The Duke Medical Ethics Journal (DMEJ) is a golden opportunity to listen to the ways the world around me hurts and heals. It means asking questions – who is being marginalized in my communities? Where is the injustice in my community? What can I do about it? And when these questions feel too big and too heavy, DMEJ means having a community of mentors, friends, and soul-strengtheners to ask the questions with me. Some of my most cherished experiences at Duke since freshman year have been those rooted in exploring the humanities.
Engaging with the field of ethics through the Kenan Institute of Ethics Living Learning Community as well leading the Duke Medical Ethics Journal (DMEJ) has given me a strong appreciation for the utilization of humanities in healthcare.
Before I saw the Spring 2021 DMEJ edition come together, I never realized how deeply identity could influence health. I had always thought of peoples’ identity in terms of cultural identity, not enough in terms of fertility or neurodiversity, until I read the pieces written by my fellow DMEJ writers. I realized more than ever that healthcare at its deepest level is not just about the biomedical model but it’s also about care, care for the values the lives of its practitioners and patients.
COVID-19 has also naturally brought up questions on the importance of mask-wearing, social distancing, and now, vaccinating. Though most students interested in entering the healthcare field typically fall on one side of the argument, it is safe to say that all of us had to take up more responsibility for ourselves and for others. What does it take to do what is right? The ethics (and effort!) surrounding this responsibility makes for deep conversations puts the “care” in healthcare. And these deep conversations are what DMEJ is all about.
Our upcoming issue, winter 2021, will be about the post-covid era. What does a return to normalcy even mean in an age where normal has been changed forever? And two of our bloggers have already written deeply affecting pieces on post pandemic mental health. To stay up to date on what DMEJ is up to, subscribe to our listserv. We’re always looking for more voices to join our conversation. 🙂
Collaborating with a colleague in Shanghai, we recently published an article that explains the mathematical concept of ‘in-betweening,’in images – calculating intermediate stages of changes in appearance from one image to the next.
Our equilibrium-driven deformation algorithm (EDDA) was used to demonstrate three difficult tasks of ‘in-betweening’ images: Facial aging, coronavirus spread in the lungs, and continental drift.
Part I. Understanding Pneumonia Invasion and Retreat in COVID-19
The pandemic has influenced the entire world and taken away nearly 3 million lives to date. If a person were unlucky enough to contract the virus and COVID-19, one way to diagnose them is to carry out CT scans of their lungs to visualize the damage caused by pneumonia.
However, it is impossible to monitor the patient all the time using CT scans. Thus, the invading process is usually invisible for doctors and researchers.
To solve this difficulty, we developed a mathematical algorithm which relies on only two CT scans to simulate the pneumonia invasion process caused by COVID-19.
We compared a series of CT scans of a Chinese patient taken at different times. This patient had severe pneumonia caused by COVID-19 but recovered after a successful treatment. Our simulation clearly revealed the pneumonia invasion process in the patient’s lungs and the fading away process after the treatment.
Our simulation results also identify several significant areas in which the patient’s lungs are more vulnerable to the virus and other areas in which the lungs have better response to the treatment. Those areas were perfectly consistent with the medical analysis based on this patient’s actual, real-time CT scan images. The consistency of our results indicates the value of the method.
Part II. Solving the Puzzle of Continental Drift
It has always been mysterious how the continents we know evolved and formed from the ancient single supercontinent, Pangaea. But then German polar researcher Alfred Wegener proposed the continental drift hypothesis in the early 20th century. Although many geologists argued about his hypothesis initially, more sound evidence such as continental structures, fossils and the magnetic polarity of rocks has supported Wegener’s proposition.
Our data-driven algorithm has been applied to simulate the possible evolution process of continents from Pangaea period.
The underlying forces driving continental drift were determined by the equilibrium status of the continents on the current planet. In order to describe the edges that divide the land to create oceans, we proposed a delicate thresholding scheme.
The formation and deformation for different continents is clearly revealed in our simulation. For example, the ‘drift’ of the Antarctic continent from Africa can be seen happening. This exciting simulation presents a quick and obvious way for geologists to establish more possible lines of inquiry about how continents can drift from one status to another, just based on the initial and equilibrium continental status. Combined with other technological advances, this data-driven method may provide a path to solve Wegener’s puzzle of continental drift.
The study was supported by the Department of Mathematics and Physics, Duke University.
Dr. Bryan Batch, a Duke endocrinologist and researcher, studies treating metabolic disorders (like diabetes) with non-pharmacological approaches. But, she says, her parents’ medical professions, and the hard work that went into them, resulted in her not wanting to pursue science at all as a child.
When she took biology in middle school however, it clicked. It didn’t feel like “the slog of math,” she says, because she enjoyed studying life in its different forms. This infatuation with science combined with a love for other people pushed her to pursue medicine.
Now, Dr. Batch focuses on racial disparities. She says that a huge issue with disparities, whether they involve race, poverty, food insecurity, educational opportunity, or health insurance, is that they are often driven by policy. “We are not trained to know how to affect change in policy in medical school — it’s not something we are taught. But I do think if physicians got more involved in politics and policy we would be able to make significant positive impact.”
What she does try to do is adapt to individual patient needs in the moment. Her work at Duke signifies what she, as a healthcare provider, can do within the time spent with patients to interact in the best way possible. For example, she can understand if someone has a literacy issue and adapt her methods of explanation so that their literacy doesn’t hinder their understanding. While it can be challenging for one person to change systemic issues or share lived experiences with people of different backgrounds, Dr. Batch makes every effort to create a comfortable environment where she is able to leave a positive impact.
These impacts have no doubt been affected by COVID-19, which Dr. Batch describes as one of the most challenging experiences in her twenty years of practicing medicine. Although telephone and video conferencing have been available for years, Dr. Batch explains that only now is there a drive to put them to use. “It was like someone came up behind you and just whacked you on the head,” she says — no warning, no time to get organized.
Dr. Batch feels lucky to be in endocrinology, where there is flexibility for remote visits. Yet, even when patients do have the chance to have an in-person visit, some don’t want to. If they do, the physical separation, masks, and face shields create a feeling of distance. Dr. Batch spends much of her clinical time at the Durham Veteran Affairs Hospital, across the street from Duke Hospital, where many hearing-impaired patients have difficulty understanding her words because her mask takes away the ability to read lips.
Dr. Batch says that even after the pandemic has passed, more than 30% of visits may remain over the telephone, which can give patients increased access to their doctors.
The challenges have infiltrated her research too, where now the only people she can bring in are those who need to visit the VA Medical Center for another reason anyway, like going to the eye doctor. Overall, she says, she has been surrounded by phenomenal people who rolled up their sleeves and said “let’s get it done.” Still, it has been exhausting.
To her, family is everything, and she tries her best to stay in touch with the people who matter most as a way to get through it all.
Even before COVID-19, Dr. Batch has been intentional about living her life to the fullest and staying true to her core values. If that means rescheduling things at work to be with her kids, she is unapologetic. She chose endocrinology as a specialty in part because it’s very family-oriented, and she feels lucky to have colleagues who understand the flexibility she values. Her ultimate goal is to leave a mark on the world but she also wants her happiness to come from what matters, so she stays close to her big family and lots of friends.
While sacrifices are inevitable in any career, Dr. Batch tries not to make large ones on the homefront. She takes it day by day, week by week, she says, to make it such that “work” and “life” are in harmony as much as possible. It is easy to get caught up and have the years go by, one day realizing that the important people have pulled away. Dr. Batch is deliberate about making the time for these people, including her two children and husband.
Dr. Batch is a role model for young people, particularly for women of color. She shared an anecdote about her inattentive high school counselor, to whom she went for a signature on her college application list. Seeing Yale, Harvard, and Brown, he told her that she was “reaching too high.” Batch responded, “I’m not here for your opinion on this list. I’m here for you to sign this form..
She ended up at Yale.
She says she had the courage to talk back to the counselor because her parents instilled the idea of working hard and pushing higher. What matters, she says, is believing in yourself and surrounding yourself with people who believe in you.
Unfortunately, Batch said, underestimation by others resonated throughout her college, medical school, residency, and fellowship, because she is a woman or because she is Black.
At the end of the day, Dr. Bryan Batch never let other people define her experience but instead allowed her hard work to prove her value and propel her to always reach higher.
Guest Post by Viha Patel, Class of 2021, NC School of Science and Math
Over the past decades, we have adopted computers into virtually every aspect of our lives, but in doing so, we’ve made ourselves vulnerable to malicious interference or hacking. I had the opportunity to talk about this with Miroslav Pajic, the Dickinson Family associate professor in Duke’s electrical and computer engineering department. He has worked on cybersecurity in self-driving cars, medical devices, and even US Air Force hardware.
Pajic primarily works in “assured autonomy,” computers that do most things by themselves with “high-level autonomy and low human control and oversight.” “You want to build systems with strong performance and safety guarantees every time, in all conditions,” Pajic said. Assured Autonomy ensures security in “contested environments” where malicious interference can be expected. The stakes of this work are incredibly high. The danger of attacks on military equipment goes without saying, but cybersecurity on a civilian level can be just as dangerous. “Imagine,” he told me, “that you have a smart city coordinating traffic and that… all of (the traffic controls), at the same time, start doing weird things. There can be a significant impact if all cars stop, but imagine if all of them start speeding up.”
Since Pajic works with Ph.D. students and postdocs, I wanted to ask him how COVID-19 has affected his work. As if on cue, his wifi cut out, and he dropped from our zoom call. “This is a perfect example of how fun it is to work remotely,” he said when he returned. “Imagine that you’re debugging a fleet of drones… and that happens.”
In all seriousness, though, there are simulators created for working on cybersecurity and assured autonomy. CARLA, for one, is an open-source simulator of self-driving vehicles made by Intel. Even outside of a pandemic, these simulators are used extensively in the field. They’ve become very useful in returning accurate and cheap results without any actual risk, before graduating to real tests.
“If you’re going to fail,” Pajic says, “you want to fail quickly.”
Guest Post by Riley Richardson, Class of 2021, NC School of Science and Math
The beauty of research is that it allows you to take control of your own path.
“We are very lucky to be in the position to decide what we love to do and do it,” says Tai-ping Sun, a Duke biology professor studying the plant hormone GA. Researchers get to take control of their own path, she said. Every day is an opportunity to learn something new, design and analyze experiments and decide what direction to take.
Sun studies the GA signaling pathway because it regulates plant growth and development. She got interested in GA when she was a post-doctoral fellow at Harvard University in 1988. At the time, a lot of tools needed to be developed. As she was developing new tools to clone plant genes, she came across a GA mutant that was different. Her research is very important to understanding how the mutations in the GA signaling pathways can control the height of a plant. In fact, she says, GA mutations were one of the reasons for the success of the “Green Revolution” in the 1960s.
Sun’s current research revolves around identifying the mechanisms of the cell that make GA hormones and identifying how GA mutations have affected this pathway. Her team has identified important facets of the pathway, such as the structure and function of the nuclear receptors that allow for transcription that drives the GA response. Her team has also identified transcription factors that control the rate of the signaling pathway such as the DELLA proteins that act as master growth repressors to inhibit GA response. In fact one of her favorite discoveries is that GA triggers destruction of the DELLA proteins to activate the GA signaling pathway.
“As a scientist, the most exciting thing is to discuss experimental data, and then trying to deduce hypothesis or modify models and then come up with new experiments for testing,” she said.
But research is not without its challenges, Sun says “not everything that you do works out the first time.” That’s why she says that as a researcher the most important thing is to have an interest in your field as well as perseverance.
Guest post by Anika Jain, Class of 2021, NC School of Science and Math
We are all born with defining physical characteristics. Whether it be piercing blue eyes or jet black hair, these traits distinguish us throughout our entire lives. However, there is something that all of our attributes have in common, a shared origin: genes.
Beyond dictating our individual features, genes instruct cells to create proteins that are essential for a variety of processes, from controlling muscle function to managing digestive systems. Despite their importance in the workings of our body, genes can also code for detrimental diseases, such as Huntington’s disease or Duchenne muscular dystrophy.
These types of diseases are exactly what Raluca Gordân, Ph.D. is battling through her research. She and her group are trying to figure out how to decode the non-coding genome, the DNA apart from protein-coding genes. They are deepening their understanding of the role non-coding areas of the genome play in the expression of the coding genes and the production of proteins.
Gordân, an associate professor in biostatistics and bioinformatics at Duke, said a majority of disease-causing genetic mutations derive from the genome outside of genes.
“That is a huge search space,” she says, chuckling. “Genes only make up about 2% of the genome. If we don’t understand what those non-coding regions are doing, it’s hard to make predictions about what the mutation in those regions would be doing and how to connect that to the development of a disease.”
Gordân recently published a paper, entitled “DNA mismatches reveal conformational penalties in protein–DNA recognition,” which focuses on transcription factors and their exceptional ability to bind to mispaired DNA, misspellings that occur as DNA is copied. During regular replication, nucleotide bases (the building blocks of our DNA) are paired correctly, where adenine pairs with thymine and cytosine goes with guanine. However, when an error occurs during replication, mispairs start to appear, as adenine may pair with guanine instead.
“Normally, those are mistakes that get repaired by specific mismatch repair pathways but that repair might not happen if one of these transcription factors sits on the replication error and doesn’t allow the repair mechanism to see it,” Gordân explains. “Normally, one would expect the transcription factors not to bind to those errors. But we found that they can bind way better than their actual genomic targets.”
To expand on her computational discovery, Gordân is now following up with a study of transcription factor binding to mismatches in living cells, observing whether they adopt their usual role of regulating gene expression or contribute to the development of mutations.
Gordân’s research is a product of her passion and desire to make change. It also can be attributed to a series of realizations she made during college and inspirational mentors who guided her along the way.
While pursuing her undergraduate degree, Gordân was a purely computer science major, concentrating on cryptography. However, as she was nearing the end of her four years of college, she soon found herself yearning for the opportunity to do more. She began looking into machine learning applications and enrolled in a course based around genetic algorithms which she credits for launching her career path.
At that point, she attained what she describes as her “first taste of genetics” and her interest in bioinformatics was irrevocably piqued. Thereafter, Gordân applied for a PhD at Duke, where she worked with advisor Alex Hartemink investigating transcription factor proteins in regulatory genomics. At Duke, her work was primarily computational. But with her postdoctoral advisor Martha Bulyk of Harvard Medical School, Gordan was exposed to the more experimental aspects of biology.
Today, she recognizes these experiences as integral to her ongoing research, which requires her to frequently iterate between observational approaches and computational work.
Gordân is acclimating to the newly quarantined world. While she strives to continue her research, in the pandemic, it has changed her routine.
“I think what was affected a lot since the pandemic started is the fact that we don’t meet in person,” she says. “A lot of the quick progress was being made when we were in the same physical space and were able to get feedback immediately, with students learning about each other’s results in the lab, in real time. That was replaced with Zoom meetings, where students get to see the other students’ results mainly at lab meetings, weeks or months later. Those continuous discussions that were going on in the lab all the time. We’re missing that.”
Gordân offered some thoughtful parting advice to aspiring computational biologists, like me.
“I was trained as a computer scientist, so I wasn’t really sure about experimental work. But after actually doing the experimental work, I realized how much value there is in doing both,” she said. “You have to pick what you’re strongest at, either the computational or experimental part, but you should not be afraid of the other side.”
Guest Post by Akshra Paimagam, Class of 2021, NC School of Science and Math
We offered fruit-eating ruffed lemurs at the Duke Lemur Center fresh lettuce each afternoon for 10 days. They happily ate it and their gut microbiomes shifted, suggesting that leafy greens could be incorporated into the lemurs’ standard dietary regimen to boost foraging opportunity and fiber intake.
Red-ruffed lemurs and black-and-white ruffed lemurs are some of Madagascar’s most iconic wildlife. Sporting a long snout and a neck ruff to rival those of the Elizabethan court, these primates naturally live in the rainforests, where they mostly eat fruits and flowers, and make their living as seed dispersers and pollinators.
Ruffed lemurs also live in zoos worldwide, where they are given fruit-rich diets to match those foraged by their wild peers. But scientists are starting to realize that the fruit eaten by wild lemurs is quite different from the domesticated fruit provided at zoos. Wild fruits are seedy, pulpy, and thick-skinned, whereas orchard fruits are fleshy, plump, and sweet. From a nutritional standpoint, wild fruits contain more fiber, whereas orchard fruits contain more sugar.
Our team wondered if a fiber boost might benefit Duke’s ruffed lemur colony. But would these fruit-loving lemurs eat their veggies?
Cue the salad bar.
To test this idea, we offered ruffed lemurs at the Duke Lemur Center a lot of lettuce. Lettuce seemed like a pretty palatable way to stimulate foraging behavior, while boosting fiber intake.
With help from the research department, we offered 19 ruffed lemurs 150-200 grams of romaine lettuce each day, which is about double the weight of their standard diet. We repeated this regimen every day for 10 days, while recording the lemurs’ feeding behavior and collecting fecal samples for gut microbiome analysis. Because gut microbes are chiefly responsible for converting plant fiber into energy for the lemurs, measuring changes to the lemurs’ microbiomes offered a way to ‘see’ the impact of lettuce consumption.
It turns out that ruffed lemurs really like lettuce. They consistently ate lettuce every day and showed no decline in consumption across the study. Younger animals ate more lettuce than did geriatric lemurs, but all lemurs spent more time crunching on lettuce stalks than the leaves.
And their gut microbiomes responded. We noted two microbes that were more abundant on the lettuce diet: a known fiber digester from the Ruminococcaceae family, and a microbe known for its positive association with host health in other animals called Akkermansia.
Despite their classification as fruit eaters, ruffed lemurs readily eat lettuce. We think lettuce can be used to extend the lemurs’ foraging time while boosting dietary fiber. And it might just help replicate the lifestyles experienced by wild ruffed lemurs in their native Malagasy rainforests. At the Duke Lemur Center, lettuce is now a routine item offered to ruffed lemurs (and other species too!). Next time you come out for a tour (once it’s safe to do so), you might get to see them crunching away on their new favorite snack!
Like wine, cheese, and savvy financial investments, many tropical trees become more valuable with age. This is particularly true when it comes to carbon storage, because old trees are often the biggest trees and the larger the tree, the more carbon it stores.
The value of big, old trees in combating climate change was underscored in a recent study of Gabon’s forests, led by the Nicholas School of the Environment’s John Poulsen. The team’s striking finding — that half of Gabon’s wealth of carbon is found in the largest 5% of trees — has implications that reach far beyond the sparsely populated Central African country’s borders.
Tropical forests play a key role in the global carbon cycle by keeping carbon out of the atmosphere. Trees take in CO2 — one of the infamous, heat-trapping greenhouse gases — during photosynthesis and use the carbon to grow, making new leaves, thicker and taller trunks, and more expansive root systems.
Scientists can estimate how much carbon a tree holds by measuring its trunk. So, like rainforest tailors, trained technicians traveled to all corners of the country to measure the girth and height of tens of thousands of trees.
This extraordinary two-year long effort was one of the first nationwide forest inventories in the tropics, making Gabon a leader in comprehensive forest monitoring.
Poulsen and collaborators used the tree measurements to estimate the amount of carbon stored in Gabon’s forests and to determine why some forests hold more carbon than others.
“The field techs deserve all the credit”, Poulsen explained, “as they often walked for days through thick forest, traversing swamps and enduring humid, buggy conditions to measure trees. We turned their sweat and toil into information that could be used by Gabon’s government to prioritize areas for conservation.”
The team analyzed a suite of environmental factors to see their effects on carbon storage. Of the natural factors, only soil fertility had a noticeable positive effect on tree biomass. Much more important was the impact of humans. As human activities such as agriculture and logging tend to target large trees, more heavily human-disturbed forests had a much different structure than pristine forests. The farther a study area was from human settlements, the more likely it was to host large trees and consequently, higher amounts of carbon.
The paper notes that Gabon stands out as a country with “one of the highest densities of aboveground forest carbon.” In fact, Gabon’s undisturbed forests store more carbon than those in the Amazon, which have been referred to as the lungs of the planet.
According to Poulsen, “Gabon is the second most forested country in the world with 87% forest cover, a deforestation rate near zero…” Because of its impressive forest cover and its location straddling the equator, Gabon’s forests host an incredibly diverse array of plants and animals, including many threatened and endangered species. Rural communities depend on these forests for their livelihoods.
However, Gabon’s impressive forests are valuable to more than just wildlife, climate researchers, and local communities. The logging industry also sees these forests as a chance for profit. More than half (about 67%) of Gabon’s forests are under contract with logging companies to harvest timber, putting them at risk of losing many of their carbon-storing giants.
Poulsen’s study highlights the importance of a more nuanced approach to forest conservation in Gabon. One that doesn’t simply focus on stopping deforestation or promoting restoration, as is prescribed in many international climate change plans, but an approach that recognizes the necessity of preserving high conservation value, old growth forests.
Guest Post by Anna Nordseth, a graduate student in the Nicholas School of the Environment.
Imagine for a moment that you’re 6,000 pounds, living in one of the wildest places on Earth, with no schedule, nowhere to be. How do you decide where to spend your time? Where to go next? Do you move where food is most plentiful? Is water your main priority?
These are some of the questions addressed by Duke Ph.D. candidate Amelia Meier and former postdoctoral researcher Dr. Chris Beirne in Dr. John Poulsen’s lab. Their recent study published in Trends in Ecology and Evolution focused on the African forest elephant–the slightly smaller yet still undeniably huge cousin of the savanna elephant.
The team wanted to know what influences certain aspects of elephant behavior. Specifically, how much climate and resource availability drives elephant movement and influences their diet. To do this, the team looked at fruit abundance (a high-energy staple of elephants’ diets), water availability from rainfall, and elephant identity and how those factors affect how an individual moves and eats.
One might think that such a massive animal is easy to spot in the forest. However, the dense vegetation of Central African rainforests can be an impenetrable wall, allowing the massive animals to move unseen through the forest, leaving broken branches and steaming dung piles in their wake.
To better track them, the researchers fitted individual elephants with GPS collars that turn an iPhone into an elephant-tracking tool. This also allowed trackers to follow the elephants at a distance and avoid conflict with the sometimes temperamental animals.
Meier, Beirne, and colleagues also wanted to know more about the diets of the tracked elephants to see if what they ate changed with how much fruit is available. This less-than-glamorous job was done by dissecting fresh dung piles, estimating the proportions of leafy and woody material, and counting the number of seeds in each one.
Tropical rainforests are lush, yet have patchy resources, making it important for many frugivores to have flexible diets. Some trees only produce fruit in the wet season. Others fruit every other year. To gauge fruit availability, the research team conducted “fruit-walks” at the beginning and end of each day of following an elephant, in which trackers counted all of the ripe fruit on the ground.
A key finding of the study was that the most important factor driving movement was an elephant’s individuality; some respond to food or water availability differently and some simply move around more than others.
Interestingly, elephants appear to be affected by resources differently depending on the timescale the authors looked at. Water was important on both a day-to-day and month-to-month basis. Yet on a daily basis, fruit and water were more equally matched, with water still maintaining a slight lead.
Fruit availability was also critical in determining how much elephants moved and what they ate. When there was more fruit available, the elephants ate more fruit, as evidenced by the proportion of seeds in dissected dung piles.
Aside from being an awe-inspiring species, forest elephants are important to the health of their native ecosystems. They are unwitting gardeners, planting seeds of the fruits they consume in piles of dung and giving those seeds a better chance of survival. That’s part of why understanding what motivates forest elephant movement is more than the satisfaction of an elephant enthusiast’s curiosity; it is critical to managing and conserving a species that is vulnerable to multiple threats from humans.
Meier’s dissertation research focuses on elephant social behavior and the effects of human disturbance on elephant social groups, allowing her to pursue her long-term interest in animal behavior with a practical conservation application.
“I was living in Congo and I knew I wanted to keep working in the region. There, you have elephants–this amazing, highly intelligent, social species that is surrounded by conflict.”
Poachers seek elephants for their ivory tusks, which are valuable on the black market. The pachyderms are also prone to conflict with humans when they start foraging in village plantations, destroying crops and damaging livelihoods.
The team’s findings open the way for new questions about why different elephants exhibit different patterns of movement. What underlying factors affect behavior, and why? Does it have to do with age? Sex? Their social environment?
These questions remain unanswered for now, but the work of Meier and colleagues represents a critical step in understanding elephant behavior to improve forest elephant management and conservation strategies.
Guest Post by Anna Nordseth, a Ph.D. Candidate in the Nicholas School of the Environment
The novel coronavirus pandemic has now resulted in more than 3 million confirmed cases globally and is pushing scientists to share ideas quickly and figure out the best ways to collaborate and contribute to solutions.
Recently, Duke researchers across the School of Medicine came together for an online symposium consisting of several short presentations to summarize the latest of what is known about the novel coronavirus, SARS-CoV-2.
This daylong event was organized by faculty in the Department of Molecular Genetics and Microbiology and researchers from different fields to share what they know about the virus and immunity to guide vaccine design. This conference highlighted the myriad new research pathways that Duke researchers are launching to better understand this pandemic virus.
One neat area of research is understanding viral processes within cells to identify steps at which antivirals may block the virus. Stacy Horner’s Laboratory studies how RNA viruses replicate inside human cells. By figuring out how viruses and cells interact at the molecular level, Horner can inform development of antivirals and strategies to block viral replication. Antivirals stop infections by preventing the virus from generating more of copies of itself and spreading to other cells. This controls damage to our cells and allows the immune system to catch up and clear the infection.
At the symposium, Horner explained how the SARS-CoV viral genome consists of 29,891 ribonucleotides, which are the building blocks of the RNA strand. The viral genome contains 14 areas where the RNA code can be transcribed into shorter RNA sequences for viral protein production. Though each RNA transcript generally contains the code for a single protein, this virus is intriguing in that it uses RNA tricks to code for up to 27 proteins. Horner highlighted two interesting ways that SARS-CoV packs in additional proteins to produce all the necessary components for its replication and assembly into new viral progeny.
The first way is through slippery sequences on the RNA genome of the virus. A ribosome is a machine inside the cell that runs along a string of RNA to translate its code into proteins that have various functions. Each set of 3 ribonucleotides forms one amino acid, a building block of proteins. In turn, a string of amino acids assembles into a distinct structure that gives rise to a functional protein.
One way that SARS-CoV-2 packs in additional proteins is with regions of its RNA genome that make the ribosome machinery slip back by one ribonucleotide. Once the ribosome gets offset it reads a new grouping of 3 ribonucleotides and creates a different amino acid for the same RNA sequence. In this way, SARS-CoV-2 makes multiple proteins from the same piece of RNA and maximizes space on its genome for additional viral proteins.
Secondly, the RNA genome of SARS-CoV-2 has regions where the single strand of RNA twists over itself and connects with another segment of RNA farther along the code to form a new protein. These folds create structures that look like diverse trees made of repetitive hairpin-like shapes. If the ribosome runs into a fold, it can hop from one spot in the RNA to another disjoint piece and attach a new string of amino acids instead of the ones directly ahead of it on the linear RNA sequence. This is another way the SARS-CoV-2 packs in extra proteins with the same piece of RNA.
Horner said a step-by-step understanding of what the virus needs to survive at each step of its replication cycle will allow us to design molecules that are able to block these crucial steps.
Indeed, shapes of molecules can determine their function inside the cell. Three Duke teams are pursuing detailed investigation of SARS-CoV-2 protein structures that might guide development of complementarily shaped molecules that can serve as drugs by interfering with viral processes inside cells.
For example the laboratory of Hashim Al-Hashimi, develops computational models to predict the diversity of structures produced by these tree-like RNA folds to identify possible targets for new therapeutics. Currently, the Laboratories of Nicholas Heaton and Claire Smith are teaming up to identify novel restriction factors inside cells that can stop SARS-CoV-2.
However, it is not just the structures of viral components expressed inside the cells that matter, but also those on the outside of a virus particle. In Latin, corona means a crown or garland, and coronaviruses have been named for their distinctive crown-like spikes that envelop each virus particle. The viral protein that forms this corona is aptly named the “Spike” protein.
This Spike protein on the viral surface connects with a human cell surface protein (Angiotensin-converting enzyme 2, abbreviated as ACE2) to allow the virus to enter our cells and cause an infection. Heaton proposed that molecules designed to block this contact, by blocking either the human cell surface protein or the viral Spike protein, should also be tested as possible therapies.
One promising type of molecule to block this interaction is an antibody. Antibodies are “Y” shaped molecules that are developed as part of the immune response in the body by the second week of coronavirus infection. These molecules can detect viral proteins, bind with them, and prevent viruses from entering cells. Unlike several other components on our immune defense, antibodies are shaped to specifically latch on to one type of virus. Teams of scientists at Duke led by Dr. Sallie Permar, Dr. Georgia Tomaras, and Dr. Genevieve Fouda are working to characterize this antibody response to SARS-CoV-2 infection and identify the types of antibodies that confer protection.
Infectious disease specialist Dr. Chris Woods is leading an effort to test whether plasma with antibodies from people who have recovered can prevent severe coronavirus disease in acutely infected patients.
Indeed, there are several intriguing research questions to resolve in the months ahead. Duke scientists are forging new plans for research and actively launching new projects to unravel the mysteries of SARS-CoV-2. With Duke laboratory scientists rolling up their sleeves and gowning up to conduct research on the novel coronavirus, there will be soon be many more vaccine and therapeutic interventions to test.
Guest post by Tulika Singh, MPH, PhD Candidate in the Department of Molecular Genetics and Microbiology (T: @Singh_Tulika)