Surveillance of toxic threats by electronic supervision of synthetic neurons in 3D

Threats in combat situations include the release of toxic chemical or biological weapons. These are relatively cheap and easily made so that they are available to a wide range of organisations. In fact recent history shows that the biggest threat is from small groups rather than states waging conventional warfare. For known examples such as the sarin nerve poison used on the Tokyo underground and the anthrax toxin used against the US postal service, highly specific and sensitive tests can be created using existing technology such as enzyme assays or immuno assays. These are similar to those used in hospital laboratories to detect disease markers. However there exists the possibility of the emergence of newly engineered agents for which a bespoke test is not yet developed. Such agents may affect cells, such as nerve cells or muscle cells, in a variety of ways including the blocking of specific electrical, biochemical or genetic processes. In order to detect such threats we need a modern day miner's canary, a biological system that can rapidly react to threats and warn personnel of imminent danger. The proposal here is to use synthetic biology approaches to create a miniaturised cell system that being complex is likely to contain the target sites for a wide range of toxins. The read out with be a rapid electrical signal. The synthetic biology will be developed at three levels, firstly a silicon chip will be made using micro technology in which nerve cells will cells will grow. We will design an electrode which has a nanotechnology based surface similar to that of a nerve cell. This will encourage cells to stick closely to the electrode and this will made our system very sensitive even though it uses only one recording electrode to listen in on the electronic chatter between cells. Secondly we will synthesise novel protein nets and pillars to direct nerve cell growth to make the isolated cells more like those in the human brain. This will replace the natural scaffolding which surrounds cells in living tissue, stabilising them and guiding their growth. Finally we will use mouse nerve cells derived from embryonic stem cell lines to give us the future power to design specially sensitive cells for new toxin detection systems. This means that no animals will be used in these experiments and the results will be much more reliable. The result of this one year project will be the proof of principle demonstration of our ability to use miniaturised cell culture as a field technology for the detection of toxic threats to our cities and armed forces. In future the technology can have wider applications in medical research and screening for new drugs.

Weapons based upon biological or chemical toxins are well established, relatively low tech and cheap to make. They have a high terror value . Rapid detection can mitigate this and conventionally we use tests against known agents, e.g. acetylcholine esterase assays to detect nerve agents and immunoassays for anthrax. This still leaves us vulnerable to newly developed toxins for which specific tests are not available and the first signs of which would be symptoms in human victims. This project seeks to develop synthetic cell systems which will report their general state electronically allowing a broad range of threats to be detected. Cell based sensors already exist and this project seeks to develop a next generation device eventually comprising of more than one cell type to represent the sensitivity of living tissue The challenges are to make a three dimensional culture which may provide a more lifelike cell environment including additional neuronal connections. In this first stage we will use differentiated neurones from mouse ES cells to provide a reproducible source of cells which, in future, could be modified to yield new cell types; e.g. expressing different surface receptors; or incorporate muscle cells creating the neuromuscular junction which is the target of current nerve agents. The three dimensional scaffold will consist of two parts, protein hydrogels and functionalised silicon structures. This synthetic extracellular matrix will span a range of length scales from nano to micrometer and will stabilise the cells both physically and in the correct differentiated state. The silicon device will provide the synthetic physical structure at the micrometer scale together with fluid interfaces and a single electrode which allows low power consumption and simple read outs. By creating interlinked cells and functionalised single electrodes, rather than a complicated array to detect changes in cell activity, we aim to create a new standard in cell recording.

The impact in the defence sector will be to provide a technology which will lead to low power, low cost, durable sensors for toxins in combat and civilian situations. This will open the way to portable technology which has the possibility of saving may lives by alerting the possible victims of the need for rapid protective measures. By developing the technology within the UK it has the possibility of providing us with a technological lead that will be reflected in an expanding industrial sector and associated jobs possibly resulting in an export led manufacturing opportunity.
As a research tool in the neurosciences and in tissue regeneration and repair the new technology may speed the path towards new treatments within academic research and within the Uk pharmaceutical industry who we will engage towards the end of the project once the defence objectives are clearly met. There will be an opportunity to screen for new drug functions more rapidly and this may in turn generate a spin off industry exploiting this ground breaking project.
Home analysis by chronic patients is a growing business but, so far, cell based sensors are too complicated and expensive. This may enable people to be treated at home with large saving s in health bills.
The PI has established two spin out companies in the NE of England which are both export led technology businesses and should the opportunity arise would like to see the creation of yet more jobs based upon this technology. This could be via a new Newcastle University spin out or by collaboration with the existing companies of Orla Protein Technologies and OJ-Bio Ltd. The latter are developing a hand held diagnostic sensor with wireless capability so there may be possibilities for rapid impact by this collaboration.