Princeton Weekly Bulletin April 27, 1998
Block studies the unimaginably small
By JoAnn Gutin
You don't want your lab in an earthquake-safe building," says Molecular Biology professor Steven Block, trotting briskly though a basement hallway in Schultz Lab. "Earthquake-resistant buildings sway. What you want is an old brick building like this, with nice thick walls." He pauses for a nanosecond to pat the wall affectionately. "It's not going anywhere."
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In Block's line of work a steady infrastructure is essential. That's because he spends his time in the realm of what he calls "the unimaginably small," holding individual protein molecules still enough to probe their secrets. For that reason, the physicist-turned-biologist has spent much of the four-plus years he's been at Princeton designing and outfitting a unique, vibration-proof microscopy lab in the basement of Schultz. The result has been a room with so many features to insulate its microscopes from the world outside that it seems to owe more to Ian Fleming than Antony van Leeuwenhoek.
A visitor enters though a pair of doors separated by an air pocket and sealed at the bottom by a retractable panel that fits flush against the floor. A giant, slow-moving fan in another room provides quiet ventilation: the lazy motion eliminates acoustic noise that might disturb the delicate instruments. Power comes from 15 separate circuits to avoid possible interference created when two sensitive instruments draw juice from a single line. The microscope table weighs nearly half a ton and floats on a cushion of compressed air; it sinks at the slightest pressure, then rebounds with a soft sigh. "You could construct a very nice house for the money it cost to build this room," Block confides.
Force of one protein molecule
The reason for all this effort is that in this room Block and his research group measure and record the infinitesimal forces exerted by single protein molecules. The molecule the group studies, kinesin, belongs to the family of motor proteins, or mechano-enzymes, responsible for nearly all biological motion, from the muscle contraction that powers the split-finger fastball to the unwinding of the strands of DNA. The existence of such motor proteins has been known for a hundred years, but not until the past decade did anyone figure out how to pin down one of these molecules long enough to look at it.
One of those people was Steven Block. Block had completed a degree in physics at Oxford University when, in 1974, he decided to switch to biology. That science, he felt, had reached a point at which some of its most profound questions could be tackled through physics. Block wrote to a number of eminent scientists who had made the switch he was contemplating, asking for advice. He was soon taken on as a student by Max Delbrück of Caltech (who had won the 1969 Nobel Prize in Physiology or Medicine).
Block began his crash course in biology the summer after leaving Oxford, at Cold Spring Harbor Lab on Long Island. "I used the total immersion method," he says, "the way you might learn Japanese. The last time I'd tried to learn biology, I was in high school watching videos on `The World Under the Microscope.'" After after a stint at the University of Colorado, Block went to Caltech, where he obtained his PhD in biology with a dissertation on sensory transduction, the process by which physiochemical processes become sensation. (He now teaches a course in the same subject at Princeton.)
In the 1980s Block began working at the Rowland Institute for Science in Boston, a privately funded institute known for encouraging daring research. It was there he helped to develop applications of the so-called "optical tweezers" that have made study of motor proteins a reality.
The device, which was coinvented by Arthur Ashkin and Steven Chu at Bell Labs in 1986, depends on a phenomenon of which most nonscientists are unaware: Light exerts a tiny but measurable force, or radiation pressure. Thus, a laser trained on something tiny can immobilize it. Motor proteins, being individual molecules, are much too small to see; indeed, because they're smaller than the shortest wavelength of light, they are invisible in the strictest sense of the word. However, they can be immobilized by attaching them to microscopic spheres made of glass or plastic, which can be used as handles that optical tweezers can grasp.
In a series of experiments published in the journal Nature, Block and his colleagues immersed microscopic plastic balls in a "soup" of purified motor proteins. The proteins would attach themselves to a ball, like an ant shouldering a bread crumb. Then, using an infrared laser, Block exerted the force of light to immobilize a single plastic ball and measured how hard the protein tugged on the ball. He has learned that these forces are measurable in piconewtons (a piconewton is roughly the weight of a single red blood cell in air). In subsequent experiments, he and his students have measured the strength of different molecular proteins and determined the length of the "steps" they take.
Bigger--though smaller--game
Work on those problems continues, but Block now has set his sights on bigger--though smaller--game. Block will be implanting a sequence for green fluorescent protein, or GFP, into these molecular motors, an addition that will cause them to fluoresce when hit by light. Block will then angle a lightsource so it glances off the cover-slip of his microscope preparation, penetrating only about half a millionth of a meter so as not to illuminate more of the specimen than absolutely necessary. The result will be a pinprick of light.
"The pinprick can't be any smaller than about 500nm, because that's as small as light gets," Block explains, "But somewhere in there, there will be a motor protein." Then Block can track the protein down with his microscope, train his optical tweezers on it, "and do all sorts of really cool experiments" designed to explicate the physiology of single molecules.
But at that level of refinement, a single speck of dust will cause light to backspatter and ruin the experiment. And in the basement lab, which has been in use for four years, "there's a lot of schmutz," says Block, as he draws a finger through the dust film on a tabletop like a fastidious housekeeper. So, while a full research program will continue at the Schulz lab, within a few weeks Block will be expanding his operation across Washington Road to a new, even more futuristic lab at the Princeton Materials Institute.
There, he and his students will continue tracking motor proteins in "the only microscopy rooms in the world, to my knowledge, that will be not only sound and vibration proof, but almost totally dust free." In these labs, whose construction was funded by grants from the Keck Foundation and the National Science Foundation, the scientists will carry out experiments wearing coveralls and helmets like Silicon Valley chip makers. And the atmosphere in which they work, thanks to a special (and very quiet) air filtration system, that will be at least 20 times cleaner than the air outside.
Soon, perhaps, the unimaginably small will have nowhere to hide.