published journal article.

Holistic knowledge of Rett Syndrome is completely dependent on genetic research. A mutation on the MeCP2 gene causes errors in transcription, the reading out of DNA in your cells which leads to the production of proteins.

The mutated gene’s MeCP2 protein is then lacking the ability to do its job, which is helping other genes be expressed, or actively transcribed.

It’s a vicious cycle; like when you go to sleep late one night, so you sleep in the next day, then go to sleep late the next night, then sleep in the next day, and so forth.

In order to simulate and measure the effect of different kind of mutations on the MeCP2 gene, Zoghbi and her team studied genetically modified mice. While Rett Syndrome is caused by a lack of MeCP2 function, an overactive MeCP2 gene causes MeCP2 duplication syndrome. Varying degrees of gene efficiency then produce varying degrees of severity in the syndrome’s traits, with fatality at either end of the curve.  

Varying degrees of phenotype severity.

Zoghbi’s talk focused mainly on the mechanics of the disorder on a genetic level, familiar territory to both Nobel Laureate Lefkowitz and Duke Medicine Dean Mary Klotman, who shared some discussion with Zoghbi.

This medicine on a microscale is applicable to treating genetic disorders, not just identifying them. Zoghbi has been able to experimentally correct MeCP2 duplication disorder in mice by modifying receptors in a way that reverses the effects of the disorder.

The symptoms of Rett Syndrome are physical; they present themselves as distinct phenotypes of a subtle difference in genotype that’s too small to see. The field of genetics in medicine is responsible for making that connection.

Post by Olivia Ares, Class 2025

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Introducing Muser – A Better Way to Find Student Research

An effortlessly simple research platform where Duke students and Duke research projects can connect? Yes, please!

If you are anything like me, Duke University’s incredible research opportunities were extremely enticing when considering this school. One of the top 10 research institutions in the United States, Duke University’s research community spends over 1 billion dollars annually to fund its projects, which includes notable research facilities like the Duke Center for Human Genetics, the Duke Cancer Institute, the Duke Center for AIDS Research, and the Duke Human Vaccine Institute.

However, the amount of opportunity in this area can be overwhelming to approach, and as a student you often have no clue where to start.

Summer undergraduate research in cancer biology at the Duke University School of Medicine.

That’s where Muser comes in.

Duke introduces: Muser.com

Muser is a website created by Sheila Patek, a Duke biology professor who used grant money from the National Science Foundation to create a more equitable and straightforward way to connect undergraduates with professors with research opportunities. The resource allows researchers to post ongoing research positions with a direct application through the website.

Muser can sort research projects by compensation, hours, year, and project category, simplifying Duke’s incredibly complex research community by a lot.

“Muser posts research projects in 4 rounds throughout the year, a Fall round (August), a late Fall round for Spring projects (October/November), a Spring round for Summer projects (February/March), and a Spring round for Fall projects (March/April),” according to its website. Muser makes it easy to accommodate research positions into the part of your semester that works with your busy schedule.

I connected with some Duke students who have found success with the growing research platform, and though their interests were diverse, the success was all-encompassing.

“My experience with my Muser Project for the summer of 2021 was great overall,” said Elaijah Lapay, class of 2025. “It was essentially a history research assistantship helping a professor in the history department conduct research on elderly and eldercare in North Carolina. I was able to go to the NC State archives as well as archives across eastern North Carolina to really dive into the question of treatment of the elderly during the 20th century.”

Lapay’s research is so fruitful that the professor, James Chappel, the Gilhuly Family Associate Professor of History, is continuing to pursue this project for the rest of the school year. “I truly felt one-of-a-kind… I definitely feel like I’ve learned a lot and it’s sparked a passion in me for geriatrics and eldercare.”

A look inside Dr. Laurie Sanders’s lab here at Duke University.

“I got the chance to work in the Sanders lab under principal investigator Dr. Laurie Sanders and post-doctorate Dr.Claudia Gonzalez-Hunt!” said Shreya Goel, class of 2025. This lab was the first to link a genetic mutation to mitochondrial DNA damage which was ultimately discovered to be a marker for sporadic Parkinson’s disease.

“I get to work with human cells to induce and track mitochondrial and nuclear DNA mutations to determine their effect on the progression of the cell cycle,” Goel said. Her research position is making a difference and it allows her to gain tangible experience in a field she is passionate about.

The success stories are copious, and the opportunity that this platform has brought to prodigious students like these is without question.

At a billion-dollar research school, understanding where to begin can be intimidating. Muser alleviates these worries by connecting researchers and students through an accessible platform.

Have more questions? Visit Muser’s FAQ page to get more information and get into contact with one of Muser’s staff.

Post by Skylar Hughes
Class of 2025

Blake Fauskee and the ‘Little Typos’ of Fern DNA

Blake Fauskee, third-year Biology PhD student, initially pitched his graduate project to advisor Kathleen Pryer (Ph.D.) as an undergrad.

Fauskee, who researches RNA editing sites in ferns, told me about the project that he’s been working on for the last several years. His research could push back against the idea that DNA is the end-all, be-all molecule for encoding life as we know it.

Blake Fauskee, third-year Biology PhD student

Fauskee broke down RNA editing for me. “RNA editing is this extra step in the whole central dogma, the whole gene expression process, that happens in plant organellar DNA,” he said. This process takes place in plant mitochondrial and chloroplast genomes.

Fauskee uses a lot of metaphors to describe his work, which I find both helpful and admirable. Science can often be dense and lack feasible connections to processes that most of us are familiar with. “Basically, in [plant] DNA, there are little typos almost. The wrong nucleotide is encoded at certain spots. When those genes are going to be expressed, they get turned into RNA and then other proteins from the nucleus come in and find the little typos so that in the end you get the correct protein.”

This image shows a simplified diagram of how RNA editing works.

Fauskee calls RNA editing an “interesting and strange process” that neither animals nor humans have. His work attempts to study the evolution of this process, the patterns of RNA editing, and why it came to be. He uses DNA and RNA sequence data and the help of computational tools to do his work. He explains that when sequencing DNA, you can think of the fragmented base pairs “as little puzzle pieces.”

“So, I take all those little puzzle pieces and try to put back together the chloroplast genome, which is about 150,000 base pairs. It’s like a thousand-piece puzzle.”

Next, he figures out where the fern’s gene sequences are on the DNA strands, making use of genomic databases that contain known genomes. He then aligns RNA sequences to the genes he has mapped. Fauskee looks for the “typos” or “little differences” between the DNA and RNA: “That’s how we find the RNA editing sites.” Finally, he evaluates how the proteins would be changed by the typos in the DNA if the RNA was not edited after being transcribed.

“So, a lot of these fern genes will have a STOP codon right in the middle, which is really, really bad if you don’t fix because you are only going to get half a protein,” Fauskee said. STOP codons signal to the protein-building ribosomes that the protein is finished once it reads this portion of the RNA. Fauskee explained that these types of errors are the ones would expect organisms to lose, but it turns out they are the ones that are conserved in ferns. “Is there an extra function there? Is it helpful? Is it adaptive?” Fauskee asked.

An image of different ferns.

Comparative analyses between fern species are important. By looking at whether there are common editing sites and common amino acid changes, Fauskee says, “we’re trying to understand if certain editing sites may be advantageous and what kinds of fluctuation we see between certain types of changes.”

Fauskee underscored the importance of his work. “RNA editing is a really interesting process that kind of undermines what I learned in molecular biology…They always tell you DNA is the bedrock, it’s the be-all, end-all. But what happens when the DNA is wrong? What’s the other added layer on this?”

Simply put, Fauskee, says that because of RNA editing, “We have to rethink central dogma a little bit.” In some plants, 10% of all their gene products contribute to RNA editing, Fauskee tells me. “That’s a big chunk and that’s got to be important,” Fauskee said, “Why would evolution keep such a burden going?”

Biology’s central dogma is the idea that DNA is transcribed into RNA and then translated into proteins. RNA editing adds an extra step before translation and protein production.

There may also be implications for how RNA editing sites affect the way that genetic relationships are mapped through phylogenetics. If differences between the DNA of different species at RNA editing sites, this could be misleading. Though the DNA indicates a change in base pair, RNA editing could lead to the same output in protein despite the seeming change. “If you took [RNA editing] into account,” Fauskee says, “does it give you a different answer?”

Fauskee studies ferns because of the amount of editing sites found in these plants. While flowering plants have lost editing sites over time, ferns have not. “For RNA editing, you can look at all angiosperms (flowering plants) and for the whole chloroplast genome, they might have 30-50 RNA editing sites. When you get into ferns, that number jumps up to 300-500 and I am trying to understand why.”

Botanical science first captured Fauskee’s interest while he completed his undergraduate degree in his home state at the University of Minnesota Duluth (UMD). As a sophomore at UMD, Fauskee was taken under the wing of Amanda Grusz (Ph.D.). Grusz received her PhD in biology from Duke and worked under Pryer during her own time at the university. “I’m like my advisor’s academic grandson, which is kind of funny.” Clara Howell, who is part of Fauskee’s PhD cohort and who I spoke with last Fall, is also an academic grandchild in her own lab.

Being an “academic grandson” has worked out well for Fauskee. His key advice to me for any person considering a PhD, “Make sure your advisor is not someone you just admire as a scientist, but as a person.” On a day-to-day basis, Fauskee says that advisor Katheen Pryer “is pretty hands off” but is also “one of the most supportive people ever. I’m pretty much the driver of my own ship. If I am falling off the road, she’ll push me back on the road, but she’ll give me freedom to swerve around on that road.”

Fauskee also emphasized a piece of wisdom that Pryer passed down to him. “If whatever you’ve got going on is working and everyone else is doing something different, who cares?” he said.

Though Fauskee says that “lab work can be frustrating,” getting his long analyses to run after wrangling lots of data is very rewarding. Fauskee, who does not have a background in coding or computer languages, likes to “tell people that [his] floor of biology combined is one competent coder.” When he’s not stealing bits of his biology neighbor’s code, Fauskee loves to attend Duke Basketball games and is a fan of the television show Survivor.

Post by Cydney Livingston, Class of 2022

Nobel Laureate Dr. Jennifer Doudna and Groundbreaking Applications of CRISPR

In 2011, Dr. Jennifer Doudna began studying an enzyme called Cas9. Little did she know, in 2020 she would go on to win the Nobel Prize in Chemistry along with Emmanuelle Charpentier for discovering the powerful gene-editing tool, CRISPR-Cas9. Today, Doudna is a decorated researcher, the Li Ka Shing Chancellors Chair, a Professor in the Department of Chemistry and Molecular as well as Cell Biology at the University of California Berkeley, and the founder of the Innovative Genomics Institute.

Doudna was also this year’s speaker for the MEDx Distinguished Lecture in October where she delivered presented on “CRISPR: Rewriting DNA and the Future of Humanity.”

“CRISPR is a system that originated in bacteria as an adaptive immune system” Doudna explained.

Dr. Jennifer Doudna holding the Nobel Prize in Chemistry

When bacterial cells are infected by viruses those viruses inject their genetic material into the cell. This discovery, a couple decades ago, was the first indication that there may be ways to apply bacteria’s ability to acquire genetic information from viruses.

CRISPR itself was discovered in 1987 and stands for “Clustered Regularly Interspaced Short Palindromic Repeats.” Doudna was initially studying RNA when she discovered Cas-9, a bacterial RNA-guided endonuclease and one of the enzymes produced by the CRISPR system. In 2012, Doudna and her colleagues found that Cas9 used base pairing to locate and splice target DNAs when combined with a guide RNA.

Essentially, they designed guide RNA to target specific cells. If those cells had a CRISPR system encoded in their genome, the cell is able to make an RNA copy of the CRISPR locus. Those RNA molecules are then processed into units that each include a sequence derived from a virus and then assemble with proteins. This RNA protein then looks for DNA sequences that match the sequence in the RNA guide. Once a match occurs, Cas9 is able to bind to and cut the DNA, leading to the destruction of the viral genome. The cutting of DNA then triggers DNA repair allowing gene editing to occur.

“This system has been harnessed as a technology for genome editing because of the ability of these proteins, these CRISPR Cas-p proteins, to be programmed by RNA molecules to cut any desired DNA sequence,” Doudna said.

Jennifer Doudna holding a Model of CRISPR-cas9

While continuing to conduct research, Doudna has also been focused on applying CRISPR in agriculture and medicine. For agriculture, researchers are looking to make changes to the genomes of plants in order to improve drought resistance and crop protection. 

CRISPR-cas9 is also being applied in many clinical settings. In fact, when the COVID-19 pandemic hit, Doudna along with several colleagues organized a five-lab consortium including the labs of Dan Fletcher, Patrick Hsu, Melanie Ott, and David Savage. The focus was on developing the Cas13 system to detect COVID-19. Cas13 is a class of proteins, that are RNA guided, RNA targeting, CRISPR enzymes. This research was initially done by one of Doudna’s former graduate students, Alexandra East-Seletsky. They discovered that if the reporter RNA is is paired with enzymes that have a quenched fluorophore pair on the ends, when the target is activated, the reporter is cleaved and a fluorescent signal is released. 

One study out of the Melanie Ott group demonstrated that Cas13 can be used to detect viral RNA. They are hoping to apply this as a point-of-care diagnostic by using a detector as well as a microfluidic chip which would allow for the conduction of these chemical reactions in much smaller volumes that can then be read out by a laser. Currently, the detection limit is similar to what one can get with a PCR reaction however it is significantly easier to run.

Graphical Abstract of Cas13 Research by the Melanie Ott lab

“And this is again, not fantasy, we’ve actually had just fabricated devices that will be sitting on a benchtop, and are able to use fabricated chips that will allow us to run the Cas13 chemistry with either nasal swab samples or saliva samples for detection of the virus,” Doudna added.

Another exciting development is the use of genome editing in somatic cells. This involves making changes in the cells of an individual as opposed to the germline. One example is sickle cell disease which is caused by a single base pair defect in a gene. Soon, clinicians will be able to target and correct this defect at the source of the mutation alleviating people from this devastating illness. Currently, there are multiple ongoing clinical trials including one at the Innovative Genomics Institute run by Doudna. In fact, one patient, Victoria Gray, has already been treated for her sickle cell disease using CRISPR.

Victoria Gray being treated for Sickle Cell Anemia
Meredith Rizzo/NPR

“The results of these trials are incredibly exciting and encouraging to all of us in the field, with the knowledge that this technology is being deployed to have a positive impact on patient’s lives,” Doudna said.

 Another important advancement was made last summer involving the use of CRISPR-based therapy to treat ATR, a rare genetic disease that primarily affects the liver. This is also the first time CRISPR molecules will be delivered in vivo.

In just 10 years CRISPR-cas9 has gone from an exciting discovery to being applied in several medical and agricultural settings. 

“This powerful technology enables scientists to change DNA with precision only dreamed of a few years ago,” said MEDx director Geoffrey Ginsburg, a Professor of Medicine at Duke. “Labs worldwide have redirected the course of research programs to incorporate this new tool, creating a CRISPR revolution with huge implications across biology and medicine.”

Examples of further CRISPR-Cas9 research can also be found in the Charles Gersbach lab here at Duke. 

By Anna Gotskind, Class of 2022

Trust-Building, Re-Visited History, and Time Pertinent to Achieve Health Equity for Black Americans

Along with being a beautiful person and leading a productive life, Henrietta Lacks is the mother of modern medicine. Her scientific child was born without Henrietta’s consent through the clinical breakthroughs and medical miracles achieved with the help of her cervical cells – HeLa cells – stolen without her knowledge when she sought healthcare. Ironically, the same treatments developed from the cells of this Black woman are inaccessible for many Black Americans contemporarily. Though Ms. Lacks passed away from cervical cancer at the premature age of 31, her unique cells have become immortal. Her story lives on as a pertinent reminder of the importance of building trust between medicine and the Black community. In honor of her birthday, expert panelists met to both celebrate Ms. Lacks and discuss the path forward in trust-building, equity, and reckoning with our history to change the narrative of healthcare for Black Americans.

The panel honored Henrietta Lacks through discussion of the path forward for biomedical research and Black communities. The panel was hosted in August in remembrance of Ms. Lacks’ birthday on August 1st.

The panel, which took place on Tuesday, August 31, began as a conversation between Nadine Barrett (Ph.D.), Robert A. Winn (M.D.) and Vanessa B. Sheppard (Ph.D.). Among their many other titles and positions, Barrett is Director, Center for Equity in Research, Dukev CTSI and Associate Director of Equity, Community and Stakeholder Strategy, Duke Cancer Institute, Dr. Winn is the Director of the Virginia Commonwealth University (VCU) Massey Cancer Center, and Sheppard is the Associate Director of Community Outreach Engagement and Health Disparities at VCU Massey Cancer Center. The trio were joined by Reuben Warren (D.D.S., M.P.H., Dr. P.H., M.DIV.), Director of Tuskegee University’s Bioethics Center, along with a handful of other contributors including Veronica Robinson – Henrietta Lacks’ great-granddaughter and a registered nurse who represents the Lacks family on the NIH panel that reviews applications to conduct research using the HeLa genome.

A screenshot of panelists who took part in Tuesday’s conversation.

Winn began by referencing the U.S. 1932 public health service study that took place in Tuskegee, Alabama. The experiment exploited Black men in Tuskegee when an effective form of treatment for syphilis was discovered 15 years into the study but withheld from participants “to track the disease’s full progression.” In 1972, 40 years after the study began, it was the associated press, not the scientific community that finally led to the experiment’s demise and the issue of an apology from the U.S. President.

As Warren pointed out, the issue with the study was less about the treatment and more about the dishonesty, the falsifying information, and lies. “Stop calling them poor, stop calling them all sharecroppers,” Warren said of the Black men who participated in the study, “They were far more than that.” “[The study] was an issue of trust, not an issue of ignorance,” he continued. Unfortunately, when talking about this story, Winn said that Black Americans “don’t always talk about the power of us standing up and saying not again.

Bioethics violations have been a continuous part of the biomedical research enterprise in the U.S., and race and racism have been part of scientific inquiry, which continues to be of great concern, Warren said. Often, rather than putting preventative protections in place, bioethics regulations have come as a reaction to extreme violations of justice. Thus, Warren laid out a central theme of the panel that “You build trust by making yourself trustworthy and that takes time.” Rather than initiating transactional research with Black communities when the scientific and medical community needs something, Warren offered that they should start when they want to help with something.

Dr. Rueben Warren presenting examples of bioethics violations in the history of biomedical research, with most examples stemming from the United States

As Sheppard said, “[Black people] have earned a mistrust” for medical communities. This is largely hinged on Barrett’s argument that the American systems from health to education to criminal justice “are working as they were designed” – to ensure that the very inequalities that exist today came to be. Using the analogy of a marathon, Barrett said while white men in the U.S. started the race 450 years ago, Black men and women only began running this race hundreds of years later. “Those who start the race are going to…ensure that they thrive,” Barrett said. This has led to Black people dying disproportionately from often treatable diseases, Sheppard said, continuing to add that these sorts of disparities were front and center for the world to see during the COVID-19 pandemic.

In the creation of our structural inequalities, the system created “two bookends: Black and white.” But there has to be a narrative that keeps this story alive. “In order to create the change, we have got to do the work to change the narrative,” said Barrett.

Nadine Barrett (Ph.D.), Director of Health Equity and Disparities at Duke Cancer Institute

Robinson pointed to the importance of history, paralleling Warren’s comments that in focusing on health equities we are fully focusing on the future in a way that ignores the past and does not deal with “what really brought us into health disparities” in the first place. Robinson said that we “can no longer sweep [conversations on the historical injustices of medical racism] under the rug.” She continued to say that the reason why Tuesday’s conversation and the ongoing dialogue that is sure to follow is so powerful is because “we are no longer victims in our own legacies” by taking over conversations at the table rather than being the topics of discussion at the table.

Mistrust in the Black community for systems of medicine and healthcare are based on hundreds of years of action. Hesitancy – from Covid-19 vaccinations to participation in clinical trials for cancer research – amongst Black Americans “aren’t us saying no,” said Robinson, “We’re saying something happened.” Sharon Ribera Sanchez, Founder-Director of Saving Pennies 4 A Cure, is a cancer survivor and advocate for people of color to engage in clinical trials because of the difference they can make in medical developments that draw on more diverse and robust data.

But there is a bigger conversation than just having more Black folks take place in research and clinical trials, Winn said. “How are you going to look at my biology without looking at my history?” he asked, referencing the genetic implications of environmental conditions and stressors from socially constructed race that impact DNA.

An image of HeLa cells

The dialogue, which was opened and closed with a prayer, also spoke to the importance of establishing regular, ongoing, transparent relationships between the Black faith community and the medical community. This should happen, not just in times of crisis, because “mass hysteria is prime for miscommunication,” Ralph Hodge, pastor of the Second Baptist Church in South Richmond, Virginia, said.

“Today was a big way of us looking back at the past, looking at where we are at now, and moving forward to the solutions,” said Barrett. This comes by letting communities know that we care, said Winn, along with “doing things with our communities, not through them.”

A key factor in deconstructing this issue and achieving health equity is time. Time to reflect on the past in order to avoid reliving it; time to generate innovative solutions to the problems at hand; and time to invest in Black communities – to learn from them, support them, and earn their trust not because they can offer science something, but because science has something to offer them.

Post by Cydney Livingston

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