Biophysicist Michelle Wang uses a laser trap as molecular "tweezers" to secure DNA during gene transcription studies.Photo by Charles Harrington

Win, lose or draw, each time Cornell's Michelle D. Wang plays tug-of-war with an energetic molecule she reveals more about DNA transcription and gene expression.

The molecule is RNAP (for ribonucleic acid polymerase) and a bead-like molecule of that enzyme moves along the DNA template when an RNA copy is synthesized. Without RNA copies there would be no gene expression, no way for DNA to tell living cells which proteins to produce. And without RNAP working as a biological catalyst, the chemical code of DNA could not be transcribed to RNA.

Wang's key contribution to the understanding of DNA transcription was to help prove that RNAP functions as a true "molecular motor." Other molecular motors already were shown to produce motion from chemical reactions. Myosin is one of the best-known for its role in muscle contraction.

If molecular mechanics was happening, Wang wanted to discover why the mini-motor starts, accelerates and sometimes stalls. Equipped with a Ph.D. in biophysics (1993) from the University of Michigan, she worked as a postdoc in the Princeton laboratory of Steven M. Block, the biophysicist known for using optical "tweezers" to hold molecules and measure forces that they exert.

Diagram explains Wang's strategy for measureing the poweer of a molecular motor, the bead of RNA polymerase that catalyzes the transcription of RNA from the DNA template.

Apparatus designed by Wang, Block and their colleagues proved that RNAP really is a molecular motor. Subsequent experiments, including a series reported in a recent issue of Science, are elucidating what turns out to be a powerful motor.

Each experiment is a tug-of-war, because that's the safest way to follow a moving molecule that can't stand the heat. Substituting for the transcribing molecule of RNAP, the way a stunt double stands in for the movie star, is a polystyrene microsphere about 1 micron in diameter. The microsphere is large enough to be seen through a light microscope, which can't resolve RNAP, and tough enough to take what comes next.

Wang glues the microsphere to one end of a molecule of DNA. Elsewhere on the DNA template, the molecule of RNAP is moving like the slider part of a zipper, separating DNA so that information can be transcribed to RNA, then allowing the DNA to come together again and moving on.

Except that Wang affixes the RNAP molecule to a glass plate so it can't move. Instead the DNA template moves through the stationary molecule of RNAP. Meanwhile at the other end of the DNA molecule, the polystyrene microsphere is caught in a trap -- an optical trapping interferometer -- where polarized laser light provides the tweezers that hold the 1-micron stunt double.

By measuring displacement of the microsphere in the optical trap, Wang can gauge the force generated by the transcribing molecular motor. Or by tugging with the laser tweezers, she can simulate the stops, starts and pauses of an RNAP molecule as it moves, relative to the DNA template.

Of course the measurement procedure isn't quite that simple. "DNA is like a sloppy spring," says Wang, who has designed feedback and correction circuits into her instrumentation, along with sophisticated data analysis techniques, to account for DNA stretching. Among her findings are these: The RNAP molecular motor is the most powerful yet described, some six times more powerful than myosin.

Also, the transcribing RNAP molecule oscillates rapidly along five to 10 base pairs at a time -- almost as if the enzyme were performing a quality-assurance check of its work -- before moving on to catalyze the transcription of more bases.

A member of the Cornell physics faculty since July 1998, Wang is building a special laboratory in Clark Hall, aided by a two-year, $200,000 fellowship from the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation. The lab is double-walled, isolated and soundproofed to exclude vibrations that would disturb the sensitive procedure.

Not even talking is allowed in the Wang lab when an experiment is under way. All the better to concentrate and imagine the inaudible grunts and groans in a high-stakes tug-of-war.