Vassie Ware’s explorations of the inner workings of ribosomes leads toward new understandings of how proteins form
Let’s say you’re waltzing across a ballroom with a partner you’ve known for a long time. The two of you are comfortable and adroit, and you glide across the floor with precision and ease. There’s just one problem: Unlike you, your partner is a bumbler at other dances. So during a break with Partner A, along comes Partner B, who—paired with you—is fantastic at the tango. In both cases, you’re engaged in dancing. But with each partner, you’re doing something very different.
Vassie Ware, professor of molecular biology in the department of biological sciences, is fond of using illustrations like this to convey concepts to her students. In this case she’s not really talking about waltzing versus tangoing (though she did once take a ballroom class). Instead, she’s alluding to curious discoveries about the molecular dances of ribosomes.
Ribosomes are at the heart of life, providing the molecular machinery that synthesizes proteins in all living cells.
“We clearly know that all ribosomes have the goal or function of making protein,” Ware says. “Does that mean all ribosomes are the same? The answer is no.”
Certain major differences between ribosomes are not controversial. “Some components of ribosomes in bacteria are very different than those typical of animals and humans,” Ware says. In fact, we exploit those differences with antibiotics designed to kill bacteria. “But open any biology textbook to the section on translation [the process by which ribosomes synthesize proteins through gene expression and the action of various forms of RNA] and none of them give much information on structural or behavioral differences between ribosomes in eukaryotic organisms,” she says. “The idea that human or animal ribosomes might be specialized or behave differently from each other is not dogma now. But that’s my area, and that’s where we’re headed—to understand such differences.”
In short, to use her analogy, she’s working to show that ribosomes that normally only seem to waltz may, under certain circumstances, unexpectedly start to tango.
Ware’s interest in ribosomal protein-making machinery stems from a long-standing fascination with how things work. “Even as a youngster, I would take mechanical devices apart step by step and try to figure out how they functioned on the inside,” she says. Her formative educational experiences weren’t always encouraging. “I liked biology but had a high school teacher who presented it as if there were no more interesting questions left to answer,” she says. “I would think things like, ‘If we’ve solved all the riddles, how come people still get cancer?’” Instead of killing Ware’s interest, the teacher unwittingly spurred her on. “Biology could not possibly be that dull,” Ware decided.
As an undergraduate at Brown University, she encountered mentors who made biology fascinating and exciting. One was Susan Gerbi, whose lab researches (among other things) ribosomal RNAs. “People at Brown encouraged me to get involved with research as an undergraduate and apply to grad school,” Ware recalls. She went on to Yale, where she worked in reproductive biology and developed an interest in how hormones affect follicle development in ovaries. That led to questions about gene expression, which in turn steered Ware toward the process of making proteins with ribosomes, an interest she brought with her to Lehigh in 1985.
Knowing more about that process could foster development of more effective pharmaceuticals, as some drugs beyond antibiotics selectively target ribosomes. What’s more, certain genetic diseases such as a bone marrow disorder known as Diamond-Blackfan anemia seem related to ribosomal defects. More broadly, understanding ribosomes at the molecular level could shed light on fundamental mysteries of genetics. “The diversity of proteins—hundreds of thousands of them—is enormous,” Ware says. “Yet the Human Genome Project found only 28,000 genes—far fewer than expected. So how do we get all that diversity?”
It could be that ribosomal proteins have yet-to-be-determined differences or functions beyond what’s known or expected. “We’re now working on protein components of the ribosome that in one case function as part of the ribosome and in other cases are totally not associated with the ribosome and doing something else,” Ware ways. “It’s like the difference in the partner you’re dancing with.”
Much of this work has focused on studies of fruit flies and a ribosomal protein family known as rpL22e. Two proteins in the family—rpL22 and rpL22-like—are duplicates, or paralogues. Such duplication is not uncommon, Ware says. But having two proteins that can do the same thing takes pressure off at least one of them because it has a backup, potentially freeing it to perform other functions. Curiously, rpL22-like isn’t expressed everywhere in the fly like its paralogue is—it only functions in the testis and the eye. “Why is it there and what is it doing?” Ware wondered. “Do the two proteins have different functions?”
Research suggests they might. “We’ve done cool experiments where, when we knock out rpL22 in the fly, it’s lethal,” Ware says. Manipulated rpL22-like can take over and save the organism. “There’s redundancy, but rescued organisms are also deficient in two ways,” Ware says: “They die earlier and in some cases develop tumors. So there’s something different between the proteins.” Other research shows that when paired with different chemical groups, rpL22 exhibits functional traits outside of the ribosome that are unrelated to protein synthesis. “We’re trying to uncover what that non-ribosomal function is for rpL22 and the significance of having two populations in particular cells,” Ware says.
Ware has also developed an interest in bacteriophages, viral units that infect and kill bacteria. She runs Lehigh’s participation in a program sponsored by the Howard Hughes Medical Institute (HHMI) known as SEA-PHAGES. It’s part of the Science Education Alliance, which exposes undergraduates at colleges and universities across the country to research-based curricula and scientific discovery early in their academic careers. In the PHAGES (Phage Hunters Advancing Genomics and Evolutionary Science) program, students collaborate with other labs to isolate new phages, sequence their DNA, carry out bioinformatics and annotate entries that are published in a database called GenBank. “It’s real discovery,” Ware says. “Students love it.” Once annotated, newly discovered phages present interesting questions about what their genes and proteins do. “Our program is at the point where we’re asking those questions now, and amazing things are coming out of it,” Ware says. “It’s a treasure trove of new developments.”
With Neal Simon, professor of biological sciences, Ware co-directs another HHMI-sponsored program in which two four-year grants have allowed students to take part in a multidisciplinary program called the Biosystems Dynamics Summer Institute. Participants engage with faculty from a variety of disciplines to explore life science research in a 10-week summer program. HHMI has also made possible a virtual class called Bioscience in the 21st Century, in which lecturers from a variety of departments offer cross-disciplinary perspectives on fundamental problems in bioscience.
“All these efforts and contributions transcend me,” Ware says. “It’s about bringing together different groups of students and faculty to interact and explore important, interesting questions”—and better understand the dance of life.