Seeing Is Believing: Following the Trail of Discovery Inside the Cell
NICHD cell biologist Jennifer Lippincott-Schwartz, Ph.D.—a self-described visual learner—wants to
see what is happening inside living cells. So it's no surprise that she has developed new ways to view the tiniest pieces of these complex entities at work.
At the NICHD, Dr. Lippincott-Schwartz heads the
Section on Organelle Biology within the
Cell Biology and Metabolism Program of the
Division of Intramural Research. She also serves as president of the American Society for Cell Biology for 2014, is editor of Current Protocols in Cell Biology and the
Journal of Cell Science, and is on the editorial boards of other journals, including
Cell. She has been a member of the National Academy of Sciences since 2008 and a member of the Institute of Medicine of the National Academies since 2009.
In the video below, Dr. Lippincott-Schwartz explains how studying the biology of individual cells can help in developing new approaches to cancer.
A text alternative is available at
http://www.nichd.nih.gov/news/profiles/researchers/lippincott-schwartz/Pages/transcript1.aspx
Read more about her path to a career in science, learning to be open to discoveries, and the role of technology in spurring advances in the sections below
The Inspiration for a Career in Science
Peering Inside Cells
A Surprising Discovery
Sparking Advances in Technology
Following Discovery into the Future
More Information
The Inspiration for a Career in Science
When Dr. Lippincott-Schwartz finished college, she decided to take some time before deciding on her exact career path: "One thing that I did recognize when I finished college was that I really needed to learn more about the world before I was going to make a commitment to a graduate program or a particular profession."
Her father was a chemistry professor, and she began college as a science major but later gravitated to philosophy and psychology. After graduating from Swarthmore College, she went to Kenya to teach science in a girls' school. "It was a complete eye-opening experience, and it was there that I really decided that I wanted to do science," she said.
After returning to the United States and teaching high school science for another 2 years, Dr. Lippincott-Schwartz began a graduate program in biology at Stanford University and later entered a doctoral program at Johns Hopkins University, where her mentor, Douglas Fambrough, Ph.D., had a fluorescence microscope.
"I'm a very visual person, and for me, concepts are always filtered through a visual landscape," Dr. Lippincott-Schwartz said. "I remember the first time looking under one of those microscopes and seeing the cell and particular organelles—small, self-contained compartments within cells that have specialized functions—being lit up. And I knew: This is what I wanted to do. I wanted to understand the language of the cell from this visual perspective. So that's what drew me to cell biology."
Peering Inside Cells
Cells are the basic units of life, but they are also complex, and there is still much to learn about how they function. Cells contain a variety of structures, including a "cytoskeleton" that defines their 3-dimensional shape; a nucleus that contains DNA and acts as the cell's control center; organelles; and cytoplasm, the gel-like substance enclosed by the cell membrane.
Many things are happening simultaneously within a cell. For example, molecules are moving in set traffic patterns or pathways within the cell, and the cell may be secreting molecules to the outside along other designated pathways. One of the basic questions that cell biologists ask is how these processes are set into motion and how they are so well choreographed.
Dr. Lippincott-Schwartz focuses on the organelles: what they do, what sets them into motion, and how they work together. Researchers in her laboratory have helped develop imaging technology to see the organelles at work and find out how they fit into the choreography of the living cell.
"I think the work in my lab related to these organelles is fundamentally driven by basic questions about how the cellular system can function as a unit of life that's persisted for over 3 billion years on earth," Dr. Lippincott-Schwartz said. "What are the features of that system that allow it to be so robust to occupy pretty much all of the surface of the earth? It's really, really remarkable."
A Surprising Discovery
When Dr. Lippincott-Schwartz was a postdoctoral fellow, she observed one type of organelle, the
Golgi apparatus, disappearing in the presence of an antibiotic, brefeldin A. This was the first time, to Dr. Lippincott-Schwartz's knowledge, that anybody had seen an organelle disappear within a cell. Up to that point, it had been assumed that organelles were stable structures.
Brefeldin A has since become a staple of cell research because of its ability to block the secretory pathway—that is, the path that molecules take when they are being secreted from the cell.
"Seeing that brefeldin A could cause an organelle as significant as the Golgi—which is involved in regulating secretory trafficking—suddenly disappear, was just mind-blowing," she said. After years of work, she and other researchers observed that brefeldin A inactivates a binding protein, which in turn short-circuits the process of maintaining the Golgi apparatus.
Sparking Advances in Technology
Until recently, imaging technology limited observation to two, perhaps three, organelles at a time, but technological advances now allow imaging of six or seven organelles at a time. Dr. Lippincott-Schwartz's laboratory has played a part in these advances.
She was an early adopter of green fluorescent protein technology to study organelles, and her laboratory developed a photoactivatable form of green fluorescent protein. Her laboratory also was the first to use a method known as photobleaching of green fluorescent protein as a way to look at organelle dynamics and diffusion.
Building on their use of photoactivatable fluorescent protein, Dr. Lippincott-Schwartz and her colleagues teamed up with physicists
Eric Betzik, Ph.D., and Harald Hess, Ph.D., to develop a new technique,
PALM (photo-activated localization microscopy) that provides 10 times the resolution of conventional light microscopy.
"Initially we just used fixed samples, but now we're doing live cell samples. And there are a lot of interesting things that we're doing, looking at how molecules are moving on a surface of the cell and how they're moving along
cytoskeletal filaments and so forth," Dr. Lippincott-Schwartz said of PALM. The new technology has allowed researchers in her laboratory to see some striking things.
"Because the technology is new, we're seeing for the first time things that people haven't seen, and we're seeing things that we're not sure how to interpret," Dr. Lippincott-Schwartz said. "This is not unusual when technological advances happen. When electron microscopy was first developed, people often questioned what they were seeing. The same applies to these super-resolution imaging approaches."
Using cutting-edge imaging technology, Dr. Lippincott-Schwartz and her colleagues made an important observation about autophagy, the process by which a cell gathers damaged and stray bits of organelles and proteins from within the cell and recycles them for reuse by a starving cell. The process of autophagy starts with the formation of an organelle, the
autophagosome, which delivers the nutrients to a separate cell structure, the lysosome, which recycles the nutrients.
Autophagy is important because when it does not occur as it should, it can lead to diseases such as cancer. But cell biologists had long been vexed by the question of where the membrane that forms the autophagosome originates. The Lippincott-Schwartz laboratory answered that question. In fact, they watched it happen right before their eyes.
Following Discovery into the Future
Dr. Lippincott-Schwartz has spent her professional life watching this microscopic, basic unit of life—the cell—at work. While a great deal has been achieved in understanding cells, there is much more progress to be made, and Dr. Lippincott-Schwartz continues to follow the science wherever it leads.
"What I love about being a scientist is it's just a continuous activity of discovery, where every day there are just so many fun things that you're learning, and how you put them together to synthesize ways of thinking about the world is so exciting. It's really fun."
More Information
For more information about Dr. Lippincott-Schwartz's laboratory and her work on cells, please select from the following links:
National Library of Medicine Genetics Home Reference:
What Is a Cell?
Sources
Klausner, R. D., Donaldson, J. G., & Lippincott-Schwartz, J. (1992). Brefeldin A: insights into the control of membrane traffic and organelle structure.
Journal of Cell Biology
, 116, 1071–1080.