Once Upon a Vacuole

By Brittani Sonnenberg

The first day that Lois Weisman became a postdoc in Bill Wickner's lab at UCLA, she learned that the project that she had looked forward to was off limits. Instead, Wickner gave her a list of ten other prospective projects on protein translocation. Her heart sank. "I wasn't interested in any of them," she said.

Eventually Wickner leaned forward and said, "I know what you're thinking: you're thinking, this is boring." There was a long silence. Finally Bill laughed, "That's okay, I think these projects are boring too. I'm ready for something new, something really wild...For instance, people study how proteins traffic to the yeast vacuole. But nobody has asked, 'How does the vacuole get there in the first place?' How about starting this study by developing an assay for vacuole fusion?" He handed her a stack of review articles about yeast organelles.

A tangential sentence in one review sparked Weisman and Wickner to look through a fluorescence microscope at a slide of an ADE2 yeast mutant. What they saw was unexpected and thrilling. It was the image of an intensely fluorescent vacuole from an ADE2 yeast mutant that they would go on to publish in Science, and would become the basis of Lois's studies in her future lab. The fluorescent vacuoles of the ADE2 yeast mutant provided a way to see organelles move in living cells. More generalized techniques for seeing movement in living cells would not be discovered for another eight years.

Years later, over a cup of coffee, Wickner and Weisman reminisced about that day. "It was as if I said, 'Let's go to the moon,'" Wickner stated, "'And you said, 'How great, I've always wanted to see Mars!'" Today, Weisman tries to provide her own students with similar latitude. "It is the feeling of freedom to pursue new subjects," she said, "that makes it worthwhile to do the hard work often required in scientific research."

According to Weisman, science could be considered an "art form of the 21st century." She compared it to fiction writing or painting, but said it has "constraints that are different," specifically that you "have to be scrupulously truthful." Although it may delay papers, being rigorously truthful is always ultimately more rewarding, she said, because you are building a foundation of facts that can be trusted. Weisman sees her work as "weaving stories" to explain scientific questions, complete with dramatic plots and awe inspiring details.

Many scientists bring an aesthetic sensibility to science, Weisman said. She cited the scientist John Heuser (Washington University), whose photographs of deep-freeze, quick-etch, electron micrographs of coated vesicles in cells continues to drive an entire scientific field. Weisman recalled being at a scientific conference in which John Heuser was a participant. One day when Weisman was swimming at a lake near the conference center she saw a man taking pictures of kids who she presumed to be his children or grandchildren. "It was so lovely," she said, "You could see how much this man loved his children by the energy pouring out of him." When she got closer to the shore she realized the man was John Heuser, and that he did not know the children he was photographing. "And that's when the light bulb went off and I realized that John Heuser, who is recognized as an eminent scientist, is also an extraordinary photographer. He has dedicated his life to taking pictures of things that no one has ever seen and then showing you their beauty."

Aside from science's visual allure, Weisman loves working on experiments because she believes that "no matter how basic your question, if you're studying a pathway that is fundamental to cell function, ultimately the answers uncovered will contribute to understanding human health." When Weisman's lab discovered that a low-abundance lipid in yeast was also present in people, and learned that reduced amounts of this lipid resulted in massive neurodegeneration in mice, they began collaborating with Miriam Meisler's lab, who serendipitously, and independently, converged on a similar finding. Their combined efforts resulted in a paper published in Nature last July and a second paper published in Proceedings of the National Academy of Science last October. One future goal, Weisman said, is testing whether elevating levels of this lipid has therapeutic value.

Weisman describes the environment as the LSI as "very unusual, with a tremendous amount of energy." She especially values the institute's emphasis on collaboration. Outside of the lab, Weisman enjoys reading fiction and watching movies, which go hand in hand with her visual approach to science. "I try to keep developing my analytical side so that the stories from our research can become as good as possible, because the choice of which questions to answer, the ability to figure out the best way to set up the question, and then to determine the best way to analyze the data, are what ultimately provide the story."