Japan_IPAP: Novel nanotechnologies for on-site expression and reconstitution of membrane-embedded machineries in synthetic cells
Lead Research Organisation:
Imperial College London
Department Name: Chemical Engineering
Abstract
Cells are the building blocks of life. They have been sculpted over billions of years of evolution to perform some of the most complex tasks known to humankind. However, at their core, they can be thought of as a web of interacting molecules, albeit a very complex one. We can ask ourselves: what if we could create entirely artificial cells from scratch? Can we make life from inanimate matter? Achieving this ambitious objective will underpin disruptive applications and address some of the grand societal challenges of our time. Building a new biology will also transform our understanding of living systems.
The ultimate aim of artificial cell research is to manufacture synthetic microrobots that possess the hallmark behaviours of cellular life, including the ability to move, harvest and covert energy, communicate with each other and with biological cells, adapt to the environment, replicate, make 'decisions', repair themselves, grow, divide, and even evolve. One of the key aims of the field is to engineer synthetic cells that are capable of making their own machinery from a genetic programme, which will allow them to be autonomous. This is critical if synthetic cells are to have applications beyond academic environments as therapeutic agents, tools in drug discovery, bioremediation, sensing and chemical manufacture.
Proteins are the molecular machines that give cells their functions. The scientific community are now broadly able to engineer synthetic cells that can produce soluble proteins, such as the enzymes that catalyse chemical reactions. There is a whole other class of proteins that due to technological limitations, are out of reach when it comes to autonomous synthetic cell design: membrane proteins. This is a damaging bottleneck, as these proteins are responsible for diverse cellular behaviours, ranging from motility, communication and signalling through to energy generation, replication and cell-cell adhesion.
In this project, by bringing together world-leading researchers in the UK and Japan, and combining our expertise in membrane biophysics, molecular biology, DNA nanotechnology and microfluidics, we will remedy this oversight. We will conduct the feasibility studies that enable the design and construction of synthetic cells that can generate their own membrane-based machinery.
We will also organise activities to bring together vibrant communities in Japan and the UK in this space. This level of international cooperation and engagement is required if the scientific community is to achieve the grand challenge of engineering synthetic life.
The ultimate aim of artificial cell research is to manufacture synthetic microrobots that possess the hallmark behaviours of cellular life, including the ability to move, harvest and covert energy, communicate with each other and with biological cells, adapt to the environment, replicate, make 'decisions', repair themselves, grow, divide, and even evolve. One of the key aims of the field is to engineer synthetic cells that are capable of making their own machinery from a genetic programme, which will allow them to be autonomous. This is critical if synthetic cells are to have applications beyond academic environments as therapeutic agents, tools in drug discovery, bioremediation, sensing and chemical manufacture.
Proteins are the molecular machines that give cells their functions. The scientific community are now broadly able to engineer synthetic cells that can produce soluble proteins, such as the enzymes that catalyse chemical reactions. There is a whole other class of proteins that due to technological limitations, are out of reach when it comes to autonomous synthetic cell design: membrane proteins. This is a damaging bottleneck, as these proteins are responsible for diverse cellular behaviours, ranging from motility, communication and signalling through to energy generation, replication and cell-cell adhesion.
In this project, by bringing together world-leading researchers in the UK and Japan, and combining our expertise in membrane biophysics, molecular biology, DNA nanotechnology and microfluidics, we will remedy this oversight. We will conduct the feasibility studies that enable the design and construction of synthetic cells that can generate their own membrane-based machinery.
We will also organise activities to bring together vibrant communities in Japan and the UK in this space. This level of international cooperation and engagement is required if the scientific community is to achieve the grand challenge of engineering synthetic life.
Technical Summary
Bottom-up synthetic biology is concerned with the engineering of biomimetic entities from rationally combined non-living components. Often referred to as 'synthetic cells', these constructs are designed to possess features that we associate with living systems. Building cells from molecular building blocks is a powerful way to decipher the rules of life via a 'learning by building' approach, which is central to much bioscience research. Synthetic cells also have significant potential as engineered autonomous microdevices in applications ranging from therapeutics and diagnostics to regenerative medicine, bioremediation and biochemical synthesis.
In 2022, the BBSRC made synthetic cells a key priority for collaborative UK / Japan research, allowing us to bring together our international team of experts to lead a synthetic cell project. Our project aims to design new classes of synthetic cells capable of autonomously synthesising and reconstituting their own membrane protein machinery, without human intervention, just as they do soluble membrane proteins. This is critical given the importance of membrane proteins in universal cellular phenomena (movement, signalling, communication, energy generation, replication etc). We will explore two different philosophies to achieve this. First, will attempt to directly emulate biology by incorporating the machinery that cells use to guide proteins into the membrane. Second, we will develop a new non-native biology, and principles of DNA nanotechnology, nanodiscs, and biomembrane engineering, coupled with microfluidics to achieve in situ expression and reconstitution of membrane proteins via a genetic programme. As a proof-of-concept, we will focus on three membrane proteins of increasing complexity. More broadly, we have designed a programme of activities which will help forge long-lasting links between synthetic cell communities in the UK and Japan, which will enable more substantial follow-on work between both countries.
In 2022, the BBSRC made synthetic cells a key priority for collaborative UK / Japan research, allowing us to bring together our international team of experts to lead a synthetic cell project. Our project aims to design new classes of synthetic cells capable of autonomously synthesising and reconstituting their own membrane protein machinery, without human intervention, just as they do soluble membrane proteins. This is critical given the importance of membrane proteins in universal cellular phenomena (movement, signalling, communication, energy generation, replication etc). We will explore two different philosophies to achieve this. First, will attempt to directly emulate biology by incorporating the machinery that cells use to guide proteins into the membrane. Second, we will develop a new non-native biology, and principles of DNA nanotechnology, nanodiscs, and biomembrane engineering, coupled with microfluidics to achieve in situ expression and reconstitution of membrane proteins via a genetic programme. As a proof-of-concept, we will focus on three membrane proteins of increasing complexity. More broadly, we have designed a programme of activities which will help forge long-lasting links between synthetic cell communities in the UK and Japan, which will enable more substantial follow-on work between both countries.
