Alicia Angelbello

By Dr. Luca Gebert

Alicia Angelbello is a fifth-year PhD student at The Scripps Research Institute, Florida, in the group of Dr. Matthew Disney, where she developing small molecules able to cleave specific RNA sequences for therapeutic targeting. While this approach is somewhat similar to using antisense oligonucleotides or small interfering RNAs, the Disney lab uses cell-permeable small molecules that recognize the 3D structure of a target RNA. The effect on the target is achieved either by conjugating these small molecules to the natural product bleomycin A5, to invoke direct cleavage of the targeted RNA, or by recruiting a cellular nuclease to the site, creating ribonuclease targeting chimeras, termed RIBOTACs. 

Alicia has successfully targeted the RNA repeat that causes myotonic dystrophy type 1 (DM1), a disease caused by a non-coding expanded r(CUG) repeat. By conjugating a small molecule that recognizes the structure of expanded repeat to bleomycin A5, Alicia was able to selectively cleave the disease-causing RNA in a mouse model of DM1. This treatment improved DM1-associated defects in mice, including the myotonic phenotype. Alicia’s work is a successful example of therapeutically targeting RNA with small-molecule conjugates, which holds the promise to develop treatments for RNA-centered diseases that have so far eluded our attempts. 

Alicia, who majored in chemistry at Villanova University, was drawn to the graduate program of TSRI, Florida, by the possibility to expand her knowledge of chemistry and biology. She said, “It’s fascinating to be at a place where multiple scientific disciplines are so interconnected and where it’s easy to form collaborations.” She initially joined the Disney lab because she was “excited at the idea to probe complex biological systems with chemical tools.” A few months into her rotation in the Disney lab, she realized the huge potential of using small molecules to study and target RNA. 

The Disney lab also gave Alicia the opportunity to be involved in all aspects of her project, from making small-molecule RNA probes to testing them in vitro, in cells, and finally in mouse models. Although this broad approach has been exciting, transitioning from a chemistry background to an RNA chemical biology lab was also one of the biggest challenges Alicia has faced. “Since I was only used to synthetic chemistry from my undergraduate research experience,” she explained, “I had to learn countless new techniques and skills during my first few years of graduate school.” However, she was fortunate to have incredibly helpful lab mates that had gone through the same learning curve and a supportive PI who was always there to answer any questions. Her experience in graduate school has shown her the potential of expanding one’s scientific horizons. For current trainees, she said, “Having a diverse skill set will open up so many opportunities, and I think being able to adapt and push yourself out of your comfort zone is a crucial skill to have in science.” 

“Having a diverse skill set will open up so many opportunities, and I think being able to adapt and push yourself out of your comfort zone is a crucial skill to have in science.”

One major source of inspiration for Alicia is Prof. JoAnne Stubbe. “Professor Stubbe was the first woman to receive tenure in the MIT chemistry department and pioneered biochemical studies of radical enzyme mechanisms including ribonucleotide reductases,” Alicia said. “She also discovered the mechanism by which bleomycin cleaves DNA, so I have enjoyed reading her papers, which have directly related to my research using bleomycin to cleave RNA.” Last year, Alicia had the opportunity to attend a seminar JoAnne Stubbe gave a TSRI Florida. “I could tell from her seminar how genuinely excited and enthusiastic she is about science. I think it’s inspiring to see what one can accomplish when you have the drive to succeed and are truly enthusiastic about your work.” 

Alicia attended her first RNA Society Meeting last year in Poland, and “it was a great experience to attend a meeting covering so many diverse topics”, she said. She particularly liked the events organized by the RNA Society Junior Scientist Committee, and she encourages all junior scientists to attend these events at future meetings. 

Alicia has a soft spot for structured RNAs that she can target with small molecules, and you can follow Alicia on twitter @aliangelbello, and connect with her on LinkedIn.