Joan A. Steitz: The ‘Queen of RNA’ and Her Scientific Feats

Dozens of empty champagne bottles line a high shelf in the office of Joan A. Steitz, PhD, each signed by a newly minted doctor on the day of their dissertation defense.

It is a sparkling record of mentorship for Steitz, Sterling Professor of Molecular Biophysics and Biochemistry at Yale School of Medicine (YSM). Bound copies of the students’ dissertations, with masters’ theses mixed in—Steitz, ever meticulous, points out—take up the shelf beneath.

Steitz, the 85-year-old “queen of RNA,” is best known for discovering the molecular machinery that splices raw genetic data into functional instructions, a breakthrough that explained the origin of many hereditary diseases and paved the way for revolutionary messenger RNA (mRNA) technologies, including the COVID-19 vaccine.

And while the laboratory is what lured her and her late husband, Thomas A. Steitz, PhD, to Yale in 1970, her teaching legacy and service to Yale and fellow female scientists are as remarkable as her foundational contributions to molecular biology.

Alongside her lab, funded by the Howard Hughes Medical Institute for 35 of its 50-plus years, Steitz taught "Introduction to Biochemistry" and "Medical Impact of Basic Science" to Yale College undergraduates, the latter of which she taught for the last time this past fall semester.

“She had a huge influence on not just graduate students and postdocs but on the undergrads. At least 40 times, people I have never met come up to me and say, ‘I went to Yale years ago and I had Joan Steitz in biochemistry,’” says Anthony Koleske, PhD, Ensign Professor of Molecular Biophysics and Biochemistry at YSM.

Much later, Koleske filled in teaching Steitz’s undergrad class during an early-2000s sabbatical. “I survived, but there was no comparison. I had the luxury of sitting through her lectures the year before because I knew this was coming, and watching her made me a better teacher,” he says. “Every discovery she talked about, she knew the person who made it personally—and might have a picture of herself skiing with them.”

Indeed, starting in the 1980s, Joan and her husband—who was a co-recipient of the 2009 Nobel Prize in Chemistry—organized annual ski events in the Rocky Mountains called RiboSki (a play on ribosome). Leading RNA scientists, plus their families, gathered for black-diamond runs by day and meals and science chats at night.

Despite her formidable intellect and insatiable curiosity, it wasn’t easy for Steitz to cement her place in this elite class of researchers who were rewriting the role of RNA in cells—showing that it was much more than a simple messenger for DNA. Early on, men in her field told her she should get married and have children or work in a library or as an assistant instead of chasing scientific pursuits.

Steitz, however, proved she could be a wife, a mother, and also a world-renowned scientist. Along the way, she inspired an impressive class of future RNA leaders.

“If you look at the sheer number of trainees from her lab, people of my generation who are international leaders in their field, so many of them trace back to her,” Koleske says. “I can name dozens of people who are superstars in their field who were either students or postdocs in her lab.”

Steitz’s proteges have ascended to the highest echelons of science—one served as the first female dean of Duke University School of Medicine, another leads a department at the National Institutes of Health, and others have earned election to the National Academy of Medicine or the National Academy of Sciences.

Nurturing future scientists has been an unexpected perk in her career. “They start off and don’t know anything. And then you watch them get the feel and discover something and get excited,” Steitz says. “I love that aspect of mentoring.”

At the most basic level, it has always been about the joy of discovery for Steitz.

“It's a feeling of learning something that nobody else on earth knows because you've asked a particular question and gotten a particular answer,” says Steitz in an interview in her medical school office, as she fiddles with a No. 2 pencil. “It’s thrilling to know this one thing that nobody else does because only you have done the experiment.”

And while she didn’t have any female mentors early on, she didn’t lack for male role models in the then-burgeoning field of RNA. She carved her path with doses of serendipity but mostly tenacity.

Joan Argetsinger Steitz grew up outside Minneapolis with her mother, a speech therapist, her father, a guidance counselor, and a younger brother. She gravitated toward math and science but there were few classes for her to take at her private girls’ high school.

She turned down an offer from Radcliffe College and attended Antioch College in Ohio. Her father had gone to Antioch and encouraged her to do so because of the school’s strong co-operative work-study program.

“My parents believed women should not just be incubators for kids, that they should have careers. They encouraged my interest in science and the best start for me was having such wonderful parents,” says Steitz.

While at Antioch, Steitz spent time in a molecular biology lab at the Massachusetts Institute of Technology. This was the early 1960s, and, following the discovery of the double-helix DNA structure, the field was brand new.

“There were maybe 30 labs in the world doing this kind of work and I ended up at one of them,” Steitz recalls. “I was absolutely enthralled and flabbergasted. I was so, so excited about what the meaning of all this might be. I was just captivated.”

There, she also met James Watson, PhD, co-recipient of the 1962 Nobel Prize in Physiology or Medicine for his contributions to uncovering the structure of DNA, who became a friend and advocate.

As much as she loved science, though, Steitz didn’t see a path forward. There were no women doing this type of work. When she graduated from Antioch in 1963 with a degree in chemistry, she figured medicine was the only logical choice. She planned to enroll in Harvard Medical School that fall, but decided to return home for the summer to spend time with her family. At the University of Minnesota, she found a job as a bench scientist in the lab of Joseph Gall, PhD, a cell biologist and Yale alumnus.

“Working there solidified my realization that I liked making discoveries and I shouldn’t give that up and go to medical school,” Steitz says. “Harvard had a new PhD program in molecular biology and thanks to Gall and Watson, I got into it, working in Watson’s lab instead of going to medical school.”

Steitz was the only woman in the program and its first female graduate. Her future husband Tom was a year ahead of her. Their initial connection was musical. She was a talented flute player and had played with a chamber orchestra group in Minneapolis alongside Tom’s advisor, William Lipscomb, PhD, who won the 1976 Nobel Prize in Chemistry. Lipscomb played the clarinet and Tom the saxophone.

Joan and Tom married in 1966. She earned her Harvard doctorate in 1967. Tom had lined up a postdoc at the Laboratory of Molecular Biology at the University of Cambridge in the United Kingdom. “Cambridge was the mecca for crystallography and structural studies, which was Tom’s area and where he had to go,” Steitz says. “Now it happens it wasn’t too bad in molecular biology either, having a few Nobel Prize winners hanging about, making important advances.”

But the postdoc job she thought was awaiting her wasn’t what she anticipated. She turned down an offer to pursue library research, knowing she belonged in a lab. Determined, she made the rounds, talking to the many American scientists to see what projects might be up for grabs.

“There was one that no one dared take on because it sounded too hard and might fail. And then you wouldn’t have anything to show for it at the end of the postdoc period,” she says.

Figuring she’d never get hired as a scientist anyway, Steitz decided to give this project a try. Besides, it piqued her interest. One scientist gave her three feet of bench space and Steitz set to work.

Ribosomes are small cellular structures that attach to mRNA and assemble proteins based on instructions encoded in mRNA.

Steitz sought to answer a fundamental question: How does the ribosome know where to start reading mRNA instructions to build proteins? By studying the RNA of bacteriophage—tiny viruses that can invade bacterial cells—she pinpointed the exact nucleotide sequences where the ribosome latches on.

Her 1969 paper in Nature redefined RNA as a multifaceted molecular powerhouse. Steitz proved it was far more than a passive bridge between DNA and proteins, and could act as a biological catalyst and a sophisticated viral defense.

Still, not all universities rolled out the red carpet for female scientists. Tom had been hired by the University of California, Berkeley, but when he asked his department chair about a position for Joan, he was told, “All of our wives are research associates and they love it. Wouldn’t your wife like to do that as well?”

Fortunately, in the fall of 1970, Yale offered both Tom and Joan assistant professor jobs in the year-old Department of Molecular Biophysics and Biochemistry. After briefly living in New Haven, the couple built a home on the water in Branford’s Stony Creek, where they enjoyed sailing and hiking.

Their child, Jon, was born in 1980. Jon graduated from Yale with a degree in molecular biophysics and biochemistry, but was drafted by Major League Baseball’s Milwaukee Brewers. He played professionally for three years before injury sidelined him. He went on to graduate from Yale Law School and now lives in California with his wife and two children. Joan proudly showed their most recent holiday card, which she plucked from a spot amidst stacks of folders and science textbooks crowding her office. Mixed in are mementos from decades past, including photos of Tom, who died in 2018 from pancreatic cancer.

As discoveries in the RNA field unfolded at a fast clip, Steitz shifted her focus from bacteria to more complex cells.

In 1976, Joan and Tom went to the prestigious Max Planck Institute for Biophysical Chemistry in Germany for a year-long sabbatical.

Around this time, other researchers showed that eukaryotes—organisms, like humans, defined by having nuclei in their cells—produce rough drafts of mRNAs laden with introns, non-coding sequences or “junk DNA” that are then removed when the final mRNA is produced.

Steitz wanted to figure out what was responsible for removing introns and she had a hunch that RNA-protein complexes called small nuclear ribonucleoproteins (snRNPs or “snurps”) were the “editors” responsible. While many snRNPs had been identified, their function was unknown. What had been discovered was that there were proteins that immediately bound to newly synthesized mRNA. Steitz thought that if she could create antibodies that recognized those proteins, she’d be able to capture them and characterize their function. But her first attempts at doing that were unsuccessful.

The opportunity to chase her hunch reemerged in the form of autoantibodies, antibodies that target the body’s own proteins rather than foreign invaders.

In Europe, Steitz had heard about diseases where autoantibodies were implicated. Back at Yale in 1978, she read a letter in Nature that described how the autoantibodies in lupus patients recognized a substance that was a mix of RNA and protein.

An MD-PhD student in her lab, Michael Lerner, knew a doctor across the street at Yale New Haven Hospital who could provide a blood sample from a patient with lupus.

That afternoon, the researchers used the patient’s antibodies as molecular tools to pull particles from the contents of cell nuclei. They turned out to be snRNPs, and the findings showed for the first time how cells recognize where an intron ends and an exon, the coding region, begins. By identifying five specific particles, they demonstrated how a cell cleans up its genetic instructions before turning them into proteins.

With a letter, published in Nature in 1980, Steitz and Lerner launched an entire subfield of molecular biology.

“This broke open the field and our understanding of the pathophysiology of human genetic disease. It was amazing,” says Susan Baserga, MD, PhD, William H. Fleming, M.D. Professor of Molecular Biophysics and Biochemistry at YSM. “The name of the piece was ‘Are snRNPs involved in splicing?’ She was completely right that they are. And then everyone else spent the next 20 years proving this.”

Building on this framework, Steitz and her colleagues clarified how proteins are built and how complex systems—from the brain to the immune system—are constructed. Plus, it revealed how genetic mutations can disrupt the splicing process, triggering hereditary diseases.

For example, in spinal muscular atrophy (SMA), a rare genetic disease that causes progressive muscle weakness, a mutation at a critical splice site effectively hides instructions from the cell. This causes the splicing machinery to malfunction, leaving introns in the final message and preventing the body from producing a protein essential for muscle function.

Steitz’s “snurps” discoveries laid the foundation for targeted therapies for SMA, approved in 2016, which act as molecular guides to restore proper splicing. The work represents a bedside-to-bench-to-bedside approach, with physicians’ knowledge enabling the basic research that uncovered fundamental biology, which then went on to inform treatment development.

The champagne bottles in Steitz’s office represent only a slice of the lives she has impacted.

Koleske recounts first meeting Steitz when he was a graduate student at MIT. His advisor, a graduate of Steitz’s lab, introduced them before he gave a poster presentation.

“This was probably 1991 and I was starstruck and even a little terrified. She was a giant in the field,” Koleske says, adding that he was fortunate to be hired by her at Yale in 1998. Steitz was the first female chair of the Department of Molecular Biophysics and Biochemistry, serving from 1996 to 1999.

“Over the years, she has been my mentor both officially and informally. She has always had her eye on me in a positive way,” he says. “Some people think the job of a professor is to sit in their office and write grants and papers. But her point to me early on was, ‘You’re a skilled experimentalist and it would be beneficial to you and your career and your lab if you were out there doing experiments.’ That stuck with me. In fact, I’m running a gel right now.”

And if Steitz supports you, it comes with an ask, he adds.

“If she gets behind you and champions you, you have her unconditional support. She’ll fight for you behind the scenes. But she’s also going to push you,” he says. “And if anyone is going to invest in me that heavily, the last thing I’m ever going to do is let her down.”

Koleske describes Steitz as detail-oriented. “She comes to our research and progress talks and she listens and asks very specific questions. But she also has this ability to zoom out,” Koleske says. “It’s as though she’s feeding presenters and trainees with both questions and guidance that makes them stretch.”

Baserga, who was a postdoc in Steitz’s lab from 1988 to 1993, agrees.

“She makes sure you know what you’re talking about. She trained us to be critical thinkers and to do that, you must read the literature,” she says. “She’d get a paper to review for some fancy schmancy journal, and she would ask us to read it and write something up and then discuss it with her. At a postdoc stage, it's a huge privilege to be able to do that, to see unpublished work and to figure out if it makes any sense.”

Steitz is an “eternal optimist,” Baserga adds. “That allows her to take risks, but she also knows when it’s time to stop and take a different path,” she says. “She’s intensely curious and that’s what drives her. She was a phenomenal, dedicated leader in the lab. And she was always above the fray with personality conflicts and focused our goal on getting our papers out.”

Steitz has secured nearly every major honor in her field, including the National Medal of Science, the Warren Alpert Prize, the Wolf Prize in Medicine, and the Lasker-Koshland Award for Special Achievement in Medical Science.

Likewise, her tireless commitment to boosting the next generation of scientists, especially women, is outstanding. In 2006, she co-authored “Beyond Bias and Barriers,” a landmark National Academy of Sciences report that showed women were leaving science not because of a lack of ability, but because of systemic institutional barriers. Never one to ignore the pursuit of a solution to a difficult problem, Steitz has turned her trophies into practical support and lifelines for others.

In 2008, she used her 2006 Canada Gairdner International Award winnings to establish an endowment at the Jane Coffin Childs Memorial Fund at YSM, then bolstered it with a significant portion of her 2018 Lasker Award to provide childcare stipends for postdocs.

On a personal level, she often came up with creative solutions for her trainees. When one postdoc asked to work part-time after giving birth, Steitz convinced the funding organization to bend the rules to allow it.

Steitz also donated her entire 2021 $100,000 Wolf Prize to the Yale Center for RNA Science and Medicine. The donation was used to establish the Tom and Joan Steitz RNA Fellows Program.

Five years ago, Steitz entered a phased retirement with plans to fully retire this fall. But she says she’s not ready until her current postdocs are set up for success. That is typical of Steitz, Baserga says.

“She keeps two lists of publications from her lab: one that has her name and another that has only the name of her trainees. You don’t see that very much, but it’s her way of launching careers, of pushing people out of the nest,” she says.

She’s also not done with research. Recently, she’s been focusing on viruses that make non-coding RNAs. “And the question is what do they do?” Steitz says, adding that the research options in RNA are limitless. “There are hundreds of people in the field now discovering new structures and new functions for RNA. It’s just wonderful.”