But scientists have found it difficult to wire the
components together to form larger circuits that can function as "genetic
programs." One of the biggest obstacles? Dealing with a small number of
A team of biologists and engineers at UC San Diego
has taken a large step toward overcoming this obstacle. Their advance, detailed
in a paper which appears in this week's advance online publication of the
journal Nature, describes their development of a rapid and tunable
post-translational coupling for genetic circuits. This
advance builds on their development of "biopixel" sensor arrays reported in
Nature by the same group of scientists two years ago.
The problem the researchers solved arises from the
cellular environment that tends to lead to highly variable circuit
performance. The components of a cell are intermixed, crowded, and constantly
bumping into each other. This makes it difficult to reuse parts in different
parts of a program, limiting the total number of available parts and wires.
These difficulties hindered the creation of genetic programs that can read the
cellular environment and react with the execution of a sequence of instructions.
The team's breakthrough involves a form of "frequency
multiplexing" inspired by FM radio.
"This circuit lets us encode multiple independent
environmental inputs into a single time series," said Arthur Prindle, a
bioengineering graduate student at UC San Diego and the first author of the
study. "Multiple pieces of information are transferred using the same part. It
works by using distinct frequencies to transmit different signals on a common
The key that enabled this breakthrough is the use of
frequency, rather than amplitude, to convey information. "Combining two
biological signals using amplitude is difficult because measurements of
amplitude involve fluorescence and are usually relative. It's not easy to
separate out the contribution of each signal," said Prindle. "When we use
frequency, these relative measurements are made with respect to time, and can be
readily extracted by measuring the time between peaks using any one of several
While their application may be inspired by
electronics, the UC San Diego scientists caution in their paper against what
they see as increasing "metaphorization" of engineering
"We explicitly make the point that since biology is
often too intertwined to engineer in the way we are accustomed in electronics,
we must deal directly with bidirectional coupling and quantitatively understand
its effects using computational models," explained Prindle. "It's important to
find the right dose of inspiration from engineering concepts while making sure
you aren't being too reliant on your engineering metaphors."
Enabling this breakthrough is the development of an
intracellular wiring mechanism that enables rapid transmission of protein
signals between the individual modules. The new wiring mechanism was inspired by
a previous study in the lab on the bacterial stress
response. It reduces the time lags that develop as a consequence of using
proteins to activate or repress genes.
"The new coupling method is capable of reducing the
signaling time delay between individual genetic circuits by more than an order
of magnitude," said Jeff Hasty, a professor of biology and bioengineering at UC
San Diego who headed the team of researchers and co-directs the university's
BioCircuits Institute. "The state of the art has been about 20 to 40 minutes,
but we can now do it in less than one minute."
"This study is an outstanding example of the power
of interdisciplinary systems biology approaches, which treat our cells like
integrated pathways and networks instead of a collection of individual
components," said Sarah Dunsmore, a program manager at the National Institute of
General Medical Sciences, which finances a National Center for Systems Biology
at UC San Diego that supported the research. "By combining the complexity of
naturally occurring biological processes with engineering principles, Dr. Hasty
and colleagues have produced a model that will provide the basis for creating
genetic circuits that can be used to study human health and disease."
"What's really exciting about this coupling method
is the particular way we did it," said Prindle. "Rather than trying to build
from scratch, we made use of the enzyme machinery that the cell uses for rapid
and precise signaling during times of stress. This is an appealing strategy
because it lets us take advantage of the advanced machinery that nature has
Hasty credited Prindle for coming up with the idea
for the study and carrying it through. "Beyond his modeling and bench skills,
I've been extremely impressed by Arthur's ingenuity and drive," said Hasty.
"This project arose from his creativity at the outset and he had the raw energy
and excitement to carry it to the end."
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