OTS Member Highlight – David Corey, PhD
Former Oligonucleotide Therapeutics Society (OTS) President David Corey grew up being inspired by his father’s love of science, noting that his father was not only good at what he did but he also enjoyed it.
“I never measured myself against him because I knew I could not expect to be one of history’s greatest scientists,” Corey explains. “What I could be was someone who enjoyed his career.”
While he found school-taught science uninspiring, as a teen, he enjoyed reading about science and making things. When starting his post-secondary career at Harvard University, he majored in chemistry because he was unsure what else to do. He enjoyed spending summers in his father’s lab, and while he knew he could never follow in his footsteps as a synthetic organic chemist, he loved the problem-solving nature of the field.
“My father had always told me that the best science would be at the interface of chemistry and biology, so that is where I went,” he says.
Harvard offered the degree as a Bachelor of Arts, not as a Bachelor of Science, giving Corey the flexibility to take as many biology/biochemistry and non-science courses as he did chemistry classes.
“I had great professors, Tom Maniatis, Mark Ptashne, E.O. Wilson, Stephen Jay Gould, Yoshito Kishi, William von Doering, Martin Karplus, George Whitesides, and others,” he says.
Corey graduated from Harvard in 1985 and received his PhD in chemistry from the University of California at Berkeley in 1990. During his PhD project in Peter Schultz’s lab, he was involved in attaching an oligonucleotide to a nuclease and says he owes everything to having Peter Schultz as his graduate advisor and later Charly Craik as his postdoctoral advisor.
“Looking back, it was a tremendous privilege to be among the first to attempt site-directed mutagenesis, structure-guided protein engineering, automated synthesis of chemically modified nucleic acids, and bioconjugation,” he says. “Mano Manoharan sent me the plasmid I used to express staphylococcal nucleus, a connection I did not learn about until many years later.”
Always do good science: challenges, collaborations, and mentorship
As a journal editor for Nucleic Acids Research, he handles 250 manuscripts annually and has had over a decade of viewing uniformly thoughtful reviews. In contrast, one of the biggest challenges he faced was during his time working on nuclear RNAi with his wife, Bethany Janowski, when there was a lot of resistance to the science, and the reviews they received about their research were often negative in an unhelpful and argumentative way.
“We always fought our way to publication,” he remembers. “But the work never did get the attention it deserved.”
Projects Corey is particularly proud of include work on protease specificity in the 1990’s; research on telomerase inhibition by ASOs and PNAs; work showing that locked nucleic acids are versatile and powerful agents; an early study showing that duplex RNAs could tolerate chemical modifications; his early paper demonstrating that peptide-oligonucleotide-conjugates enhance hybridization rates; and the RNAi work he did with his wife, especially her monumental COX-2-paper; Jiaxin Hu’s discovery of small binding RNAs and their ability to allele selectively inhibit mutant human huntington; his collaboration with Thazha Prakash highlighting that single-stranded silencing RNAs could allele-selectively block huntington expression in vivo; his collaboration with Vinod Mootha on targeting the RNA responsible for Fuch’s dystrophy, which he says opened his eyes to the immense potential of working with a practicing physician; Keith Gagnon’s 2014 paper that definitively showed that protein RNAi factors and miRNAs resided in mammalian cell nuclei; and Krystal Johnson’s work showing that environmental conditions could cause argonaute to be a nuclear protein.
“I’ve collaborated with dozens — no exaggeration — of companies and academics. Collaborations are what makes a career in science worthwhile,” he says, adding that he’s worked on a lot of rewarding projects and couldn’t choose a favorite. However, he says his most significant contribution to oligonucleotide research is training students who have gone on to fulfilling careers.
When it comes to being a mentor, he remembers the impactful role Schultz and Craik had on his career, both of whom created a fantastic supportive environment, gave him projects that fit his personality, and allowed him to flourish.
“I’ve tried to return a small part of their impact to my mentees,” he says. “I hope they think that I did right by them.”
He’s mentored dozens of technicians, graduate students, postdoctoral fellows, and visiting scientists, and almost all who have worked in his laboratory have left with at least one — and in many cases several — first-author publications.
“This is a very difficult career. It can also be the best job in the world,” Corey said at NAT RIM. He went on to remind young scientists of the benefits of good collaborations with good people and the importance of rigor, doing the work in a mechanistically based way, and of doing good science and seeing where it leads you.
“Do this because you love doing it,” is his advice to young scientists interested in the field. “Don’t expect any praise, and don’t expect it to be easy. Always do good science.”
Continuing high standards and sound science: the future of the oligonucleotide field
Throughout his career, the oligonucleotide field has continued to impress him with its commitment to sound science, rigor, and collegiality. He notes that the field has been blessed with leaders capable of combining their scientific passion with excellent business skills. However, he also states, “The only thing stopping the field would be corporate leaders who value short-term rises in stock prices over the long-term vision needed to solve tough problems.”
Though Corey had feared the oligonucleotide field was maturing and could be running out of ideas, he says the chemists in the field never disappoint and continue moving the research forward, advancing and enabling chemistries — a trend he says most excites him in the field.
While Corey notes artificial intelligence and machine learning could be useful in advancing oligonucleotide research, he cautions that it’s not magic and people should not suspend their disbelief.
“High standards and transparent experimental verification should be demanded,” he states. “History teaches us fluttery promises and superficial data are never enough. Hard data is the language that helps patients.”
Personal insights: faculty, family, and football
In 1992, Corey joined the faculty of the Department of Pharmacology at the University of Texas Southwestern Medical Center in Dallas as an assistant professor. In 1996, he received a secondary appointment to the Department of Biochemistry, and in 1998, he was promoted to associate professor and full professor in 2003. Despite having excellent facilities, faculty, community support, and hospital connections, Corey explains that UT Southwestern has had difficulty attracting students and postdocs because it is not on a coast. However, the small labs encourage collaboration, which Corey says creates an efficient working environment.
“We do not need to work 70 hours a week to be productive,” he says. “Also, I worked with my wife, Bethany Janowski, for ten years. She is a phenomenal scientist and probably the most insightful and productive experimentalist I have known. We ran the lab like a family business, which freed up more time to enjoy our daughters Kate and Sara.”
Outside of work, Corey enjoys running and spending time with his family, noting that they try to take at least one family trip every year. During the pandemic, Corey also became a massive fan of watching the then third-tier English football team, Sunderland.
“I’m pleased to say that they are heading for the second-tier playoffs this year, and one of my greatest ambitions is to one day watch a game in the Stadium of Light,” he says. Indeed, since this interview Sunderland have been promoted to the Premier League after a series of last minute Playoff goals.
David Corey’s lasting impact on the oligonucleotide field and its scientists
David Corey’s scientific journey illustrates a commitment to innovation, perseverance, and the importance of a supportive academic environment. Through his research and collaborative spirit, he has not only contributed significantly to the understanding of oligonucleotides but has also nurtured the next generation of scientists.
“Whatever small contribution I have made to overcoming the many difficult obstacles to the development of oligonucleotide therapies, as well as helping my students find careers that make them happy,” he says when asked what he would most like to be remembered for.
To stay updated on Corey’s research and contributions, find him on LinkedIn, PubMed, or email him.
References and Key Publications:
- Herbert, B-S., Pitts, A. E., Baker, S. I., Hamilton, S. E., Wright, W. E., Shay, J. W. and Corey, D. R. Inhibition of telomerase leads to eroded telomeres, reduced proliferation, and cell death. Natl. Acad. Sci. USA 96, 14726-14781 (1999).
- Braasch, D. A., Jensen, S., Liu, Y., Arar, K., White, M. A., and Corey, D. R. RNA interference in mammalian cells by chemically modified RNA. Biochemistry 42, 7967-7975 (2003).
- Janowski, B. A., Huffman, K. E., Schwartz, J. C., Ram, R., Hardy, D., Shames, D. S., Minna, J. D., and Corey D. R. Inhibiting gene expression at transcription start sites in chromosomal DNA by antigene RNAs. Nature Chemical Biology 1, 216-222 (2005).
- Yu, D., Pendergraff, H., Liu, J., Kordasiewicz, H.B., Cleveland, D. W., Swayze, E., Lima, W., Crooke, S. T., Prakash, T., and Corey, D. R. (2012). Single-stranded RNAs that function through RNAi are potent and allele-selective inhibitors of huntingtin expression. Cell 150, 895-908.
- Matsui, M., Zhang, H., Chu, Y., Gagnon, K. T., Manoharan, M., Corey, D. R., and Janowski, B. A. (2013), A Network of noncoding RNAs links transcription of inflammatory pathway genes COX-2 and PLAG24A. Nucleic Acids Res. 41, 10086-10109.
- Gagnon, K.T., Li, L., Chu, Y. Janowski, B.A., and Corey, D.R. (2014). RNAi factors are present and active in human cell nuclei. Cell Reports 6, 211-221.
- Johnson, K.C., Kilikevicius, A. Hoffman, C., Hu, J., Liu, Y., Aguilar, S., Graswich, J., Han, Y., Wescott, J.M., Brekken, R.A., Peng, L., Karagkounis, G., and Corey, D.R. (2024) Nuclear localization of argonaute 2 is affected by cell density and may relieve repression by microRNAs. Nucleic Acids Research 52, 1930-1952.
- HSTalks – Activation of gene expression by double-stranded RNA
- David Corey: Guidelines for Experiments using Antisense Oligonucleotides and Double-Stranded RNAs
