Antibiotics which break down before bacteria can evolve resistance to them; perfumes which release the heady scent of freshly cut flowers as your body heats up; and powerful cancer drugs directed to exactly where they are needed are some of the potential applications of microscopic chemical robots under development in Europe.
The tiny robots – just micrometers across – are being developed by Professor František Štĕpánek and colleagues at the Chemical Robotics Laboratory at the Institute of Chemical Technology in Prague, Czech Republic. The idea is that these smart structures, which resemble single-celled organisms, swarm where they are needed – at a tumour site or industrial spill, and release chemicals when triggered.
Prof. Štĕpánek, who had previously worked in the pharmaceutical industry, realised that a lot of potentially useful molecules were simply not stable enough for industry to make easily and package into pills.
So he shrank the lab. The tiny robots, called ‘chobots’, are designed to act as mini drug factories – mixing component chemicals and synthesising short-lived drugs where and when they are needed, and on command.
‘They are entities similar in structure and size to single-celled organisms like bacteria, but they are not living,’ said Prof. Štĕpánek, who moved from Imperial College in London back to the Czech Republic after receiving a European Research Council grant for the CHOBOTIX project. ‘And they can only do something when given a command, like a machine.’
He is now working as part of the EU-funded MICREAgents project, which brings together researchers from Germany, Denmark, Italy, the Czech Republic, the Netherlands, Israel, and New Zealand to make microscopic electronically active agents for chemical information processing.
Professor František Štĕpánek, Institute of Chemical Technology in Prague, Czech Republic.
Prof. Štĕpánek said his chobots could, for example, be triggered by a magnetic nanoparticle attached to the robot cell. In this case, applying a radiofrequency field for a short period of a few minutes would increase the temperature of the robots but nothing else, so that if the chobots were in body tissues these would be unaffected. This field would raise the temperature such that storage reservoirs inside the chobot would melt, releasing their contents and so allowing the synthesis of the target drug.
‘The nice fact is that the opening of the reservoirs is a reversible process,’ said Prof. Štĕpánek. ‘It’s possible to open and close them repeatedly.’ The potential of this is that the researchers could control a sequence of doses over time.
But how do the chobots know where to go? The team has been looking at tagging their surfaces with specific markers to drive them to the desired location. In the human body, this is by attaching antibodies to them which can recognise cancer cells. Tumour cells, for example, have many known markers which they carry on their surfaces, so it is possible to engineer the chobots to carry antibodies which will home in on, and only stick to tumour cells.
Prof. Štĕpánek’s team showed in a study published online in October that by using an antibody called M75, they could get their artificial cells to specifically attach to markers associated with common cancer cells.
The concept of using tiny vehicles for drug delivery in this way is not new. But synthesising drugs on location sets this project apart from previous work, Prof. Štĕpánek said.
Another clinical use could be to help beat antibiotic resistance in patients, Prof. Štĕpánek said, because the drugs they can manufacture are short-lived. ‘If they are released to where the bacteria are present, they will either kill them, or they don’t. But they are unstable so they don’t stay in the environment long enough for bacteria to evolve (resistance),’ he explained.
They might also be used for agrochemicals to fight against plant pests and fungi; and even in perfumery to produce short-lived molecules which give the ephemeral scents of freshly cut flowers or sliced cucumber, he said.
In all of these potential applications, the chobots will harness the strength of numbers, in what is known as ‘swarm robotics’. Inspired by nature – the swarming of ants and bees – relatively complex tasks can be carried out by the simple actions of thousands of individuals. The quantity of chemicals each chemical robot could release is negligible, said Prof. Štĕpánek. By luring large numbers to the same location and triggering them at the same time, they can have a significant co-ordinated effect.
‘They are entities similar in structure and size to single-celled organisms like bacteria.’
Professor František Štĕpánek, the Institute of Chemical Technology in Prague, Czech Republic
So far, Prof. Štĕpánek’s team have studied their chobots in cell cultures, but he hopes they will move on to animal safety studies in the next year. And if all goes well, they may be looking at the first human safety studies in 2015 or 2016.
The project is ‘exciting’ said Dr Omid Farokhzad, associate professor at Harvard Medical School and director of the laboratory of nanomedicine and biomaterials at Brigham and Women’s Hospital in Boston, US. He looks forward to seeing the team demonstrate the effectiveness of their approach in validated animal models. Dr Farokhzad predicts that in the next 10 or 20 years ‘smart therapeutics’ like this, which harness nano- or micro-particles, will be seen in the clinic.
The biggest challenge to developing these artificial cells, Prof. Štĕpánek said, is making sure they are safe in humans and do not trigger an immune response. To help overcome this, the team uses biocompatible materials to build the chobots, for example by using materials already known to be accepted by the human body like food additives or lipids.
Another challenge in the future may be the cost of scaling up the manufacture of these complex, artificial cells.
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