CTEGD member Chet Joyner and CTEGD director Dennis Kyle receive a grant from the Bill & Melinda Gates Foundation for malaria drug development and testing
Two UGA researchers are working to make it easier to develop effective treatments for malaria, a disease that sickens millions worldwide and kills hundreds of thousands each year.
In tropical climates around the globe, malaria poses a grave risk to already vulnerable populations. In 2019, the World Health Organization estimated that there were 229 million clinical cases of malaria worldwide and 409,000 deaths, usually in children below the age of five.
Currently, developing and testing drugs for malaria requires scientists to work in areas where the disease is prevalent or to work with expensive, hard-to-source equipment. Chester Joyner, an Assistant Professor in the Center for Vaccines and Immunology, and Dennis Kyle, Professor of Infectious Diseases and Cellular Biology, are working to reduce those barriers to malaria drug testing and development.
Joyner and Kyle aim to establish systems that rely on equipment most researchers can obtain: a petri dish. If successful, Joyner says this new culture system will reduce costs and be distributed more easily to advance drug and vaccine research. The University of Georgia College of Veterinary Medicine received a grant for malaria drug development and testing from the Bill & Melinda Gates Foundation.
Worldwide, there are many malaria-causing parasites that result in varying degrees of illness. Joyner and Kyle’s research focuses on defeating one of the most challenging: Plasmodium vivax. Unlike many other malaria parasites, P. vivax can lie dormant in the livers of its hosts—allowing the infected to travel abroad completely unaware that they’re carrying a potentially deadly passenger.
“Most infections with P. vivax are not due to new infections,” says Joyner. “These infections come from this parasite activating and potentially causing disease and sustaining transmission.”
Malaria disproportionately affects the poorest communities in the world, creating a cycle of disease and poverty that current treatments have improved but been unable to stop. However, treating the dormant forms of P. vivax has been particularly challenging because they can cause more harm than good in at-risk populations like pregnant women and people with certain blood conditions.
“We want researchers to have access to technologies to study P. vivax and develop new approaches to control and eliminate this parasite,” Joyner explains.
Belen Cassera is leading a research team that will test two new drugs for the treatment of malaria. The team’s work will be funded by a $3.7 million grant from the National Institutes of Health. (Photo credit: Amy Ware)
Though malaria was eliminated from the U.S. 70 years ago, the mosquito-borne disease caused by the Plasmodium parasite is still rampant in many parts of the world – nearly 40% of the world’s population is at risk of contracting it, and nearly 450,000 people die each year from it. With the rise of drug resistance, the current medical treatments aren’t enough to end this disease.
“Every drug treatment currently in use for malaria is showing resistance or reduced efficacy,” said Belen Cassera, a member of the University of Georgia’s Center for Tropical and Emerging Global Diseases. “Furthermore, there are very limited treatments for the most vulnerable – children and pregnant women. Over 60% of deaths are children under the age of 5.”
Cassera is co-leading the research team that recently received a $3.7 million grant from the National Institutes of Health to test two new drug candidates.
“These compounds are really promising as they are easy to synthesize, cheap, reliable, have a low toxicity profile, and kill the parasites fast,” said Cassera, associate professor in the Department of Biochemistry and Molecular Biology, part of the Franklin College of Arts and Sciences.
What’s unique about these compounds is that they can kill the parasite in three development stages in humans. Current treatments only target the blood stage, which is when clinical symptoms appear.
The life cycle of the Plasmodium parasite is complex. When an infected mosquito bites a person, just a small number of parasites – usually less than a hundred – are injected into the bite site and then travel to the liver, where they multiply in number to thousands. Once their numbers are sufficient enough, they invade the bloodstream and infect red blood cells.
When the number of parasites reaches 100 million, symptoms occur and some of the parasites develop into a sexual form, also known as the gametocyte stage. This is when symptoms occur. The sexual form is then transmitted back to the mosquito when the person is bitten again.
This complex life cycle makes it difficult to find a treatment that will eradicate the disease. Breaking the cycle of transmission between humans and mosquitos is key to accomplishing that goal. That’s why the team is excited about discovering compounds that can attack the parasite on multiple fronts.
“We are really a powerhouse team,” said Cassera. “We have a leading medicinal chemistry expert in Paul Carlier, the robust parasitology resources of UGA, and Max Totrov brings the machine-learning expertise to tie it all together.”
Cassera is a UGA Innovation Fellow, and she also credits the knowledge gained at UGA’s 2019 Innovation Bootcamp with helping her prepare a grant proposal that would be of particular interest to drug manufacturers.
Cassera has been working for several years to identify new drug candidates, along with Carlier, a professor in the Virginia Tech College of Science’s Department of Chemistry and director of the Virginia Tech Center for Drug Discovery, and Max Totrov, a computational chemist at Molsoft.
“We started working with the Malaria Box from Medicines for Malaria Venture, and the discoveries we made in basic malaria biochemistry and medicinal chemistry really springboarded us to a new level and led us in this new direction,” Cassera said.
Cassera is leading the testing of the new chemical variations of the antimalarial compounds prepared by Carlier for effectiveness in cellular and animal models.
“My lab will be looking at levels of toxicity, the potential for resistance, and how well they work both directly on the parasite and in infected mice,” she said. “We’ll be performing the studies for making the go/no-go decision for these compounds.”
A joint patent application for both drug candidates was recently filed, and the team is optimistic that their research will yield fast-acting candidates for advanced pre-clinical evaluation.
Associate professor Belen Cassera is one step closer to introducing her research to the marketplace. Having spent the summer as UGA’s newest Innovation Fellow, Cassera has learned a lot about how to bring parasitic disease therapeutics arising from her research to market.
“In fall 2019, I was among the 18 chosen women from UGA who participated in the inaugural Innovation Bootcamp, where we learned about the Innovation Fellow program, among several other opportunities designed to guide faculty seeking to commercialize their discoveries,” said Cassera, an associate professor in biochemistry and molecular biology and member of the Center for Tropical and Emerging Global Diseases. “The bootcamp was the ‘switch on’ I needed to refocus my research, and being chosen as an Innovation Fellow is the ‘takeoff’ of this new journey for me.”
Cassera’s research focuses primarily on the discovery and development of novel anti-parasitic drugs, aiming to understand how therapeutics work at the biochemical and cellular levels. A month into her fellowship, Cassera is already gaining new insight into the commercialization process and how it can inform her approach to research.
“I have experienced a great transformation in my research goals,” she said. “In every aspect that we have addressed, I see a translation back to my lab—everything is connected. For instance, I now understand how to utilize knowledge and resources that we already have to expand and grow into other areas that will bring in more funding, new knowledge and potentially new products.”
Launched in 2019 as part of UGA’s Innovation District initiative, the Innovation Fellows program encourages faculty and staff to pursue commercialization and development of their research through Innovation Gateway. Fellows are trained in how to successfully translate their research projects into a marketable products, receive mentorship from a fellow faculty and/or industry partner, and receive up $10,000 to support their activities.
“Belen is a very technical person with a very precise end goal in mind,” said Ian Biggs, director of programming for the Innovation District and director of Innovation Gateway’s startup program. “The goal of the Gateway team is to provide her with the tools, expertise and guidance she needs to turn her vision into a commercialized reality.”
Thanks to the Innovation Fellows program, the future is not only bright for Cassera’s research, but also for the rest of her academic career as well.
“The insights and knowledge I’ve gained from this fellowship will help me substantially improve my teaching, training and mentoring of students pursuing their careers in the biotech and pharmaceutical industries,” she said.
Applications for the 2021 fall cohort are now open. The deadline to apply is Aug. 15.
PhD Candidate Ale Villegas and Advisor Dr. Vasant Muralidharan (Photo Courtesy of Vasant Muralidharan)
Malaria’s connection to Georgia goes back to the colonial period. The Southeastern United States provided prime conditions for a thriving mosquito population which ensured the spread of the disease. The state capital moved from Louisville to Milledgeville in 1806 in part because of malaria outbreaks among the state’s General Assembly.
Later, the federal Office of Malaria Control in War Areas was established in Atlanta instead of Washington D.C. because of its proximity to malaria. The center was succeeded in 1946 by the Communicable Disease Center which is now the Centers for Disease Control. While Malaria was mostly eliminated in the U.S. by 1951, it still impacts millions of people around the globe. Cue Ale Villegas, a doctoral candidate in Cellular Biology.
Villegas and her advisor, Dr. Vasant Muralidharan, were recently awarded a Gilliam Graduate Fellowship from the Howard Hughes Medical Institute. The goal of the fellowship is to increase the diversity among scientists who are prepared to assume leadership roles in science. The program selects pairs of students and their dissertation advisers based on their scientific leadership and commitment to advance diversity and inclusion in the sciences.
Villegas’s research is on the edge of the unknown. She works with Muralidharan in UGA’s Center for Tropical and Emerging Global Diseases where they aim to understand the parasite that causes malaria.
“I’m exploring the mechanisms by which malaria parasites develop in human red blood cells,” said Villegas. “I am studying Plasmodium falciparum, the most common and deadly species that infects humans. These studies can inform therapeutic treatments in the future.”
PhD Candidate Ale Villegas. Villegas is in the cellular biology department. (Photo Courtesy of Ale Villegas)
Villegas specifically studies a malaria parasite glycosyltransferase or an enzyme that adds sugar molecules to other biomolecules. These enzymes may be needed by the parasite to survive and resist the immune response. There are few experts or studies in this area, but Villegas saw beyond those challenges to the critical importance of understanding malaria immune response.
“She is a very talented young scientist who has undertaken a challenging and high-impact research project,” said Muralidharan. “Her initial work was fraught with technical difficulties and setbacks, most of which are attributable to the difficulties in working with the hard-to-study malaria parasite. I am very impressed by her toughness and intellectual capacity as she solved one technical issue after another. She is now poised to move the field forward in a meaningful way.”
Villegas has also worked with Dr. Robert Haltiwanger and his graduate students in the Complex-Carbohydrate Research Center at UGA to advance her research. Haltiwanger is a leading expert on fringe-like glycosyltransferases like the enzyme she studies.
“Having Dr. Haltiwanger on campus is amazingly lucky,” said Villegas. “He and his graduate students go above and beyond when I need help or need to try out experiments. I’m glad to have access to his knowledge, experienced grad students, and sometimes his reagents!”
“What these parasite-derived sugar modifications are and how they form could inform a better vaccine or other drug therapies for malaria,” said Villegas.
Rings of P. falciparum in a thick blood smear. (Photo Courtesy of CDC)
Malaria still kills around 450,000 people each year. Most of these victims are children under the age of five. There are no effective vaccines and the parasite has gained resistance to all antimalarials currently in clinical use. Villegas’ research on this parasite sugar-adding enzyme could have important implications for future treatments and vaccine development.
The Gilliam Fellowship allows Villegas to pursue other passions in addition to science. She is a leader in student advocacy and devoted to helping students gain access to resources to advocate for themselves.
“I practice and promote student and self-advocacy by serving on the UGA Graduate Student Association and the student science policy group (SPEAR),” said Villegas. “With fellow SPEAR members, I have organized advocacy days workshops to empower students to advocate for themselves and issues they are passionate about.”
“I have found that those who are most successful understand failure very well,” said Muralidharan. “We need to normalize this. We are working to figure out the unknown. Failure in science is normal, and it is critical for discovery.”
Dr. Vasant Muralidharan’s lab utilizes molecular genetics, cell biology, and biochemistry to study the biological mechanisms driving the disease.
The award also provides funding for Muralidharan to develop mentoring skills and to share those skills with other faculty members at UGA. He has served as a mentor for many either first-generation or underrepresented students in STEM. He explains that scientists need strong support systems, especially when they experience failure in the lab. The people around them help the most.
When Villegas graduates, she hopes to continue working on and learning about science policy and advocacy. Her ideal job would allow her to be a scientist in addition to being an advocate for graduate students and a creator of equitable graduate education policies.
The Gilliam Graduate Fellowship provides Villegas an opportunity to move closer to her goals and to contribute to potentially life-saving research that could reduce the global threat of malaria.
Last summer, biochemistry associate professor and Center for Tropical and Emerging Global Diseases member Belen Cassera was named the parasitology section editor for Current Clinical Microbiology Reports and has produced her first issue of reviews.
Before former Editor-in-Chief Alan Hudson from Wayne State University School of Medicine stepped down, he recruited Cassera based on a recommendation from Robert Cramer at the Geisel School of Medicine. She met Cramer during an NIH study section.
“Networking is really important if you want to get involved in the editorial side of academic journals,” said Cassera.
In addition to participating in study sections and attending conferences, participating in the peer-review process at journals can also help get your name out there, particularly for senior trainees. She believes that having senior trainees review scientific articles is an important teaching tool.
“Reviewing papers can enhance your own critical thinking,” said Cassera. “Can you ask questions to improve the study or see something missing from the research – reviewing other’s reports helps you to think out the box.”
As section editor, Cassera is responsible for determining the content for the yearly parasitology issue. And she has lofty goals for the parasitology section. She is particularly interested in topics other journals are not covering and that expand the reader’s thoughts on the subject.
“I want readers to have more questions than answers after reading the review,” said Cassera. “I want the articles to spark new ideas.”
For her first issue, she came up with a list of topics and approached researchers that could write on the subjects. However, she is open to unsolicited submissions.
“I would like to include papers for different parasites, but what I’m really looking for are papers that bring new questions to the topic,” said Cassera. “If the scientific community would benefit – if it will lead to new questions or shift our thinking, then I’m interested in it.”
If you have an idea for a possible white paper or review that you think would be a good fit for the parasitology section of Current Clinical Microbiology Reports, then contact Cassera.
Also, be sure to check out the latest reviews, two of which come from former CTEGD members:
Ronald Drew Etheridge, UGA assistant professor of cellular biology, was awarded a five-year grant from the National Institutes of Health to continue his gene-editing work on Trypanosoma cruzi, the parasite that causes Chagas’ disease. (Photo by Donna Huber)
Ronald Drew Etheridge’s scientific career can be characterized by one word—serendipity.
After completing his bachelor’s degree in biochemistry and molecular biology with a Spanish language minor at the University of Georgia, Etheridge set out for Spain, where he traveled and worked as an English teacher. On his return home, and in need of a job, a former coworker mentioned a potential opening for a technician at UGA in the lab of Rick Tarleton, a leader in studying Trypanosoma cruzi, the protozoan that causes Chagas’ disease. While having worked in many labs as an undergraduate conducting basic scientific research, he had never really considered pursuing a study of immunology or parasitology. As luck would have it, his time in the Tarleton lab would spark his scientific curiosity like never before.
“It was the first time science was truly fun for me,” said Etheridge. “I really enjoyed the interesting scientific debates and rigorous research environment fostered in Rick’s lab.”
Realizing he needed further training to be a competent parasitologist, he went on to pursue a Ph.D. at the University of California, Irvine, and postdoctoral training at Washington University School of Medicine. In 2016, Etheridge returned to his alma mater and joined the faculty in Franklin College of Arts and Science’s Department of Cellular Biology and the Center for Tropical and Emerging Global Disease as an assistant professor.
By the time he returned to UGA, his focus had shifted slightly from immunology to molecular parasitology as he delved into host-pathogen interactions involving the protozoan parasite Toxoplasma gondii. But serendipity struck again. Upon his return to UGA he realized that Tarleton and colleague Roberto Docampo had pioneered the use of the gene-editing system CRISPR-Cas9 in Trypanosoma cruzi. Their research opened up the possibility of studying this highly neglected parasite at the molecular level for the first time. This work ultimately led Etheridge to pilot gene-editing projects in T. cruzi with a focus on explaining how this parasite directly interacts with and manipulates its host.
“One of the great things about academic research is the ability to be flexible and go down new avenues of research when they present themselves,” said Etheridge.
As part of these pilot studies, Etheridge’s group identified the first protein components of what can be considered the digestive tract of this single-cell parasite. This unique feeding structure starts as a pore on the parasite surface (the cytostome) and is followed by a tubular structure called the cytopharynx that ultimately ends with captured food being sent for digestion in endocytosed vesicles. The Etheridge lab refers to this endocytic feeding organelle as the cytostome/cytopharynx complex, or SPC for short.
“That’s what is cool about science—by chance you find novel things,” said Etheridge.
When this project began, very little was known about how T. cruzi fed on its host to obtain nutrients. Since this initial discovery, the Etheridge lab has identified dozens of SPC-targeted proteins and has uncovered the protein machinery parasites use to catch and bring in food they want to digest.
“Virtually nothing was known about how this structure actually worked,” said Etheridge. “There have been some electron microscopy studies that described the structure, but that’s all we had when we first started. It has been really exciting to work on something so fundamental yet so poorly understood.”
The National Institutes of Health awarded Etheridge a new five-year grant to continue down this path in hopes of deciphering how the SPC works and the role this structure plays in T. cruzi’s parasitic life cycle. The answers to these questions could have wide implications.
“Not only can it help us to devise potential drug treatments for Chagas’ disease, an often debilitating and sometimes fatal disease which adversely affects 10 million people in the Americas,” said Etheridge. “But more broadly, it can also tell us something fundamental about the basic biology of many species of protozoa that also use the SPC structure to capture and digest food.”
Mayara Bertolini is a third year Ph.D. trainee in the laboratory of Dr. Roberto Docampo. She has recently been awarded a predoctoral fellowship from the American Heart Association.
Please tell us a little about yourself.
I am from São Paulo, Brazil and I have always been a very curious person that likes to discover unique things. Over time, I realized that biology was one of my favorite subjects, especially when it came to diseases. I decided to major in Biomedical Sciences at the Faculdade Anhanguera de Santa Bárbara D’Oeste (São Paulo, Brazil). After my graduation, I performed voluntary research training at the Laboratory of Bioenergetics of the Department of Clinical Pathology (School of Medical Sciences) of the State University of Campinas (Campinas, São Paulo, Brazil) under the supervision of Dr. Anibal Vercesi. Thereafter, I joined the Master’s program to continue my training as a scientist. There I met Dr. Roberto Docampo, who has collaborated with Dr. Vercesi for many years. Since then, I joined his research group, where Dr. Miguel Angel Chiurillo and Dr. Noelia Lander were also members of a very productive team, which has stimulated my fascination for research in parasitology. During my master’s, I was awarded a fellowship from the São Paulo Research Foundation (FAPESP) to perform a functional study of the regulatory subunits Mitochondrial Ca2+ Uptake 1 (MICU1) and 2 (MICU2) involved in calcium signaling in the parasite that causes Chagas disease, Trypanosoma cruzi. My master’s project elucidated some questions and opened doors to interesting new topics, which our group is very excited to explain.
Why did you choose UGA?
I wanted to continue working with the same model to improve my scientific thinking and to complete my laboratory training, and the Center for Tropical and Emerging Global Diseases (CTEGD) at UGA has a wide range of researchers working with trypanosomes. Pursuing my Ph.D. at UGA is an extraordinary opportunity because of CTEGD’s unique infrastructure, which consists of extremely qualified professionals and resources that facilitate the development of research projects.
What is your research focus?
T. cruzi is one of the least well understood neglected tropical disease agents and current treatments remain inadequate partly due to a general lack of knowledge of this parasite’s basic biology. We are particularly interested in establishing the role and interaction between mitochondrial proteins involved in Ca2+ uptake in this organelle. Understanding the mechanisms of adaptation and survival of the parasite upon environmental challenges, as changes in concentration of free Ca2+, will lead to important insights into the biology of this parasite and the evolution of Ca2+ signaling in eukaryotic cells. Considering that disruption of Ca2+ homeostasis by toxic agents is related to the loss of cell viability, the identification of the possible differences in mitochondrial Ca2+ transport between these parasites and the host cells could be useful for the development of new chemotherapeutic agents against Chagas disease. The purpose of the AHA predoctoral fellowship is to enhance the training of students who intend to pursue careers as scientists aimed at improving global health and wellbeing, and I feel like I can contribute to this mission.
What are your future professional plans?
After my graduation from UGA, I hope to continue for a postdoctoral research position. In the future, I would like to establish a research group in Brazil using trypanosomatids as biological models for studying the structure and function of proteins.
Any advice for a student interested in this field?
Don’t be afraid to try new things and learn from it.
Support trainees like Mayara by giving today to the Center for Tropical & Emerging Global Diseases.
Dr. Dennis Kyle, director of CTEGD and professor in the departments of cellular biology and infectious diseases, is the featured guest on Episode 5 of the People, Parasites & Plagues Podcast. He talks about a deadly disease caused by Naegleria fowleri, also known as the brain-eating amoeba.
People, Parasites & Plagues is a podcast aimed at delivering information about the fascinating pathogens among us from the impressive professionals who study them.
Join hosts Dr. David Peterson and Dr. Liliana Salvador, two infectious disease researchers from the University of Georgia, as they explore the past, present, and future of science.
Tune in every other week for a new and enlightening episode as they unpack the details surrounding some of Earth’s most perplexing diseases. Look for the People, Parasites & Plagues Podcast on your favorite Podcast service!
