Jennifer Lippincott-Schwartz’s lab group meets on Monday mornings. A dozen or so team members watch slides click by, laptops and coffee mugs warming the conference room’s large table. Lippincott-Schwartz, a cell biologist, sits a couple of seats down from the projector screen.
Across from her, postdoctoral researcher Heejun Choi is explaining his latest work tracking protein-building ribosomes as they move through the tubes of the endoplasmic reticulum (ER), which stretches from the nucleus to the outer membrane of cells. Just last fall Lippincott-Schwartz’s lab upended the conventional wisdom about how that organelle is structured, revealing a system of densely packed tubes instead of the maze of membrane sheets that has appeared in textbook diagrams for decades.
Now the group is building on that finding. Lippincott-Schwartz has made a habit of aggressively pursuing new directions. “She’s fearless in terms of going forward and trying things,” says Carolyn Ott, a senior scientist in the lab, who has been with her for 12 years.
Lippincott-Schwartz has spent her career making fundamental discoveries about organelles. The basic cellular functions they perform are key to yielding secrets about cancer, neurodegenerative diseases like Parkinson’s and Alzheimer’s, viral infections that cause developmental disorders, the fate of stem cells, and even how long we live. And to ask these questions, she’s often had to invent whole new technologies.
Choi thinks that other researchers have overlooked the effects he’s seeing, with ribosomes seeming to cluster at the junctions of tubes in the ER. Lippincott-Schwartz, who moved her lab from the National Institutes of Health to HHMI’s Janelia Research Campus in March 2016, pops out of her chair to explain a concept to the rest of the group. Other members pipe up with questions and suggestions for Choi. One idea gets her attention, and Lippincott-Schwartz is jotting rapid notes, her brow furrowed in concentration.
Choi wants to analyze the data he’s already collected, but Lippincott-Schwartz is firm. She tells him he needs to go back and get more data first, better data, using a different kind of microscope. Other members give specific advice about using that instrument. The entire discussion is additive and organic. The researchers pick up their laptops and coffee, leaving the conference room with energy and a sense of purpose.
Lippincott-Schwartz’s methods are disarmingly easy to describe: to tackle stubborn problems, try to develop new technology to spy on the inner workings of living cells in higher resolution – both temporal and spatial – and then use those observations to answer questions about biological processes that seem so fundamental it feels ludicrous that we’re just solving them now. Her work is likely to inform discoveries for decades or centuries to come.
Lippincott-Schwartz likes biology because it’s historical and complicated. That’s how evolution works. Fundamental and timeless laws guide physicists. But the world biologists see is a system shaped by millennia of interactions, each one inextricable from the rest. Her story is a bit like that, too. So is her approach to scientific discovery, which was on full display at her Monday morning meeting.
For one thing, Lippincott-Schwartz doesn’t believe in managing her lab too fussily. Her postdocs usually choose their own research projects and decide which avenues to explore. What she provides is guidance and a big-picture perspective (and decades of experience, though she doesn’t mention that).
There’s no rigid mold for her group, which includes physicists, biologists, and biophysicists. One thing she requires is brilliance; another is social skills. “That’s vital,” says Lippincott-Schwartz, who abhors competition within the team.
Being able to talk about your ideas with the group, she explains, lets you fine-tune your questions and come up with new ways to attack them. She wants them teaching one another, finding intersections, and generating collaborations based on their abilities and interests.
Lippincott-Schwartz claims she’s just going with the flow. “I don’t plan out where I’m going to be in five years,” she says. “I just sort of experience the moment.” When she told Choi he needed to take another look at his ribosomes before he tried to start analyzing his data, that’s because observations are her dogma.
Tackle stubborn problems, try to develop new technology to spy on the inner workings of living cells in higher resolution...and then use those observations to answer questions about biological processes.
“Many of my projects that turned out to be breakthrough discoveries came from an observation in an experiment. If I had not been observant and willing to stop the path I was taking and redirect, that would never have happened,” says Lippincott-Schwartz.
A paper published by Lippincott-Schwartz’s group and colleagues at Janelia in October 2016 in Science epitomizes her approach. Aubrey Weigel, one of her research associates, was using a new technique – a total internal reflection fluorescence structured illumination microscopy (TIRF-SIM) – to look at the endoplasmic reticulum, and what she saw was hard to believe.
Everyone thought of the ER a mix of tubes and sheets, but under Weigel’s microscope the sheets were looking more like densely packed webs of tubes. Lippincott-Schwartz describes the moment Weigel told her what she’d seen: “My first reaction was…”.
Weigel won’t let Lippincott-Schwartz whitewash the story, finishing the sentence for her: “… ‘What did you do wrong?’” she says with a laugh
They collected more data, until Lippincott-Schwartz was convinced. “I was hooked into the old model,” she explains, a little sheepish that she’d been so stuck on the old way.
In the ER, proteins are synthesized and folded into the right shapes. Lipids and some hormones also come from the ER. Scientists are still processing the group’s discovery, but Lippincott-Schwartz believes one reason tubes might make more sense than sheets is that, as a cell moves, its organelles must move, too. A network consisting only of tubes would be easier to rearrange and reconfigure as the cell stretches.
The team’s striking image of the ER that appeared in Science – which, at first glance, looks like a Hubble image of a distant nebula – is startling in its detail. The focused ion beam-scanning electron microscope (FIB-SEM) instrument made it possible. There’s a limit to how closely any microscope can focus. Previously, even the very best microscopes would typically produce a single two-dimensional image for every vertical 90 nanometers of a sample viewed. The resulting, cumulative image flattened the ER’s mesh of tubes into what looked like a continuous sheet. The FIB-SEM, however, is capable of vertically sampling an image every 7 nanometers. The result is an extreme close-up picture that reveals the ER’s hidden structure.
Origin of the species
Still, Lippincott-Schwartz’s path to Janelia group leader wasn’t arrow-straight. Her career took shape after a lengthy evolution – though science clearly had her attention from an early age. Her family lived on a farm in northern Virginia, where she had a horse and spent her days outside, learning to observe the world around her. Her father, a physical chemist, hung a periodic table in their kitchen.
Her leadership skills surfaced early as well. In rural Virginia, mid-1960s, Lippincott-Schwartz talked her principal into letting her run the high school for a few days. He agreed, on the condition that she would be able to tell him where every student was at any given time. So she enlisted a classmate, an early computer user, to build a digital scheduling system. It was an early lesson for her in harnessing other people’s skill sets. Her schoolmates spent the week attending lectures by local experts Lippincott-Schwartz had invited.
She studied psychology and philosophy at Swarthmore College, near Philadelphia. At loose ends after graduation, Lippincott-Schwartz went to Kenya to teach at a girls’ high school. One story she tells about that year feels like another key to understanding how her research approach developed. She asked her physics class to draw a cube. She was stunned when none of them could do it, she says. They had never learned how to represent a three-dimensional object in 2D.
Sometime later she was preparing to teach the same students a knot-tying class. She’d done it before, with college kids in the United States, and they were usually hopeless at learning the task. Imagine her shock, then, when the Kenyan girls effortlessly produced complex bowlines and taut line hitches after seeing her do them once. It was a vital lesson for her about how differently people’s brains work, a lesson that would serve her well later in life, as she built a diverse research team and raised two daughters.
After returning from Africa, she spent a couple more years teaching high school physics and chemistry in California at an all-boys school run by Benedictine monks while her husband, Jonathan Schwartz, was attending law school. Then she was ready to get back to doing science. She earned a master’s degree in biology at Stanford University and completed a PhD in biochemistry at Johns Hopkins University.
Soon she was at NIH with Richard Klausner, her postdoctoral advisor. She jumped on the confocal microscopy train early, Lippincott-Schwartz says. “I wasn’t afraid of physics because I had taught physics,” she explains. It was her first time seeing proteins moving inside cells, the kind of process she’s been following ever since.
Lippincott-Schwartz credits Klausner for teaching her flexibility and fearlessness in science. While at the NIH lab in the early 1980s, she was trying to understand how the ER breaks down proteins that don’t pass the cell’s quality control mechanisms. At one point, she was trying to replicate an experiment from the scientific literature in which a drug was shown to block one of the ER’s processes. But what she saw when she followed the steps didn’t make sense.
Klausner suggested she might move on to a new approach. “Maybe a normal postdoc would have just said yes to him,” Lippincott-Schwartz says. Not her. She was too intrigued by what she was seeing. Lippincott-Schwartz pressed on, collecting more data. Eventually, she realized the drug she’d been using was causing an organelle called the Golgi apparatus, which packages and moves proteins around the cell, to fall apart and return its components to the ER.
When she went back to Klausner with her new results, she says he was immediately convinced. “He thought big,” she says, and he juggled a wide range of projects. It’s a style she’s obviously embraced, and to great effect.
One reason Lippincott-Schwartz moved to Janelia is because she’s ready for a new challenge. “I’m very intrigued with looking at neurons, looking at the brain,” she says. “It’s a system that’s pretty new to me.”
Plus, Lippincott-Schwartz is always willing to take on something a little bit unconventional. “She’s incredibly creative and open-minded,” says postdoc Chris Obara. At times perhaps too open-minded, he adds, which is why she surrounds herself with group members who know when to rein her in if she’s getting too far out.
One of those unconventional ideas eventually led to a Nobel Prize. In 2005, Eric Betzig, who went on to become one of the original group leaders at Janelia, was dreaming up a new kind of microscope. It would be able to see individual molecules and then compile them into a single, super-high-resolution image. But he didn’t know how to take a picture of an isolated molecule amidst a large ensemble of molecules.
As it happens, just a few years earlier George Patterson, a postdoc in Lippincott-Schwartz’s NIH lab, had been working with green fluorescent proteins (GFPs), which light up when exposed to certain wavelengths of light. Patterson made a modified GFP that stayed dark until he hit it with a laser of a specific wavelength. Then it lit up like a beacon. Betzig says when he heard about this photoactivatable GFP, his wild microscope idea suddenly became practical.
With Patterson and Lippincott-Schwartz’s photoactivatable GFP – and their vow of secrecy – Betzig worked in her lab with his collaborator Harald Hess, now a Janelia group leader, to develop photoactivated localization microscopy (PALM). It earned Betzig a one-third share of the 2014 Nobel Prize in Chemistry, for the development of super-resolved fluorescence microscopy.
“One of the things that really makes Jennifer special among cell biologists is her willingness to do anything new,” says Betzig.
Still, Lippincott-Schwartz admits, “Once we got the PALM to work, it wasn’t clear what we were going to do with it.”
But, true to form, it didn’t take long for her to apply the powerful technology. “If you’ve got the super-duper imaging capabilities, you’ve got a shot at answering questions you haven’t been able to answer before,” Lippincott-Schwartz says. Using the PALM and the subsequent enhancements she helped to pioneer, Lippincott-Schwartz’s lab has been able to explore topics ranging from HIV assembly to receptor clustering on the plasma membrane.
That newly acquired information has already expanded our understanding of basic life processes – by revealing, in unprecedented detail, the structures of organelles and the myriad ways in which they interact with one another.
"Even with the best technology," says Lippincott-Schwartz, “unless you take a broad-based, survey kind of approach, you’re not going to see these connections.” As ever, her next act will be to reveal those relationships in even finer detail. ■
Story by Sam Lemonick
Photography by Eli Meir Kaplan