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RNA Researchers Making an Impact on Modern Medicine and Graduate Education

Matthew D. Disney, Ph.D.Ian J. MacRae, Ph.D.

Matt Disney is on a roll. With a recent series of high-profile studies published in major journals and several significant new grants that extend and deepen his research, his momentum is almost as obvious as his enthusiasm for his science.

Speaking with him about the potential his research holds for transforming the treatment of diseases that affect millions, one is immediately infected by his contagious exuberance. This enthusiasm is also borne out by the word he selects to describe students’ experience pursuing doctoral studies in his lab: intense.

“I’m excited about the science we do,” said Disney, a professor in the Department of Chemistry on TSRI’s Jupiter, Florida campus. “Students here have a great opportunity. There’s no syllabus, no timecard. We’re tackling difficult problems and we’re working hard to solve them. To do so, we’ve got to bring creative solutions and think outside current paradigms.”

The solutions they’re working toward focus on using RNA as a weapon in the fight against diseases that are currently incurable or have a poor prognosis. Their pursuit of this endeavor is creative indeed—one particularly innovative approach they’ve developed essentially reprograms the RNAs responsible for causing a disease to instead produce medicine—inside the cells—that fights the condition. It’s an approach made possible by genetic sequencing, a relatively recent advance that famously culminated with the Human Genome Project’s mapping of the human genome in 2003.

“When you sequence someone’s genome or DNA, you also read out their RNAs,” said Disney. “This gives you a diagnostic tool. For example, if a patient has a tumor you know which RNAs are up- and down-regulated. What we try to do is take this sequence information on RNAs that cause a disease and very rapidly turn that data into a lead, or drug-like molecule.”

The Disney lab is targeting so-called orphan diseases—incurable and often genetic conditions that that affect a relatively small number of people—such as amyotrophic lateral sclerosis (ALS, also known as Lou Gherig’s disease), muscular dystrophy, autism, as well as certain cancers that have a poor prognosis and are currently very difficult to treat. The project already has met with tremendous success.

“We’ve been able to take someone’s genomic sequence, and if they have a genetic orphan disease we can make a drug to target the RNA product of the defective gene or if they have cancer, we can target an oncogene to kill the cancer cell,” said Disney.

Programmed to Persevere

His projects all share a common, but powerful strategy. In recent years, researchers have increasingly recognized RNA’s key role in a large number of human diseases. RNA molecules “fold” over upon themselves, resulting in various small pockets. Small molecules of precisely the right size and shape can fit snugly into these pockets. A powerful computer program can search a database to identify small-molecule drugs that both meet this fit requirement and have the ability to turn the combined assembly into a guided missile targeted only at the disease.

The computer program enabling this extraordinary process was largely the product of two key events in Disney’s early academic career: a bold research question and a particularly stinging rebuke that came in the form of a grant rejection tied to that very question. Fortunately, the grant reviewers’ negative feedback only served to motivate him to redouble his efforts.

“I remember the study section said that I had had demonstrated no creativity and no innovation previously, so why should they give me this?” recalled Disney with a laugh. “So I just put my head down and kept plodding away.”

The question he sought to answer was this: Are there specific RNA fold configurations that enable RNAs to bind to small-molecule drugs just as they would to proteins? If so, what are the folds and what are the drugs? The software he developed to answer these questions, dubbed Inforna, was hugely successful and led to groundbreaking findings, published in the journal Nature Chemical Biology, wherein he designed small molecules that targeted cancer-causing oncogenes and shut them off.

“We’ve now advanced this Inforna technology and have a few papers in press, including one describing how we produced drugs that kill triple negative, or hard to treat-breast cancer in mouse models,” said Disney. “For a long time, (pharmaceutical companies) knew that these RNAs were causing disease, but were unable to make a selective small molecule to target them. We showed that by using this calculation, you could design a small molecule to target a RNA that was as selective as using Watson-Crick base pairing. That’s basically using the DNA code, which was one of the more remarkable things that came out of that study.”

So transformative was this approach, he recently applied for and won one of the most prestigious grant awards a biomedical researcher can receive: the National Institutes of Health Director’s Pioneer Award, an honor given to only about a dozen of the most innovative scientists in the United States each year.

Microfilm Machines and Making a Difference

From an early age, Disney had a passion for hands-on projects and solving difficult problems. He recalls many times as a child helping his father repair microfilm machines for Eastman Kodak.

“We’d have these big microfilm machines in the basement and we’d take them apart and put them back together. When I went to college, I was initially an engineering student. I was interested in doing work with my hands and I liked problems that didn’t have a known solution. Maybe that’s due to being in a large family—there are many problems, very few of which have a solution,” he recalled, laughing.

As a sophomore taking a required organic chemistry course, he was advised to consider getting some research experience. It was a recommendation that ended up being a key turning point.

“So I thought, ‘Oh, I’ll just ask my organic chemistry professor,’ thinking nothing of it, and ‘I’ll just try this out.’ So I started undergraduate research in Jeff Davis’s lab and I was hooked, because it was working with my hands, like with my father and the microfilm machines. It was problems that I immediately recognized could never be solved, so my desire to be obsessive about things and just work to solve problems fit in with that.”

With undergraduate research behind him, Disney looked to graduate school at the University of Rochester. Working in the laboratory of Doug Turner, a biophysical chemist, Disney earned his doctoral degree in chemistry, focused on RNA thermodynamics and folding.

“Toward the end of my Ph.D., I started to think that we can take an RNA sequence and figure out what its biological fold is,” said Disney. “Can we push this ability farther and use it as a design platform to design small molecules against an RNA of interest? So I came up with the proposals that are now my research project. However, I knew I first needed training in organic synthesis, because I needed to synthesize molecules to execute my research goals.”

He acquired this training with a postdoctoral fellowship at the Massachusetts Institute of Technology (and later at ETH, the Swiss Federal Institute of Technology in Zurich), working with Peter Seeberger, an organic chemist. His first faculty position at SUNY Buffalo brought all of his experience to bear—RNA folding, chemical synthesis, bioinformatics—to advance his research goals, a process that continues today on the Florida campus of The Scripps Research Institute (TSRI), where he has served as a faculty member since 2010. While at TSRI, he has been a strong supporter of the graduate program, teaching the institute’s Medicinal Chemistry course and mentoring doctoral students in his lab.

Mentoring students and building a collegial environment in his laboratory is a source of great satisfaction for Disney.

“Tackling a difficult problem together as a team is what I find most rewarding,” he said. “The graduate students, the postdocs, the technicians, and myself… all talking about problems in a project and then overcoming those problems. I like having an idea that someone might think isn’t going to pan out or is crazy, and then making progress towards getting the idea to work. I’m also happy about publishing it! [laughs] You have to like what you’re doing and take advantage of the opportunities that are in front of you.”

This philosophy and his contagious enthusiasm for research were heavily influenced by values Disney learned as a child in Catholic school.

“In Catholic school, part of what you need to figure out is what your vocation in life is,” he explained. “I think that is partly what motivated me to have a career in science—you have a vocation, not a job. You have something that you think you should do. All of those things came together to tell me that chemistry was my vocation—that’s what I was here to do. In the morning, I don’t tell my son I’m going to work—I call it ‘school.’ That’s because I don’t view this as work; I view it as an enriching experience. Ultimately, I hope that my vocation will help me have an impact on the world and leave it a better place.”

Scripps Education Reporter

Edition 5, Summer 2016


Edition 5 Home
TSRI Celebrates 24th Commencement

Graduate Faculty Profiles 
New Philanthropic Fellowships
Alumni Website Update
2016 DiVERGE Dates Announced
Catching Up with TSRI Alumni



Scientists Create Compound that Erases Disease-Causing RNA Defects

Researchers Pioneer a Breakthrough Approach to Breast Cancer Treatment

Grant Advances Development of RNA-Based Therapeutics

TSRI Chemist Wins NIH Director’s Pioneer Award of $4.8 Million

Scientists Design Targeted New Drug Candidates Based on Detailed Picture of Muscular Dystrophy Defect




Disney Research Image

The red coloration in the center pane of the top row indicates diseased cells producing their own drug within the cell.
(click to enlarge)















The Disney Group

The Disney Group
(click to enlarge)











Link to Matt Costales Youtube Video

In this video, meet Graduate student Matt Costales, who is a chemical biologist studying in the Disney lab.
(click above to watch on YouTube)