Synthetic biology: building life

Richard Feynman famously said: ‘What I cannot create, I do not understand’. That’s why Bert Poolman and several colleagues are trying to build a synthetic cell with components from all over the living world. Trying to make these components work together will help us understand how life works.

University of Groningen biochemistry professor Bert Poolman is involved in an ambitious project: to create a synthetic cell. ‘I have been working on aspects of this for many years already’, says Poolman. ‘At first, a few of us were working more or less independently in what is called bottom-up synthetic biology, but we began to work together three years ago.’ Scientists at the University of Groningen are focusing on energy metabolism and membrane synthesis, while their colleagues at Radboud University Nijmegen are working on gene networks and protein synthesis, and at Delft University of Technology on creating a reproduction system.

‘We build cells from scratch but use molecular components from biology. The reason is that ultimately, we need to construct an artificial genome that specifies the components, and this is not possible with molecules that have been designed and synthesized chemically. The aim of the entire exercise is to increase our understanding of how life works.’ Poolman is therefore also involved in the Origins Centre, which was established to answer questions from the public on the origin of the universe and life on Earth.

Equilibrium

How does Poolman define life? ‘The definition that I use in my lectures is that life is a system which maintains itself, produces its own components and is capable of dividing into daughter cells. Importantly, it is a system that maintains a state of non-equilibrium, which is typical for biology but no mean feat in chemical systems. A biological system that reaches an equilibrium is no longer alive, and one of the challenges is to create synthetic cells that operate in far from an equilibrium.’

The approach that Poolman and his colleagues are taking is to use components from different organisms. These components include systems that generate energy or that sense and maintain pH and similar factors. They select the simplest components with the minimum required functions, and try to get them working in a synthetic system. ‘Different cells use different molecules for similar functions, and there is a lot of biological redundancy that we try to minimize.’ Furthermore, they focus on reactions (such as the synthesis of ATP, the universal energy carrier in all cells) and processes (cellular homeostasis) that are common to all forms of life.

Poolman gives an example of how building synthetic systems can deliver new insights. ‘We created a synthetic cell that could regulate its volume. It worked, but we noticed that the system made the cell’s interior acidic, which was not predicted from in vivo studies. The synthetic cell produced carbon dioxide, which reacted to form bicarbonate and protons and thus lowered the pH.’ Living cells don’t acidify their cytoplasm; they appear to have a system to cope with it. ‘And we didn’t realize this. We only found out that it had to be there from our synthetic cell.’

Switches

Apart from volume regulation, the synthetic cell has a metabolic pathway that sustainably produces ATP, which is of immediate importance for the scientists on the project who are focusing on protein synthesis and cell division. Another challenge is to combine the ATP production pathway with a system for producing lipids from the long chain fatty acids designed by the team led by microbiology professor Arnold Driessen. Furthermore, sensors have been developed to measure physical and chemical properties in the cells, such as acidity, ionic strength and macromolecular crowding .

But Poolman and his colleagues still face huge challenges. ‘For example, in the synthetic cell it is very difficult to get anywhere near the concentrations that you find in normal cells of all kinds of molecules.’ Another problem is how to combine different components and get them to work at the right time. ‘We might be able to fuse a number of synthetic cells with different properties, and use photochemical switches to control the timing.’

Commitment

The first cell to show signs of real life is unlikely to be fully autonomous. ‘I expect it to be more like an endosymbiont, a cell living inside another cell which provides it with some vital ingredients.’ Even so, if such a cell were able to make its own components and replicate a few times, this would be a phenomenal breakthrough.

What will this work tell us about the origin of life? ‘Not much’, says Poolman. ‘We use today’s biomolecules instead of the simple molecules that may have constituted the first forms of life, so we largely skip the evolutionary process leading towards increasing complexity. But we will uncover basic principles of how life works. It may end up giving us some idea of how life started.’ For example, the synthetic cells underline the importance of high concentrations of biomolecules and why they need to be in close proximity to react. ‘We are tackling very big and challenging questions. Finding answers will be a long-term commitment.’

This is the third part of a series on University of Groningen research into the origin of life and the Universe.
Part 1: New research centre on the origins of life, the universe and everything
Part 2: Evolving molecules point to principles of life

Part 4: The mystery of life’s broken symmetry
Part 5: Life amongst the stars
Part 6: Origins on a computer