2018 Lasker~Koshland Special Achievement Award in Medical Science

Leadership in RNA biology and in scientific mentorship

For four decades of leadership in biomedical science—exemplified by pioneering discoveries in RNA biology, generous mentorship of budding scientists, and vigorous and passionate support of women in science

The 2018 Lasker~Koshland Award for Special Achievement in Medical Science honors an individual whose lifetime contributions have engendered among her colleagues the deepest feelings of awe and respect. For four decades, Joan Argetsinger Steitz (Yale University) has provided leadership in biomedical science. She has made pioneering discoveries about RNA biology, generously mentored budding scientists, and vigorously and passionately supported women in science. She has generated a cascade of discoveries that have illuminated wide-ranging and unanticipated functions for RNA molecules within our cells, and has served as a role model in multiple ways, especially for rising female investigators. Steitz has campaigned for full inclusion of all members of the scientific community, fueled by the conviction that reaching this goal is necessary to ensure a robust and innovative scientific enterprise.

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.

Inspiring trainees

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.

What Makes a Piece of Art or Science a Masterpiece?

What Makes a Piece of Art or Science a Masterpiece?

Critics of art and philosophers of science have long wrestled with the question of what elevates a piece of art or a set of experiments to masterpiece status.

Opening remarks by Lasker Jury Chair Joseph Goldstein

Award overview by Harold Varmus


Most Lasker Prizes celebrate great discoveries by honoring those most responsible for making them.  But the Special Achievement award celebrates great people who have met an especially imposing standard: their work and character inspire “the deepest feelings of awe and respect within the biomedical community.”  

I am especially pleased to introduce this year’s recipient, Professor Joan Argetsinger Steitz of Yale University, because I bear personal witness to a remarkable feature of her ability to “inspire awe and respect”—its longevity.

In 1969, nearly fifty years ago, when Joan was a post-doctoral fellow at the Laboratory of Molecular Biology in Cambridge, England, she visited the NIH to give a lecture about her recent work.  I was then, like some others on this podium, a recently trained physician trying to learn the rudiments of modern biology while doing government service during the Vietnam War. Joan was already well beyond the rudiments, exploring ideas I hadn’t even thought about, with methods I didn’t know. Despite her youth, she spoke with a clarity and self-assurance that already prompted respect, even awe.

My job today is to tell you how she got to that point—and how she has sustained the performance for another five decades. To do that succinctly, I need a rhetorical device.  One of her many fans has written that she is a “persuasive missionary for molecular biology.”  The phrase is accurate, but too limited, in ways I will illustrate.  Still, it helps me frame her story: the origins of her faith in science and evidence; her training in the “high church” of molecular biology; the revelations that allowed her to expand its doctrines; and the passions that brought others to embrace her broader view of life’s mysteries and to build a more diverse scientific community.

Let’s begin with her baptism. Sara Hall, a physics teacher at the Northrup Collegiate School in Minneapolis, encouraged Joan to build an oscilloscope and introduced her to the joys of collecting data. (Incidentally, Sara Hall also taught Marcia McNutt, now president of the National Academy of Sciences. We need more Sara Halls!)  

In choosing a college to study science, Joan was influenced by her father, a high school guidance counselor with an abiding faith in practical applications of learning, as embodied in the Antioch College work-study program. In 1961, that program gave Joan her first encounter with molecular biology, when she was apprenticed to one of its early acolytes, Alex Rich, at MIT.  

Long and frustrating hours at a spectroscope, trying to make ribosomes behave physically like DNA, as Alex hoped, did not dampen her enthusiasm for a career in science. But she didn’t see any successful women with independent scientific careers. Medicine seemed a bit more promising, so she applied to (and was accepted by) Harvard Medical School. But between her graduation from Antioch and matriculation at medical school, she had a productive time working with Joe Gall—a cell biologist (who, incidentally, also received this award a few years ago). So, when a single place suddenly opened up for a biology graduate student at Harvard and was offered to her, she took it.

Not all the faculty welcomed her, the sole women in her class. But some of the leading clergy in her new field were supportive: Jim Watson, Wally Gilbert, and her former mentor at MIT, Alex Rich. Watson accepted her in his group and encouraged her to do independent work on bacterial viruses. Later, he and others used their priestly contacts—with Francis Crick, Fred Sanger, Sidney Brenner, Mark Bretscher—to help her obtain a position at the Laboratory of Molecular Biology in Cambridge—the temple where her new husband, Tom Steitz, was determined to train with the world’s best structural biologists. And to become one himself (which, as we all know, he did).

At this time, just fifteen years after the revelation of the double helical structure of DNA, the doctrine of molecular biology was dominated by Crick’s Central Dogma. In the catechism, information flowed from DNA to RNA to protein; it was encoded in triplets of four letters; and the message, transcribed from DNA to RNA, was translated by ribosomes to make proteins. These tenets were profound, correct, and essentially universal. But was that all we needed to know? 

The work that I heard Joan describe at NIH in 1969 was among the first to indicate that DNA and RNA did more than dictate the order of amino acids in proteins. In the experiments she had performed, independently and courageously, ribosomes were also being told where to sit on the RNA message to begin making proteins.  

After Joan and Tom accepted independent positions at Yale, she persisted. And she discovered how RNA in the ribosome perceives novel signals in messenger RNA to find the place to start protein synthesis.   

But that was just the beginning. Other kinds of RNAs seemed to be doing important things, conveying significant signals, without encoding proteins or without even getting to the cytoplasm (the place where proteins are made in eukaryotic cells). Some small RNAs were already known to transfer amino acids into proteins to execute the dictates of the Central Dogma. But Joan and her Yale students found that many other small RNAs appeared to work in realms beyond the Dogma; these were often associated with specific but still mysterious proteins, forming protein-RNA complexes of uncertain purpose.  

In one especially significant set of studies, Joan and a student, Michael Lerner, discovered that patients with auto-immune diseases made antibodies that reacted with subsets of those complexes.  This deepened our understanding of some important diseases, like lupus erythematosis, but also helped to categorize the RNA-protein complexes, allowing systematic study.  Some of the particles recognized novel signals in RNA sequences and were able to knit together parts of newly synthesized RNA, accurately forming the mature, spliced molecules that are then read by ribosomes to make proteins.

These and many other unexpected properties of RNAs—produced by all kinds of cells and by many pathogenic viruses—provided founding principles for an imposing new wing of the church of molecular biology. These were not heresies, and did not produce schisms. Instead they were “new testaments” that convey biological complexity. Together they have helped to change our thinking about living systems and their origins. They have inspired a vision in which RNA, not DNA, is central to the history of life.  

At a more pragmatic level that Joan’s father would have appreciated, this vision became the defining element of a scientific club—a very “nice” club, as Joan is fond of saying—in which RNA and its novel features are the central objects of inquiry.

The discoveries I’ve been describing go well beyond what a missionary is expected to do for a church. But Joan has also excelled in the missionary’s central role: the recruitment and training of disciples. Virtually every Yale undergraduate who has dipped a toe in modern biology extols Joan’s lectures. Many have also been taken into her laboratory to taste what she cares about most—the gathering and interpretation of data—just as Sara Hall once did for Joan. These students and more senior trainees are united in praise for her virtues as a mentor: her enthusiasm for results, her rigor in interpreting them, and her integrity in allocating credit. For instance, she often returns the favor that her own mentors conferred on her—by allowing work done independently by trainees in her lab to be independently authored.

To this point in my introduction, I have been nearly gender-neutral. Joan’s achievements would be remarkable for anyone, regardless of gender. But this moment should not pass without recognizing the effects of her career on the status of women in science, including molecular biology.  

Most churches begin as patriarchies, not necessarily maliciously; but that cannot persist without grievous loss. Early in life, Joan was nearly lost to science because she didn’t see a path to an independent career. But, against odds, she has cut a trail that others can follow. Because she knows the significance of this trail, she has worked, locally and nationally, to make it better marked for those who might take it and better appreciated for the joys it can bring.

In that sense, today’s award for “special achievement” takes on even greater meaning and importance.

Thanks for listening and for honoring Joan Steitz by your presence.

Joan Argetsinger Steitz

Cell interview


Acceptance Remarks, 2018 Awards Ceremony

I feel extremely privileged to have been a part of the 20th-century revolution in Biology. I was in junior high school in 1953 when the double-stranded structure of DNA was first proposed and by the time I reached college, it was still too new to have found its way into textbooks or courses. As an undergraduate at Antioch College, I was fortunate to be assigned a work-study job in Alex Rich’s lab at MIT. I recall being completely enthralled by learning about the DNA structure because it provided a possible molecular explanation for the genetic phenomena that had intrigued me in high school. Yet, I decided I should go to medical school since I had simply never encountered a female science professor or lab head. On the other hand, I did know several women physicians.

My goals changed only during the summer before I was to enter Harvard Medical School when I worked in the lab of cell biologist Joe Gall, then at the University of Minnesota. I was so exhilarated that I decided my future prospects did not matter.  I wanted to make scientific discoveries and switched instead to the PhD program at Harvard.

The new field of molecular biology that I entered when I became a graduate student in Jim Watson’s lab was small and eclectic. Molecular biologists focused exclusively on simple systems, like bacteria and the viruses that infect them.  It was reasoned that you could never learn anything about the underlying principles without starting simple.  Investigators who at that early time were endeavoring to work with mammalian cells were even derided as wasting their time on something that was too complex to ever be understood.

It was therefore unimaginable to me what would happen in Biology within my lifetime.  For instance:

  • It was inconceivable that we would ever know the sequence of the 4 billion base pairs of DNA in the human genome. A co-graduate student in the Watson lab wrote his entire thesis on the sequence of one base—namely, what was at one end of the RNA genome of a bacterial virus! We had to start somewhere!
  • Also unimaginable was the impact Molecular Biology would have on the practice of medicine, with new drugs and new diagnostics, even the prospect of personalized medicine, with treatments based on knowledge of the exact sequence of the DNA from each patient.
  • That it would spawn a multibillion-dollar biotech industry, benefitting not only medicine but agriculture.
  • Even forensic science has been revolutionized.
  • Finally, it was inconceivable that women would hold important leadership roles in science and academia.

As far as science goes, I have been surprised by how important serendipity is to discovery in science. In my case, it was chance comments by that led to our using sera from patients with autoimmune diseases to discover a new class of tiny particles in cells called snurps.  Snurps are essential for pruning out the nonsense segments that interrupt almost every gene in humans through a process called RNA splicing.  Snurps therefore allow the information in our genes to be converted into working proteins in our cells.

A final surprise has been finding that it is almost as much fun to share the joy of discovery with a younger colleague as doing it oneself.  I have been immensely privileged to work with a cadre of very talented younger scientists—PhD students, postdocs and undergraduates—at Yale. It is to them that I owe this very great honor.

Jury

2018 Lasker Medical Research Awards Jury

Seated, left to right: Xiaowei Zhuang, Harvard University ● J. Michael Bishop, University of California, San Francisco ● Lucy Shapiro, Stanford University ● Joseph Goldstein, Chair of the Jury, University of Texas Southwestern Medical Center ● Robert Horvitz, Massachusetts Institute of Technology ● Erin O’Shea, Howard Hughes Medical Institute ● Paul Nurse, Francis Crick Institute

Standing, left to right: K. Christopher Garcia, Stanford University ● Jeffrey Friedman, Rockefeller University ● Marc Tessier-Lavigne, Stanford University ● Dan Littman, NYU Langone Medical Center ● Jeremy Nathans, Johns Hopkins School of Medicine ● Charles Sawyers, Memorial Sloan-Kettering Cancer Center ● Bruce Stillman, Cold Spring Harbor Laboratory ● Richard Locksley, University of California, San Francisco ● Craig Thompson, Memorial Sloan-Kettering Cancer Center ● Laurie Glimcher, Dana-Farber Cancer Institute ● Richard Lifton, Rockefeller University ● James Rothman, Yale University ● Harold Varmus, Weill Cornell Medical College ● Michael Brown, University of Texas Southwestern Medical Center ● Christopher Walsh, Harvard University

Not pictured: Titia de Lange, Rockefeller University