DNA barges for nano-scale force sensing and regulation in biological membranes
Lead Research Organisation:
Imperial College London
Department Name: Chemistry
Abstract
Forces are ubiquitous in biology; they allow organisms to survive under extreme conditions, are involved in giving shape to early embryos or control cellular organization; and they can also drive pathological processes including cancer, malaria or atherosclerosis. Therefore, there has been a long-standing interest in understanding and replicating the mechanisms by which cells react to these physical cues. Fundamental knowledge of how cells respond to mechanical stimuli promises to open new ways of understanding, diagnosing, and treating diseases and, in addition, could significantly impact the engineering and development of artificial cells.
Synthetic or artificial cells are man-made constructs designed to mimic, or extend, the capabilities of biological cells. By combining biological building blocks - such as lipids, proteins, or nucleic acids - artificial cells have been designed to replicate biological processes including energy transduction, motility, decision making, or communication; and have found applications in biomedical therapies, or energy production. Overall, synthetic biology - including artificial cells - is believed to be instrumental in the fifth industrial revolution, where biotechnology is expected to play a pivotal role. However, development of fully biomimetic synthetic cells has not yet been achieved. In this Fellowship, I aim to address one of the challenges in engineering artificial cells: How to make them sense, and react, to external forces; similar to their biological counterparts.
While cellular membranes are highly dynamic, the membranes of artificial cells mostly resemble a passive chassis which displays a limited response to extracellular forces. In this work, I will combine DNA nanotechnology, membrane engineering, environmentally sensitive membrane dyes, advanced microscopy, and simulations to develop a molecular toolkit capable of sensing the forces acting on biological membranes and reacting to this stress by altering the membrane's biophysical behaviour. In this Fellowship, I will:
1) Investigate how lipid-lipid and protein-lipid interactions occurring within membranes are affected by mechanical forces.
2) Implement a circuit capable of releasing a chemical signal in response to an applied force onto the membrane.
3) Develop a synthetic scaffold supporting the artificial cell membrane, capable of modulating its biophysical behaviour.
4) Integrate the above systems to provide artificial cells with the ability of sensing and reacting to changes in extracellular mechanical cues, replicating the capabilities of their biological counterparts.
This Fellowship is set to advance our ability to monitor and manipulate molecular interactions within cellular and artificial membranes. Altogether, this will lead to a better understanding of fundamental biological processes involving membrane deformation, including viral infection or cell migration. Given that membranes and membrane proteins account for >50% of current druggable targets, this research could be a game-changer in the drug discovery market. Furthermore, the proposed technology could lead to the production of advanced drug delivery vehicles that respond to mechanical cues, such as the increased stress in atherosclerotic regions. Additionally, by controlling the biophysical behaviour of lipid membranes, we could engineer rugged synthetic cells that are more durable and better suited for scaled-up industrial applications, such as vaccine delivery vehicles.
Synthetic or artificial cells are man-made constructs designed to mimic, or extend, the capabilities of biological cells. By combining biological building blocks - such as lipids, proteins, or nucleic acids - artificial cells have been designed to replicate biological processes including energy transduction, motility, decision making, or communication; and have found applications in biomedical therapies, or energy production. Overall, synthetic biology - including artificial cells - is believed to be instrumental in the fifth industrial revolution, where biotechnology is expected to play a pivotal role. However, development of fully biomimetic synthetic cells has not yet been achieved. In this Fellowship, I aim to address one of the challenges in engineering artificial cells: How to make them sense, and react, to external forces; similar to their biological counterparts.
While cellular membranes are highly dynamic, the membranes of artificial cells mostly resemble a passive chassis which displays a limited response to extracellular forces. In this work, I will combine DNA nanotechnology, membrane engineering, environmentally sensitive membrane dyes, advanced microscopy, and simulations to develop a molecular toolkit capable of sensing the forces acting on biological membranes and reacting to this stress by altering the membrane's biophysical behaviour. In this Fellowship, I will:
1) Investigate how lipid-lipid and protein-lipid interactions occurring within membranes are affected by mechanical forces.
2) Implement a circuit capable of releasing a chemical signal in response to an applied force onto the membrane.
3) Develop a synthetic scaffold supporting the artificial cell membrane, capable of modulating its biophysical behaviour.
4) Integrate the above systems to provide artificial cells with the ability of sensing and reacting to changes in extracellular mechanical cues, replicating the capabilities of their biological counterparts.
This Fellowship is set to advance our ability to monitor and manipulate molecular interactions within cellular and artificial membranes. Altogether, this will lead to a better understanding of fundamental biological processes involving membrane deformation, including viral infection or cell migration. Given that membranes and membrane proteins account for >50% of current druggable targets, this research could be a game-changer in the drug discovery market. Furthermore, the proposed technology could lead to the production of advanced drug delivery vehicles that respond to mechanical cues, such as the increased stress in atherosclerotic regions. Additionally, by controlling the biophysical behaviour of lipid membranes, we could engineer rugged synthetic cells that are more durable and better suited for scaled-up industrial applications, such as vaccine delivery vehicles.
