Art and science are often considered opposites, but Beatriz Praena Garcia sees overlap.
“I think in this job you need to be very artistic,” Praena said. “I have a basic methodology to do the essays … then I read a little bit online. You can search in another paper and do some research to see how you can apply it to your work. You can be more creative, so it’s not always the same.”
The postdoctoral researcher studies influenza vaccines in the Henry Wan lab, tackling them from three angles. She works to improve vaccine effectiveness by growing it in different types of cell lines and eggs. She also works to improve mouse model systems for her lab and studies the influenza virus receptors.
Praena worked on antivirals for herpes before coming to Mizzou, and the switch to vaccines was a welcome change for her.
“I always wanted to study vaccines. . . there are a lot of antivirals already in the war against viruses. I want to give something [new] to the community,” Praena said.
Praena started in the lab right out of high school in a two-year technical training program where she worked in a biology lab.
“In high school, I was not a very good student, so when I finished high school I didn’t go to the university directly,” Praena said.
Once exposed to the lab, Praena knew that was where she wanted to be.
“I realized this is good for me. My score was very high in the class, and I said, ‘Oh, I will try to go to the university,’” Praena said.
Growing up in Spain, Garcia attended Autonomous University of Madrid for undergrad where she started research on herpes antivirals and its receptors. She stuck with that research for the next eight years, working in the same lab for her masters and Ph.D. studies.
Praena came to MU at the height of the pandemic in 2020. She had to gain a special visa, which she also worked on in the Wan lab during the pandemic. After accepting the position at MU, Praena remembers consulting a large map on her wall to find the landlocked state of Missouri.
“At the beginning it was complicated because when I accepted the position, I didn’t know where Columbia, Missouri was,” Praena said.
For Praena, finding passion for her work is vital to her success.
“You need to be a hard-worker, and you need to have a lot of resilience, because in academia you will never be rich, and you have to work a lot,” Praena said. “So, the first thing you need is to love your job [and] the science.”
Her hard work translates to outside of the lab where she competes in triathlons and bikes trails in Columbia.
“I like to take my bike to the trails. I like the Katy Trail, the MKT Trail and I went to the Ozarks,” Praena said.
Praena and her husband also camp and explore different states. Over winter break, Praena took advantage of having two weeks off and traveled to Arkansas, Texas and Oklahoma.
Praena enjoys Columbia and traveling in the U.S., but she hopes to one day return to Spain and have her own lab. While in the Wan lab she works to improve her research skills and develops project ideas.
“You always have to ask ‘why’ and ‘how,’” Praena said.
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.
Invested in two to three hobbies at a time, Lynden Voth is not afraid to try something new. His flexible mindset – applied equally in his personal life and research – led Voth to discover his passion for molecular pathogenesis and therapeutics.
“I was kind of in a completely different headspace when I first came here, and then as I started to do some research and understand what the labs were working on, I ultimately found an interest that I was not aware of before,” Voth said.
Voth is a second-year graduate student in the Donald Burke lab at the Bond Life Sciences Center. Most of his work focuses on how cells make different proteins, a pivot from his undergraduate work in virology.
“I came in wanting to do viruses, and I ultimately chose [a lab] that was just completely out of left field that I had some interest in but was definitely not my top choice,” Voth said. “Then I got in and really found an interest and enjoyment of the kinds of questions and the kinds of things they were wanting to ask.”
As an undergraduate he studied coronaviruses in the Anthony Fehr lab at the University of Kansas. Transitioning into undergraduate research at the start of the pandemic, Voth experienced cutting-edge research from the start.
“We were in a period of understanding certain factors in coronaviruses that might be important for the immune system,” Voth said.
Growing up in the small town of Newton, Kansas, Voth’s interest in science began from a young age. The transition to college opened the world of research as he navigated opportunities at KU.
“Ever since I was a little kid, I really wanted to do something involved in medicine or science, but I think my interest in research science has really increased in the college years,” Voth said.
Voth waited until junior year to look for undergraduate research opportunities when he realized the importance research experience before applying for graduate school. Fortunate to get into Fehr’s lab during the pandemic, Voth gained two years of research experience before graduating KU.
“It was definitely one of those things that came late in the game, and I’m glad that I was able to figure it out before it was too late,” Voth said.
When it came time to decide on a direction for his graduate studies, Voth leaned on support from Fehr while remaining open-minded about his field of study. Fehr encouraged Voth to seek out opportunities at MU and find a field of study he enjoyed.
“I really like to work on viruses, but I also just wanted to expand to see what was out there and test things out,” Voth said.
Once he came to MU and tried out new fields of research, he found interest in the Burke lab. Currently undecided on his thesis question, Voth works on several projects in the lab, but his research all focuses on diversity-generating retroelement systems – cellular processes that allow for diversity in protein production.
This process usually happens when viruses or bacteria are trying to create a protein that will allow it to infect a cell. With these systems, the virus or bacteria can create many different proteins to find which is most effective.
“For me personally it’s super cool to see how there’s this constant competition, and the mechanisms of that,” Voth said. “And it’s one of those things that is starting to be studied but there’s a lot of questions that are still available.”
Voth finds his schedule as a graduate student manageable, balancing his time between classes, experiments, reading and research.
“I personally really like that somewhat freedom where you can have a day where you just sit down and read a bunch of papers and then come in on the weekend and do an experiment for six to eight hours,” Voth said.
Voth also finds time for outside interests, and his main hobby involves learning the specifics of growing different plant species. He spends time outside the lab growing carnivorous plants and learning the specifics of airflow, temperature and amount of light required for their growth.
His other hobbies include playing instruments and learning new languages, and he often must fight the inclination to learn many subjects at once.
“I’m trying to focus on one [instrument] right now. There was a time I was trying to learn guitar and bass and what ever else, but [I’m] trying to just get more specifically good at one thing versus another,” Voth said.
His intention for learning new languages is personal with extended family living in Germany.
“I want to get a good solid base in German and then maybe look into other languages. Russian is also super interesting,” Voth said.
Voth educates himself when it comes to his hobbies, and in the lab he now teaches younger students the basics of research, but he attributes much of his success in the Burke lab to the people he learned from when he first started. His mentor from his initial rotation with the Burke lab, Jordyn Lucas, helped familiarize him with many new techniques.
“Her mentorship was super great for understanding how to not only learn things about the Burke lab, but also how to learn about … things in the future. If I go to a different lab, I can use some of the things she taught me to be able to understand techniques wherever I go,” Voth said.
Finding his passion through the rotation phase of his graduate studies, Voth encourages other students to seek out the best learning environments for them.
“I’m just really thankful for Mizzou and specifically for the Burke lab. I think it’s a great environment, and I would encourage anyone to rotate and find the environment that works for them,” Voth said.
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.
The best piece of advice Ph.D. candidate Billy Schulze ever received was from his father before a baseball game in high school. In past games, Schulze kept striking out. He wasn’t getting any runs. Things seemed bleak.
Schulze’s father pulled him aside and said with a smile, “Don’t suck.”
“That just kind of made me giggle,” Schulze said. “I think the real message behind that story is don’t think about it too hard. Relax. Have some fun…You can’t take things too seriously, having a sense of humor is so important. Working hard and pushing through problems is vital, especially in science where failure is so common.”
Schulze has brought that mentality to his research in the Margaret Lange lab at Bond Life Sciences Center since he joined in 2019. Whether he’s working on innate immunity or becoming one of the first biomedical engineer graduates at Mizzou, Schulze understands balance is vital in and out of research.
Taking after his father, Schulze wanted to become an engineer. However, it didn’t quite tick all his boxes.
“I have always been fascinated with biology,” Schulze said. “I just distinctly remember being in eighth grade when we went out to the pond water behind my middle school and looked at the pond water with a microscope. Seeing all of the protozoa and stuff that are in the pond water was really cool to me, and that just kind of stuck with me.”
Schulze merged engineering and biology when he became one of the first four students to graduate from biomedical engineering in 2018.
Soon after going back for his Ph.D., Schulze founded the Molecular Pathogenesis and Therapeutics Graduate Student Organization (MPTGSO). It’s aimed at improving the MPT degree by facilitating student feedback to faculty.
“I think that’s the thing I’m most proud of that I’ve done here, just being president of [MPTGSO], founding that and really just trying to be a voice for the entire student body of the program to the faculty in an attempt to just make everybody’s lives better within the program,” Schulze said.
When not helping graduate students, Schulze is in the Lange lab studying viruses, the innate immune systems and what causes Toll-like receptors (TLRs) to activate. TLRs are a class of receptors that can recognize various structures and molecules to trigger an immune system response. The Lange lab focuses on nucleic acid detecting TLRs.
Schulze is using a piece of the poliovirus genome (PV-5) known to bind to these specific receptors to create an immune response to the virus. This allows him to see which receptors activate and why.
“We’re asking what specifically is in PV-5 that is activating the receptor,” Schulze said. “So as opposed to looking at the receptor from the amino acids and what amino acids are required for binding, we’re looking at the RNA, and what RNA structures and motifs are required for binding to TLR.”
The Lange lab is creating a library of RNA sequences based on the genetic information of PV-5 to find which receptors activate.
“In this pandemic-affected world, viruses are at the forefront of health right now, and it’s something that everybody’s thinking about, and we’re specifically looking at the host-virus interface, something that is not necessarily the best understood,” Schulze said. “But at the same time, if we can help to modulate the immune response to viruses, we can potentially have better…potential antiviral therapeutics.”
When Schulze joined Bond LSC in 2016 as part of the Marc Johnson lab, he still had to learn all basic bench skills. Johnson lab supervisor Terri Lyddon was the one who showed him the ropes.
“He was definitely a worthwhile undergraduate student to have in the lab,” Lyddon said. “He was dependable, and he liked the work and came in with a positive attitude every day.”
Lyddon remembers how Schulze was always the one to speak up in lab meetings and ask questions about anything from the lab equipment to why they used particular procedures.
“There are certain levels of enthusiasm and inquisitiveness that come with almost anybody that comes to the lab because you have to want to do this kind of work in the first place…but he brought it to the lab in a unique way,” Lyddon said. “He was curious, and while some others may be curious, they don’t go on to find out the answers to those questions.”
When Schulze’s time in the lab eventually ends, he hopes to move on to a biotechnology company he truly believes in. For now, he’ll be in the lab keeping his dad’s advice in the back of his mind.
“Frankly, I think [science] is a frustrating field to work in, but it is also one of the most rewarding fields for that reason because you’ve overcome so much to find what you found, to prove what you’ve proven,” Schulze said. “I think it’s really cool, but it does require a lot of persistence.”
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.”
Building a community through screens and limited interaction can be difficult. However, it’s no problem for Margaret Lange at Bond Life Sciences Center.
“I’ve met such wonderful people,” Lange said. “It really is true that if you surround yourself with the right kind of people who are positive, who think creatively and who ask good questions, it shows you how to model that behavior yourself. It teaches you to be better and helps you think better.”
Lange was originally part of the Donald Burke lab until she became an assistant professor of Molecular Microbiology and Immunology in the School of Medicine and established her own lab in Sept 2019, getting her start in Bond LSC lab space. Even though March 2020 brought shutdowns and restrictions, Lange still found herself in a mentoring role.
“I’ve had some mentoring experience but never as the primary investigator (P.I.) of the lab, so it’s a new experience for me,” Lange said. “I’m learning from that and learning from them and, hopefully, they’re learning some things from me as well.”
Lange understands that establishing a lab requires equipment and published papers, but also a good team.
“The reason I joined her [lab] is that women in science in a leadership role is very important and that needs to be encouraged,” said Rachna Aneja Arora, research scientist in the Lange lab. “I see her as a good leader and a good mentor. She has a very inspirational role and can be a role model for the young girls and women in science to take on the challenging role to be a P.I.”
However, Lange’s path towards science began before she even arrived at Mizzou.
Growing up in rural Missouri, Lange attended a small high school that didn’t offer many science classes beyond the traditional chemistry and anatomy classes.
“I didn’t even know at that time that you could do research in a lab,” Lange said. “I had no idea what opportunities were available.”
She did have some knowledge of microbiology since her mother was a medical technologist at the local hospital where she spent time identifying microbes that were causing infections in patients. So, Lange decided to enroll in a microbiology class once she started college. Not too long after, the professor asked Lange to help her with her research.
“If it wasn’t for her, I never would have probably tried doing research at all,” Lange said. “It’s really fun to design experiments and to answer questions. And so that was really kind of where my love for that started to show, or at least become evident to me, anyway.”
Since then, Lange has been interested in how cells can sense viruses and how that shapes immune signaling.
Humans have many receptors that can recognize different parts of viruses and can cause different immune responses based on what they’re recognizing.
“We really try to understand what is working at the level of the virus to shape those responses and how that influences how our immune system is able to fight those viruses,” Lange said.
The Lange lab is currently looking to improve the host-virus interaction regarding vaccines.
Vaccines generate a response that is specific to a certain component of a virus. However, just focusing on a single protein or nucleic acid is not enough to generate a robust and specific immune response. So, researchers like Lange are working towards improving adjuvants — immunostimulants in vaccines — to create a stronger response that helps shape antibody and T cell responses.
“Investigating what types of nucleic acid motifs can actually bind and signal through these pattern recognition receptors helps us design better adjuvants that can better shape the immune response for a specific pathogen,” Lange said. “For example, if you use a nucleic acid from the SARS coronavirus, it might shape the immune response in a specific way targeted to that specific virus, and then you hopefully get a better efficacy for your vaccine.”
For now, Lange and her team are working towards developing their lab and getting manuscripts underway.
“I really admire her for all she’s doing,” Aneja Arora said. “I think we will work harder to get things moving forward. So, I just wish her all the best and wish her good luck setting up a very established lab.”
Science is a pyramid. Every breakthrough and discovery are reached through incremental steps that build off the previous level.
Shrikesh Sachdev, a senior research associate in the Michael Roberts lab, thoroughly understands this.
“It takes many small steps to get to a treatment or a cure,” Sachdev said. “It very often takes decades, but it’s nice to be able to put in your little piece of the puzzle that might help lead to the discovery, if not a cure.”
Sachdev began his path to Bond Life Sciences Center when he left his home country of Canada in 1991 to earn his master’s degree in fisheries and wildlife from Mizzou.
Once he graduated in 1993, he felt his heart being pulled towards another field — disease and disease-related processes. That led him to conduct his Ph.D. in biochemistry doing cancer research with Mark Hannink lab in the Biochemistry Department at Mizzou.
After receiving his Ph.D. in 1998, Sachdev went to Munich, Germany as a Leukemia and Lymphoma Society Fellow for his postdoctoral research in Rudi Grosschedl’s lab, where he researched a developmental signaling pathway that has been implicated in cancer.
“Every scientist thinks, ‘I want to cure cancer, or I want to cure HIV,’” Sachdev said. “You always want to contribute to that, but I think the pursuit of knowledge should be our primary goal. Once we can understand the basics of how things work, then we can try and understand what is causing the diseases.”
While in Munich, Sachdev found a new type of SUMO E3 ligase enzyme that modulates a developmental signal transduction pathway. That was one of those underappreciated incremental steps.
“Science is incremental, but those ‘aha moments’ are what you live for,” Sachdev said. “I was thinking to myself, ‘I am the only person in the world that knows this right now…And it’s going to help people understand other things.’”
Currently, Sachdev works with research professor Toshi Ezashi to characterize and analyze induced pluripotent stem cells from patients with Smith-Magenis neurodevelopmental syndrome.
A mutation in the Retinoic Acid-Induced one (RAI1) causes the Smith-Magenis syndrome. Sachdev and Ezashi convert fibroblasts — skin tissue cells — into pluripotent stem cells which can turn into certain different types of tissue cells. Researchers use this method to understand the effects of the disease on a molecular level.
“Dr. Ezashi had a huge impact on introducing me to stem cells and really igniting a passion within me,” Sachdev said.
Ezashi has known Sachdev for more than eighteen years. The two started collaborating while Sachdev was near the end of his time in Munich.
“He’s very friendly and kind,” Ezashi said. “Whenever I need help, he never rejects me. He tries to help every time, which I do appreciate.”
While Ezashi has been working with pluripotent stem cells since 2003, Sachdev brings biochemistry and molecular biology expertise to the project.
“We have complementary backgrounds,” Ezashi said. “He has strengths that I don’t have, so we complement each other. We can cover each other’s deficiencies.”
The induced pluripotent stem cells will help the researchers do more since they won’t have to use embryo-derived materials that are restricting and complicated. However, both researchers have a long way to go in their study.
With a little luck, Sachdev’s multiple ongoing collaborations will each have their own set of incremental steps waiting to be found.
Geese will soon fill the skies as they migrate south in V-formation as the weather gets colder and the leaves start changing color. For a month or so, migrating birds take over, crossing roads, sitting in parks and stopping to eat leftover seeds in farm fields or swim in ponds as they travel south for the winter.
What people may not realize is that some of these birds are carrying something harmful, yet invisible to the naked eye. That something is influenza A viruses that can transmit from birds to pigs and then to humans.
Henry Wan, influenza researcher in Bond Life Sciences Center, and his collaborators recently identified which influenza A viruses pose a risk for the pigs and are studying how the viruses transmit from pig to pig.
“We hope to identify risk which is very important,” Wan said. “I feel good about the study because we believe this would be the foundation for people be able to do the risk assessment on how the bird flu can go to pig and go to humans.”
By identifying which influenza A viruses are a risk for pigs, it helps to determine which viruses can ultimately be a risk for the human population, a more typical concern for the researcher’s usual work to improve influenza vaccines.
“It’s difficult to make a universal vaccine,” Wan said. “If I know which viruses are a risk then I can tell which ones to protect against.”
Influenza A can have a massive impact on people — causing outbreaks like the 1918 influenza pandemic — and more rapidly mutating genetically and antigenically, compared to other viruses. Understanding how it spreads is crucial in pandemic preparedness and creating vaccines.
Pigs, typically by direct contact or breathing in droplets in the air, contract an influenza A virus in the environment contaminated by birds migrating through the area. Some viruses go to the lungs, which means it cannot escape the pig and cannot be transmitted. Other viruses however, go to the upper respiratory tract of the pig where it can shed and transmit to other pigs, quickly infecting other pigs. How this happens on a molecular level is more of a mystery.
Wild birds serve as a reservoir for diverse viruses across many bird species. While not all of the viruses are a risk to pigs, Wan’s lab wanted to identify which ones are a risk to pigs and how it is transmitted to other pigs.
“Many viruses in nature are not likely to go to humans, only a small portion can. How you detect them is key,” Wan said.
Through analyzing characteristics, Wan found that cells and tissues that support influenza A viruses affect their transmission from birds to pigs. This phenotype — a set of characteristics resulting from the interaction of being with their environment — was determined by markers across the structures of genomes. For example, those in an RNA complex.
To do this, Wan collaborated with researchers from the National Wildlife Research Center and the National Veterinary Services Laboratory at the United States Department of Agriculture, Mississippi State, The Ohio State University, and The United States Department of Agriculture, among other labs. Wan’s lab initiated this study which led to collaborations across labs.
“Different people have different expertise. I really enjoy collaborations and different ideas,” Wan said.
Wan also found only a small portion of the virus can grow and adapt to different pigs and then transmit to other pigs. He then mapped the distribution of these risky viruses across multiple wild bird species.
Now that Wan and his team know how influenza A virus is transmitted into the pig, they are working on the next step, predicting a pig has a risky virus using artificial intelligence (AI).
“I think we have reached one stone and are ready to move to the next one,” Wan said, “Of course, everybody’s pretty excited.”
He plans on furthering his research of pandemic preparedness by looking at if the virus adapts to the pig and gains a receptor or an additional feature in order for it to easily transmit from pig to pig.
“That’s how this virus goes to endemic or even pandemic.”
Vaccine development remains a central goal to get the current COVID-19 pandemic under control. While vaccines are highly vital in the fight against the current pandemic, what if scientists could prevent the virus from entering cells altogether? Researchers at Bond Life Sciences Center are working to do just that and, so far, they’re the only ones at Mizzou on the case.
For the Gary Weisman lab, that starts with their study of a family of purinergic receptors which are found on the plasma membrane of cells. Molecules outside the cell bind to receptors and serve as signals to trigger an action, whether it’s transporting something into a cell, alerting its defenses or initiating programmed cell death. The specific receptors they study sound off one of the first alarms to alert host immune cells when a cell is damaged.
Weisman, Bond LSC principal investigator and Curators’ Distinguished Professor of biochemistry, noticed that the spike protein in the virus that causes COVID-19, SARS-CoV-2, shares an amino acid sequence — arginylglycylaspartic acid or RGD — with one of the receptors his lab studies named, P2Y2.
“So, we had this one niche that no one I think has followed,” Weisman said. “Even though people understand RGD sequences are important for protein to protein interactions, and possibly viral entry, no one has looked at this with respect to coronaviruses.”
While ACE2, a plasma membrane receptor, serves as the primary cell-surface receptor for SARS-CoV-2 binding, a potential role for the RGD sequence in the spike protein is to bind to alternate receptors and subsequently enhance viral infectivity.
“We postulated that if there was a way to use our receptor, it might be to block the entry of the virus,” Weisman said. “The virus can’t replicate on its own. It has to get inside the cell to be replicated, so if we prevent the entry, we can potentially stop the infections.”
They found plasma membrane receptors like ACE2 and P2Y2 all share this sequence that binds to other cell-surface receptors called, integrins. The lab is currently exploring ways to block these pathways without blocking other functions.
Few other labs have made this connection because RGD is not known to be present on many of the membrane receptors. In addition, the Weisman lab already has the supplies and connections to study these receptors.
“We, as the lab, have been studying this receptor and this family of receptors for so long that if there is a lab that has the tools and the knowledge to answer this question, I definitely think that is us,” said Kevin Muñoz Forti, Ph.D. candidate for the department of biochemistry.
The lab partners with Kamal Singh, assistant director of the Molecular Interactions Core at Mizzou and associate research professor in the department of veterinary pathobiology, who works with viruses in a way that won’t infect workers.
Singh achieves this by using look-alikes, or pseudovrises, of the spike protein on SARS-CoV-2. To the cell, this mimics the outer shell of SARS-CoV-2, but is not contagious.
Even though the Centers for Disease Control and Prevention and Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, expect a vaccine soon, this work is for the long run.
“I can guarantee you this isn’t the last coronavirus that will come up,” Singh said. “There will be many because it has been kind of periodic lately. Coronaviruses have been emerging, so the research done in collaboration with Gary’s lab will definitely be available for… future coronaviruses.”
Coronaviruses are a family of viruses which may cause respiratory illness in humans. The most recent diseases, before COVID-19, caused by previous coronaviruses were Severe Acute Respiratory Syndrome (SARS) from 2002 and Middle East Respiratory Syndrome (MERS) from 2012. Severe Acute Respiratory Syndrome Coronavirus 2 is the virus that causes COVID-19.
“This is the virus that causes COVID-19 or SARS-CoV2,” said Lucas Woods, Weisman research lab manager. “If this type of research were to have been investigated during the first coronavirus epidemic, there might have been some type of lead on the type of work we’re doing… so, absolutely this work will be useful after a vaccine or treatment is available.”
Looking ahead, the study has two years of funding from the American Lung Association in addition to grants from the National Institutes of Health. The Weisman lab hopes to eventually make it to clinical trials, but the road from basic research to clinical trials is long and arduous.
“What’s on our side, at least for the future, is that with some of these pathways we’re looking at, there are already available drugs that target these particular pathways,” Woods said.
These pathway-blocking drugs aren’t approved for humans yet, but this research could facilitate clinical scientists to test the safety of these or related drugs in humans.
The Weisman lab’s research of P2 receptors can be applied to many systems in the body and other diseases. This also allows for more ways to receive grants to fund studies longer. Along with the COVID-19 studies, they study P2 receptors in diseases that affect salivary glands.
Cheikh Seye, Mizzou professor of biochemistry, studies vascular diseases that relate to the receptors studied by the Weisman lab. Seye understands that one of the complications of COVID-19 in humans is vascular related.
“I mean there’s a lot of interaction between the vasculature and other systems, so it doesn’t stay with the salivary gland,” Seye said. “It’s all interconnected, so that’s why we need to have a multi-dimensional approach.”
In addition, the lab has found commonalities between oral and lung epithelial tissue that may contribute to COVID-19.
While this study has quite a bit of potential, it’s a long way away from seeing practical results.
“All the people in the lab have confidence because they have been successful on their own doing this before,” Weisman said. “So, it’s just another challenge, but we know how to get the answers, we have the tools and we’re optimistic that we’ll find out something.”
Researchers working on this study include Gary Weisman, Kamal Singh, Lucas Woods, Cheikh Seye, Jean Camden and Kevin Muñoz Forti.