Artificial Abiogenesis: creating life from scratch.

It’s alive! Is what Dr Frankenstein shouted upon the successful animation of his monster in the 1931 adaptation of Mary Shelley’s classic .

The Frankenstein story is not so much a story about scientific endeavour as it is a re-imagining of old myths. Nevertheless, like Frankenstein, some scientist hope that science can lead to a level of understanding such that we will be able to create life.

Scientific research is driven by our desire to know how the universe works, see if by looking under the bonnet we are able of making sense of it all. For example, what is “life” is and why are we self-conscious. Many scientists, including myself, believe that both life and conscience are “emerging properties” that spontaneously arise from systems with the appropriate level of complexity. We believe that if we find the mechanism that links the system composition to its function we may be able to learn how to create life and even conscience.

Some computer scientists are developing artificial intelligence which may lead to self-aware computers and robots in the not-to-distant future. But while conscience they may have, it is unclear we could say they are alive.

Although it seems easy to recognise life, to define life in simple terms can be difficult. There have been several historical attempts at formulating an ultimate definition. For example, NASA’s working definition, widely used, states that “Life is a self-sustained chemical system capable of undergoing Darwinian evolution”. A more modern version that is gaining acceptation has been proposed by my fellow countrymen Ruiz-Mirazo, Pereto and Moreno, which states that ‘a living being’ is any autonomous system with open-ended evolutionary capacities. While the definition does not tell us how a living system is meant to look like, it does clearly apply to a living cell but not so much to a computer.

A typical animal cell is incredibly complex from the chemical point of view, full of molecular machines that are much more complex than the most complex computer created. This machinery allows it to respond to environmental changes. For example, they are capable of incorporating matter from the environment (nutrients) and extract the necessary energy to survive and reproduce. They may be also capable of detecting the depletion of a nutrient and move in search of it, or the presence of harmful substances and move away from them. They can associate with other cells, each of them with very specific roles, to create larger, multicellular organisms (as ourselves). In sum, cells, or the multicellular system they are part of, are autonomous.

The way cells reproduce allows for small changes in the cell design to be incorporated so the next generation of daughter cells, or the multicellular organism they are part of, has slightly different abilities. This very fact allows for open ended evolutionary capabilities (or Darwinian evolution), where next generations appear that are better suited for a changing environment.

But how did life started in the first place? In what conditions does autonomous system with open-ended evolutionary capacities form spontaneously?

Advances in molecular biology have opened the possibility of building up functioning cells by putting together the necessary molecular elements. These “artificial minimal cells” typically contain a discrete number of proteins, which provide the essential molecular machinery, and nucleic acids, which provide the template for the production of more proteins and to reproduce.

Research in the development of these minimal cells, a branch of Synthetic Biology, aims to design living cells with tailored functions. These developments could not have happened without an excellent understanding of molecular cell biology. Reciprocally, detailed study of the minimal cells will further increase our understanding of the molecular biology of the cell. Crucially, from the point of view of creating living organism, the components of these artificial cells are obtained either directly from pre-existing cells or, at the very least, copying the design of pre-existing cells. Therefore, this research does not address the question of how life can arise from non-living matter.

A branch of Chemistry has been developing in the last two decades that focuses in studying the behaviour of mixtures of molecules: how they associate with each other, how they react with each other, and how these mixtures change and evolve with time. Termed Systems Chemistry, this branch of chemistry is expected to improve our understanding and our ability to manipulate the behaviour of increasingly complex mixture of molecules, to the extent of allowing the design of nano and micro sized devices with their function programmed within their molecular structure. An early example of what is possible to achieve is illustrated by the artificial molecular machines and motors that have been developed in the last two decades and that led to the 2016 Novel Prize in Chemistry.

Living cells are the ultimate example of what can be achieved with the appropriate level of complexity and molecular programming. Clearly, they are immeasurably more complex than the artificial molecular machines developed so far. However it is hoped that, at the fullest of its development, Systems Chemistry will offer the tools to create, from scratch, devices that are as complex as living cells, based perhaps on molecules that are different to known biomolecules. It is also hoped that the approaches, tools and scientific principles that will be developed in the course of this research will make it possible solving the origin of life (or abiogenesis) problem.

To summarize, Synthetic Biology uses a “Frankenstein Film” adaptation approach to “create” life, where the monster is generated from pre-existing (“dead”) bits of matter. Systems Chemistry on the other hand strives to use the “Frankenstein Novel” approach, where non-living matter is used to generate the monster. It must be noted that, after all, Shelley’s Frankenstein *was* a chemist.

It is not alive. Yet. Certainly, not if built from scratch. In fact, I do not expect it will happen in my lifetime. But I expect that the road towards creating life from scratch will yield cell-like soft robots that, while not quite alive, may be pre-programmed for specific applications. Most promising amongst these applications, and perhaps within our grasp, is that of drug carriers capable of delivering drugs exclusively to the site of the illness (for example, a tumour in cancer), eliminating side effects completely.

In abiogenesis (i.e., origin of life) research, the term protocell is used to describe cell ancestors with various level of complexities, from lipid vesicles (i.e., roughly spherical, cell-sized sacks delimited by a thin membrane composed of simple lipid molecules), to more complex constructs that incorporate some form of primitive DNA or proteins.

The term protocell is being thus used to describe artificial constructs created for the study of abiogenesis (that is, as models of the protocells that are thought to have been involved in the process of abiogenesis). Increasingly, the term protocell is also being used to describe prototypes of cell-like devices outside abiogenesis research. After all, it is a reasonable expectation that the evolution in complexity and efficiency of artificial cell-like devices will somehow mirror the natural process of abiogenesis, which originally led to living cells from non-living matter. I therefore suggest that we use artificial abiogenesis to describe the development of these cell-like soft-mater based nano-robots .

As mentioned above, the formation of the earlier protocells involved the assembly of simple lipid into lipid vesicles in the earlier stages of evolution. Many scientists, including myself, believe that the formation of lipid vesicles is a key step, possibly one of a handful of easily identifiable single chemical events that enabled abiogenesis. The reasoning behind this belief is straightforward: in lipid vesicles a membrane separates a small region of space that can keep together the essential components of a protocell. The membrane is semipermeable, allowing the incorporation of chemical from the environment and the release of unwanted waste products.

Other properties of lipid vesicles are being found that support their central role in abiogenesis. For example, recent research, including from my own lab[1],[2], strongly suggest that the properties of the inner compartment of a vesicle offer the optimal environment for the formation and accumulation of complex molecules from simple ones, and essential step in the formation of proteins and nucleic acid polymers, while promoting molecular self-assembly, a phenomenon that could ultimately enable the assembly of complex molecular machines.

But I am getting ahead of myself…

Next: Life and thermodynamics