New RNA nanodevices can perceive and analyze a variety of complex signals in living cells.

Ribonucleic acid (RNA) is used to create logic circuits capable of performing various calculations. In new experiments, Green and his colleagues have included logical RNA valves in living bacterial cells acting like tiny computers. Image: Jason Drees for the Biodesign Institute

The combination of biology and engineering, known as synthetic biology, is developing very rapidly, opening new perspectives that could hardly have been imagined until recently.

In a new study, Alex Green, a professor at the ASU Bio-Design Institute, demonstrates how living cells can be used to perform calculations like tiny robots or computers.

The results of the new study are very important for intelligent design and targeted delivery And drugs, the production of green energy, inexpensive diagnostic technologies and even the development of futuristic nanomachines capable of hunting for cancer cells or disabling aberrant genes.

"We use easily predictable and programmable RNA-RNA interactions to adjust the circuits," Green says. "This means that we can use computer software to develop RNA sequences that behave the way we want, which makes the design process much faster."

The study appeared in the online journal Nature .

Projected RNA

This approach uses circuits consisting of ribonucleic acid or RNA. These circuits, similar to conventional electronic circuits, self-organize in bacterial cells, which allows them to perceive incoming messages and react to them, creating a definite conclusion (in this case a protein).

In a new study, specialized circuits, known as logic gates, were Developed in the laboratory, and then incorporated into living cells. Tiny switches work when messages (as RNA fragments) are attached to their complementary sequences in the circuit, activating the logic gate and creating the desired output.

RNA switches can be combined in various ways to create more complex logic elements that can evaluate and Respond to multiple inputs, just like a normal computer can take several variables and perform sequential operations, for example, addition and subtraction, to obtain the final re ultata.

New research greatly increased ease of implementation of cellular computing. RNA approach to the production of cellular nanodevices is a significant step forward, as previously they required the use of complex intermediaries, such as proteins. Now the necessary components of the ribocomputer can be easily developed on a conventional computer. The pairing of the four RNA letters (A, C, G and U) ensures a predictable self-assembly and functioning of these parts in a living cell.

Green's work in this field began at the Weiss Institute in Harvard, where he helped develop the central component used In cellular circuits, known as the toehold RNA switch. The work was done at a time when Greene was a postdoctor working with nanotechnology expert Peng Yin, along with synthetic biologists James Collins and Pamela Silver, co-authors of the new article. "The first experiments were in 2012," says Green. "Basically, toehold switches worked so well that we wanted to find a way to best use them for cellular applications."

The video demonstrates the basic principles of the RNA toehold switch. Video source: Arizona State University

Upon arrival at ASU, Duo Ma, the first graduate student of Green, worked on experiments at the Bio-Design Institute, and another postdok, Jongmin Kim continued similar work at the Weiss Institute. Both of them are co-authors of the new study.

Biological Pentium

The possibility of using DNA and RNA, molecules of life, to perform computer calculations was first demonstrated in 1994 by Leonard Edlman of the University of Southern California. Since then, progress has made great headway, and recently such molecular calculations have been made in living cells. (Bacterial cells are commonly used for this purpose because they are simpler and easier to manipulate.)

The technique described in the new article uses the fact that RNA, unlike DNA, is single-stranded when it is produced in cells. This allows researchers to create RNA schemes that can be activated when the complementary RNA chain binds to an open RNA sequence in the design scheme. Binding of complementary strands is regular and predictable, and adenine always mates with uracil, and cytosine with guanine.

With all the elements of the circuit created using RNA that can take an astronomical number of possible sequences, the real power of the newly described method is In his ability to perform many operations simultaneously. Parallel processing provides faster and more complex calculations for efficient use of limited cell resources.

Just as computer scientists use a logical language for their programs to do precise AND, OR and NOT operations, "ribocomputers" (painted in yellow), Developed by the team at the Weiss Institute, can now be used by synthetic biologists to receive and interpret multiple signals in cells and to instruct their ribosomes (colored blue and green) for the production of various proteins. Authors: Weiss Institute at Harvard University

Boolean Results

In the new study, logical gates, known as AND, OR and NOT, were developed. AND starts the output in the cell only when there are two messages A and B RNA. The OR valve responds to either A or B, while NOT blocks the output if an RNA molecule is present. The combination of these gates leads to a complex logic capable of responding to multiple inputs.

Using the switches toehold RNA, the researchers released the first devices for the ribocomputer, with four AND inputs, six OR inputs and 12 inputs capable of performing a complex combination of AND, OR and NOT , Known as a normal disjunctive form. When the logic gate meets the correct RNA sequences leading to activation, the toehold switch is opened and the protein translation process takes place. All these detection and output functions can be integrated into one molecule, making the systems compact and easy to implement in the cell.

The study is the next step in the current work on the use of RNA toehold universal switches. In earlier works, Green and his colleagues demonstrated that an inexpensive array of switches toehold RNA can act as a high-precision platform for diagnosing the Zika virus. The detection of viral RNA in the array activated the toehold switches, causing the production of a protein that was recorded as a color change in the array.

The basic principle of using RNA-based devices to regulate protein production can be applied to almost any RNA input, Accurate, inexpensive diagnostics for a wide range of diseases. The cell-free approach is particularly well suited to new threats and during outbreaks in the developing world, where medical resources and personnel may be limited.

The computer inside

According to Green, the next phase of research will focus on the use of RNA technology toehold to create neural networks in living cells. Neural networks are able to analyze the range of excitatory and inhibitory signals, averaging their values ​​and producing a signal to the output if a certain activity threshold was crossed, just as in ordinary neurons. Eventually, researchers hope to induce cells to communicate with each other through programmable molecular signals, forming a truly interactive, brain-like network.

"Since we use RNA, the universal molecule of life, we know that these interactions can also work in others Cells, so our method provides a general strategy that can be transferred to other organisms, "says Green, referring to the future in which human cells become fully programmable objects with extended Biological capabilities.

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