For decades,
biologists have modified plants and animals by snipping genes from
one organism and popping them into another in a process called
genetic engineering. Corn will produce its own pesticide – a toxin
harmful to caterpillars – when spiked with a bacterial gene. And
copies of the human gene for insulin have been slipped into
bacteria, transforming them into biological drug factories and
reducing the need to extract the hormone from slaughtered pigs.
RON WEISS / Princeton
University
Bacteria exchange signals generated by
synthetic circuits to form colorful patterns. The bulls-eye
pattern (left) formed around a patch of turquoise cells, which
send a chemical message. Surrounding cells turn green near the
center, where the message is strong, and red farther away,
where the message is weaker. Multiple patches of messenger
cells (center and right) create more complex patterns. Similar
multi-cell communication circuits could form complex
biological structures such as liver or skin.
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Until recently, those useful genes
had to be found in nature and transferred from one organism to
another. Now our ability to manipulate biology to suit our needs has
taken a startling new turn. Scientists are using custom-designed
DNA, synthesized from scratch, to create novel biological "circuits"
they hope will do anything they can program them to do.
Their goal is to plan new biological tasks, such as detecting
pathogens and rendering them harmless, with the kind of precision
and control exercised by designers of electrical circuits. They call
themselves synthetic biologists, and they have set out to engineer
life.
Is this a good idea? The goals sound promising: create tiny
packets that travel through the bloodstream to find and treat
diseased cells, design cells to generate replacement organs or
bridge a severed spinal cord, weave high-tech fabrics of proteins
from spider silk.
These possibilities have arisen largely from technical advances
over the past few years that have made chemical synthesis of DNA
relatively inexpensive. Custom-designed DNA is available by mail and
can be ordered through the Internet. Researchers specify the
sequence of the gene they desire and pay as little as a dollar per
letter of the genetic code.
The problem is that the sequences of dangerous things, such as
the virus that caused the 1918 influenza pandemic, are public
knowledge. Some worry that a renegade group of synthetic biologists
could unleash something horrifying.
"In an overall sense, the security situation is grave," said
Roger Brent, president and CEO of Molecular Science Institute in
Berkeley. "One can re-synthesize flu. The people who call themselves
synthetic biologists didn't bring this situation about, but they
bear some measure of the responsibility for keeping us safe."
SCOTT LINNETT /
Union-Tribune
Natalie Ostroff prepared to measure a
signal from a synthetic circuit she designed and inserted into
yeast cells. |
Brent isn't concerned
about the field's pioneers. "They're the products of long
apprenticeships, acculturated to using the technology only for good
and never for evil." But he worries about younger people. A
self-taught teenager can pore deeply through a computer operating
system, he said. At this point, manipulating genes requires more
specialized training, but the future may be different.
"Possibly the best protection is promulgation of ethical
standards. If people act now, they can stop a hacker culture from
the start." Scientists and policy makers have begun discussions, but
few existing regulations apply to this new endeavor.
Leaders in the field convened the intercollegiate Genetically
Engineered Machine, or iGEM, competition at the Massachusetts
Institute of Technology in Cambridge last month. Nine teams fielded
by universities and colleges from San Francisco to Zurich presented
projects in a prize-less contest.
"We could have made this another 'robot wars' scenario and got
the kids all excited about bashing each other's biology," said
geneticist George Church, of Harvard University, who helped organize
the meeting. "But we specifically discouraged that and instead
encouraged a more constructive way of looking at things."
Each team picked a goal, some task for their bacteria to
accomplish, then designed a biological circuit to do the job using
plug and play components call BioBricks. Each component is a piece
of DNA that can do a single simple thing, like make a protein to
sense light, relay a signal or fluoresce. The students strung
together BioBricks, much like assembling a simple electrical circuit
from an electronics kit, and stuck them into cells to see if they
would boot up properly. Revisions are always needed.
The UC Berkeley team exploited a bacterial trick called
conjugation. Bacteria naturally exchange bits of DNA through tunnels
they form when they come into close contact. "One of bacteria's
favorite things to do is to spread resistance to antibiotics," said
graduate student Jonathan Goler, who helped coach Berkeley's team.
Instead, the students used the channels – by sliding a strip of
DNA from cell to cell – to send messages they designed. In this
case, the message was the order to make a protein that glows and
also an "address" for the next cell to send the message to. The
practical use isn't yet clear, but the organizers hailed it as a
creative new approach to controlling a group of cells.
Promising directions
Goler's own work addresses a more pressing need. He is
part of a team led by professor Jay Keasling that is engineering
bacteria to produce a drug to treat malaria. The team is using at
least 10 genes from three organisms to forge new machinery within
bacterial cells that will manufacture artemesinin. The potent
protein is naturally found in the wormwood shrub, but in small
amounts. Isolating it from the plant is inefficient and expensive.
But if easily grown bacteria can be made to do the job, the drug
could be produced in volume, dropping its price and making it more
widely available.
Former Keasling lab member Christina Smolke, now at the
California Institute of Technology, is working on "smart
therapeutics." Her research group is designing DNA-based probes to
detect a type of viral infection that transforms a normal cell into
a cancerous one. "We're working on small delivery vehicles that
could deliver therapy once they detect the errant cells," she said.
SCOTT LINNETT / Union-Tribune
Glowing green colonies of engineered
bacteria cells spotted a Petri dish.
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Ron Weiss and colleagues at
Princeton University have programmed bacteria from the human gut to
communicate with each other to produce colorful designs. They have
created a "Goldilocks" circuit that lights up when the concentration
of a target chemical is just right.
In one experiment, they designed cells to glow green when they
sensed a high concentration of a signal chemical and red when the
concentration was low. They placed a different set of cells designed
to secrete the signal chemical in a center of a plate of bacteria
food. When the chemical bled out through the goo, like a wine stain
on a table cloth, the sensor cells responded by forming a bull's-eye
pattern – green ringed by red.
If the sensing bacteria could be programmed to detect a
contaminant, they could be sprayed over a chemical spill to
highlight the most dangerous zones with their color patterns, Weiss
said.
Arrays of cells could also form more complex patterns as the
basis for generating tissues, even organs. Current attempts
encourage cells to arrange themselves on artificial scaffolding.
"The way we're doing tissue engineering right now, one could claim,
is very unnatural," Weiss said. "Clearly cells make scaffolds
themselves. If we're able to program them to do that, we might be
able to embed them in the site of injury and have them figure out
for themselves what the pattern should be."
Hello world
An early success in the field, reported in 2000, was a
three-gene program that made bacteria blink on and off like
fireflies. That system mimicked biological clocks that cycle on and
off. Most biological rhythms, though, are regularly reset by cues
from the outside world, such as daylight. Jeff Hasty's lab at UCSD
is designing rhythmic circuits in yeast and mold that synchronize
with light cycles.
"I'm trying to design a minimal circuit needed to maintain these
cycles," said graduate student Natalie Ostroff, who works with
yeast.
Light is a favorite signal for synthetic biologists, perhaps
because nature has provided so many examples. For now, most teams
have created cells that signal with colored fluorescent proteins
found in jellyfish.
A team from UC San Francisco and the University of Texas in
Austin hopes to use light detectors tuned to various wave lengths to
turn on specific synthetic circuits. For a start, they borrowed a
protein from blue-green algae that is activated by red light, linked
it to an enzyme that deposits a black pigment and inserted this
simple circuit into bacterial cells. When the cells are spread in a
thin sheet and exposed to light, they act much like a photographic
film.
For their inaugural outing at a meeting last year, the team
shined light on their film to form the words "Hello World."
Subsequent efforts produced an image of one of their advisers and
the name of the journal that published their work.
But these are just demonstrations. At UC San Francisco,
Christopher Voight imagines something more useful – creating
materials composed of multiple proteins, like those that make up
spider silk, each contributing properties of strength and
elasticity, each controlled by a color of light.
Keeping it safe
Much of this work is preliminary: jellyfish lights and
cells that make pictures. Getting them to work remains quite a
challenge, even for the brightest minds, so the threat of using the
process for intentional harm is unlikely for the moment. Everyone
interviewed for this article agreed the risk of accident or
inadvertent introduction of something harmful was minuscule.
"You have to remember all these experiments are done in a petri
dish," Weiss said. "Once you go outside the petri dish, the
environment becomes so complex, the engineered cells have a hard
time surviving. It's easy to imagine dangerous, but to realize it is
much more difficult."
Still, scientists, ethicists and government advisers are meeting
now to decide how best to manage and control this new power. They
are discussing means of monitoring the genes ordered, codes of
conduct and the possibility of licensing scientists.
One emerging practice is the
notion of stamping the work with an identifying mark. "When we
synthesize genes, we add a bar code or signature into the DNA that
identifies it as something we made. That makes it easy to detect,"
said Drew Endy, of the Massachusetts Institute of Technology.
The National Science Advisory Board for Biosecurity is currently
considering a code of conduct. Less clear is what the consequences
of violating the code should be and how a code would stop people who
intend to do harm.
Current laws require a permit to work with certain dangerous
pathogens such as anthrax. But those pathogens are listed by
species, not by specific sequences of DNA. "We would like to see
regulations expressed in terms of sequences," said John Mulligan,
president and CEO of Blue Heron Biotechnology. He said his company
does screen orders and has yet to receive one for a suspicious
sequence.
But what should happen if Blue Heron or another company does?
"Let's say you're starting up a new company and you're screening and
you find something that looks really horrible," Endy said. "Who do
you talk to?"
Even the controls are preliminary. Weiss advocates constructing
synthetic "self destruct" circuits. "You can actually engineer them
to kill themselves after some amount of time. When it counts to 10,
the cell dies."
That requires cells to count, which happens to have been one of
the projects in the iGEM competition this year.
"We began by talking about counting to infinity," said Robin
Künzler, a member of the team from Zurich. But that proved too high
a hurdle. Instead they designed a cell that could count to two.
Susan Brown is a Quest intern.
