PRECISE, PROGRAMMABLE BIOLOGICAL CIRCUITS
Bio-engineers are
working on the development of biological computers with the aim of designing
small circuits made from biological material that can be integrated into cells
to change their functions. In the future, such developments could enable cancer
cells to be reprogrammed, thereby preventing them from dividing at an
uncontrollable rate. Stem cells could likewise be reprogrammed into
differentiated organ cells.
The researchers have
not progressed that far yet. Although they have spent the past 20 years
developing individual components and prototypes of biological computers,
bio-computers today still differ significantly from their counterparts made of
silicon, and bio-engineers still face several major obstacles.
A silicon chip, for
example, computes with ones and zeros -- current is either flowing or not --
and it can switch between these states in the blink of an eye. In contrast,
biological signals are less clear: in addition to 'signal' and 'no signal',
there is a plethora of intermediate states with 'a little bit of signal'. This
is a particular disadvantage for bio-computer components that serve as sensors
for specific biomolecules and transmit the relevant signal. Sometimes, they
also send an output signal if no input signal is present, and the problem
becomes worse when several such components are connected consecutively in a
circuit.
A biosensor that does
not 'leak'
ETH doctoral candidate
Nicolas Lapique from the group led by Yaakov Benenson, Professor of Synthetic
Biology in the Department of Biosystems Science and Engineering at ETH Zurich
in Basel, has now developed a biological circuit that controls the activity of
individual sensor components using internal "timer." This circuit
prevents a sensor from being active when not required by the system; when
required, it can be activated via a control signal. The researchers recently
published their work in the scientific journal Nature Chemical Biology.
To understand the
underlying technology, it is important to know that these biological sensors
consist of synthetic genes that are read by enzymes and converted into RNA and
proteins. In the controllable biosensor developed by Lapique, the gene
responsible for the output signal is not active in its basic state, as it is
installed in the wrong orientation in the circuit DNA. The gene is activated
via a special enzyme, a recombinase, which extracts the gene from the circuit
DNA and reinstalls it in the correct orientation, making it active. "The
input signals can be transmitted much more accurately than before thanks to the
precise control over timing in the circuit," says Benenson.
To date, the
researchers have tested the function of their activation-ready sensor in cell
culture of human kidney and cancer cells. Nevertheless, they are already
looking ahead to further developing the sensor so that it can be used in a more
complex bio-computer that detects and kills cancer cells. These bio-computers
will be designed to detect typical cancer molecules. If cancer markers are
found in a cell, the circuit could, for example, activate a cellular suicide
programme. Healthy cells without cancer markers would remain unaffected by this
process.
New signal converter
developed
Still, combining
various biological components to form more complex bio-computers constitutes a
further challenge for bio-engineers. "In electronics, the different
components that make up a circuit are always connected in the same way: with a
wire through which the current either flows or not," explains Benenson. In
biology, there are a variety of different signals -- a host of different
proteins or microRNA molecules. In order to combine biologic components in any
desired sequence signal converters must be connected between them.
Laura Prochazka, also
a doctoral candidate student under Benenson, has developed a versatile signal
converter. She published her work recently in the magazine Nature
Communications. A special feature of the new component is that not only it
converts one signal into another, but it can also be used to convert multiple
input signals into multiple output signals in a straightforward manner.
This new biological
platform will significantly increase the number of applications for biological
circuits. As Benenson says, "The ability to combine biological components
at will in a modular, plug-and-play fashion means that we now approach the
stage when the concept of programming as we know it from software engineering
can be applied to biological computers. Bio-engineers will literally be able to
program in future."
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