Henninger Explores Targeting RNA in Cancer Prevention, Treatment
Heidi Opdyke
- Associate Dean of Marketing and Communications, MCS
- Email opdyke@andrew.cmu.edu
- Phone 412-268-9982
Imagine a future where cancer treatments are tailored with molecular precision — targeting the disease at its genetic roots. At Carnegie Mellon University, Jonathan Henninger is helping make that future a reality.
Henninger, an assistant professor of biological sciences, is part of a growing movement in the life sciences exploring how ribonucleic acid, known as RNA, can be harnessed to develop transformative therapies.
RNA’s role in gene expression and cellular organization
Henninger studies gene expression, how the DNA genetic code is read out by the cell to instruct protein production. For a cell to express a gene, RNA molecules are first made as copies of the DNA and used to make specific proteins.
Henninger and others have found that RNA molecules can do more than carry a message from DNA: they directly influence multiple steps in gene expression. One way is by controlling tiny compartments inside cells formed by proteins and nucleic acids, called biomolecular condensates. These condensates act like specialized workstations, concentrating molecules that work together to orchestrate ongoing biological activity.
“RNA acts as a very important scaffold that these condensates form around,” Henninger said. “If proteins were like chess pieces, where each one moves differently and plays different roles, DNA and RNA would be like the chessboard, which dictates how the pieces arrange and limits how they can move. There’s an intimate linkage between thinking about RNA’s structures and properties and how that affects both the formation and dissolution of condensates involved in gene expression.”
Precision medicine at the genetic level with RNA-based therapies
Many human diseases, including cancer, result from mistakes during gene expression. However, there are few drugs that can specifically target gene expression to correct the process and rejuvenate cellular function. The genome revolution has also revealed thousands of genetic variants linked to disease, many of which lie in regions that regulate gene activity. Henninger said he believes some of these variants disrupt RNA function — a possibility that his lab is actively investigating.
His team is developing new tools to study RNA and visualize transcription — the first step in the process by which genes are activated in cells. One major focus is understanding how mutations in RNA-binding proteins contribute to blood cancers like acute myeloid leukemia.
“Mutations in RNA-binding proteins or alteration of RNA levels obstruct condensates and gene expression, which promotes cancer development. We plan to extend these findings to primary cancer cells in collaboration with clinicians at UPMC,” Henninger said. “Our lab is also working with Dr. Andreas Pfenning and Dr. Martin Zhang at CMU, who are experts in machine learning and genomics.”
Henninger’s lab is also exploring antisense oligonucleotides (ASOs) — synthetic single-stranded RNA molecules designed to bind to specific messenger RNA (mRNA) sequences. These molecules can be used to correct gene expression errors, treating disorders at their source. Subha Das, associate professor of chemistry, and Bruce Armitage, head of chemistry and co-director of the Center for Nucleic Acid Science and Technology, have been helping with these efforts.
“We're very interested in more automated approaches to testing a bunch of these ASOs and using AI to learn rules for their design,” Henninger said.
Thanks to support from the Shurl and Kay Curci, Charles E. Kaufman and Samuel and Emma Winters foundations, Henninger’s lab is rapidly advancing. The funding enables key experiments, development of new RNA assays and unprecedented imaging of gene expression.
“Our lab’s early efforts and exciting data would not be possible without the generous support of foundations interested in fundamental science, so we are extremely grateful,” Henninger said.
Collaborative Science in Pittsburgh
Henninger returned to the Pittsburgh region in early 2024 — he grew up about an hour away in Indiana, Pennsylvania — to join Carnegie Mellon.
“Pittsburgh has an incredibly unique combination of chemistry, physics, AI and biology all working together toward common goals. It's been incredibly impactful,” he said. ”I’m at the center of this perfect spot where there are experts I can interact with for everything that our lab is interested in.”
That collaborative spirit was on full display at a recent conference at Carnegie Mellon where more than 100 researchers from fields including biology, chemistry, physics, engineering and medicine gathered to discuss condensates.
Training the next generation of researchers
In the past 18 months, Henninger has built a dynamic research team with half a dozen graduate students.
“I'm a huge proponent of team science and working together, because people can work toward shared efforts using parallel paths, which makes discovery much more efficient and especially more fun,” he said.
Henninger said he has been particularly impressed with the undergraduates at Carnegie Mellon who have also joined the lab.
“They're working at the level of graduate students,” Henninger said. “They're incredibly brilliant, bring great ideas to the table and they're fun to work with. It's been very exciting to see their enthusiasm and aptitude.”
