Phillips turns parasite’s metabolic weakness into hope for human health
Much like the parasitic life cycle we learn in microbiology classes, the American Society for Biochemistry and Molecular Biology's 2024 Herbert Tabor Research Award also comes to a full circle.
The winner, Margaret “Meg” Phillips at the University of Texas Southwestern Medical School, studies which biochemical pathways are critical for parasitic protozoans to grow and survive and how to use this information to fight them.
“A substantial part of Dr. Phillips' work has been on the synthesis and function of polyamines, a field pioneered by Herbert and Celia Tabor,” Anthony Pegg of Pennsylvania State University noted when supporting Phillips’ nomination for the award.
Phillips said that her father, a radiation oncologist, greatly influenced her career choice: “My father loved basic science research and always encouraged my siblings and me to go into science. I ultimately decided to orient myself toward biochemistry because it combined my two passions, biology and chemistry. I wanted to know everything about enzymes and study how they were regulated.”
After earning her bachelor’s at the University of California, Davis, Phillips worked for two years at a company developing diagnostic kits to measure drug levels in biological fluids. “This was a great experience and made me realize that, if I wanted to lead my research agenda, I needed to get a Ph.D. Having this gap to think and reflect … was very positive for me; my motivation and focus were higher than if I had just kept going through school without a pause,” she added.
She went on to earn her Ph.D. at the University of California, San Francisco, where she also completed postdoctoral training. She started her lab at UTSW in 1992.
Phillips said she enjoys that her research sits at the intersection of parasitology, biochemistry and chemistry and that it can make a tangible impact on people’s lives. “The most fun I had was getting an anti-malaria compound into clinical development. To see your science going from understanding enzyme structure to finding inhibitors to clinical trials is very rewarding,” she said.
Fighting parasites one enzyme at a time
Together, Trypanosome brucei (responsible for African trypanosomiasis) and Plasmodium falciparum (the causative agent of malaria) affect over 2 billion people worldwide. Research led by Phillips on the structure and function of critical enzymes in these parasites has paved the way for new treatments.
“By exploiting metabolic vulnerabilities of these parasites, Meg made high-impact discoveries on novel drug targets resulting in innovative chemical therapies,” Kim Orth of UTSW and the Howard Hughes Medical Institute explained in her letter nominating Phillips for the Tabor award.
Phillips’ work on the regulatory mechanism of polyamine pathway enzymes S-adenosyl methionine decarboxylase and deoxyhypusine synthetase in T. brucei has been groundbreaking. “She found that both enzymes require oligomerization with inactive paralogs — pseudeoenzymes — for activity, revealing a trypanosomatid-specific form of enzyme regulation,” Orth explained.
Michael Ferguson of the University of Dundee said Phillips’ work “is the stuff of legend … Everyone should read it for sheer enjoyment.”
Phillips’ team has led the effort to target dihydroorotate dehydrogenase, a critical enzyme for pyrimidine biosynthesis in Plasmodium. Through a combination of protein biochemistry, crystallography and enzymology, they have generated “one of the best structure-based drug discovery opportunities — period,” Ferguson said.
Phillips will give an award lecture at Discover BMB, the annual meeting of the ASBMB, March 23–26 in San Antonio.
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Alice and C.C. Wang Award in Molecular Parasitology: David S. Roos
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