See Inside July 2008

How Cells Make Use of Random Biochemical Reactions

New studies reveal how cells exploit biochemical randomness

Just as identical twins raised in the same home often grow up to be different, identical cells grown in the same environment frequently exhibit distinct characteristics. These differences are the result of random fluctuations in biochemical reactions. Biologists had always thought of such biochemical blips as liabilities, but recent studies suggest that cells and bacteria sometimes utilize this randomness to their benefit.

Small systems such as cells are inherently sensitive to the random effects scientists call stochasticity—or noise—because they contain only a few active copies of individual proteins or nucleic acids. Minor fluctuations in the levels of some cellular components, for example, affect whether a particular gene turns on and makes a protein. Such noise seems to suggest that some aspects of cell fate are left to chance; the lack of control forces cells to evolve backup plans, such as redundant biochemical pathways.

Until recently, scientists had trouble studying the phenomenon, because doing so requires the ability to visualize individual cells and molecules; averaging the behavior of groups of cells cancels out noise’s effects, much as fabric viewed from a distance looks flawless. In the past decade, however, a handful of new tools, including fluorescent markers that bind to molecules and light up under microscopes, have given scientists the ability to see noise in action. What researchers are finding is surprising: cells sometimes appear to use noise to help them survive in changing environments and make decisions during development. “Normally, living things have to cope with noise, but sometimes they exploit it,” says Richard Losick, a biologist at Harvard University, who in April co-authored an article on stochasticity in Science.

For example, one fifth of bacteria in Bacillus subtilis colonies live in a specialized state called competence, in which they stop growing and incorporate DNA from the environment into their genomes. Whether a cell enters this state is determined stochastically, and despite its costs—competent cells do not grow and divide—competence is thought to provide an evolutionary advantage in that it allows a colony to expand its genetic toolbox. Competent cells are most likely “on the prowl for new genetic sequences that could improve their fitness for changed circumstances in the future,” Losick remarks.

More complex organisms also use noise to their advantage. The eye of the common fruit fly, Drosophila melanogaster, comprises smaller units, each consisting of eight cells. When each cell develops, it makes a choice determined by the presence or absence of a regulatory protein. This protein becomes active only in a random subset of the cells, and its occurrence determines whether the cell will respond to a particular hue of ultraviolet light. Random expression of this regulatory protein ensures that the two cell types are apportioned throughout the eye by chance so as to avoid repetitive patterns that could limit the fly’s overall vision. Even though the cells “are in an identical environment and they all come from an identical ancestor, they acquire different phenotypes,” or physical traits, says Mads Kaern, a systems biologist at the University of Ottawa.

Although noise plays an important role in a cell’s fate, much remains to be learned about the sources of this noise and the extent to which it affects cells and other organisms, including humans. “We know a few [mechanisms], but there’s a lot of evidence that there are tons more,” notes Edo Kussell, a biophysicist at New York University. Another difficult task will be deciphering their biological relevance. For instance, speculating why bacteria become competent is easy, but proving that speculation is next to impossible. “Can we find a way to demonstrate that a particular stochastic mechanism has really been tuned to evolution? How do we conclusively demonstrate that?” Kussell asks.

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