Fulfilling a seemingly impossible dream
When Steitz encountered the molecular basis of genetics in the early 1960s as an undergraduate lab technician, she was enchanted, but despite her passion and curiosity, she could not envision a future for herself as an academic researcher. The absence of female biology professors shrouded that potential career path. She did know that women could be physicians, so she decided to become a doctor.
The summer before medical school, Steitz joined the lab of Joseph Gall (Albert Lasker Special Achievement Award in Medical Science, 2006), where she undertook her first independent project. Thrilled by the joy of discovery and the challenges of steering her own experiments, she could no longer resist the draw of research. So, rather than medical school, she went to graduate school in 1963 and earned a Ph.D. in biochemistry at Harvard University, even though she still couldn’t imagine that she would ever run her own lab.
As a postdoctoral fellow at the Medical Research Council in Cambridge, UK, Steitz tackled and solved a technically challenging and intellectually pressing question. At the time, no one knew how the ribosome—the protein-RNA machine that translates genetic information from messenger RNAs (mRNAs) into proteins—finds the right place to sit down on an mRNA template. She identified such attachment sites in bacterial mRNAs. She deciphered “start” sequences in bacterial mRNAs. This triumph won international acclaim, and she joined the Yale faculty in 1970.
There she discovered that a particular RNA component of the ribosome adheres to mRNA target sites by binding in a sequence-specific manner. This result rocked the field because it established that ribosomal RNAs behave not just as a framework for their protein partners. Rather, they perform specialized tasks through intimate interactions with the mRNA template.
In the meantime, scientists who study more complex organisms were puzzling over the observation that mammalian cells destroy most of the RNA they make before it escapes the nucleus. The discarded portions came from internal portions of mRNAs and, in 1977, researchers discovered that mammalian cells splice out stretches from within a precursor mRNA (referred to as “introns”) to create a whittled-down product that provides the template for protein synthesis (referred to as “exons”). Steitz reasoned that whatever performs this reaction must reside in the nucleus. When she learned that people with the autoimmune disease lupus carry antibodies that bind to poorly defined but abundant components of their own nuclei, she wondered whether the antibodies might lead her to the splicing machinery.
In 1979, she and her M.D.-Ph.D. student Michael Lerner discovered that the antibodies target a set of molecular conglomerations, each composed of a unique small RNA molecule and a group of proteins. Steitz and Lerner noted that the sequence of one of the small RNAs matches the splice point within precursor mRNAs. They suggested that the small ribonucleoprotein particles (snRNPs) might promote mRNA splicing.
Steitz and others confirmed this idea. The autoimmune antibodies enabled the first molecular insight into splicing—an intricately choreographed event by which a dynamic molecular apparatus, whose core is composed of snRNPs, removes internal spans of mRNA with exquisite precision.
Through a rich and varied array of studies, Steitz went on to uncover a panoply of RNA-based processes within mammalian cells. These varied functions illustrate the versatility of RNAs—this class of molecules performs many roles in addition to their classic one as the DNA-to-protein intermediary—and touch multiple aspects of health and disease.
Reaching for equity, realizing potential
In 2005, Steitz was invited to join a U.S. National Academy of Sciences committee that was exploring how to maximize the potential of women in academic science and engineering. The resulting report, Beyond Bias and Barriers: Fulfilling the Potential of Women in Academic Science and Engineering, defines the problems women face, articulates their causes, and presents strategies for remediation. In preparation, Steitz dug into the psychological literature about unconscious bias, which was gaining widespread recognition at the time. To counteract its effects and the other conditions that have created the current predicament, the panel concluded, leaders and institutions must take numerous defined actions because the United States cannot afford to squander some of its brightest minds.
Steitz has devoted herself tirelessly to disseminating the committee’s findings and recommendations. She gives talks at universities and international conferences about how to create inclusive cultures, and she routinely meets with female students and postdocs to educate them about the forces that limit their opportunities and advancement, to illuminate how prejudice manifests, and to help women navigate the situations they encounter.
In her efforts to broaden the nation’s talent pool and unlock female scientists’ full potential, Steitz has continued to inform herself and broadcast new, relevant ideas. For instance, she is raising awareness about the documented effects—physiological and psychological—of membership in an undervalued minority group. Cues such as being outnumbered can influence memory, heart rate, and other attributes, and Steitz is helping women recognize this phenomenon so they can make skillful decisions about how to respond productively.
Steitz has brought these ideas to her own mentoring practices, and she takes conscious steps toward ensuring that her female trainees feel valued. In so doing, she works toward empowering women to take full advantage of the possibilities that surround them and to avoid unnecessarily constraining their choice of projects, approaches, and so on.
Steitz has trained almost 200 students and postdoctoral fellows, launching the careers of many successful scientists, several of whom have been elected to the U.S. National Academy of Sciences. She cultivates a collaborative environment and encourages her trainees to solicit ideas from one another and provide mutual help. She also touts the benefits of soaking up ideas from scientists who work far afield from RNA biology and fosters interdisciplinary thinking in multiple ways. Of the 360 papers that have originated from her laboratory, 60 of them do not include her name in the list of authors—a gesture of generosity that reflects her belief that students and postdoctoral fellows who work completely independently should be allowed to publish on their own.
Propelled by an unmitigated thirst to learn, Steitz has crafted an impressive career. It began at a time when female biologists were scarce and the environment held more formidable barriers than those that still exist today. She persisted to become a leader not just in the realm of RNA biology, but in biomedicine more broadly. Her bold spirit has helped her break new ground in multiple areas. She has worked fervently to pass along her inquisitive, open-minded approach and to ensure that the next generation of scientists will inherit a healthy research enterprise.
by Evelyn Strauss
Key publications of Joan Argetsinger Steitz
Steitz, J.A., and Jakes, K. (1975). How ribosomes select initiator regions in mRNA: Base pair formation between the 3′ terminus of 16S rRNA and the mRNA during initiation of protein synthesis in Escherichia coli. Proc. Natl. Acad. Sci. USA. 72, 4734-4738.
Lerner, M.R., and Steitz, J.A. (1979). Antibodies to small nuclear RNAs complexed with proteins are produced by patients with systemic lupus erythematosus. Proc. Natl. Acad. Sci. USA. 76, 5495-5499.
Lerner, M.R., Boyle, J.A., Mount, S.M., Wolin, S.L., and Steitz, J.A. (1980). Are snRNPs involved in splicing? Nature. 283, 220-224.
Mount, S.M., Pettersson, I., Hinterberger, M., Karmas, A., and Steitz, J.A. (1983). The U1 small nuclear RNA-protein complex selectively binds a 5′ splice site in vitro. Cell. 33, 509-518.
Tycowski, K.T., Shu, M.D., and Steitz, J.A. (1993). A small nucleolar RNA is processed from an intron of the human gene encoding ribosomal protein S3. Genes Dev. 7, 1176-1190.
Cazalla, D., Yario, T., and Steitz, J.. (2010). Down-regulation of a host microRNA by a Herpesvirus saimiri noncoding RNA. Science. 328, 1563-1566.
Tycowski, K.T., Guo Y.E., Lee, N., Moss, W.N., Vallery, T.K., Xie, M., and Steitz, J.A. (2015). Viral noncoding RNAs: more surprises. Genes Dev. 29, 567-084.