A biofactory for natural products
Amy Fraley dives deep into nature to grasp its complexity – literally as a passionate scuba diver, but also as a chemist in the laboratory. Together with her team, the new Assistant Professor of Medicinal Chemistry roams through all the kingdoms of life in search of new biosynthetic strategies to produce therapeutics. She finds them everywhere: from microbes associated with bat guano and marine sponges to inconspicuous plants.
Eerie, but invigorating. This is how Amy Fraley describes shipwreck diving deep in cold water environments; the only sounds are her heartbeat and her breath rushing in her ears. Sometimes she dives for fun, sometimes out of scientific curiosity.
The new assistant professor of medicinal chemistry at D-CHAB is interested in hidden molecular treasures, whether in water or on land. Her focus is on unnoticed microorganisms and plants that produce enzymes and biologically active substances with amazing properties. With her group, Fraley wants to research such compounds and find out how they can be sustainably produced, optimized, and used as therapeutics or probes to better understand disease mechanisms.
“My goal is to establish biofactories for these complex molecules: for instance systems where we put all the necessary genes in one laboratory-cultivable organism to produce the final product.”Prof. Amy Fraley
The stimulus for these big plans was a small creature. As an undergraduate student, the basketball and yoga enthusiast from Pennsylvania discovered her passion for scuba diving: “At the time, we were performing laboratory experiments to study the effects of chemical signals on the vertical migration of zooplankton. While scuba diving, I was able to observe this phenomenon in the wild and literally immerse myself in my research. This fascination has been with me throughout my career, studying small organisms that many people overlook, and learning about their great potential."
Using fungi to combat cardiovascular disease
Amy Fraley has since found her objects of study in all kingdoms of life – primarily in places where hardly anyone looks. At the University of Michigan, she researched a bioactive fungus that was discovered growing on bat guano in a cave. During a student-led Chalk Talk*, Fraley and a colleague recognized the potential for using the natural compounds from this fungus (Malbrancheamide) to probe a protein complex that plays a vital role in cardiovascular diseases. *Presentation with chalk on a blackboard
This method led them to describe in greater detail the protein-protein interactions between two key players in cardiac hypertrophy (Beyett et al. 2019), a pathological thickening of the heart muscle. Furthermore, they could show that the compound is able to block hypertrophy and has therefore therapeutic potential.
"The success of this student-driven project was a pivotal milestone in my academic career. By gaining independent funding and thus autonomy for a risky project, my colleague and I were given the freedom to explore innovative methods for studying heart failure," explains Fraley. The importance of fresh perspectives and creative thinking is something that she continues to foster in her research group.
Marine life as a source of bioactive substances
However, molecular treasures are not only found in unusual fungi on bat excrement. During her postdoc at the Institute of Microbiology at ETH Zurich, Fraley researched cytotoxic substances produced by microbial symbionts of marine sponges: substances such as oocydin-type polyketides, for example, exhibit potent anticancer bioactivity.
These natural products are made by polyketide synthases, megaenzymes that produce polyketides in an assembly line-like fashion. Led by Amy Fraley, researchers in the Piel group were able to characterize two novel components of this complex, and demonstrate their ability to modify the growing polyketide, for instance by adding acyl groups or introducing halogens into the compound. Structures of the proteins provided valuable insight for biocatalyic design (Fraley et al. 2022, Fraley et al. 2023).
On the way to the new biofactory
However, Amy Fraley is not only interested in finding, characterizing, and optimizing bioactive substances but also in producing them sustainably; her current projects reflect this passion. At D-CHAB, the first project that she and her growing team plan to investigate involves plant natural products that target neurological disease mechanisms.
"Bioactive natural products from plants are often difficult to access without exploiting the natural source," Fraley explains. "That's why we are modifying cultivable organisms to produce the desired compounds in our laboratory – we use natural biofactories, so to say, instead of pure chemical synthesis. This is more sustainable because there are hardly any harmful waste products. However, it is also a challenge because less is known about the biosynthetic pathways necessary for producing plant natural products," Fraley admits.
Let's chalk talk!
The assistant professor also aims to introduce her students to the complexities of nature, having already participated in outreach initiatives and created two practical courses. "In pharmaceutical sciences, many students will have to deal with natural extracts. They should understand what regulates the production of bioactive compounds," Fraley emphasizes, "but in the end, it's not just about the science, it's also about how you communicate it." Thus, Chalk Talks will also be part of Fraley's teaching methods and encouraged as a communication method for members of her group.
Overall, Amy Fraley hopes to be as supportive to her students as her mentors David Sherman, Janet Smith and Jörn Piel were to her: "I want to motivate my students and empower them to achieve great things. In terms of research, I am so excited about all the planned projects and will certainly keep my own bench in the lab, even as a professor. I'll be frequently popping in to chat with people, and hear how things are going, ensuring that we maintain a positive environment conducive to innovation."
In terms of her own positive attitude, Fraley seems to have found a good recipe – whether it's the good feeling of shooting hoops or an impressive dive among swirling zooplankton that reminds her how many great things still await their discovery in the smallest life forms.
Amy Fraley earned her bachelor's degree in chemistry from Millersville University of Pennsylvania in 2014. In 2019, she received her PhD in medicinal chemistry from the University of Michigan College of Pharmacy, working in the labs of Prof. David Sherman and Prof. Janet Smith. She then moved to the Institute of Microbiology at ETH Zurich as a postdoctoral fellow in the laboratory of Prof. Jörn Piel. Since 2024, she has been Assistant Professor of Medicinal Chemistry at the Institute of Pharmaceutical Sciences in D-CHAB at ETH Zurich. Amy Fraley has developed different courses for students at both the University of Michigan ("Pharmaceutical Discovery from Cyanobacteria") and the Institute of Microbiology at ETH Zurich ("Pharmaceutical Discovery from Microbial Communities") and has received several awards throughout her career.
Further information
Beyett T.S., Fraley A.E., Labudde E., Patra D., Coleman R.C., Eguchi A., Glukhova A., Chen Q., Williams R.M., Koch W.J., Sherman D.H., Tesmer J.J.G. (2019): Perturbation of the interactions of calmodulin with GRK5 using a natural product chemical probe. Proc Natl Acad Sci U S A. ;116(32):15895-15900. doi: external page 10.1073/pnas.1818547116.
Fraley A.E., Dieterich C.L., Mabesoone M. F. J. , Minas H. A., Meoded R.A., Hemmerling F., Piel J. (2022): Structure of a Promiscuous Thioesterase Domain Responsible for Branching Acylation in Polyketide Biosynthesis. Angew Chem Int Ed Engl. 61(39):e202206385. doi: external page 10.1002/anie.202206385
Fraley A.E., Dell M., Schmalhofer, M., Meoded R.A., Bergande C., Groll M., Piel J. (2023): Heterocomplex structure of a polyketide synthase component involved in modular backbone halogenation. Structure. external page doi:10.1016/j.str.2023.02.010