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Nice to see the Times critiquing genetic determinism for once. --PG

http://www.nytimes.com/2008/04/22/health/research/22coli.html

April 22, 2008

Expressing Our Individuality, the Way E. Coli Do

By CARL ZIMMER

We humans differ from one another in too many ways to count. We are 
shy and bold, freckled and pale, truckers and hairdressers, Buddhists 
and Presbyterians. We get cancers in the third grade and live for a 
century. We have fingerprints.

Scientists have only a rough understanding of how this diversity 
arises. Some of it stems from the different experiences we have, from 
our time in the womb on through childhood and into our mature years. 
These molding influences include things like the books we read and 
the air we breathe. Our diversity also stems from our genes - the 
millions of typographical differences between one genome and another.

We put a far bigger premium on nature than nurture when it comes to 
our individuality. That's one reason why reproductive cloning 
inspires so much horror. If genes equal identity, then a person 
carrying someone else's DNA has no distinct self.

But there's a deep flaw in this way of thinking, one that blinds us 
to how biology - human or otherwise - really works. A good 
counterexample is E. coli, a species of bacteria that lives 
harmlessly in every person's gut by the billions. A typical E. coli 
contains about 4,000 genes (we have about 20,000). Feeding on sugar, 
the microbe grows till it is ready to split in two. It makes two 
copies of its genome, almost always managing to produce perfect 
copies of the original. The single microbe splits in two, and each 
new E. coli receives one of the identical genomes. These two bacteria 
are, in other words, clones.

Surely, then, E. coli must be all nature and no nurture. A colony 
descended from a single E. coli ancestor is just a billion identical 
cousins, all responding to the world with the same set of genes.

Yet as plausible as this sounds, it's far from the truth. A colony of 
genetically identical E. coli is, in fact, a mob of individuals. 
Under identical conditions, they will behave in different ways. They 
have fingerprints of their own.

If two genetically identical E. coli are swimming side by side, for 
example, one may give up while the other keeps spinning its 
corkscrew-shaped tails. To gauge E. coli's stamina, the late 
biologist Daniel Koshland once glued genetically identical bacteria 
to a glass cover slip. They floated in water, tethered by their 
tails. Dr. Koshland offered the bacteria a taste of aspartate, an 
amino acid that attracts them and motivates them to swim. Stuck to 
the slide, the bacteria could only pirouette. Dr. Koshland found that 
some E. coli clones twirled for twice as long as others.

E. coli expresses its individuality in many other ways, as well. 
Under identical conditions, some clones cover themselves in sticky 
hairs that let them stick to host cells, while others remain bald. 
Feed a colony of E. coli lactose (the sugar in milk), and some will 
respond by slurping it up through special channels and digesting it 
with special enzymes. Others will turn up their microbial noses.

These quirks of E. coli's personality can mean the difference between 
life and death for the bacteria. In times of stress, some members of 
a colony respond by building thousands of toxin molecules and then 
burst open, killing off the unrelated E. coli around them. Their 
fellow clones survive, though, and thrive without the competition.

Certain viruses slip into E. coli through one of the many kinds of 
channels in its membrane. In a colony of genetically identical 
bacteria, some may be covered with these channels like pincushions. 
Others have none at all. The viruses will kill the vulnerable clones, 
while the other clones live on.

E. coli's quirks can be a matter of life and death for us, as well. 
Some strains cause infections in the gut, the bladder, the blood and 
even the brain. In many cases, doctors try to kill the bacteria with 
antibiotics, which jam up the normal workings of their genes and 
proteins. In a susceptible colony of E. coli, a strong antibiotic 
will kill most of the bacteria, but not all of them. Some will 
survive.

The survivors escape death because they are trapped in a strange 
twilight existence called persistence. They make hardly any new 
proteins and grow barely, if at all. Antibiotics can't kill 
persisters because there's nothing in them to attack. The difference 
between normal cells and persisters cannot be found in their DNA. 
After persister cells survive an attack of antibiotics, some of their 
offspring switch back to normal growth and rebuild the colony. Most 
of their descendants will be normal E. coli. But some will be 
persisters. The colony remains the same motley crew of clones.

The key to understanding E. coli's fingerprints is to recognize that 
the bacteria are not simple machines. Unlike wires and transistors, 
E. coli's molecules are floppy, twitchy and unpredictable. In an 
electronic device, like a computer or a radio, electrons stream in a 
steady flow through the machine's circuits, but the molecules in E. 
coli jostle and wander. When E. coli begins using a gene to make a 
protein, it does not produce a smoothly increasing supply. It spurts 
out the proteins in fits and starts. One clone may produce half a 
dozen copies of a protein in an hour, while a clone right next to it 
produces none.

Michael Elowitz, a physicist at Caltech, put these bursts on display 
in an elegant experiment. He and his colleagues incited E. coli to 
produce its proteins for feeding on lactose. Dr. Elowitz and his 
colleagues added extra genes to the bacteria so that when they made 
lactose-digesting proteins, they also released light.

The bacteria, Dr. Elowitz found, did not produce a uniform glow. They 
flickered, sometimes brightly, sometimes dimly. And when Dr. Elowitz 
took a snapshot of the colony, it was not a uniform sea of light. 
Some microbes were dark at that moment while others shone at full 
strength.

These noisy bursts can have long-term effects on how E. coli behaves. 
It is delicately balanced between very different states, and a little 
nudge can sometimes push it one way or the other.

Under some conditions, for example, it is very easy to make E. coli 
an eager lactose-feeder, or a reluctant one. By pure chance, a 
microbe may make a lot of lactose-sucking channels, causing it to 
draw in a lot of the sugar. Lactose can pull repressing proteins away 
from E. coli's genes, causing the microbe to make more channels along 
with enzymes. That causes even more lactose to pour into the cell. 
The microbe becomes locked in a sugar-feasting feedback loop.

On the other hand, the same microbe, through pure chance, may not 
produce that burst of channels. It cannot pull in any extra lactose. 
The few lactose molecules that can seep through its membrane are too 
few to pull off the repressor proteins. Its lactose-digesting genes 
stay switched off, and it cannot enjoy a snack of milk sugar. It is 
trapped in its own negative feedback loop.

Other studies suggest that the unpredictable noisiness in E. coli's 
cellular machinery is also responsible for persistence, hairy coats, 
selfless suicide and vulnerability to viruses. The big question for 
many scientists is why E. coli has evolved so that noise can produce 
such drastic changes in its biology.

Mathematical models suggest E. coli uses noise as a way to hedge its 
bets. A colony of E. coli can't simply wait until they're doused with 
antibiotics to slip into persistence. They'd be killed before they 
were done. Instead, noise causes a fraction of them to be persisters. 
If they do get hit with antibiotics, at least a few of them will 
survive. If the antibiotics never come, the majority of the bacteria 
can continue to grow and divide.

E. coli appears to follow a universal rule. Other microbes exploit 
noise, as do flies, worms and humans. Some of the light-sensitive 
cells in our eyes are tuned to green light, and others to red. The 
choice is a matter of chance. One protein may randomly switch on the 
green gene or the red gene, but not both.

In our noses, nerve cells can choose among hundreds of different 
kinds of odor receptors. Each cell picks only one, and evidence 
suggests that the choice is controlled by the unpredictable bursts of 
proteins within each neuron. It's far more economical to let noise 
make the decision than to make proteins that can control hundreds of 
individual odor receptor genes.

Identical genes can also behave differently in our cells because some 
of our DNA is capped by carbon and hydrogen atoms called methyl 
groups. Methyl groups can control whether genes make proteins or 
remain silent. In humans (as well as in other organisms like E. 
coli), methyl groups sometimes fall off of DNA or become attached to 
new spots. Pure chance may be responsible for changing some methyl 
groups; nutrients and toxins may change others.

Identical twins may have nearly identical genes, but their methyl 
groups are distinctive by the time they are born and become 
increasingly different as the years pass. As the patterns change, 
people become more or less vulnerable to cancer or other diseases. 
This experience may be the reason why identical twins often die many 
years apart. They are not identical at all.

These different patterns are also one reason that clones of humans 
and animals can never be perfect replicas. DNA from a calico cat 
named Rainbow was used to create the first cloned kitten, named Cc. 
But Cc is not a carbon copy of Rainbow. Rainbow is white with 
splotches of brown, tan and gold. Cc has gray stripes. Rainbow is 
shy. Cc is outgoing. Rainbow is heavy, and Cc is sleek. Changes in 
methyl groups probably account for some of those differences. Clones 
may also be altered by the unique pattern of protein bursts in their 
cells. The very molecules that make them up turn them into 
individuals.

At the very least, E. coli's individuality should be a warning to 
those who would put human nature down to any sort of simple genetic 
determinism. Living things are more than just programs run by genetic 
software. Even in minuscule microbes, the same genes and the same 
genetic network can lead to different fates.

Adapted from Microcosm: "E. coli and the New Science of Life," by 
Carl Zimmer. Pantheon, May 2008.