One goal of ‘synthetic’ biology is to manipulate the systems inside living cells to produce valuable molecules for biomedical or industrial applications. However, progress has been slow – until now.
‘The current approach is based on trial and error,’ says Diego di Bernardo, coordinator of the EU-funded COSY-BIO project. The problem is that the interior of a cell is a ‘noisy’ place where the behaviour of a molecule is influenced by the many processes going on around it. In an analogy to electronics, researchers speak of biological ‘circuits’ to achieve controlled outcomes but the components are not as reliable as silicon chips. ‘You build circuits and the cell does completely different things.’
The eight partners working on COSY-BIO are aiming to employ the well-known principles of control engineering to impose some discipline on the noisy interior of the cell, in an emerging field known as cybergenetics.
‘Control engineering was created to force complex systems to behave in a simple and reliable way,’ di Bernardo explains. ‘It is a set of methodologies that tell you how to build a circuit in order to make it work in a robust way independently of the individual parts which may not be robust.’
The team members are developing three different ways to regulate the function of a biological circuit.
First, they have used a computer as an external controller. The production of protein in a cell is monitored with a microscope, then the computer signals to the cell – either with light or the infusion of small molecules – when the desired level is reached. So far, this has been implemented in bacterial and yeast cells, although it has also been investigated using mammalian cells.
A more advanced solution is to embed the controller within the cell itself. To do this, the team initially designed a computer simulation of a biological circuit analogous to a thermostat and have now got it working in living cells. ‘This is basically bread and butter for control engineers,’ di Bernardo says. The rate of production is controlled by the balance of two complementary molecules. ‘These are already present in cells – we are just repurposing them.’
The team is now working on a third, ‘multicellular’ controller where an embedded controller in one cell is used to control the production of protein in another set of cells. ‘So you have two populations of cells, one which you engineer to produce your protein of interest, and the other which controls the behaviour of the producer cells.’ The two populations communicate with each other by releasing two types of molecule, each of which is sensed by the other cell.
Molecules on demand
COSY-BIO was due to end in September 2020 but due to the coronavirus pandemic it is now expected to be extended until March 2021.
The potential of cybergenetics is huge. The ability to command bacteria or other cells to produce controlled quantities of molecules to order would have major benefits for biomedicine. For example, the method could be applied in antibody therapy of the type now being discussed for combatting COVID-19, as well as gene therapy and medical diagnostics, not to mention environmental sensing and novel materials.
Cybergenetics has been led by engineers but di Bernardo looks forward to the day when it becomes an accepted discipline within modern biology. ‘If all of this works as it seems to be working, and the field keeps growing, we will be able to realise what synthetic biology wanted to do 20 years ago.’