X-Message-Number: 26835
From: 
Date: Wed, 17 Aug 2005 22:15:24 EDT
Subject: It's a start...

It's a start...

This week in the New York Times

Regards,

David C. Johnson
___________________

August 16, 2005

Building a Virtual Microbe, Gene by Gene by Gene

By CARL ZIMMER

Michael Ellison has a dream: to reconstruct a living thing inside a computer, 
down to every last molecule. It is, he said, "the ultimate goal in biology to 
be able to do this." 

It's a dream that Dr. Ellison, a biologist at the University of Alberta, 

shares with other scientists, who have imagined such an achievement for decades.

Understanding how all of the parts of an organism work together would lift 

biology to a new level, they argue. Biologists would be able to understand life
as deeply as engineers understand the bridges and airplanes that they build. 

"You can sit down at a computer, and you can design experiments, and you can 
see the performance of this thing, and then you can figure out why it's done 
what it's done," Dr. Ellison said. "You're not going to recognize the full 
return of the biological revolution until you can simulate a living organism."

In the past few years this fantasy has become plausible and now Dr. Ellison 
is part of an international team of biologists who are now trying to make it a 
reality. They have chosen to recreate Escherichia coli, the humble resident of 
the human gut that has been the favorite species for biology experiments for 
decades.

"We picked the simplest organism about which we know the most," Dr. Ellison 
said.

Scientists may know more about E. coli than they do about any other species 
on earth, but that doesn't mean that creating a virtual E. coli will be a snap.

Many mysteries remain to be solved, and at the moment even a single E. coli 
may be too complex to recreate in a computer. 

But the effort is still worthwhile, some scientists argue, because it would 
become a powerful tool for drug testing, genetic engineering and for 
understanding some of life's deepest mysteries.

Discovered in 1885, Escherichia coli soon proved easy to raise in 

laboratories. Its popularity boomed in the 1940's when scientists figured out 
how to use 
it to pry open the secrets of genes.

In the 1970's scientists figured out how to insert foreign DNA into E. coli, 
turning them into biochemical factories that could churn out valuable 
compounds like insulin.

"Everybody studies E. coli for everything," said Gavin Thomas, a 
microbiologist at the University of York in England.

Research on E. coli accelerated even more after 1997, when scientists 
published its entire genome.

Scientists were able to survey all 4,288 of its genes, discovering how groups 
of them worked together to break down food, make new copies of DNA and do 
other tasks. 

Some scientists speculated that before long they might understand how all of 
the pieces of E. coli worked together.

Such speculations were not new. In 1967, Francis H. C. Crick, the 

co-discoverer of DNA, and the Nobel Prize-winning biologist Sydney Brenner had 
called for 
"the complete solution of E. coli."

But the call went unheeded for over 30 years. After all, E. coli contains an 
estimated 60 million biological molecules. Simulating all of them at once was 
an absurdly difficult task. 

But by the late 1990's, it began to look plausible, although not necessarily 
easy. Despite decades of research, many of E. coli's genes still remain a 

mystery - "probably around 1,000 genes," Dr. Thomas said. "There's a lot more we
need to know about E. coli before we can build a really solid model."

To find out more, E. coli experts have been joining forces.

In 2002 they formed the International Escherichia Coli Alliance to organize 
projects that many laboratories could do together.

In one project, researchers have created over 3,900 different strains of E. 
coli, each missing a single gene. "It would have been foolish for two or three 
labs to carry this out at the same time and compete with each other," said 
Barry Wanner of Purdue University, who led the project.

Soon scientists will be able to order the entire collection of these strains 
for their own research. "We've done a variety of simple tests, but we can't do 
every conceivable experiment," Dr. Wanner said. "But a hundred other 
laboratories can do hundreds of other ones."

As knowledge of E. coli grows, scientists are starting to build models of the 
microbe that capture some of its behavior. "This field is moving forward very 
aggressively," said Bernhard Palsson of the University of California, San 
Diego. 

Dr. Palsson models E. coli's metabolism. Like other living organisms, E. coli 
breaks down food with enzymes, whittling molecules down bit by bit.

It then uses other enzymes to refashion the fragments into new molecules. Dr. 
Palsson and his colleagues have reconstructed the interactions of over 1,000 
metabolism genes. 

They can predict how fast the microbe will grow on various sources of food, 

as well as how its growth changes if individual genes are knocked out. Based on
experiments with real E. coli, the researchers find the model gives the right 
predictions 78 percent of the time. Now they are expanding their model to 
2,000 genes.

Meanwhile, researchers at the laboratory of Philippe Cluzel at the University 
of Chicago have been focusing their efforts on making E. coli swim. 

The microbe swims with several spinning tails, each driven by a motor 
revolving 270 times a second. 

If the tails turn counterclockwise, they all wrap into a bundle that can 
propel E. coli forward. If the microbe makes the motors turn clockwise, on the 
other hand, the tails fly apart and send E. coli into a tumble.

By alternatively swimming and tumbling, E. coli can navigate through its tiny 
world. It "decides" which way to spin its motors based on the information it 
gets from sensors that stud its outer membrane. "It's a big 

information-processing network," said Thierry Emonet, a research scientist at 
the University of 
Chicago. 

To understand this microbial computer, Dr. Emonet and his colleagues have 

created a virtual E. coli that can sense its surroundings and decide how to 
swim. 
They simulate the chemical reactions that carry signals from sensors to 

motors, and then track the path a virtual E. coli takes through 
three-dimensional 
space. 

Their virtual E. coli turns out to swim very much like the real thing. In one 
experiment, the scientists put virtual microbes in a gradient of food. "The 
higher you go, the more food there is, so their goal is to go up," Dr. Emonet 
said.

And they do, although they don't go in a straight line. "You see single cells 
go up, but then they lose track of their original direction, and they go down 
at some point," Dr. Emonet said. "The sensory system reacts, and they tumble, 
and then they go up again. It's pretty cool."

Dr. Emonet said he hoped that his model would allow scientists to understand 
other sorts of decisions made by cells. Cells "decide" to divide in response 
to certain signals, for example, and runaway cell division can lead to cancer. 
Understanding the simple decisions of E. coli may help researchers understand 
the decisions of more complex cells like those in our own bodies.

"If you can't understand how a single E. coli is able to find food by passing 
information from the outside to the inside, there's very little hope for 
understanding a system like cancer," Dr. Emonet said.

A full-blown model of E. coli would be able not only to swim, but eat food, 

fight off invading viruses, make copies of its DNA, and do many other tasks all
at the same time. Scientists agree that building a multitasking model would 
be a daunting job. "Technically, that's incredibly more difficult," Dr. Thomas 
said.

Dr. Ellison and his colleagues have decided to take the first steps toward 
creating a full-blown model. 

They want to begin by simulating a simplified E. coli. "We're going to strip 
E. coli down to about one-quarter of its original size," Dr. Ellison said. 

Dr. Wanner is working with colleagues in Japan to make this minimal E. coli. 
"We're trying to knock out groups of 100 genes at a time," Dr. Wanner said. 

They hope to produce a stripped-down E. coli with only around 1,000 genes within
two years. Dr. Ellison and his colleagues then hope to create a virtual twin, 
in an endeavor they have dubbed Project Gemini.

"Our approach is to track every biomolecule in that cell in space and time," 
Dr. Ellison said. 

As a proof of concept, he and his colleagues have simulated a bubble-shaped 
membrane made of 13,000 particles. The membrane acts a lot like a real one, 

swelling when it is filled with extra molecules. The researchers hope to use the
model to recreate an entire E. coli, complete with genes, enzymes, membrane 
channels and other parts. 

There is one major catch, however. Even a stripped-down E. coli is so complex 
that no existing program can simulate it. "Our gamble in this is that 

computers are getting more powerful, so we build the framework and within 5 or 
10 
years the computers will be able to deal with this," Dr. Ellison said.

"Assuming the speed of computing keeps increasing, I don't see why it's not 
possible," said Dr. Emonet, who is not involved in Project Gemini. 

But, like some other scientists, he has some reservations about its 

usefulness. "Even if we could make a simulation of everything inside E. coli 
today, 
that does not mean we would understand it," he said "The trick is to build the 
thing in steps and check that you understand the phenomena one at a time."

A full-blown model of E. coli is still worth the effort, many scientists 

argue, because of its potential benefits. Scientists could adapt the E. coli 
model 
to more complex human cells to simulate how they react to different drugs. 

"Then you can really do genetic engineering," Dr. Ellison said. "I mean where 
you can actually design an organism or change it in massive ways. When people 
talk about genetic engineering today, it's really kind of a joke because they 
mean, 'I moved a gene from one organism into another organism, and I'm going 
to pray that it works.' " 

A virtual E. coli could allow scientists to see in advance how major changes 
to the microbe would affect it.

"That opens up a huge amount of opportunity," Dr. Ellison said.


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