M.D-PHD candidates Cynthia Tang and Brian Thomas share their experience applying for the NIH F30 Fellowship. | Photos by Roger Meissen
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.”
Thomas agrees.
“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.
Chandrasekaran investigates the phenotypes of the soybean plants and takes care of his plants by doing regular pruning and weeding. | Photo by Sarah Kiefer, Bond LSC
“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.
Chandrasekaran’s soybean plants are kept at Bradford Research Farm, the largest concentration of plots dedicated to research in Missouri, with 591 acres of land. He regularly goes to weed and take care of the plants, which are uneven in height and thickness because they are mutant plants. | Photo by Sarah Kiefer, Bond LSC
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.
Clayton Kranawetter, a postdoctoral fellow in the Lloyd Sumner lab at Bond LSC, recently received a USDA National Institutes of Food and Agriculture Postdoctoral Research fellowship in which he uses this mass spectrometry machine to study the significance of plant border cells. | photo by Sarah Kiefer, Bond LSC
By Sarah Kiefer | Bond LSC
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.”
Michaela Beedy, Brian Thomas, and Margaret Beecher work on aptamers in the lab of Donald Burke. | Photo by Beni Adelstein, Bond LSC
Shrinking the Target: Developing Cancer Therapies
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.
Margaret Beecher and Michaela Beedy worked in the Burke Lab over the summer.
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.”
Margaret Beecher points out the tube containing the aptamer treated with doxorubicin.
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.”
