Research skills aren’t built in a day, but Cynthia Tang’s diligence brought those skills to bear as she recently received a National Institutes of Health fellowship to further her budding career in science.
“Receiving the F30 fellowship means that the NIH sees value in my research proposal, in my training environment at the University of Missouri, and in my potential to become an independent physician-scientist,” said Tang, who works in Henry Wan’s lab at Bond Life Sciences Center.
This F30 predoctoral fellowship supports the research of students pursuing M.D.-Ph.D.’s. These awards help lighten the financial burden of a degree path that takes the better part of a decade for Tang and others pursuing their passions in research.
Tang came to the University of Missouri in 2018, started her journey as an M.D. student, then took a break to pursue her Ph.D. In the dual M.D.-Ph.D., the first two years are spent in pre-clinical studies followed by a full-time Ph.D. for three to five years and then students finish up with clinical training.
So, what project captured NIH’s attention?
Tang focused on how Covid-19 spreads and who gets it in rural areas. The aim is to identify people who have a higher chance of getting sick or being hospitalized so preventive measures can be offered earlier.
Lots of data must be gathered to accomplish this. Scientists sequence the genome of coronavirus variants to get a detailed profile and compare how that genetic makeup evolves over time. They do this by testing nasopharyngeal swabs—the Q-tips that are commonly used for covid tests—of people suspected of coronavirus infection. They use electronic health records to see who is getting sick, and add demographic information on age and location to the clues researchers analyze.
Tang focuses on rural populations in the U.S., especially in Missouri, because there is a gap in data from those communities. Once those at highest risk are identified, scientists can prioritize early prevention of COVID-19.
“Our biggest motivation for studying rural populations is so that we can better understand the way the virus changes and how to better serve those communities,” she said.
The process of planning for the grant itself enabled Tang to finetune the quality of her work.
“I feel like it helped speed up my Ph.D.,” she said. “We had to break down the research study into all the little pieces of what needs to be done and what to do when things go wrong. Everything must be so well thought out to put the grant together.”
After Tang’s initial fellowship application was rejected, she challenged herself to put together a completely new study design in under two months for her second proposal.
“It was the best thing that ever happened” said Tang, smiling. “I am extremely grateful to Dr. Wan and my thesis committee.”
This fellowship has provided many opportunities to Tang. She traveled overseas to present her findings at international conferences, which connected Bond LSC research with an international science community. Last year she was in Belfast, Ireland, and this month she will be in Valencia, Spain.
Where is Tang now?
She’s working remotely as she wraps up her Ph.D. and will graduate from Mizzou this upcoming December. Once she secures that Ph.D., she will head out to the University of North Carolina at Chapel Hill in January 2023 to finish her clinical training. Then she will enter the homestretch of her dual degree journey, finishing her M.D. in May of 2026.
Cynthia Tang currently serves as president-elect of the American Physician Scientists Association and will continue in this role next spring.
The spikes that protrude from SARS-CoV-2 present a topography of peaks that drive one MU researcher to ask more questions.
To Kamal Singh, a principal investigator at Bond Life Sciences Center, assistant professor in the MU College of Veterinary Medicine, and the director of the Molecular Interactions Core those spikes are a changing map with every new variant of coronavirus, and they lead his lab to study its constant evolution of mutations and proteins.
The Singh lab recently found an unexpectedly high number of APOBEC-mediated mutations among a patient cohort from South India, who were vaccinated and have taken remdesivir to treat COVID-19. Using data from patients from South India, Saathvik Kannan, a senior at Hickman High School and a computer programmer and researcher for the Singh lab, tracked changes to the virus’ proteins.
“Viruses are known to evolve under pressure, so what’s happening in this case is that antibodies recognize the virus in a cell, and the virus sees that, ‘okay, there is someone to stop me,’ so it makes mutations,” Sing said.
The virus’ genome often alters, by mutating, inserting, or deleting the building blocks within RNA and DNA known as nucleotides, depending upon the pressure that viruses experience. Only some of these sugar-containing nucleotides are mutated, but these small changes can form a new virus variant.
“A few months ago, we didn’t know the reason behind all of these different mutations in patients because we did not look for APOBEC-mediated changes in viral genome,” Singh said.
Kannan found that between October 2022 to January 2023, the mutations among the patient cohort varied between 114 to 83. With that information, he identified 50% of patients who have diabetes and that when they take insulin the APOBEC protein is also induced. This new discovery leads to more questions about those with underlying conditions like diabetes or hypertension, and how they are affected differently by the drug.
“Ideally if a virus were to evolve you would see a linear progression, but you don’t see that here,” Kannan said. “This shows us that APOBEC proteins are likely one of the causes of this evolution in the virus and the makers of these variants.”
When the number of mutations vary significantly, like in the cohort, it re-affirms that the COVID-19 variants evolve independently.
Viruses don’t stop to wait for researchers to find the root of the problem. They constantly change, and in cases where the patients are vaccinated and take remdesivir, the virus evolves by taking advantage of the APOBEC protein.
Singh started down this path of research early on in the pandemic. Through PCR tests — which converts tiny amounts of RNA into DNA then copies it to a measurable level — he learned more about each mutation by comparing new samples to the original viral strain. Until this point, there had only been around 40 identified mutations in the spike protein in the different XBB sub-variant, but Singh’s lab has identified two more. The details have been recently published in The Lancet Journal. The two mutations found in this process, A27S and T747I, were unique to this cohort.
“For the first time we’re able to get more clues on what is actually happening because we were able to compare it to patient samples in the XBB subvariant and we had a wealth of data to work with,” Kannan said.
The Omicron variant yields new mutations constantly — currently at 43 and counting — and presents plenty of opportunity to look for differences. Singh directs his team to comb through variant sequences to identify differences in their genetic code. Soon they begin to identify trends from one month to another.
“The main difference here was that we have high quality patient data this time, from a patient cohort in Southern India, as opposed to getting it from a database,” Singh said. “The patient cohort tells us that the mutations are more than what was reported before.”
After new variants — such as the XBB sub-variant of Omicron — materialized, Singh’s lab identified existing drugs and new drug compounds that match structural weaknesses presented by mutations.
One way Singh’s lab keeps abreast of new variants is by utilizing the tools they have available to their advantage with in-house programs either in Python or in R programming languages. Their lab can construct non-infectious, virus-like particles that contain all the same characteristics as the virus minus its genome, or its genetic material makeup.
A collaboration between University of Missouri and University of Nebraska Medical Center helped identify the new drug compound, MU-UNMC-2 in addition to the MU-UNMC-1, previously found in late 2021, as potential coronavirus treatments.
Remdesivir, ribavirin, favipiravir, and molnupiravir were among existing drugs that can be used to treat COVID-19 under certain conditions. Remdesivir — previously ineffective as an Ebola virus treatment — initially proved somewhat useful for COVID-19. Molnupavir only showed moderate promise, and the two drugs were approved for emergency use by the FDA for the treatment of COVID-19. Remdesivir now has full FDA approval.
“To address the problem, you have to find the problem. Where is the virus? What can we address? And then we go after it,” Singh said. “My lab was the first one in the world who suggested when the pandemic came that these are a few drugs that can be used and remdesivir was one of them. I’m very proud that I could contribute to human health in that way.”
With knowledge of this new protein in hand, Singh’s lab now is moving forward to focus most of their attention on the APOBEC protein mediated mutations and how underlying health conditions can affect an individual’s reaction to certain drug compounds.
“The virus has been outsmarting us, outfoxing us, until now. As soon as we get something, it changes itself,” Singh said. “That keeps us motivated as we chase it.”
The Singh lab’s research on the XBB sub-variant mutations was published in the paper ‘Omicron SARS-CoV-2 variant: Unique features and their impact on pre-existing anitbodies’ in the “Computational and Structural Biotechnology Journal” in June 2021 and their updated findings can be found in the paper ‘Clinical characteristics and novel mutations of omicron subvariant XBB in Tamil Nadu, India – a cohort study,’ published in “The Lancet Regional Health – Southeast Asia Journal” in April 2023.
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.
The hunt for emerging coronavirus variants keeps Torin Hunter busy testing samples from sewer systems across Missouri.
As a part of The Sewershed Surveillance Project, Hunter has spent the last year and a half taking each test tube and carefully filtering the samples to contribute data on how SARS-CoV-2 can be present in our communities.
But Hunter started his journey in virology like many — a student trying to sift through all the different subjects and figuring out what fit him the best. He tried out clinical jobs and considered going into the health professions, but he began to miss the lab and research more than he thought.
“I missed the freedom and the creativity you get from research while still being able to do science and complete it all by yourself. It’s more fun and satisfying to me,” said Hunter, a senior research technician in the Marc Johnson lab at Bond LSC.
Virology, the study of viruses, stuck for Hunter.
“I like the blend of molecular virology and epidemiology here because it is fascinating to see the public health implications of what we are studying,” he said. “Even though our work has focused on coronavirus in the past few years, I would still want to be doing this type of work even if it were involving a different virus.”
As a senior research technician, Hunter enjoys projects where he can think through an experiment and work backward if problems arise. Using his analytical skills, he can determine if the experiment was meant to go in a certain way or if the issues can be boiled down to human errors made along the way.
“Starting an experiment and then getting real results from it that make sense is the most exciting part of my job,” Hunter said. “Knowing that I did it by myself and that I accomplished something I worked hard on is a great feeling.”
Originally from Orange County, California, Hunter moved to Missouri when he was 16 and knew he wanted to attend the University of Missouri not long after that. In high school, he began to take an interest in the inner workings of cells, which is where biochemistry comes into his life.
He went on to earn his bachelor’s degree in health science from Mizzou and his master’s degree in microbiology and cell science from the University of Florida. When Hunter took his first undergraduate class in biochemistry, he became hooked on the subject and its value in a research setting.
“Biochemistry is when everything clicked in the life sciences for me, and it made the most sense to me, but the subject is so broad that I still didn’t know exactly where to go from there.”
Hunter works daily with samples of human waste systems across the state. He extracts viral nucleic acids (such as DNA or RNA) out of the samples using polyethylene glycol or magnetic beads and sends them off to a collaborating lab. The lab then performs digital polymerase chain reaction (dPCR) to quantify, or measure, the viral load of SARS-CoV-2 in the wastewater samples. The process can be compared to a nasal swab coronavirus test, but instead of simply measuring the virus’ presence, the amount of virus in the sample is measured as well.
The amount of each marker is graphed on a chart, and these charts are analyzed and monitored in collaboration with public health officials to compare trends across the state. Hunter finds it interesting to learn about how different viruses cause disease.
“If we can better understand why and how viruses cause harm to people, we can develop more therapeutic or preventative options like vaccines and help a lot of people in the long run,” Hunter said.
Hunter performs these steps often and finds that this type of work takes a certain amount of discipline. He meticulously combs over his notes and studies the details of his experiments and what might have gone wrong in the procedure.
“You go through every possible way that something could go wrong, but if those are still your results, you might just have to go further back in your process or go in a different direction entirely,” Hunter said. “That’s what makes this work so interesting, is that you’re always problem-solving.”
In his time away from the lab, Hunter enjoys playing video games, weightlifting, and cooking to turn his brain off after a day of experimentation.
“It’s important and healthy to have a work-life balance,” Hunter said. “I will often think of new dinner recipes to try and make as my own way of experimenting at home.”
After his research at Bond LSC, he plans to apply for Ph.D. programs this fall to continue his studies in virology. Specifically, he would like to learn more about immune responses to viral infections.
“Everybody has to work, and if you’re going to work hard at something, you might as well do the thing that you enjoy the most,” Hunter said.
Brian Thomas got the official letter in the mail Monday after months of waiting.
“It’s a long time coming,” he said, “lots of patience and collaboration.”
Thomas is one of two student scientists at Bond Life Sciences Center to receive F30 fellowships — officially the Ruth L. Kirschstein National Research Service Award (NRSA) — from the National Institutes of Health (NIH) this year, a first for MU.
The agency awards F30 fellowships to MD-Ph.D. students pursuing related areas as they work towards their doctoral degrees. Those awards add up, with up to six years of funding to cover costs of research and clinical training.
When Thomas originally applied, his proposal was rejected, but the second time was the charm. He studies cancer immunology in the lab of Donald Burke at Bond LSC.
“You learn from failure, reflect on it and grow,” he said. “You learn to think critically about your research proposal and organization.”
Cynthia Tang — also working toward her MD-Ph.D. dual degree — got official word about her award ahead of Thomas. It allows her to continue her research in the lab of Henry Wan at Bond LSC. She researches the evolution and spread of Sars-Cov2 — the cause of the Covid-19 pandemic. Her proposal was also rejected the first time, yet she persevered. She encourages other students to apply for the fellowship.
“You should really go for it. It seems like a lot, and it can be really intimidating when you look at the checklist and all the components,” Tang said. “But it is possible, and it is doable.”
Both students are thankful for what the fellowship has done for them. It pushed them to navigate the highly competitive grant application process as well as clearly outline their goals and ambitions.
“We have an incredible grants team and our faculty is amazing,” Tang said. “There are so many resources available at Mizzou.”
“We have fantastic directors doing a wonderful job growing the environment of our programs and tending to our student’s needs,” he said.
This NIH fellowship is an opportunity for students to pursue their passions in science and research while alleviating financial burdens, giving researchers like Tang and Thomas the tools to succeed.
The Tom and Anne Smith MD-Ph.D. Program at the MU School of Medicine is a seven- to nine-year course of study that combines the traditional four years of medical school with the three to five years typically required to earn a doctorate in a scientific discipline. It prepares students for a career in academic medicine.
About Bond LSC At Bond Life Sciences Center, the best answers come from working together. Our building and culture leverage expertise of faculty investigators to develop discoveries that matter. Our researchers represent diverse academic backgrounds with projects focused on infectious diseases, agriculture, informatics, the environment and other areas. By moving beyond the boundaries of departments, our research increases its impact and lays the groundwork for a better world while teaching the next generation of scientists.
With a forceful swing of his badminton racket, Vikranth Chandrasekaran propelled the shuttles across the court. A game with coworkers and friends is the perfect way to wrap up a day in the lab for the postdoctoral fellow. He’s offered to teach his colleagues the strategies of badminton at the University of Missouri Rec Center.
“When I initially embarked on my journey in badminton as a beginner, I received invaluable assistance and guidance from numerous South Korean individuals who graciously taught me the proper techniques,” he said. “Now, I feel compelled to reciprocate this kindness by offering my help to those who aspire to learn badminton.”
As a postdoc in the Bing Stacey lab at Bond LSC, Chandrakaran has the opportunity to help others through soybeans, and his path here started in South Korea with Gary Stacey.
During the joint venture conference between the University of Missouri, USA and Gyeongsang National University, South Korea, Chandrasekaran found Stacey’s research talk fascinating and made him want to visit Bond Life Science center.
“I want to find the answers behind many unknown questions and be the one to make new discoveries,” Chandrasekaran said.
Chandrasekaran is from a land of gold mines: Karnataka, India. Coming from Kolar Gold Fields, he can appreciate searching for the nutrients within our food and his past planted the seed for his future.
“My motivation for what I do comes from my strong determination and passion towards plant science for the betterment of humankind that I have,” Chandrasekaran said. “My childhood aspiration was to achieve the highest degree in the scientific field, a doctoral degree, and with unwavering support from my parents I was able to realize that dream.”
Chandrasekaran deals with soybeans and the macronutrients they provide. Soybeans are an important source of protein for a vegan diet especially, with a single seed consisting of 40% protein and 20% oil. The crop is a leading source for vegetable oil and protein production, providing 60% of global oilseed production and more than 25% of the in food and animal feed worldwide.
“Engaging with academic theories for research proved to be profoundly challenging because they often neglected the intricate trial-and-error nature inherent in research endeavors,” Chandrasekaran said. “But research entails a myriad of trial-and-error processes, involving a multitude of fine-tuning techniques that extend beyond the scope of conventional academic teachings. These trial-and-error methods lead me to learn more and help me to solve a problem in my research in a more effective way.”
In the Stacey lab he finds the genes responsible for high protein and oil content in order to then edit DNA to increase the amount of protein and oil contained in the plant. Less than 30% of the genes in soybeans and 70% of those in rice have been identified, so Chandrasekaran aims to find more.
“I was first fascinated with research because of the DNA double helix structure and how we analyze things like that,” he said. “I was always focused on the theoretical part of academics, but then all of the sudden I was really curious about the research side as well.”
When he screens the soybean plants for genes, he pays attention to the visible phenotypes, that the plant makes in response to a procedure using fast neutron radiation (ϒ rays or gamma rays), which is often used in cancer patients to treat tumors. For each phenotype there are many genes competing to express themselves, so Chandrasekaran deciphers which traits are likely distinct, or abnormal phenotypes, when compared to normal soybean plant.
He finds a calmness in this type of work much like the tranquil feeling he experiences when he travels to places such as the Rocky Mountains.
“The drive was about 13 hours and that scared me at first,” he said. “But when I was driving, I was calm and got to experience for the first-time incredibly beautiful scenery that I had never seen before which made the drive worth it.”
He also frequently makes the 405-mile trip to Chicago to visit his childhood friend and their family each month. A long drive gives Chandrasekaran time to think and makes him more motivated about his work when he returns.
“Taking short breaks from continuous lab and field work helps me to feel happier, have more energy and focus more on my research,” Chandrasekaran said.
He uses travelling and a game of badminton with coworkers and friends to wrap up a day in the lab or take time to think on the road he is paving to making scientific discoveries. He hopes to continue his work in the field and secure a position as a crop scientist or to start a research lab of his own one day.
Some of the most fascinating things in science happen at the border where one organism interacts with its environment.
That’s the case with root border cells, and Clayton Kranawetter is one individual exploring this frontier.
Kranawetter recently received a $223,000, two-year USDA National Institutes of Food and Agriculture Postdoctoral Research fellowship for his project on this group of cells. This fellowship is a part of a larger $12 million investment in multiple institutions by the USDA to expand research in the area of agricultural microbiomes. The University of Missouri is among 17 research institutions to receive funding.
“I’m still shocked by receiving the award. I was already having a good day when I received my award notice. I found a good parking spot in the garage and a quarter on the sidewalk, but then I got the email” said the postdoctoral fellow in the Lloyd Sumner lab at Bond Life Sciences Center. “I thought it was a mistake at first and then I realized, ‘oh, this is real.’”
This fellowship will sustain his work in an influential way as he dives into the secreted metabolites and mechanisms of isolated border cells and their impact on rhizosphere dynamics.
Metabolites are small molecules made or used when a cell breaks down food, reacts to certain signals or completes other essential processes. Some metabolites, such as glucose, are part of an organism’s central or primary metabolism and its basic life functions. Other metabolites, such as secondary or specialized metabolites, are less essential to sustaining life but no less integral as they help with plant defense responses. Identifying these metabolites can help researchers predict how plants will react to various biotic and abiotic conditions, such as high light, stress from salt, symbiotic interactions, and defense against pathogens.
“I love science because everything is a puzzle,” Kranawetter said. “Sometimes the puzzle is a struggle to put together and can look quite different from what you expected, but after everything is complete, it is always rewarding and empowering to see how the pieces fit together.”
Kranawetter’s work focuses on root border cells, which are vital to plant root health. These cells arise from the root epidermis, where the cell wall breaks down and the cells are physically released from the root but still surround the root tips. Border cells are held in place through a water-soluble, complex secreted matrix consisting of a polysaccharide mucilage, comprised of DNA, proteins, and metabolites. As their encasing material is water soluble, upon contact with water they wash away but are rapidly replaced within 24 hours after their removal. After border cells separate from the root tip, Kranawetter conducts large scale genetic reprogramming to divert most of their resources to secretion and specialized metabolism. In doing so, they serve a protective role against infection and environmental stress, but the scope of their functions is far from fully explored.
“Border cells are still very niche, and we don’t fully understand how they’re contributing yet, but we’re starting to see that they are more major players in the rhizosphere than we thought initially,” Kranawetter said.
Root border cells appear across most plant species. They are known influencers of dynamics within the rhizosphere — the layer of soil that is in direct contact with root secretions — but there are still a large number of unknowns about them.
Kranawetter’s previous work dealt with metabolites, or small molecules, and their differential accumulation in root tissues. He collected root border cells and separated individual root tissue types to create a metabolite atlas based on the Arabidopsis eFP browser – a computer program that shows the relative intensity of metabolites by tissue type in a heatmap context. This project builds on his work to further identify the molecules border cells secrete and how they mediate plant-microbe interactions.
Although this project does not directly correlate with his current research in the Sumner lab focused on differential metabolite accumulation in cultivated elderberry plants, it will allow Kranawetter to stay in plant tissue research, build on the foundational mass spectrometry knowledge he accumulated during his Ph.D. and incorporate microbiological techniques to border cells.
“Working on elderberry plants was a good chance for me to start a different project in a distinct plant system, which has been nice,” he said. “And this fellowship will be a great opportunity to apply my current research skills and knowledge base while also developing new abilities.”
For the NIFA fellowship, Kranawetter generated a project narrative, abstract, budget, a logic model, references, and a data management plan, among many other materials. He also utilized a three-member administrative board to support and look over the project in order to assist and give feedback each step of the way.
“This will be a project for me to get out of my comfort zone and gain new expertise compared to what I have done in the lab previously,” Kranawetter said. “It’s nice to have a different perspective when, instead of having a bunch of giant elderberry bushes in the greenhouse, I’m working with three-day-old seedlings.”
The fellowship allots Kranawetter the resources and time he needs to monitor border cell metabolite secretions and their methods of secretion. Kranawetter also observes the bioactivities within an organism living in symbiosis with its pathogens, the microorganisms that cause disease.
“The field of mass spectrometry allows me to apply novel technologies and software systems, while plant sciences allow me to explore the vast diversity of compounds that plants naturally produce,” Kranawetter said.
Kranawetter applies what he knows about border cells in experiments on Medicago truncatula — a close relative to alfalfa — and observes how border cells use their secretions to affect the rhizosphere.
“The question we’re aiming to answer is how are these secretions going into the environment and what role are they playing,” Kranawetter said. “I wanted to get back to my roots with this because as a mostly technical lab, I haven’t done a lot of molecular biology in some instances.”
Kranawetter first removes the seed coat from M. truncatula and sterilizes them in order to protect them from bacterial or fungi contaminants. Next, he places the seeds on a petri dish containing water agar overlaid with sterile filter paper so that the roots remain on top, as opposed to normal methods of plating directly on top of the agar. This ensures that the roots do not penetrate the agar, where border cells would be lost. Although some cells are still lost due to the minimal contact with the filter paper, most remain for later harvest. The final step is to dip the roots in water and harvest border cells — ones that freely come away from their root system — for closer investigation.
As part of his fellowship, Kranawetter is probing for transcripts and proteins associated with metabolite secretion. His results will help determine how border cells affect their environment through their secretions. Kranawetter’s interest in this field stems from his love of plants and technology, both of which he uses in his daily lab work.
“One of the major benefits of being in the Sumner lab is that we’re getting to use very sophisticated instrumentation and applying it to something that we probably would not have been able to examine otherwise,” Kranawetter said.
Kranawetter’s fellowship lasts 2 years, so he hopes this exploration expands our understanding of border cell interactions with the rhizosphere.
“I love this type of research because I get to do a lot of different things! I grow plants, work at the bench, and also use cutting edge instrumentation,” Kranawetter said. “Being able to work in such a diverse manner makes me feel empowered as a scientist.”
The U.S. Department of Agriculture’s National Institute of Food and Agriculture (NIFA) announced an investment of $12 Million to Advance Research in Agricultural Microbiomes. Microbiome research is critical for improving agricultural productivity, sustainability of agricultural ecosystems, safety of the food supply, carbon sequestration in agricultural systems, and meeting the challenge of feeding a rapidly growing world population. Research supported by the Agricultural Microbiomes in Plant Systems and Natural Resources program area priority within the Agriculture and Food Research Initiative (AFRI) will help fill major knowledge gaps in characterizing agricultural microbiomes and microbiome functions across agricultural production systems, and natural resources through crosscutting projects. AFRIis the nation’s flagship competitive grants program for food and agricultural sciences.
Instead of taking on more clear and straightforward science, she dove into vessel regeneration and never looked back as she works on the burning question, ‘can muscles regenerate in the absence of blood vessels and vice versa?’
“Knowing how vessels grow back can one day improve treatment options and help someone who has suffered a traumatic muscle injury and I really like contributing to that, but at the same time I want to know and do more right now” said the D Cornelison lab member.
Diller studies the interaction between regenerating muscle and blood vessels after a traumatic muscle injury and the role of ephrin-B2 (an essential protein for blood vessel formation during development) in blood vessel regeneration and when it is no longer necessary for development. While she studies these questions, she sees the connections in friends, colleagues and hobbies.
“One of my best friends works in the NICU [Neonatal Intensive Care Unit] as a social worker, and it can be hard for us to find common ground in terms of our careers,” Diller said, “but I started working on development and she was like ‘oh we see that in the babies too’ and then all of a sudden we had this crazy crossover between social work and mouse development.”
Recognizing these similarities lets Diller find new research skills and learn from others outside the field.
“It’s crazy how I can talk to an ecologist friend of mine who’s studying something completely different from me, and then they have an idea or say ‘have you tried this,’” she said. “Sometimes that leads to inspiration to help deal with a setback.”
Balance outside work helps with setbacks and obstacles within her research project. Diller tends to spend her free time on activities that prioritize her health, her relationships with her husband and friends, and her dog, Harry. She takes her dog to agility classes, but finds Harry is more in tune with the program than she is.
“I’m constantly being corrected by the trainers because you’re not supposed to step in front of your dog, and Harry just stands there and looks at me like ‘How do you not get this mom?’ But it’s a fun activity for us to do together, so I continue doing it,” Diller said. HIIT and resistance training classes bring more balance and a chance to interact with those outside the research field.
While Diller’s hobbies come in waves, her love for research persists as she expands her work in the realm of muscle regeneration.
Currently, the Cornelison lab is using conditional knockouts—a technique used to eliminate or delete specific genes from the mouse’s DNA—and pharmacological methods to inhibit angiogenesis – the process through which new blood vessels form—to study the impact impaired blood vessel regeneration has on muscle regeneration. The team looks at hints within the vessels and vessel network, such as new growth (i.e., tip cells), vessel dilation, vessel branching, as well as other structural deformities such as anastomoses (i.e., a connection between blood vessels). But Diller is always striving for more with her work.
Resilience is key when often each new discovery raises more questions about how vessels regenerate.
“As a grad student it’s really important to have coping mechanisms for the level of stress that you go through,” Diller said. “When something fails, being able to take a step back and stop thinking about it helps a lot. And once you’ve calmed down, the best way to deal with it is by talking to the people around you.”
Diller recently graduated from the University of Missouri and has accepted an NIH fellowship at the University of Florida to study the effect of hyperbaric oxygen treatment on vessel regeneration in the diaphragm in a spinal cord injury model. Diller is excited to work specifically on diaphragm recovery options and take this patient-focused opportunity.
“Science is for everyone, which sounds cliché, but I think that there is an aspect of science that almost everyone can relate to. It’s not always going to be the same thing for each person, and I like how science connects people through their differences.”
As cancer cells multiple and spread, doctors face finding treatments that destroy tumors while doing the least amount of damage.
This search for precision in cancer therapies is for good reason. It takes only a few minutes in a chemotherapy clinic to see the detriment of cancer drugs on the rest of the body.
“The issue with chemotherapeutic drugs is they have a lot of off-target effects,” said Brian Thomas, a MD-Ph.D. candidate working in the Donald Burke lab. “Our goal is to make them more targeted towards cancer cells using aptamers.”
Careful targeting of treatment is one important goal of cancer researchers, and aptamers are one way scientists at Bond Life Sciences Center work toward that goal.
Aptamers are short, single stranded DNA or RNA molecules that can bind to a target when it folds into a 3D structure. They can either serve as a vehicle for a cancer drug — delivering it to cancer cells while avoiding healthy cells — or bind itself to a cell’s receptors to interfere with its natural response.
In the Burke lab, the target of choice is epidermal growth factor receptors (EFGR), a protein that helps cells grow and spread. Mutations — mistakes in the DNA that makes this protein — can increase the number of EFGRs and cause cells to grow out of control, ultimately leading to cancer. The goal is to test how to best ensure aptamers successfully bind to cancer cells so they can be destroyed.
Michaela Beedy, an undergraduate research assistant in the Burke lab works alongside Thomas. She is focusing on pairing aptamers with the chemotherapy drug doxorubicin to better target mutated cancer cells.
“Doxorubicin is really good at killing cells that are fast proliferating, which includes cancer cells and epithelial cells,” Thomas said. “It is also really good at killing cardiomyocytes, which is not a good thing.”
The goal is to get doxorubicin to kill the cancer cells but to leave healthy cells like those heart muscle cells alone. Ideally, the cancer can be treated without posing too much risk to other vital organ functions.
Additionally, patients who undergo chemotherapy often develop resistance to a drug as newly mutated cancer cells become immune to the old therapy. That is why she is focusing on addressing specific aspects of what causes mutations.
Margaret Beecher, another Burke undergraduate, is testing a different hunch that could work in conjunction with Beedy’s work. Beecher investigates if dimeric aptamers might provide more of a targeted effect.
“Monomeric aptamers only have one spot that can bind to EFGRs while dimeric have two,” Beecher said. “Because there are two spots, this increases its avidity.”
Avidity is the combined strength of binding, and it is critical in getting a drug to interact with its appropriate target. This could be applied to Beedy’s doxorubicin approach.
“If we end up killing more EFGR-mutant positive cancer by using aptamer-doxorubicin treatment we could bring in the dimeric aspect as well to increase the effect of the therapy,” Beedy said.
The treatment in question is aptamer-doxorubicin conjugates, essentially a combination of the three.
Even if Beedy’s approach isn’t as effective at killing more mutant cells, Beecher’s research still comes in handy.
“If we saw less of a targeted effect because the aptamer wasn’t binding as well, maybe adding that dimeric aspect to it can help bring it back up to be on par with other treatments.,” Beecher explained.
New cancer therapies couldn’t come at a better time. Right now, the U.S. is in the midst of one of the worst cancer drug shortages in history due to manufacturing issues, leaving Thomas optimistic about the work in his lab.
“Right now, we’re doing in vitro…doing things in a dish. The ultimate goal is to get these treatments into animal models and, subsequently into humans to then finally create new therapies for patients in need.”
For Elaina Sculley, the word filter means much more than narrowing down your search results on a website.
The second-year animal sciences graduate student spends her days using computer programming tools as part of her bioinformatics studies and her work in Wes Warren’s lab at Bond LSC. Her focus is on the chicken immune response because they serve as invaluable models for studying immunology due to their widespread use in both commercial breeding and scientific research.
Her main objective when studying host immune response is to gain a better understanding of candidate genes and pathways involved in the immune response which is crucial to determine the underlying mechanisms of immunity and the potential in genomic selection schema.
“I think it’s something that is fascinating because it is yet to be fully understood, which sparks my interest,” Sculley said. “There are so many different components and factors that play a role in how chickens respond to a bacterial pathogen.”
Sculley earned a bachelor’s in animal sciences and a certificate in animal nutrition from Colorado State University. Her background in both wildlife animals and agriculture helps her understand the detrimental effects diseases can have on a variety of species.
In the U.S. there are billions of chicks hatched each year and they are among the world’s most important food source, which means their resilience to pathogen infection is an immense economic concern worldwide. Therefore, managing bacterial infections in the poultry industry continues to be important for protecting a global food supply. In recent years, more emphasis has been placed on enhancing host resistance, which has various external factors influencing each bird’s level of immunity. Her goal is to create strategies that enhance the hosts immune response and minimize the infectious disease impact they have on the poultry population worldwide.
She splits her time in the Warren lab working on bioinformatic analysis for 80% of the time and spending the other 20% doing wet lab procedures. Sculley isolates nuclei and high-molecular-weight DNA from tissue samples during her wet lab time and sends the samples off to the University of Missouri Genomics Technology Core for single nuclei RNA sequencing.
Once Sculley receives the snRNAseq data from the Genomics Technology Core, she determines which genes are up or down regulated in response to the bacterial pathogen.
She takes the snRNAseq results and uses a Seurat pipeline – a more specific form of bioinformatics analysis – to create cell type clusters based on similarities between cell types. For example, if a gene is up regulated or down regulated in response to a bacterial pathogen in the chicken spleen, Sculley can draw connections about why that might be based on the cell type identity of the cluster that the gene was found. The insights gained from these findings could contribute to the development of gene candidates that when selected upon offer effective new strategies to enhance immunity against bacterial infection in poultry populations.
Similar to a game of Tetris, each cluster of cells must be sorted into groups and certain elements must be removed in order to piece together the puzzle and win the game – or in this case, break down the chicken’s genetic code.
“This is mostly trial and error, where you manipulate the data in a way that is informative,” Sculley said. “It’s really complex. Sometimes I have to start over and rerun it through the same pipeline to make sure it all aligns in order to get the analysis to work. It takes a lot of patience and willingness to start over.”
As Sculley types away at her desk, she finds that minor edits she makes to the code make all the difference and contribute to an increased understanding of the chicken’s response to a bacterial challenge.
“It can be very draining and stressful when you don’t get informative output and you’ve been working on something for hours,” Sculley said. “You just have to be like, okay, I didn’t get it this time, but I’m going to go back later when I have a fresh mind because pushing myself to a point of burnout isn’t going to fix anything.”
Another way Sculley prioritizes her work-life balance is through a routine at home, free of screen time after a full day on the computer.
“I like this type of work and I work hard, but I enjoy going home, unplugging, and doing my hobbies.” Sculley said. “I love to do yoga and hang out with my French bulldog, who is very playful. She’s my bestie.”
When Sculley was in her first year of graduate school, she had classes and homework on top of laboratory work, filling her days with computer programming. But now, she finds that working with data for publication and having more flexible deadlines helps her have a work life balance.
She plans to apply for a Ph.D. program by the end of the year and continue to study avian single-nuclei studies to expand her knowledge of immune cell types in chickens, as well as their transcriptional responses to bacterial pathogens. The identified gene expression signatures and enriched immune-related pathways in her studies provide a foundation for future research in poultry immunogenetics and disease resistance. Her goal is to develop effective strategies to enhance immune responses and mitigate the impact of infectious diseases in poultry populations worldwide.
“I like science because we’re constantly changing and we’re always having to adapt and learn new things,” Sculley said. “I think some of the best people and leaders are lifelong learners.”
It takes a keen detective to sleuth out why and how particular genetic mutations present the severe symptoms seen in neurological diseases.
The labs of Chris and Monique Lorson are one step closer to understanding one piece in the puzzle for spinal muscular atrophy with respiratory distress (SMARD1) and Charcot Marie Tooth 2S (CMT). They recently identified that the protein ABT1 appears to regulate the activity of IGHMBP2 by means of its interaction with it.
Their NIH-supported studies were recently published in JCI Insight with lab member Gangadhar Vadla as first author.
IGHMBP2 is a protein that causes SMARD and CMT2S. In these two rare neurodegenerative diseases, people inherit a mutated IGHMBP2 gene from each parent. The primary clinical presentation for SMARD1 is respiratory distress and without intervention patients typically die within the first two years of life. CMT2S, while less severe than SMARD1, presents with motor function and coordination defects that substantially impact patients’ lives. SMARD1 and CMT2S patients both demonstrate degeneration of the motor neurons within the brain and spinal cord.
The Lorson’s have built a career out of investigative work, looking into spinal muscular atrophy (SMA), spinal muscular atrophy with respiratory distress (SMARD1), and Charcot Marie Tooth types 1A, 2S and 2E.
When it comes to SMARD1 and CMT2S, understanding how cellular processes are altered when IGHMBP2 is mutated, and how particular mutations present in a clinical setting, is key towards developing therapeutic options.
The Lorson labs approach these studies using genetics and biochemistry. They generated a series of mice with Ighmbp2 mutations that correlate with patient mutations, showing traits of SMARD1 or CMT2S, depending on what particular Ighmbp2 mutation is present.
“ABT1 is the first protein found to modify the SMARD1 phenotype in mice through its association with IGHMBP2”, said Vadla, a postdoctoral fellow in the Lorson Lab.
They identified ABT1 as a modifier using an ABT1 gene therapy approach.
“Animals receiving the ABT1 gene therapy showed modest improvements in lifespan and motor function tests, consistent with a modifier, while untreated animals did not, “ Monique Lorson said.
The Lorson lab addressed three primary questions: do IGHMBP2 and ABT1 associate and how stable is this interaction, second, does this interaction change any of the activities associated with IGHMBP2 and, if so, what activities, and, third, can we use this interaction to understand what the role of the IGHMBP2-ABT1 complex is within cells.
“These questions, while seemingly simple, are really important in that is unknown how mutations in IGHMBP2 lead to SMARD1 or CMT2S, “ said Monique Lorson.
Their results demonstrate a strong association between IGHMBP2 with ABT1, and that binding of IGHMBP2 with ABT1 significantly increases biochemical activity of the IGHMBP2 protein. The studies also provided evidence towards the potential role of this complex in 47S pre-rRNA processing. 47S pre-rRNA processing is necessary to generate ribosomes used in the process of translation. Translation is the process cells use to make proteins.
“Because translation is required to make proteins, if you don’t have proper 47S pre-rRNA processing, some aspects of translation will be significantly impacted, putting the cell under a lot of stress,” said Monique Lorson. “The big goal now is demonstrating that 47S pre-rRNA processing and translational defects are present in Ighmbp2 mutant mice and that these defects result in disease.”
Now, the Lorson lab is testing their findings by creating IGHMBP2 that mirror those seen in real patients to study whether the interaction between IGHMBP2 and ABT1 is altered in any of these mutants.
Why is this finding important?
ABT1 is the first protein found that modifies the severity of disease in Ighmbp2 mutant mice. This is one step towards understanding how IGHMBP2 protein functions within cells and how mutations in IGHMBP2 lead to disease. The progress is only possible with involvement from many Lorson lab members and Bond LSC collaborator Kamal Singh.
“Everyone came together and played an important role, “ Monique Lorson said. “The Lorson lab works well as a team because we all try to make each other better scientists.”
This project was special to the Lorson family as it was the first time Chris, Monique and their son, Zachary Lorson, published their findings together.
She finds this work maintains her passion for science because she hopes their contributions can someday make a positive impact on SMARD1 and CMT2S families.
“When you feel like you can make a difference and not only impact people’s quantity of health, but also quality of health,” Monique Lorson said. “That makes coming into work really easy.”