Indiana University       Research & Creative Activity       September 2000 • Volume XXIII Number 2


Cells

on the Run

by William Rozycki

H uman bodies seem rather stable: we assume that the billions of cells in our bodies will, for the most part, stay where they are. But that’s not always the case. In some common mechanisms of disease and of disease resistance, certain cells move great distances.

Take the spread of cancer, for instance. “Cells from a cancer tumor can migrate to other parts of the body,” explains Jay X. Tang, assistant professor of physics at IU Bloomington. “The larger dynamic in this spread of cancer is metastasis, but the underlying process that allows the cells to migrate is cell motility.”

A phase-contrast image of large granules formed by the protein filaments F-actin. Courtesy photo.


Tang points out that cell motility is also connected with positive processes: the body’s white blood cells, for example, fight disease by moving to attack invasive microorganisms. Yet, despite the importance of cell motility for both disease and disease resistance, little is known of the mechanics of individual cell migration or travel.
“We do know that motile cells are polarized,” Tang explains. “That is, they seem to have a front end and a back end, and researchers have noticed that motile cells develop a dense mesh of filaments in the polarity toward which there ismovement. These filaments may be crucial in understanding motility.”

The filaments are composed of a protein called actin, a biomaterial commonly found in muscle cells that is also a building block for the cytoskeletons of most cells. Tang is studying actin in its filamentous form, F-actin, as part of his ongoing research into the assembly and transition phases of filamentous proteins and related polymer biomaterials.

“Many proteins share a common characteristic,” Tang says. “When put in cationic (positively-charged) solutions, they draw together in long lines, forming rods.” But in different solutions, proteins can form into a variety of structures, including isotropic networks, liquid crystalline phases, and densely packed lateral aggregates that are referred to as bundles. Changes in valency (the balance of electrons at the atomic level that relates to electrical attraction and repulsion) seem to trigger the changes in assembly of these proteins. Tang points out that DNA, which starts out as two long strands of nucleotides, assembles this way into its distinctive helical shape. Understanding these mechanisms of assembly and transition has profound implications not only for understanding cell motility, but also for advancing the fields of biotechnology, materials engineering, and medicine.

Tang studied physics at Peking University in China. His introduction to biophysics did not occur until he came to the United States for graduate studies in 1988. At Brandeis University, his thesis director happened to be making a study of the phase transitions of a bacterio-phage—a class of long filamentous viruses that infect common bacteria such as E. coli. One aspect of the study, the effect of a magnetic field on such filaments, became Tang’s dissertation topic and set him firmly on the path of biophysical research.

A fter graduating from Brandeis with his Ph.D. in 1995, Tang went to work as a research fellow at Harvard Medical School, and in 1997, he became an instructor of medicine there. With his credentials established in the application of physics to biomedical research, Tang was an obvious candidate when the IUB physics department reached an important decision in 1998. Determined to lead in this emerging field, the department decided to fund three faculty positions in biophysics. Tang was hired last year as IUB’s first biophysicist.

“I spent the fall and winter of last year getting my laboratory established. It was a lot of work to set it up from scratch,” Tang recalls with a smile.

A tour of Tang’s laboratory shows that the task was considerable. Three shiny new centrifuge machines are used to prepare and purify samples, which are then stored in a special super-freezer that maintains a steady temperature at -80°C. A pressure tank and connecting hose stand ready to feed liquid nitrogen to the freezer in the case of a power failure. A sophisticated microscope with exchangeable lenses and filters, a CCD camera hook-up, and an attached computer and monitor for image capture and analysis allow advanced optical imaging of the protein assemblies. Petri dishes, sinks, sample-preparation tables, and other equipment, including a more mundane microscope for simpler imaging tasks, sit in another section of the lab.

Although he is the only biophysicist on the Bloomington campus, Tang anticipates the planned hiring of colleagues. “Biophysics has a long history,” he says, “but it has really started to flourish in recent years.”

Tang sees this flourishing as a driving force of change in the academic community. “Within major universities,” he says, “we’re seeing more applied research, and along with that, more public support for applied science.” Advances in technology improve the quality of life, he explains, and this in turn drives more research in applied science.

Tang points out that this model has brought changes to the structure of research funding. “Nowadays,” he says, “the National Institutes for Health give out three times the amount of funding of the National Science Foundation.” But Tang is not critical of the changing dynamic. “It’s what the public wants,” he says. “It’s natural for the public to want applications that improve our health and quality of life.”

Tang’s background, so different from physicists in traditional areas such as particle physics, has helped him to communicate with a wide range of students, especially in his introductory physics course for university division students and non-science majors.

“My perspective is broader,” he says. “It extends beyond physics, and for that reason I think I can give students an overview that is wider than what is ordinarily expected from a physics instructor.”

Tang is also inaugurating a course titled Introductory Biophysics, which is open to graduate students and undergraduates. “I’m enjoying teaching it,” he says. “It’s a chance to introduce my own specialty to students.”
In his research, Tang and his laboratory team are using microscopic imaging techniques to look in detail at the mechanisms underlying a number of intriguing protein assemblies. A few years ago, Tang discovered that at high concentrations, F-actin self-assembles to form oval, tipped granules called tactoids. His team is now hoping to observe details in the mechanisms that drive that assembly and to learn if such mechanisms are linked to similar granular structures found elsewhere (as in actin patches in yeast and dense bodies in smooth muscle cells).

Much can be understood about protein assembly by using conventional microscopy. Tang and his laboratory team use such sophisticated but standard techniques as phase contrast (differentiating indexes of refraction to make cells more visible), differential interference contrast (splitting light using prisms), and fluorescence imaging (using a light source to excite natural or chemically induced fluorescence in target cell and protein structures).

Jay X. Tang is assistant professor of phyiscs at Indiana University Bloomington. The Nikon TE-300 is specially equipped with a polarization imaging package for studying biological structures, including living cells. Photo Tyagan Miller.

But the limits of discovery can be extended further, Tang believes, by using newly developed optical imaging techniques and apparatus. Tang has a wish list of imaging equipment he hopes to obtain—at the top of the list are an atomic force microscope (AFM) and a low background total internal reflection (LBTIR) setup for use with a high-sensitivity epifluorescence microscope. The request for funding for the AFM has been a joint effort with David Baxter, an associate professor of physics whose field is condensed matter physics (see “The Era of Spin Arrives at Swain Hall,” page 20). The funding would benefit a number of laboratories. “If funding comes through for the AFM, it will be shared by all interested research groups in physics, biology, and chemistry,” Tang says.

Equally valuable for imaging will be the LBTIR, a cutting-edge technology that, in the few laboratories now using it, has advanced scientific knowledge of cell dynamics by increasing the visibility of internal cell components. LBTIR allows visualization down to single macromolecules when there is a suitable fluorescent tag on the target.

Tang does not rely solely on his own laboratory facilities for imaging. As a fellow of the Indiana Molecular Biology Institute, located in IUB’s Jordan Hall, Tang has access to its substantial equipment, including an excellent electron microscopy facility there. Tang and his lab members also have regular research meetings with the lab staffs of William Saxton and Elizabeth Raff in the IUB biology department, and Claire Walczak, IUB assistant professor of biochemistry and molecular biology.

Beyond the university, Tang collaborates with Gerard Wong, a researcher in the X-ray laboratory of Cyrus Safinya at the University of California, Santa Barbara. In this collaboration, the two use X-ray imaging to get information about the structure of F-actin complexes. For another project, a neutron-scattering study of F-actin, Tang uses the facilities at the Argonne National Laboratory in Illinois and collaborates with Jyotsana Lal, a staff scientist there.

As Tang establishes his research program at IU, his sense of excitement helps to offset the many challenges facing a pioneer in a new area of discovery.

“There are constantly new findings in the life sciences, and that produces exciting opportunities,” Tang says. “Biophysics is by its nature interdisciplinary. Applied physics and instrumentation make a contribution to understanding complex biological systems. I truly consider it a privilege to be part of this great new enterprise.”

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