How can non-living molecules combine to create a living cell?
This is a fundamental question in science: how do non-living molecules come together to form a living cell? Bert Poolman, a Biochemistry Professor at the University of Groningen, has been exploring this question for more than twenty years. His research aims to comprehend life by attempting to recreate it; he is constructing simplified artificial models of biological systems that serve as building blocks for a synthetic cell. Recently, Poolman published two papers in Nature Nanotechnology and Nature Communications. In the first paper, he outlines a method for energy conversion and the sharing of products generated from this reaction between synthetic cells. In the second paper, he presents a system for concentrating and converting nutrients within cells.
Six Dutch research institutions are collaborating in a consortium called BaSyc (Building a Synthetic Cell) to develop the components necessary for a synthetic cell. Poolman’s team is focused on energy conversion. The natural equivalents he aims to replicate are mitochondria, often referred to as the cell’s ‘energy factories.’ These organelles use ADP to create ATP, which cells rely on as their primary energy source. When ATP is converted back to ADP, it releases energy, which is then utilized for various cellular processes.
Artificial energy factories
‘Unlike the hundreds of components found in mitochondria, our energy conversion system requires only five,’ Poolman explains. ‘Our goal was to simplify it as much as possible.’ This may seem surprising, given that evolution has successfully created functional systems. However, Poolman notes, ‘Evolution is a one-directional process that builds on existing elements, often leading to complex results.’ In contrast, an artificial model can be designed to achieve a specific goal.
The five components were placed within vesicles—tiny cell-like structures—capable of absorbing ADP and the amino acid arginine from their environment. The arginine undergoes deamination or ‘burning,’ generating the energy needed to produce ATP, which is then released from the vesicle. ‘The trade-off in this simplification is that we can only use arginine as the energy source, whereas living cells utilize a variety of molecules, including different amino acids, fats, and sugars.’
Following this, Poolman’s group created a second vesicle that can absorb the ATP released, using it to power an energy-requiring reaction. The energy is released when ATP is converted back into ADP, which can then be secreted and taken up by the first vesicle, completing the cycle. This continuous cycle of ATP production and consumption serves as the basic mechanism for metabolism in all living cells and powers energy-demanding processes such as growth, cell division, protein synthesis, and DNA replication.
An artificial pumping system
The second module Poolman developed is quite different: it consists of a vesicle where a chemical process creates a negative charge inside, generating an electrical potential, similar to that of an electronic circuit. This electrical potential helps facilitate the movement of charged particles and the accumulation of nutrients within the vesicle via transporters. These proteins in the vesicle’s membrane function like a water wheel, allowing positively charged protons to flow from the outside into the negatively charged interior. This flow propels the transporter, enabling the import of a sugar molecule, lactose. Again, this is a common procedure in living cells, which usually requires many different components; however, Poolman and his team managed to replicate it with only two components.
When Poolman submitted the paper detailing this system, a reviewer suggested he utilize the transported lactose, as living cells convert nutrients into useful building blocks. Poolman accepted the challenge and incorporated three additional enzymes, which oxidized the sugar and led to the production of the coenzyme NADH. ‘This coenzyme is crucial for the proper functioning of all cells,’ Poolman emphasizes. ‘By introducing NADH production, we’ve demonstrated that it’s feasible to expand the system.’
But what about the synthetic cell?
While having a simplified synthetic counterpart of two essential life functions is intriguing, additional steps are necessary to integrate them into a self-sustaining synthetic cell that can grow and divide autonomously. ‘Our next objective is to combine our metabolic energy-producing systems with a synthetic cell division system developed by our colleagues,’ says Poolman.
The BaSyc program is now in its final years, and recent funding has been secured for a new project. A large coalition of Dutch researchers, with Poolman as one of the leading scientists, received 40 million euros to develop life from non-living components. This EVOLF project is expected to last another decade and aims to explore how many additional lifeless modules can come together to create living cells. ‘Ultimately, this could provide a blueprint for life—something that is currently missing in biology,’ Poolman concludes. ‘This may lead to various applications and also enhance our understanding of life’s nature.’
