March 18, 2000
By Robert S. Boyd, Knight Ridder Newspapers
WASHINGTON -- It's billions of times smaller than Amtrak or the Union Pacific, but your life depends on the smooth running of its miniature trains. Call it the "intracellular railroad."
With the help of powerful new microscopes and lasers, scientists are exploring a system of midget engines that haul cargo along tiny tracks inside every cell in your body.
Ronald Vale, a molecular biologist at UC San Francisco, calls them "the world's smallest moving machines." According to Vale, they can pull loads up to a thousand times their weight, burning their fuel five times more efficiently than a car engine.
These biological motors -- bits of protein less than a millionth of an inch long -- shuttle precious chemicals, such as oxygen or DNA, wherever they are needed.
Without this Lilliputian transportation network, cells couldn't divide and multiply. You could not breathe, walk or even operate the TV remote. Life and growth would be impossible.
"All movement in cells and all movement that people undergo require these molecular motors," said James Spudich, a biochemist at Stanford University.
Recent discoveries about the workings of this system give doctors a promising new weapon to fight cancer. Researchers have learned how to jam a switch on the tracks, halting the mini-trains and thereby stopping the growth of tumor cells.
Taxol, a drug for breast and lung cancer, uses this trick to "stop the cell cycle so the cell can't divide," said Susan Horwitz, a cancer researcher at Albert Einstein College of Medicine in New York City.
Conversely, a drug that repairs damaged tracks -- allowing blocked chemical signals to resume their journey along nerve cells -- might relieve some degenerative nerve diseases, such as Parkinson's or ALS (Lou Gehrig's disease).
A human cell contains at least 50 varieties of these molecular motors. They are constructed of various combinations of proteins, the basic building blocks of all living things. The motors fall into two major groups, known as kinesins and myosins (from the Greek words for motion and muscle, respectively).
The two types of engines travel along different sets of tracks. Kinesins plod slowly along microtubules -- hollow tubes built from a protein known as tubulin. Myosins, in contrast, move rapidly along rails composed of actin, another protein.
"The myosins are dancing, while kinesin is hiking, steadily chugging along step by step," said Thomas Pollard, a cell biologist at the Salk Institute in La Jolla.
The engines' duties and methods of motion also differ.
A myosin motor is equipped with a flexible arm that swings forward and grabs the actin track, pulling along the main body and its attached cargo. Scientists have identified a family of 15 myosins, each specialized to a different task or muscle type. For example, one keeps heart muscles beating. Others transmit nerve signals or lug chemicals from place to place in the cell.
The kinesin engine resembles a Rube Goldberg contraption composed of two "heads" linked by a "neck." The neck repeatedly stiffens, flinging the head in back ahead of the one in front, like a game of leapfrog. A third segment, the "tail," hauls the freight, such as a molecule of life-giving oxygen.
Perhaps kinesin's most important task is ferrying pieces of DNA from a parent cell to its offspring during cell division. This is a vital process in healthy growth, but a deadly one when a cell runs amok and divides uncontrollably, forming a cancerous tumor.
Here is where taxol and other anti-cancer drugs can save lives. Before dividing, a cell's DNA cycles through several "checkpoints" where it is inspected for mistakes. If the DNA is flawed, it is supposed to be repaired or the cell destroyed. Sometimes this system fails, and cancer may result.
Taxol blocks the tubulin track so kinesin cannot proceed. This interrupts the delivery of DNA to the two cells created when a cell divides. As a result, the cancerous tumor stops growing.
Unfortunately, some cancers develop resistance to taxol, so researchers are working on at least four other drugs that also block the molecular railroad.
As a further step, scientists are tinkering with protein motors to see if they can be made to perform useful work, such as delivering minute packets of drugs to cells or turning miniature levers and gears.
"A micro-rotor turned by kinesin could demonstrate the feasibility of creating a kinesin-powered micro-generator or micro-pump," said Russell Stewart, a bioengineer at the University of Utah in Salt Lake City.
For more information, check out the kinesin and myosin home pages at http://blocks.fhcrc.org/kinesin and http://www.mrc-lmb.cam.ac.uk/myosin/myosin.html.
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