DNA Nanobots Used Bacteria’s Chemical Communication and This Enables Intelligent Nanobot Swarms

DNA Nanobots Used Bacteria’s Chemical Communication and This Enables Intelligent Nanobot Swarms

DNA Nanobots Used Bacteria’s Chemical Communication and This Enables Intelligent Nanobot Swarms

Brian Wang |
November 16, 2019 |

Bio-inspired Quorum Sensing in robots fabricated from DNA origami can communicate by transmitting and receiving diffusing chemical signals. The mechanism has features such as programmable response thresholds and quorum quenching, and is capable of being triggered by proximity of a specific target cell. Nanoscale robots with swarm intelligence could carry out tasks that have been so far unachievable in diverse fields such as industry, manufacturing and medicine.

Quorum Sensing (QS) is a well-studied example of collective behavior. See the 2013 TED Talk below on Bacterial quorum sensing chemical communication. This mechanism of cell-cell communication in bacteria utilizes secreted signal molecules to coordinate the behavior of the group. Linking signal concentration to local population density enables each single bacterium to measure population size. This ability to communicate both within and between species is critical for bacterial survival and interaction in natural habitats and has likely appeared early in evolution. Detection of a minimal threshold of signal molecules, termed autoinducers, triggers gene expression and subsequent behavior response. Using these signaling systems, bacteria synchronize particular behaviors on a population-wide scale and thus function as multicellular organisms.

QS-inspired approaches have been adopted in artificial systems, including mobile robots and wireless sensor networks, and naturally occurring genes have been harnessed in synthetic biology to implement QS at the cellular level.

Recently we reported a new type of nanoscale robot, fabricated from DNA origami, which logically actuates between “off” and “on” states. By using various types of DNA logic based on aptamer recognition, toehold-mediated strand displacement, etc., these robots can be programmed to respond to diverse stimuli and either present or sequester molecular payloads anchored to the inside of the device. In the present study, the researchers aimed to program the robots to exhibit collective behavior, taking advantage of the more elaborate modes of control that such behaviors enable.

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1A, Schematic design of QS system. PDGF was linked chemically to an MMP2-cleavable peptide tether, to form the autoinducer. This conjugate was further linked to a DNA sequence complementary to the DNA origami-associated loading site sequence (bottom). A mixture of autoinducer and GFP was loaded inside the robot (top left, seen from the side). MMP2 releases the autoinducers from a transmitting robot (in a closed state), these reach a receiving robot, switching it from closed to open (top right). 1B-C, Population-dependent behavior of QS robots. Robots were placed in MMP2-containing buffer in various population sizes in a fixed volume and their state was monitored using dynamic light scattering (1B) or flow cytometry (1C), using beads coated with anti-GFP antibodies.

The autoinducer release mechanism can be potentially adapted to any environment. For example, one could exploit the inherent instability of RNA for the gradual release of signal from the robots. Alternatively, a UV-cleavable tether would release the signal only upon exposure of the robots to sunlight or another direct source of UV radiation. Choosing enzymes such as MMPs as releasing factors has a therapeutic rationale, as it only initiates QS where enzyme activity is enriched, such as around or directly on metastasizing tumors.

The closed robots are hollow shells enabling small molecules such as proteins to freely diffuse in and out of them. Specifically here, the protein diffusing in and out is the release factor MMP-2, which when inside releases PDGF (tethered to the robot by the MMP-2 substrate polypeptide). The released PDGF can now also freely diffuse out of the robot, and build up a concentration of PDGF in the environment. In contrast, any attached payload (e.g. reporter molecule or unreleased PDGF) is only accessible to beads or other solid phase-based assays when the robot is open. Therefore, all robots – closed and open – participate in generating the PDGF concentration in the environment, but only the open robots contribute to the detectable signal. Robots loaded with auotoinducers were placed in MMP-2-containing buffer at various population densities (from 29 to 18,000 pM). Population density-dependent activation of the robots was demonstrated using both flow cytometry and dynamic light scattering analysis. Flow cytometry clearly showed distinct, QS-driven robot activation behavior displayed between the constitutively off and constitutively on curves.

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Our QS system can be tuned also via quorum quenching (QQ), by neutralizing or sequestering the autoinducer. To achieve QQ, we used a neutralizing anti-PDGF antibody that effectively negated PDGF binding to its aptamer on the robot, causing robots to switch to off even though their concentration was high enough to induce QS-driven activation. The efficacy of QQ depended on the ability of the neutralizing antibody to compete with the aptamers for autoinducer binding.

They next loaded the robots with antibody Fab’ fragments for the human receptor Siglec-7 (CDw328), whose cross-linking on leukemic cells induces growth arrest leading to apoptosis. Jurkat cells (leukemic T cells) were chosen as target cells as they express Siglec-7 and also exhibit high levels of MMP-2 activity after activation with cytokines. The cells were treated with varying concentrations of QS-regulated robots for 24 hours. Cell cycle analysis demonstrated cell-triggered QS leading to robot activation and subsequent growth arrest, as no other releasing factor was added to the medium. This highlights the potential of QS as an artificial therapeutic control mechanism that could be utilized in a variety of conditions, given that the proper system is designed with a target-associated releasing factor in mind, such as tumor-derived proteases, bacterial restriction nucleases, etc. A library of autoinducer tethers, each cleavable by a different signal, could be constructed to fit specific needs and environmental conditions.

This work provides a platform for the engineering of more elaborate communication schemes utilizing several sub-populations differing in autoinducer type and response thresholds, with desirable features as control systems for therapeutics and manufacturing.

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We are 90-99% Bacteria and Bacteria Use Quorum Sensing to Communicate

Our bodies have one trillion human cells and 10 trillion bacterial cells. The bacteria have 100 times more DNA information than the human cells.

Nanomedicine with DNA Nanobots to Enable Nanosurgery

SOURCES- Bioxriv, Ido BAchelet, TED Talk

Written By Brian Wang, Nextbigfuture.com

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