Process of “reading” genes not perfectly predictable
Within the smoothly operating factory that is the cell, tiny molecular machines carry out their tasks with order and certainty. Or at least that’s what many scientists once believed.
In a recent issue of Science, researchers at The Rockefeller University report the first demonstration that bacterial cells intrinsically possess a significant degree of randomness or “noise.” More precisely, they show that key “gene-reading” machines may operate unpredictably, resulting in randomly fluctuating amounts of individual proteins.
“Theory has predicted the presence of cellular noise, but in this study we have explicitly demonstrated its existence in living cells,” says Michael B. Elowitz, first author of the paper and a fellow at The Rockefeller University.
Moreover, the findings hint at the possibility that noise is more than an accident of nature, instead serving a valuable role. According to Elowitz, cells may have evolved strategies to suppress the background hum of noise to function accurately — or, conversely, they may have figured out ways to use it to their advantage.
“Noise may be more than an annoying presence cells have to deal with,” says Elowitz. “It may be an important mechanism that allows cells to generate variability in a population. Our new experimental system will help us address this question.”
The researchers focused on noise that arises from gene expression — the process by which cells switch on or “transcribe” genes to make proteins. In the same way that chance can lead to long run of lucky dice rolls in a game of craps, random fluctuations in the process of transcribing genes may result in unpredictable levels of protein. This type of noise is called “intrinsic” noise.
But, while several mathematical biologists have predicted noisy genes, the phenomenon is hard to detect experimentally. Elowitz and colleagues figured out a way not only to test this theory in living cells, but literally to visualize the results.
Their trick was to genetically engineer the bacterium E. coli to express two identical genes, the only difference being that one encodes a protein that glows blue and one yellow (these colors were changed to red and green, respectively, for the sake of image analysis).
Because both of these genes are in the same cell, and thus share the same intracellular environment, and because they both are under the control of the same “promoter”(patch of DNA that regulates gene expression), they should produce the same amount of protein. With both genes making equal amounts of red and green protein, the host cell should appear yellow. But, if noise is inherent to this protein-making process, one gene may temporarily express higher levels of one protein over the other, causing the cell to appear red or green. As the mélange of colors in the image above of the genetically altered bacteria shows, noise is indeed a part of a cell’s inner life.
Less equals more
Why did theorists predict shaky gene expression in the first place? The answer is that cells possess relatively few copies of a given protein, and an even smaller number of genes. For example, E. coli bacteria have at most a few copies of every gene, each one producing an average of only a few tens of proteins per generation.
To understand why a process involving few molecules would be more susceptible to noise, think back to that lucky game of craps. A player could feasibly roll an unusually high proportion of lucky sevens and walk away a big winner. But, if, like most people, the player gets sucked into the addiction of gambling and continues to play, his or her luck would eventually run out. In other words, chance plays a greater role in a game of craps involving few throws of the dice in the same way that noise should be significant to cells containing a limited number of molecules.
Elowitz and colleagues put this notion to the test by artificially altering the rate of transcription in their system; if noise is indeed dependent upon the number of proteins produced, then it should go down as the rate of transcription goes up. As expected, the researchers observed that noise tapered off as transcription rates went up, thereby confirming the theorists’ original predictions.
Reason for randomness?
The next big question is how a cell manages to function properly in the midst of this apparent chaos. Has it evolved strategies to suppress the noise, or, more intriguingly, has it figured out ways to use its accidental outcomes to its benefit?
Elowitz speculates that noise may explain why populations of the same type of cell become variable — and consequently better able to deal with unforeseen environmental stressors.
“This possibility is analogous to mutator bacterial strains,” he says. “Certain environments select for strains that possess a high rate of mutations even though most of these mutations turn out to be deleterious. Noise might similarly help cells to adapt.”
Whether or not this is true remains to be seen, but one thing is certain: the researchers’ new bacterial system will allow them to begin to search for answers.
This study resulted from a collaboration between Peter S. Swain and Eric D. Siggia, and Elowitz and Arnold J Levine. Swain, Elowitz and Siggia also report a mathematical analysis of this research in a companion article in the Oct. 1 issue of Proceedings of the National Academy of Sciences.