Charting the Incredible Complexity of Cells
Cells are good examples of nature’s ability to build complex machinery at the micro and nanoscale. In fact, it is only recently that researchers have begun to get a glimpse into the mechanisms that control the complex interactions of cells with the outside world. Using advanced optical imaging tools that can trap molecules in cages of light, Erin Sheets and her students in Penn State’s Department of Chemistry measure, manipulate, and image the molecular interactions of nanostructured lipid membranes in living cells and model cell systems.
The cell membrane is a semiliquid membrane in which proteins and dense areas of cholesterol, called lipid rafts, float. These raft structures are believed to be involved with cell signaling, the communication that takes place between the cell and its environment through a variety of pathways. The significance of cell signaling lies in the likelihood that errors in signaling are responsible for any number of diseases, from cancer to the many autoimmune disorders to diabetes.
Prof. Sheets and her team are convinced that lipids, including lipid rafts, are crucial to understanding the ways cells talk to proteins, initiate the immune response, and possibly even how cells age. With a greater understanding of how cells communicate, and miscommunicate, their work might help other researchers find better therapies for a wide range of diseases, including those associated with growing old. In fact, one of her research projects, sponsored by the National Institute on Aging, involves looking at how the plasma membrane of T cells, the cells responsible for helping to clean out cellular debris, change with age.
Patterned arrays of lipid domains surrounded by lipids
of another composition on a biomimetic membrane
are created using a polymer lift-off approach.
(Image courtesy of Kanika Vats.)
Sheets uses tools familiar to the materials scientist to build model membrane systems to study in simpler forms the complex structures of cells. "We use microfabrication to create simpler model systems to study the cell membrane. We create patterns of molecules, called domains, to make more complex structures to study the molecular interactions that lead to the nanostructures in cell membranes." In the past they have used microcontact printing and microlithography techniques to pattern arrays of squares that are 5-10 micron across. The squares are filled with a brew of molecules called phospholipids, which under the right conditions spontaneously self-assemble into a bilayer that is very similar to a cell membrane. Other protein and cholesterol molecules are added to the lipid bilayers in patterns that simulate those dense areas on the surface of living cells that are suspected of initiating cellular signaling. Recently, they have begun to use a photolytic, or light-based, approach to pattern the microdomains.
Also among her tools is an intricate system of lasers and microscopes that is unique to her lab. This setup, largely the work of her Ph.D. student Minjoung Kyoung, is one of the first optical systems capable of looking at the dynamics of a living cell. Using optical trapping to hold specific molecules within the membrane and a low intensity laser to excite fluorescent molecules in the membrane, the researchers can watch how lipid rafts move laterally across the cell wall to initiate signaling.
"I became interested in nanobiotechnology due to my cell biology training at Cornell," Sheets says. "Penn State has similar strengths. Our group is basic research driven - we use materials and nanotechnology to study biology. In our spare time we build the equipment infrastructure you see here in the lab. Penn State defines chemistry pretty broadly," she says, laughing. "And we represent the essence of that breadth since we work at the interface of biophysics, cell biology, and molecular chemistry" looking at both model systems and living cells.
"As I see it, our duty is to train the next generation of students to be able to talk and work at the interface of disciplines," says Sheets as she enters the lab and greets two of her grad students, Angel Davey and Keith Krise, who are preparing mast cells for a project with collaborator Nick Winograd, Evan Pugh Professor of Chemistry.
Winograd will image the cholesterol-rich domains on the immune cells with time-of-flight mass spectrometry. "This will allow us to directly relate the molecular composition of the cells with the biophysical properties we measure with fluorescent lifetime microscopy and other techniques," she says.
In addition to Winograd, Sheets is also pursuing research projects with Ahmed Heikal in the Department of Bioengineering, who is another expert in cellular imaging. Heikal was profiled in the Fall 2006 issue of Focus on Materials. With Mary Beth Williams, Sheets is investigating quantum dots as bright, long-lasting probes for membrane dynamics. With Steve Benkovic, Evan Pugh Professor of Chemistry, she is studying the intermolecular interactions and dynamics of purine biosynthesis in living cells. Sheets is part of the Center for Optical Technology, a joint initiative of Lehigh University, Penn State, and industrial partners that is located at Lehigh University in Bethlehem, PA, and on the Faculty of the Materials Research Institute, and the Huck Institutes of the Life Sciences.
The Sheets group’s research is supported by the National Institute of Health, the National Institute on Aging, and the National Science Foundation.
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