Life is complex, we can agree. But millions of years ago, it was merely a bunch of chemical reactions, bubbles and lots of luck. Bearing that in mind and after having studied the vast domains of extant life, biologists have dared to formulate a brave question: are we capable of creating life?

Synthetic biology usually follows one of two major approaches to face questions [1]. The first one is commonly referred as the ‘top-down’ scheme, where we modify existing organisms, genetic circuits and molecules to obtain specific functionalities. This is the best-known part of our discipline and it has already provided the majority of breakthroughs within the field. But there is a second, complementary path, yet to reach its full potential. This approach is devoted to creating life from scratch.

What is this ‘bottom-up’ synthetic biology about and what can it provide for science and society? If the discipline was born with its ‘top-down’ twin, why is it behind in development?

LEGO in hard mode

The bottom-up perspective seeks to devise new cell-like entities by putting smaller non-living elements together. But in order to start building something we need to properly identify and characterise the building blocks we plan to use. This is a truly interdisciplinary task, since these modules can be either non-biological, such as polymers, electronic components and minerals; or biological, such as lipid layers, genetic material and protein complexes [2]. In addition, the combination of these building blocks also requires an exhaustive methodology, involving emulsion and hydration stages, vesicle formation procedures or microfluidics.

At this point, we face the first great issue in the path of building artificial cells. To harmonize these building blocks it is necessary to comprehend the organisational complexity of life itself. Biological systems are structured in a hierarchical and compartmentalised way to optimise energy and resources as much as possible. In order to build an artificial cell, it is not enough to just put pieces together: we need to do it following a compartmentalised distribution. And this task becomes near impossible if we don’t know how our modules behave both collectively and independently.

Despite the rough big picture, there have been striking breakthroughs in this area. A good example of encouraging results is the work developed by James W. Hindley and his colleagues, who have designed a protocol to obtain cell-like structures that can interact with their surroundings [3].

Better than the original?

There are many reasons to exploit the possibilities of building artificial cells rather than relying solely on top-down approaches. The most obvious one is that this approach provides useful tools to decode the drivers behind the origin of life in its early days on Earth. In fact, analysing how our pieces must be assembled to construct a cell-like structure is remarkably similar to studying how the first cells emerged.

Another good reason to invest in creating artificial cells is its simplicity. Despite following the analogy of “creating life”, the reality is that, ultimately, artificial cells do not have the same level of complexity as their original siblings in terms of composition and metabolism. Since they do not need to use energy for secondary processes, artificial cells provide simpler environments to study biological phenomena and to engineer more controlled and efficient functionalities in clinical, agricultural or environmental frameworks.

This simplicity may lead to a final advantage: regulatory and security benefits. Due to the difficulty of mimicking the complexity of life, artificial cells do not necessarily fall into the same categories than the biological ones, since, for now, they are not completely autonomous beings and they cannot self-replicate. This could facilitate policymaking and social-related issues when trying to transform some of these concepts into real-world applications.

The promising long road ahead

Although we are not yet at the stage of routinely producing artificial cells in the lab, there have been striking results. Several international consortiums and research groups are establishing powerful synergies to pave a solid ground that will improve bottom-up approaches. Standardisation will be a central topic once the whole field reaches a more mature stage, since referential protocols and well-characterised building modules will accelerate and facilitate upcoming milestones.

Although these breakthroughs belong to the ‘bottom-up’ approach, we cannot ignore the potential of combining them with top-down schemes. Also, cell-free synthetic biology is opening new ways of working with building modules, changing some of the above-mentioned rules [5] [6].

In any case, we are still at a rather naïve stage of this path. Apart from the technical challenges, there are lateral conceptual and ethical discussions around the “alive” condition that might modulate the final landscape for artificial cells.

Perhaps most importantly, we are still starting to understand the basic components of life, millions of years after it appeared. Ironically, those same components that already succeeded in the same task we are trying to finish.



[1] Elani, Y. (2021). Interfacing living and synthetic cells as an emerging frontier in synthetic biology. Angewandte Chemie International Edition, 60(11), 5602-5611

[2] Cho, E., & Lu, Y. (2020). Compartmentalizing Cell-Free Systems: Toward Creating Life-Like Artificial Cells and Beyond. ACS Synthetic Biology, 9(11), 2881-2901.

[3] Hindley, J. W., Zheleva, D. G., Elani, Y., Charalambous, K., Barter, L. M., Booth, P. J., … & Ces, O. (2019). Building a synthetic mechanosensitive signaling pathway in compartmentalized artificial cells. Proceedings of the National Academy of Sciences, 116(34), 16711-16716.

[4] Jeong, S., Nguyen, H. T., Kim, C. H., Ly, M. N., & Shin, K. (2020). Toward artificial cells: novel advances in energy conversion and cellular motility. Advanced Functional Materials, 30(11), 1907182.

[5] Lu, Y. (2017). Cell-free synthetic biology: Engineering in an open world. Synthetic and systems biotechnology, 2(1), 23-27

[6] Olivi, L., Berger, M., Creyghton, R. N., De Franceschi, N., Dekker, C., Mulder, B. M., … & van der Oost, J. (2021). Towards a synthetic cell cycle. Nature Communications, 12(1), 1-11