COVID-19

A Dual Focus: MU researcher earns $181,734 NIH grant and U.S. Public Health Service Award for COVID-19 research in the lab and on campus

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By Cara Penquite | Bond LSC

CynthiaProfile
Cynthia Tang is an M.D.-Ph.D. student in the Wan lab. Photo by Cara Penquite | Bond LSC

Cynthia Tang’s academic career is marked by her propensity to multitask. From earning a major and three minors during her undergrad to making a documentary while getting lab and clinical experience, she makes the most of her time.

Recently Tang received the Excellence in Public Health Award from the United States Public Health Service, and a $181.734 National Institutes of Health grant to be used over four years . . . all while getting an M.D. and Ph.D. simultaneously.

The funding from the grant goes towards Tang’s research on SARS-CoV-2, the virus responsible for the COVID-19 pandemic, and its effect in rural areas. By comparing DNA sequences of the virus from patients in rural and urban areas, Tang looks for differences in variants. Her goal is to understand how the virus has been evolving and why patients in rural areas experience more severe symptoms.

“I’ve always found infectious diseases really interesting,” Tang said. “This pandemic came up and it was exciting to be in the position to help contribute to the knowledge base of it.”

CynthiaCandid
Cynthia Tang creates protein structure models for the spike protein on the Sars-CoV-2 virus. Along with 3D models, Tang creates phylogenetic trees to compare the genetic makeup of variants of the virus. Photo by Cara Penquite | Bond LSC

In a family of immigrants, Tang saw the challenges in health literacy and cultural differences affecting patient care in the U.S first-hand, and she also caught a glimpse into a global view of healthcare.

“I had an opportunity to travel to Vietnam and actually see some of the health disparities of different health care structures in different countries,” Tang said.  “We were visiting my grandfather who was in the hospital, and it was alarming to see the contrast between the quality of health care and availability of health care there compared to some of the hospitals that we have here.”

Tang recalls noticing lack of supplies, physicians and space for patients. She saw similar issues in the U.S., and shined light on public health disparities here by creating a documentary about the challenges immigrants face in the U.S. healthcare system. She also held competitions across Washington University’s campus to teach students more about public health issues while working as a clinical research coordinator.

“I wanted to help improve health equity,” Tang said.

A bachelor’s in chemistry and minors in philosophy, international development and pre-health professions at the College of Idaho may start to explain Tang’s public health focus and her path to bench and clinical research.

“My minor in international development was really useful for me because that gave me a lot more exposure to the different economies of different countries of the world, their health status and how politics, economics and health care all interrelate in different countries,” she said.

Her research at Washington University led Tang to an interest in its clinical applications.

“I really enjoyed the aspect of working with patients, actually getting to talk to patients and hearing their stories,” Tang said. “I felt like with clinical research, you can see … slightly quicker results from bench to bedside compared to bench research, and that was also when I decided I was interested in becoming a physician.”

Part of an eight-year joint M.D.-Ph.D. program at Mizzou, Tang started with two years of pre-clinical medical school before transitioning to Ph.D. research and then will return to finish the clinical years of medical training.

When she came to Mizzou, Tang continued fighting health disparities for immigrants.

“We organized a group of volunteers that were able to translate COVID-19 information to different non-English speaking communities in Boone County,” Tang said.

Always one to tackle several projects at once, Tang plans to pursue a career as a pediatric physician scientist interfacing with patients while continuing lab research.

“I like the idea of doing both. As a physician, you get that one-on-one contact and you get to make a very direct contribution to someone’s life,” Tang said. “And then with research, you don’t have as much contact with patients, but what you do can affect populations.”

Competing with COVID: Researcher suggests varying from vaccines to fight virus

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CC_COVID
COVID-19 virus particles have spike proteins, represented in red, that attach to receptors on host cells. Antivirals block the receptors on host cells so the virus cannot infect more cells. | Creative Commons Photo

By Cara Penquite | Bond LSC

Vaccines were the light at the end of the tunnel throughout the COVID-19 pandemic, but virus mutations threaten to extinguish hope of a quick end to the pandemic. Kamlendra Singh turns towards antivirals as the next step.

“There will be a time we will find an antiviral which will be very difficult for the virus to mutate [and avoid],” Singh said, “That’s what we are after.”

The Singh lab studied COVID-19 antiviral compounds that prevent binding between the virus and host cells with help from Siddappa Byrareddy, professor and vice-chair of research in the Department of Pharmacology Experimental Neuroscience at the University of Nebraska Medical Center (UNMC). The first COVID-19 antiviral compound Singh’s team discovered during their in a preliminary study conducted in mouse models, has been filed for a patent while they continue to search for the antivirals that target different proteins of the virus. These compounds would prevent the virus from entering cells even after exposure to the virus.

The antiviral compound disrupts the interaction between the ACE2 receptor on the surface of host cells and the spike protein on the virus so the virus cannot infect cells. ACE2 acts as a doorway into the cell where COVID-19 binds, enters and takes over the cell. Once inside, the virus hijacks the cell and uses it to create more virus. Additionally, the virus releases its genome into the host cells, activating cell defense mechanisms which can be more dangerous than the infection itself.

While vaccines prepare the immune system to fight off COVID-19, Singh’s antivirals simply block this doorway.

“The very first thing was to find the compound that can inhibit viral entry because it is the first step of the infection,” Singh said. “If you can block the very first step then you can block everything else.”

Vaccines act as a practice round for the body where the immune response learns which antibodies are effective against the virus. But when the virus mutates, antibodies built up from vaccination or prior infection may be less effective against the mutated virus.

The antiviral compounds discovered by Singh and his team do not have this problem since they bind to the host cell’s receptors where few mutations occur. Additionally, the compounds can change their shape in response to those mutations that may occur.

“We call it ‘wiggling and jiggling,’” Singh said. “The compound has the capability to change it’s shape conformation.”

This ability to change shape is not unique to COVID-19 antivirals. Drawing on previous experience working on HIV antivirals, Singh explains that shape changing properties are common in molecules with single bonds between their component atoms.

“If you have a single bond somewhere, then they can change or they can reorient and bind someplace,” Singh said.

Singh believes antivirals may be the key to fighting COVID-19 even with emerging mutants. While vaccines mitigated COVID-19 rates and hospitalizations, they also might have played a role in the creation of new mutants.

“It’s probably too early to say, but it looks like these variants are probably evolving under the pressure of antibodies,” Singh said. “Those antibodies may have been induced by either direct infusions giving the antibodies [to patients], or they may have been induced by other vaccines or by previous infection.”

While viruses also mutate under the pressure of antivirals, Singh hopes to find an antiviral that is difficult for the virus to avoid through mutation.

“We have been working on developing a better compound using the compounds we discovered, and we have found one more compound that has at least 10 times better efficacy against [SARS-Cov-2],” Singh said.

Kamlendra Singh is a research assistant professor of molecular microbiology and immunology and assistant director of the Molecular Interactions Core at Bond LSC. Singh wished to express his sincere gratitude to Prof. Byrareddy (University of Nebraska Medical School). Without their collaboration, the discovery of the antiviral compounds would not be possible. Singh is also thankful to two students – Saathvik Kannan (a Hickman High School student) and Austin (a Mizzou undergrad). Without the help of these two talented young scientists, the research would not have been so successful. Finally, Singh mentioned that the support from the Bond Life Sciences Center has been extremely valuable in his research.

#IAmScience Reinier Suarez

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By Cara Penquite | Bond LSC

When one of Reinier Suarez’s undergraduate professors suggested he go to graduate school, he was confused.

“I had never heard of a Ph.D. in my life,” Suarez said.

Three years later, Suarez is a first-year graduate student studying COVID-19 variants. Suarez came to Mizzou as part of the university’s Post-Baccalaureate Research Education Program (PREP), a stepping-stone between his undergraduate studies at Florida International University and his graduate studies at MU. He joined Marc Johnson’s lab at Bond Life Sciences Center as a PREP scholar and liked it enough to stay and continue his studies.

“Marc Johnson is a great [principle investigator], he really takes the time to talk to the students. He’s very honest,” Suarez said.

While Suarez started with HIV research, he soon switched his focus to coronaviruses when MU shut down at the beginning of the pandemic.

“[Johnson] saw it as a good opportunity to expand the lab, and I agreed,” Suarez said.

Suarez works on pseudotyped COVID-19 particles that allow him to study variants of COVID-19 without the dangers of using a live virus. Psudeotyped particles have the COVID-19 spike protein on the surface of the cell, but the virus genome is replaced with fluorescent proteins. Similar to a live virus, the pseudotyped particles can get inside healthy cells using the spike protein, but they release the fluorescent protein instead of the COVID-19 genome. A live COVID-19 virus would use the genome to hijack the cells and reproduce more virus, but the fluorescent protein in the pseudotyped particles only change the cell’s color under a microscope.

“If the [pseudotyped particles] infect a cell, the cells turn green … and then you can measure how much green there is in compared to all the cells that you have,” Suarez said.

By measuring the amount of green, Suarez measures how many cells were infected by the particles. Suarez uses this method to test different mutations of the COVID-19 spike protein to see which version increases infectivity.

Suarez also contributes to the lab’s other COVID-19 project testing wastewater samples from various locations in Missouri and around the U.S. to identify amounts of COVID-19 spike proteins in the water.

“You can actually see when a locality is about to hit an outbreak before they get there,” Suarez said.

As the only graduate student in the Johnson lab, Suarez has taken on greater research responsibilities as well as teaching undergraduates – a long way from his start in the lab as a PREP scholar.

As a PREP scholar, Suarez worked closely with Johnson to prepare for graduate school.

“It was clear that he had holes in his background which required chiseling,” Johnson said, but he also commended Suarez’s work ethic.

“His motivation has been second to none,” Johnson said.

As an undergraduate, Suarez studied at Florida International University where he pursued dentistry. Coming from Miami, it seemed like a natural step for Suarez.

“I started off with dentistry because I didn’t know what I wanted to do, I just knew I liked science, specifically biology,” Suarez said.

It was not until his last year of undergraduate studies that one of his professors suggested he look into grad school.

“I was taking her virology class and she said, ‘hey why don’t you go to grad school,’ and I was like ‘what is that, what is grad school,’” Suarez said.

Having no prior experience working in a laboratory proved an obstacle in the graduate program admissions process, but he was accepted to PREP which allowed him to improve his education and start research before attending a graduate program.

“The PREP program basically gives students the ability to see what grad school is like without having to be in grad school,” Suarez said.

During the PREP program Suarez rotated in various MU labs, but he credits much of his learning to Margaret Lange, Molecular Microbiology and Immunology assistant professor, and Johnson.

“[Lange’s] also an HIV researcher, so her and Marc Johnson work very close together,” Suarez said, “they kind of formed a co-mentorship.”

While Suarez experienced a “very nurturing environment” at MU, he still credits his decision to start research to his mentor during his undergraduate studies who suggested furthering his education.

“She set me on a path and that’s how I’m here today,” Suarez said.

Outlining Omicron: researchers determine key mutations in the latest COVID-19 variant

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Bond LSC and UNMC scientists explain mutations unique to the Omicron variant

Austin Spratt Protein Models
Austin Spratt, undergraduate mathematics student in the Kamlendra Singh lab, shows protein models of the Omicron spike protein and the receptor it attaches to when infecting cells. “The genetic codes are used to identify the mutations, and then we use the structure to see how it would change over time. It’s going to give us more information about new mutations that occur,” Spratt said. | Photo by Cara Penquite, Bond LSC

By Cara Penquite | Bond LSC

It took eight days for Kamlendra Singh and his team to crack the code behind the Omicron COVID-19 variant. Although usually characterized by months of waiting, the peer-review process matched their pace, publishing their research a week later.

“That’s how quick it went because the editors and the general [scientific community] recognize that it’s very timely and important research,” said the Bond Life Sciences Center principal investigator.

Discovering 46 genetic mutations in the Omicron variant, their research explains Omicron’s ability to efficiently infect cells and evade antibodies. Their explanation predicted Omicron’s possibility for increased transmissibility a couple weeks before the beginning of the late December surge of COVID-19 cases  in the U.S. The work published online December 10, 2021, in the Journal of Autoimmunity.

“You will see a lot of infections now because the vaccine-induced immune responses are not able to control the [Omicron] infection,” said Siddappa Byrareddy, a collaborator on the project and Professor and Vice-Chair of Research in the Department of Pharmacology Experimental Neuroscience at the University of Nebraska Medical Center (UNMC).

Genetic mutations to the spike protein on the surface of the virus increase Omicron’s ability to infect cells and evade antibodies. In Omicron, the mutations allow for a stronger bond between the spike protein and the healthy cell. The spike protein acts as a key enable the virus to get inside the cell by attaching to receptors on the surface of healthy cells. Once inside, the virus hijacks the cell and uses it to create more copies of the virus.

“What happens is, these mutations are in the receptor-binding domain. Which means, when these two things come together, when the spike protein tries to attach to the ACE2 receptor, these mutations cause it to bind more. When that happens, we have increased transmissibility or increased infectivity,” said Saathvik Kannan, a Hickman High School sophomore, and lead author from the Singh lab involved in identifying the mutations.

The spike protein is also the primary point of contact for antibodies designed to neutralize the virus. Since antibodies are not universal, the immune system must be exposed to a virus, either through infection or vaccination, before creating antibodies to neutralize that virus. Omicron’s mutations in the spike protein make it different from other variants of COVID-19, so antibodies that can neutralize other variants seem to be less effective in preventing Omicron infection.

“Antibodies are very specific. Any one mutation can completely abolish the binding,” Singh said.

While antibodies from previous infection or vaccination may not prevent Omicron transmission, Byrareddy emphasized that they are still decreasing hospitalization.

“Even though the vaccines are not effective [against Omicron] transmission, they still help the immune response to fight against the virus. That’s why we don’t [see] a lot of hospitalization,” Byrareddy said.

One potential solution to mitigate Omicron’s effect would be to create an Omicron-specific vaccine. While a new vaccine could decrease Omicron transmission, Singh warns that it would not necessarily prevent the emergence of further variants. This is a particular concern with Omicron because of its many versions.

“We’re seeing different Omicron versions where you have the Omicron, but with a couple changes. Those couple changes are making a big impact.” said Austin Spratt, another Singh lab researcher and MU undergraduate studying mathematics involved in the project.

Spratt’s role in the project was to create computer simulations of the spike proteins to see models of the mutations.

“[Omicron] has bigger mutations and different flavor mutations [than previous variants], and there are starting to be subcategories of that,” Spratt said.

Singh and Byrareddy’s labs are taking their research in the direction of antivirals with the hope of creating a drug that could reduce COVID-19 symptoms. The antiviral would block receptors on the surface of healthy cells so that the virus’ spike protein will not fit anymore. Without a key to get into the cells, the virus would not take over the cells.

While antivirals would not cut out all variants, Spratt believes they could help the problem as they did with other pandemics such as the Spanish Flu.

“I think it’s possible that they create antivirals that will slowly but surely cut out variants over time,” Spratt said.

This research published in the Journal of Autoimmunity December 10, 2021, under the title “Omicron SARS-CoV-2 variant: Unique features and their impact on pre-existing antibodies.”

#IAmScience Clayton Rushford

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#IAmScienceClaytonRushfordBy Lauren Hines | Bond LSC

Clayton Rushford isn’t one to complain.

While in the Marc Johnson lab at the Bond Life Sciences Center, he’s the guy cheering up lab mates when experiments fail or going with the flow when he must repeat an experiment for the fifth time. As long as he’s doing science, not much can bring him down.

“It seems like a very generic answer but the fun thing about [science as a whole] is it’s more or less how we explain all the things that are going on around us with the use of evidence,” the research specialist said. “So that’s something I’ve always gravitated to because I tend not to believe things unless I see them firsthand.”

Rushford joined the Johnson lab about six months ago, originally extracting RNA from raw samples of wastewater. Now, he’s running PCR tests on the samples to look for COVID-19 mutations and early outbreaks in Missouri.

“It’s a really awesome way to track COVID on a large scale because when we test wastewater, we’re testing the entire community … So, it really provides a lot of good information for general epidemiology, and we’re hoping to maybe move out to some other viruses since it’s really close within our system,” Rushford said.

Now that he’s working at Bond LSC, Rushford found a chance to reflect on his biggest accomplishments.

“Just making it here,” Rushford said. “A lot of what I’ve done, it’s been on a whim more or less. I didn’t really go into college with a plan … But I feel like I’ve done a good job at making it up as I go, and I feel like I’ve made good use of my time while I’m here. I don’t think I’ve wasted my time in Columbia, and I think I’ve gained a lot out of it.”

While Rushford tends to live moment to moment, it has served him well. He took a chance on plant science classes at Mizzou because they sounded interesting. He graduated from Mizzou in 2017 with that plant science degree and leaped into a master’s program.

Rushford soon found himself studying dissemination through irrigation systems, which coincidently lined up very close to the Johnson’s lab focus. When Rushford graduated in 2020, he knew the Johnson lab position was one of a kind.

“I picked up this job because the parallels with my master’s program were just a little too good, and so it was really hard to pass up that opportunity to see something involving epidemiology and water systems, just be able to bounce from one lab to another,” Rushford said. “It was kind of a way to stay in this little niche area that seems to be developing in my career.”

The similarities helped him adapt quickly.

“I think when people come into the lab, they are quiet, and they do what they’re told for a while and it takes them quite some time to really start thinking on their own,” said Carolyn Robinson, Ph.D. candidate in the Johnson lab. “[Rushford] did that really quickly. So that was cool growth to see for sure.”

Robinson helps Rushford the most in the lab and they often talk about anything from movies, the Yu-Gi-Oh! card game or their puppies. The two have even taken their pups on playdates together.

However, what Robinson appreciates the most about Rushford is his attitude.

“Science can be frustrating, and it can be easy to fall into that,” Robinson said. “There’s a lot of repetition, so it is really important to be able to stay positive and to be able to keep a good morale, if you will, when things aren’t working and whatnot. So, it’s just really nice to have somebody who’s focused more on good things than something that’s not working.”

With only six months under his belt and many more to go, Rushford is happy to keep building an environment of optimism in the lab.

Turning Back the Clock

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Demonstrated Sample of Stem Cells
Megan Sheridan, a postdoctoral fellow working with the R. Michael Roberts lab, removes the base solution from a demonstrated sample of stem cells that will be grown into placental cells for study of their interaction with the Zika virus. | photo by Phillip Sitter, Bond LSC

By Lauren Hines | Bond LSC

At 24 weeks pregnant, a baby can hear the mother’s lullabies. At 30 weeks, her belly is a little over a foot large. At 40, the hospital bag is already packed and ready to go.

But imagine delivering only two weeks after the bump starts showing.

Preeclampsia makes induced birth necessary as life-threatening symptoms start 20 weeks into pregnancy, and delivery is the only cure. There is a lack of ways to detect it, and it’s difficult to ethically study the early stages of human reproduction. But what if it was possible to rewind the process to see when the source of the disorder took hold?

Different cellular models of the placenta might be that time machine researchers need to study early pregnancy disorders.

The Michael Roberts lab at Bond Life Sciences Center combines the knowledge and practices of three cellular models to learn more about early pregnancy and diseases.

“We can use these different models to study placental infection with viruses like Zika virus and, of course, COVID because there’s still a controversy as to whether COVID is a hazard in early pregnancy,” principal investigator Michael Roberts said. “And my suspicion is it probably is.”

The placenta is the brand-new organ generated by the embryo — the baby — before any of its other organs develop to give the baby nutrients and support as the embryo grows.

Megan Sheridan, postdoctoral fellow working with the Roberts lab, works on a project to combine 2D and 3D models to see how Zika and Dengue virus interact with the placenta and affect early pregnancy.

“[Complications] occur but you don’t necessarily know that until the end of pregnancy when the baby is delivered,” Sheridan said. “We really want to kind of go back in time and try to determine what’s going wrong in early pregnancy.”

Modeling early placental development is vital to see the beginning of disease complications, but the challenge is to get an accurate glimpse while not putting a healthy pregnancy at risk.

“It’s hard to get a good model to do research on that,” said Jie Zhou, postdoctoral fellow in the Roberts lab. “So that’s why we are working on different stem cells and trying to build up the best model to work on.”

So, the Roberts lab uses the BAP model. By working with a hospital, the lab first takes fibroblast cells from discarded umbilical cords after the baby is born. These fibroblast cells can be collected from mothers experiencing a normal pregnancy or pregnancies associated with complications, like preeclampsia. Then, as Sheridan puts it, they add a “cocktail of genes” to turn the cells into induced pluripotent stem cells. From there, the lab adds BAP — a mixture of growth factors and inhibitors that turn the stem cells into trophoblast cells.

Now the lab is back at the beginning of pregnancy except in a Petri dish of cells. In pregnancy, these trophoblast cells line the outside of the embryo.

From here, researchers can see what possibly caused the pregnancy complications in the first place.

“It’s trying to mimic pregnancy in a dish, essentially by using cells that will develop into placental-type cells,” Roberts said.

However, a flat Petri dish is nothing like a real placenta.

“It’s two-dimensional, and we can only culture the cells up to eight days after treatment so if we want to do long-term experiments, we can’t use this model,” Zhou said.

Two alternative models came out in 2018. The first model was by Hiroaki Okae et. al who created a 2D trophoblast cell line where trophoblasts can continually reproduce themselves long past eight days. The second model by Margherita Turco et. al also created a similar cell line, but in three dimensions.

This last model inches even closer to an early placenta. These 3D organoids float around inside a jello-like substance called Matrigel where they self-organize into a placental-like structure.

Together the two models give them a full picture. The 3D model gives a clue into how multiple cell types interact with each other while the 2D model allows researchers to see how a single cell type responds.

Since no model is perfect, the Roberts lab is combining their BAP model with protocols and growth conditions from the other two models to create a foundation for their experiments. Now researchers can start asking deeper questions.

While nothing is quite like a real womb, the Roberts lab will continue working backward.

“All of these models, put together, are really useful because we can kind of use them to their fullest potential and systematically assess which one might represent a certain disease or best answer a certain research question,” Sheridan said.

Two SARS-CoV-2 strains cause independent infections only 19 days apart

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Increasing detection of reinfections and rediscovering brand new infections within days raises concerns for herd immunity and the durability of vaccine efficacy.

Cynthia Tang
Cynthia Tang working to figure out how COVID-19 reinfections can bring us answers on how the virus is developing at Bond LSC. | photo by Davis Suppes, Bond LSC

By Davis Suppes | Bond LSC

 Like many viruses, SARS-CoV-2 continues to develop and evolve with time. As the virus evolves it becomes more infectious and can produce worse symptoms and a higher fatality rate. While more people have been infected, we also learn more about it, including how different variants of the same virus can reinfect someone who already had SARS-CoV-2.

In a recent study led by Cynthia Tang, an MD-PhD student at the University of Missouri (MU) School of Medicine and Institute for Data Science and Informatics, her lab was able to identify a patient who got reinfected with a different strain of SARS-CoV-2 just 19 days after their initial infection. Her Systems Biology Laboratory is headed by Principal Investigator, Dr. Henry Wan, who directs the MU Center for Influenza and Emerging infectious Diseases.

“We found a case of reinfection that occurred during a shorter window of time than what we see in the current US Centers for Disease Control and Prevention (CDC) guidelines,” Tang said, “so we may be missing a subset of those reinfection cases.”

In October 2020, the CDC published investigative criteria for suspected SARS-CoV-2 reinfections. These criteria included: any individuals testing positive over 90 days after their first laboratory-confirmed SARS-CoV-2 infection, or symptomatic individuals testing positive 45–89 days after initial infection with paired respiratory specimens.

For this patient, nineteen days following her initial positive test in March of 2020, she returned for another SARS-CoV-2 test due to return-to-work requirements. Despite her symptoms fading to encompass only productive cough and fatigue she tested positive again. She continued to experience persistent cough, fatigue, and difficulty breathing until 55 days after her initial positive test.

Tang showed that the two samples contained two infectious variants of SARS-CoV-2 viruses. No diverse polymorphisms, or a mixture of different viruses, were identified among the sequences of the viruses from each clinical sample, suggesting true reinfection rather than a coinfection. One good news is that this case also suggests that reinfections may not be worse than the prior infection.

The CDC has encouraged symptom-based strategies for ending isolation rather than viral retesting for asymptomatic individuals or for individuals without new symptoms during 90 days after illness onset due to findings that detectable but noninfectious SARS-CoV-2 RNA can persist in respiratory samples. This means that even if you don’t exhibit symptoms there could still be traces of SARS-CoV-2 in your system, and those traces could be from an original infection or a reinfection.

This study suggested that reinfection could pose a challenge to infection control, especially as the Delta variants are surging around and new variants continue to emerge.

“People showing influenza-like illnesses are recommended to isolate themselves for ten days or wait for their symptoms to go away. We may not be catching cases where individuals contract another COVID-19 infection within a short amount of time,” Tang said.

“The COVID-19 vaccination has been proven to be effective in reducing the chances for people to become infected and reinfected”, Tang added.

This research was published in the Journal of Medical Virology in June 2021. 

How a pandemic spreads

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COVID-19 analysis looks at variant spread

Saathvik Kannan, Kamal Signh, and Austin Spratt
Saathvik Kannan, Kamal Singh, and Austin Spratt, worked together at Bond LSC to identify new SARS-CoV-2 variants. | photo by Davis Suppes, Bond LSC

By Davis Suppes | Bond LSC

Variants of the virus that causes COVID-19 continue to plague the world with spikes in infection, keeping the current pandemic from being fully controlled as Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections remain unmanageable in some parts of the world.

Researchers at Bond Life Sciences Center and the University of Nebraska Medical Center (UNMC) have been conducting research on mutations in four new variants, B.1.1.7, B.1.351, P.1 and CAL.20C. These evolving variants appear to be more infectious and transmissible than the original Wuhan-Hu-1 virus.

It all started with a new spike in infections of a variant of SARS-CoV-2 in the UK. Despite a slowdown in infections due to precautions of masks and lockdowns, the new spike meant something about the virus had changed.

“Our goal was to find out where these variants are distributed, and how they are migrating,” said Kamal Singh, Assistant Director Molecular Interactions Core, and scientist at Bond LSC. Singh was a corresponding author on the paper and has been at Bond LSC for 12 years.

Their work showed completely different mutations in these variants based on regions, but also where variants have common lineage. That commonality can be seen between the CAL.20C and B.1.351 variants.

While related to each other, they also developed different mutations.

“B.1.1.7 was more infectious and was able to spread to more people. It slowly dominated and that’s what happened in the United States as B.1.1.7 is now the dominant variant of SARS-CoV-2 in the US,” said Saathvik Kannan, a co-author. Kannan is going to be a 10th grader at Columbia’s Hickman High School this fall but works under Singh at Bond LSC as a computer programmer and researcher.

Once they identified the related COVID-19 variants, they wanted to trace their migration. This allows them to see where the mutations are being carried and which regions have a more dense number of infections. The prevalence of variants was key in identifying where they were moving.

Their analysis looked at certain mutations in each variant to see how they were related, why some sequences have mutations that others don’t and tried to determine how they evolved from their original sequence.

By comparing the structure of each virus, they were able to illustrate how the related mutations moved state by state across the country.

Sankey diagram variant CAL.20C US.jpg
This Sankey diagram for variant CAL.20C in the United States.They aligned the first-known CAL.20C sequences from each state then grouped the sequences based upon the date collected and closely their structures matched, with cut-offs of 96, 94, 93, 92, 91 and 90 percent compared with the previous group.

“It is pretty clear that some states have a higher homology match, which helps us see a pretty linear trend of migration from the Western states to the East in the United States,” said Austin Spratt, a computer science senior and lead author on the paper. Spratt has worked under Singh at Bond LSC for two years.

The study cautions that the sequences of viruses are being deposited at an unprecedented rate, so it is possible that some conclusions may change as more sequences of variants become available.

“These variants are continuously evolving and complex in nature, but a proper understanding of what makes each variant unique, its genetic makeup and its interaction with host proteins is critical to developing the most effective vaccine,” said co-corresponding author Siddappa Byrareddy, Professor & Vice-Chair of Research, in the Department of Pharmacology & Experimental Neuroscience, at the University of Nebraska Medical Center. “Not only will this help us to design better vaccines now, but greatly help us to be prepared to deal with more mutant variants in the future.”

Although analysis indicates that mutations only in one variant do not reflect evolution of it, these genetic mistakes may increase infectiousness of a particular variant

The short period of time, volume of variants and limited travel around the world all point to a greater infectivity than the original (Wuhan-Hu-1) virus. Recent deadly surges in India caused by variant B.1.617.2 or the Delta variant will soon be added to their analysis to further understand the COVID-19 pandemic.

Their research was published in the paper ‘Evolution, Correlation, Structural Impact and Dynamics of Emerging SARS-CoV-2 Variants’ in the “Computational and Structural Biotechnology Journal” on June 19, 2021.
Funding provided by: Bond LSC, Swedish research Council, American Lung Association, National Institute of Dental and Craniofacial Research in collaboration with Prof. Gary Weisman of the Bond Life Sciences center.

Higher Viral Load May Lead to Less Severe Symptoms

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Cynthia Tang and Henry Wan | photos by Becca Wolf and Roger Meissen, Bond LSC

Cynthia Tang and Henry Wan | photos by Becca Wolf and Roger Meissen, Bond LSC

By Becca Wolf | Bond LSC

You would think that the less sick you are, the less contagious you are. That’s just logic.

However, science isn’t always logical. Especially with Covid-19.

Henry Wan, principal investigator at Bond Life Sciences Center, recently found that when a person has mild symptoms of Covid-19 they have a higher amount of viral shedding.

He also found that people with a higher amount of virus on their positive swab test are less likely to be hospitalized than those with a lesser amount.

“We are really interested in whether this may be causing more or less hospitalizations, and we found the opposite in the analysis,” Wan said. “We found that viruses that mutate a certain way can make the disease less severe. We then wondered if there are any [particular] mutations that cause this.”

Wan and his lab decided to look at different Covid-19 mutations. Using positive Covid-19 tests from throughout Missouri, they found four local lineages and several mutations. With this information, they analyzed patient data to see how people are reacting to each mutation.

“We need to understand how the community gets the mutation and how it spreads,” Wan said. “We want to understand this very dynamic process in Missouri. We’ve seen a lot of mutations introduced in the past several months. Some of them continue to spread and some of them die. We want to know what ecology factors cause this.”

Cynthia Tang, a M.D. Ph.D. student in Wan’s lab, helped with the research. She did work on the data collection and performed the analysis.

“Within the first eight months in Missouri alone we identified four new lineages, which shows just how quickly the virus can mutate and spread,” Tang said. “We also found that viral load was increasing over time. That in itself was very interesting.”

They then looked at if the specific lineages were associated with the increase in viral load but did not find any conclusive evidence. As a result, they speculated that there may be an overall selective advantage towards more viral load and viral shedding, but then found that an increase in viral load was associated with decreased severity.

Given how novel Covid-19 is, they knew they had to expect anything. From the past experience on influenza pandemics and throughout pandemic outbreaks, viruses typically evolve to adapt to the human population, to be less severe while spreading more readily to become seasonal.

“It was challenging going into the research without a lot of information,” Tang said. “There are a lot of publications out there, but our overall foundation of this virus and the disease itself isn’t that strong yet since the pandemic just started, so it’s challenging trying to figure out what the right questions are.”

Wan used this as a teaching moment.

“In the past, we are taught about pandemics in a textbook and that they are far away from us — like the 1918 flu. But now, we’re in it,” Wan said. “This is a good opportunity to lead them through real situations. I’m sure when the students grow up and maybe become a professor or a scientist in the future, they will be ready to fight the next pandemic when it comes.”

As a student, Tang has learned a lot; she has never worked on a project quite like this.

“It’s been a really interesting experience because this is my first time working on something that has a pressing timeline,” Tang said.  “We need to get answers quickly because it’s causing so much damage. You’re learning about it, and you’re discovering new things with everybody else.”

Wan and Tang are grateful for the learning experience and the findings of this research.

“This study gives us a better understanding of how the virus is adapting,” Tang said. “But I think it’s good news that the pathogenesis is decreasing for disease severity.”

As with much Covid-19 research, this work has been shared to help advance an understanding of the disease prior to peer review. You can read more about Wan and Tang’s work in the article, “Increased SAR-CoV-2 shedding associated with reduced disease severity despite continually emerging genetic variants,” in medRxiv.

#IAmScience Maddie Graham

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#IAmScience Maddie Graham

By Becca Wolf | Bond LSC

When the pandemic hit, Maddie Graham’s lab life shifted focus.

The junior biomedical engineering pre-med student suddenly started to find answers by extracting RNA out of wastewater to help detect SARS-CoV-2, the virus that causes Covid-19, which reiterated how important science is in our lives.

“I don’t think medicine would be anything without research,” Graham said. “I think it’s really important to see the other side of things, understand how things have come to be and how they’ve made these medical advances. It was cool to be able to do something related to Coronavirus when the pandemic started.”

That understanding is something Graham never thought she’d seek out when she first came to Mizzou.

“I wasn’t planning on doing research because I didn’t think I would like it,” Graham said. “Originally I thought, ‘No, that’s okay I’ll focus on other things like volunteering and stuff.’”

But as she was taking classes, her friend Braxton Salcedo suggested that she work in the lab he was in.

“She has a good personality and is very intelligent,” Salcedo said. “She was a good partner in class, she pulled her weight and was a good communicator. When the professor said that he wanted to bring on more undergrads, I knew she would be a good fit.”

Graham thought it sounded interesting. She decided to apply and got the job.

Now, Graham has spent just over a year as an undergraduate researcher in the Marc Johnson lab at the Bond Life Sciences Center.

“At first I imagined that undergraduates just wash the dishes and stuff, but it was cool when he told me that you actually get to be part of the science aspect,” Graham said.

Starting out pre-pandemic, the Johnson lab focused on HIV. Graham was making new plasmids to help manipulate genes for the graduate students and Johnson to use. Now she studies SARS-CoV-2 in wastewater and community trends associated with it.

Graham’s perspective on research has certainly changed since she started. Now that she is in upper-level courses, she is starting to see an overlap between her learning and her job.

“I’m in Cell Biology, and the things I’m learning are directly related to things I am doing in the lab,” Graham said. “It’s cool when there are moments where I see why we’re doing certain things and the reasoning behind it.”

While Graham is experiencing research, she is still unsure of what she specifically wants to do once she gets to medical school.

“I have a lot of time to figure that out,” Graham said. “So somewhere down the road, after I get experience in other areas, I’ll hopefully know.”

The research is going to help her wherever she ends up.

“She has good hands-on experience here,” Salcedo said. “Just in general, she’s a good worker and she’s nice to be around too. I think camaraderie is one thing that our lab really has that I’m not sure a lot of other labs have. For the most part, all of the students in the lab get along really well.”

Covid-19 hasn’t just impacted her job, she also ended up adopting a dog at the beginning of the pandemic.

“We fostered her for a bit and then I decided to keep her,” Graham laughed. “It’s nice taking her on walks or to the dog park — except when it’s cold.”

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