[tt] NYT: Researchers Take Step Toward Synthetic Life

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Researchers Take Step Toward Synthetic Life
http://www.nytimes.com/2008/01/25/science/25genome.html

By ANDREW POLLACK

Taking a significant step toward the creation of synthetic forms of
life, researchers reported Thursday that they had manufactured the
entire genome of a bacterium by stitching together its chemical
components.

Scientists had previously constructed the complete DNA of viruses,
but this is the first time it has been done for bacteria, which are
far more complex. The genome is more than 10 times as long as the
longest piece of DNA ever synthesized.

The feat is a watershed for the emerging field called synthetic
biology, which involves the design of organisms to perform
particular tasks, like making biofuels. Synthetic biologists
envision being able to design an organism on a computer, press the
"print" button to have the necessary DNA made and then put that DNA
into a cell to produce a custom-made creature.

"What we are doing with the synthetic chromosome is going to be the
design process of the future," said J. Craig Venter, the
boundary-pushing gene scientist.

Dr. Venter assembled the team that made the bacterial genome as
part of his well-publicized quest to create the first synthetic
organism. The work was published online Thursday by the journal
Science.

But there are concerns that synthetic biology could be used to make
pathogens, or that errors by well-intended scientists could produce
organisms that run amok. The genome of the smallpox virus can in
theory now be synthesized using the techniques reported on Thursday
since it is only about one-third the size of the genome
manufactured by Dr. Venter's group.

In any case, there are many hurdles to overcome before Dr. Venter's
vision of "life by design" is realized. The synthetic genome made
by Dr. Venter's team was not designed from scratch, but rather was
a copy, with only a few changes, of the genetic sequence of a
natural bacterium called Mycoplasma genitalium.

Moreover, Dr. Venter's team, led by a Nobel laureate, Hamilton O.
Smith, has yet to accomplish the next -- and biggest -- step. That
would be to insert the synthetic chromosome into a living microbe
and have it "boot up" and take control of the organism's functions.

If that happened, it would be considered by some to be the creation
of the first synthetic organism. The failure to achieve that
tempered the reaction of some outside scientists to the announced
achievement.

"Right now, all they've done is shown they can buy a bunch of DNA
and put it together," said George M. Church, a professor of
genetics at Harvard Medical School.

Dr. Venter's team last year reported successfully doing such a
chromosome transplant, but it was with the natural genome of one
type of Mycoplasma transplanted into another species of that
bacterium.

Dr. Venter said in a telephone news conference Thursday that each
pair of donor genome and recipient cell presented unique problems.
The scientists also think they interrupted the functioning of one
crucial gene, a correctable problem.

"It's not a slam dunk or we would be announcing it today," Dr.
Venter told reporters. Still, he said, "I will be equally surprised
and disappointed if we can't do it in 2008."

The bacterial genome that was synthesized consisted of 582,970 base
pairs, the chemical units of the genetic code represented by the
letters A, C, G and T. The longest stretch of synthetic DNA
reported in a scientific paper was about 32,000 bases long, though
some companies say they have made ones with about 50,000.

The machines that string bases together make many errors, so it is
impractical to make a string of more than 50 to 100 bases at once.
But some companies -- the foundries of the biotechnology era -- now
make genes thousands of bases long by splicing the shorter strings.

The Venter team ordered 101 such sequences, each 5,000 to 7,000
bases long, from these companies. It then joined them into
ever-bigger pieces. Finally, four big pieces were put into yeast,
which hooked them together using a natural gene repair mechanism.

The process was started in late 2002, Dr. Venter said, and cost
millions of dollars. That led some scientists to question why
someone would want to synthesize an entire organism when existing
organisms can be modified through genetic engineering.

"To some extent, it's something that was driven by `I want to be
the first person to do it,' " surmised Jeremy Minshull, chief
executive of DNA 2.0, a company that supplied some of the DNA
stretches to the Venter team.

Dr. Minshull said that scientists did not yet know enough about how
living things work to design an entire genome. "Our synthetic
capability way outpaces our understanding of what we want to do,"
he said.

For now, that is the case, Dr. Venter concedes. He runs a company,
Synthetic Genomics, that is using genetic engineering to produce
biofuels. But he and other scientists say that DNA synthesis is
following the path of computer chips, with capability rising
rapidly and costs -- now about $1 per base -- falling swiftly. At
some point, they say, it will become faster and cheaper for
scientists to synthesize an organism from scratch rather than cut
and paste genes from one organism to another.

The ability to synthesize genomes would allow for more scientific
experimentation. Dr. Venter said he would now be able to create
organisms missing dozens of genes to answer the initial question
that inspired the research in 1995: What is the minimum set of
genes needed for life?

Dr. Venter, who runs the nonprofit J. Craig Venter Institute in
Rockville, Md., is most known for sequencing the human genome in a
race with the publicly financed Human Genome Project.

Some activist groups say that Dr. Venter is going too far, too
fast, this time, and that synthetic biology needs outside
regulation to prevent the introduction of dangerous organisms,
created by evil intent or by innocent error.

"The fact that he's pushing ahead with this without any societal
oversight is very worrying," said Jim Thomas, a program manager at
the ETC Group, a technology watchdog group based in Canada. He also
said it was worrisome that Dr. Venter was applying for very broad
patents in synthetic biology.

Dr. Venter said that the field had discussed ethics and safety
since it started and that his work had been reviewed by ethicists.

In the new genome, he said, one gene was changed to make any
resulting organism noninfective. (Mycoplasma genitalium, which can
be transmitted sexually, is associated with inflammation.)

The team also added some DNA segments to serve as "watermarks,"
allowing scientists to distinguish the synthetic genome from the
natural one.

These watermarks, Dr. Venter noted, contain coded messages. Sleuths
would have to determine the amino acid sequence coded for by the
watermarks to decipher the message.

"It's a fun thing that has a practical application," he said.