In a First, an Entire Organism Is Simulated by Software
By JOHN MARKOFF
New York Times
July 20, 2012
http://www.nytimes.com/2012/07/21/science/in-a-first-an-entire-organism-is-simulated-by-software.html

STANFORD, Calif. - Scientists at Stanford University and
the J. Craig Venter Institute have developed the first
software simulation of an entire organism, a humble
single-cell bacterium that lives in the human genital
and respiratory tracts.

The scientists and other experts said the work was a
giant step toward developing computerized laboratories
that could carry out complete experiments without the
need for traditional instruments.

For medical researchers and drug designers, cellular
models will be able to supplant experiments during the
early stages of screening for new compounds. And for
molecular biologists, models that are of sufficient
accuracy will yield new understanding of basic
biological principles.

The simulation of the complete life cycle of the
pathogen, Mycoplasma genitalium, was presented on Friday
in the journal Cell. The scientists called it a "first
draft" but added that the effort was the first time an
entire organism had been modeled in such detail - in
this case, all of its 525 genes.

"Where I think our work is different is that we
explicitly include all of the genes and every known gene
function," the team's leader, Markus W. Covert, an
assistant professor of bioengineering at Stanford, wrote
in an e-mail. "There's no one else out there who has
been able to include more than a handful of functions or
more than, say, one-third of the genes."

The simulation, which runs on a cluster of 128
computers, models the complete life span of the cell at
the molecular level, charting the interactions of 28
categories of molecules - including DNA, RNA, proteins
and small molecules known as metabolites that are
generated by cell processes.

"The model presented by the authors is the first truly
integrated effort to simulate the workings of a free-
living microbe, and it should be commended for its
audacity alone," wrote the Columbia scientists Peter L.
Freddolino and Saeed Tavazoie in a commentary that
accompanied the article. "This is a tremendous task,
involving the interpretation and integration of a
massive amount of data."

They called the simulation an important advance in the
new field of computational biology, which has recently
yielded such achievements as the creation of a synthetic
life form - an entire bacterial genome created by a team
led by the genome pioneer J. Craig Venter. The
scientists used it to take over an existing cell.

For their computer simulation, the researchers had the
advantage of extensive scientific literature on the
bacterium. They were able to use data taken from more
than 900 scientific papers to validate the accuracy of
their software model.

Still, they said that the model of the simplest
biological system was pushing the limits of their
computers.

"Right now, running a simulation for a single cell to
divide only one time takes around 10 hours and generates
half a gigabyte of data," Dr. Covert wrote. "I find this
fact completely fascinating, because I don't know that
anyone has ever asked how much data a living thing truly
holds. We often think of the DNA as the storage medium,
but clearly there is more to it than that."

In designing their model, the scientists chose an
approach that parallels the design of modern software
systems, known as object-oriented programming. Software
designers organize their programs in modules, which
communicate with one another by passing data and
instructions back and forth.

Similarly, the simulated bacterium is a series of
modules that mimic the different functions of the cell.

"The major modeling insight we had a few years ago was
to break up the functionality of the cell into subgroups
which we could model individually, each with its own
mathematics, and then to integrate these sub-models
together into a whole," Dr. Covert said. "It turned out
to be a very exciting idea."

M. genitalium, a parasite that causes sexually
transmitted disease, has the smallest genome of any
independent organism. It played a role in 2008 in the
Venter institute's synthesis of the first artificial
chromosome; the researchers were able to stitch together
the entire genome of the bacterium.

The bacterium, with its 525 genes, is far less complex,
for example, than another more traditional bacterium
used in traditional laboratory experiments, E. coli,
which contains 4,288 genes. The researchers said that
more complex cells would present significant challenges.
Currently it takes about 9 to 10 hours of computer time
to simulate a single division of the smallest cell -
about the same time the cell takes to divide in its
natural environment.

"The real question on our minds is: what happens when we
bring this to a bigger organism, like E. coli, yeast or
even eventually a human cell?" Dr. Covert said. He noted
that E. coli divides every 20 to 30 minutes and that the
number of molecular interactions in E. coli is a much
higher multiple, which would significantly extend the
time required to run the simulation.

"I'll have the answer in a couple of years," he wrote.

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