In schools all over the world students learn that the secrets of life are encoded in the DNA molecule. Mainstream science is a true believer in DNA as the only stable genetic information storage, and understanding and modifying this monopolistic biopolymer has become the ultimate goal in contemporary bio-based R&D. Some scientists, however, have started to search for alternatives. They belong to apparently very different science fields and their quest for biochemical diversity is driven by different motivations.1–3 The science fields in question include four areas: origin of life, exobiology, systems chemistry, and synthetic biology (SB). The ancient Greeks, including Aristotle, believed in Generatio spontanea, the idea that life could suddenly come into being from non-living matter on an every day basis. Spontaneous generation of life, however, was finally discarded by the scientific experiments of Pasteur, whose empirical results showed that modern organisms do not spontaneously arise in nature from non-living matter. On the sterile earth 4 billion years ago, however, abiogenesis must have happened at least once, eventually leading to the last universal common ancestor (LUCA). LUCA's genetic code must have been based on DNA with four bases that form the three-nucleotide codons coding for 20 amino acids.4, 5 The origin of life community tries to understand the processes of abiogenesis that caused LUCA (and all known life forms on earth) to use exactly this chemistry and this code to store genetic information. Why did it happen this way and not another? Some researchers have even proposed the idea that there could also be other more exotic life forms. Such postulated weird life could be a remnant of a different (earlier or even later) abiogenesis on earth. If it were to exist, it could be distinguished by its reliance on different chemical processes, biochemical building blocks, codes, or metabolism. In contrast to the earth-bound origin of life community, astrobiologists search for (unusual) life forms beyond Earth. Many people will have heard media reports about the Search for Extra-Terrestrial Intelligence (SETI) in the universe: the search for signals from extra-terrestrial life forms capable of sending them. Meanwhile, there is another less-known aspect of astrobiology. In this second field of activity, called exobiology, the aim is to search the solar system for evidence of non-intelligent life forms (such as microbes). On some celestial bodies “alien” life forms may have developed, say through the use of a solvent other than water or the use of very different chemical elements, e.g., silicon rather than carbon.6 Of course, there could also be other possibilities such as variations in the tripartite DNA-RNA-protein architecture found in earth life forms.7 Another research field that explores unnatural biochemical systems or biological subsystems is systems chemistry, that includes research on chemical self-organization, self-replicating, and self-reproducing chemical systems.8, 9 While systems chemistry looks at the chemical level, SB is the design and construction of new biological systems not found in nature. SB aims at creating novel organisms for practical purposes, but also at gaining insights into living systems by re-constructing them. SB is developing rapidly as a new interdisciplinary field, involving microbiology, genetic engineering, information technology, nanotechnology, and biochemistry. SB as a scientific and engineering field includes the following subfields:3, 10–12
Engineering DNA-based biological circuits, including but not limited to standardized biological parts;
Defining a minimal genome/minimal life (top-down approach);
Constructing so-called protocells, i.e., living cells, from scratch (bottom-up approach);
Production of gene fragments and genes by DNA synthesis machines; and
Creating orthogonal biological systems based on a biochemistry not found in nature.
So far most SB scientific papers and conference presentations deal with engineering biological circuits and finding the minimal genomea. Less attention has so far been placed on protocells and orthogonal systems; however, some excellent work has been carried out by a couple of very dedicated research groups.13–18 Protocell research aims to identify ways to produce life out of non-living matter, trying to understand the origin of life and identify new biotech production systems. Researchers working on orthogonal biological systems, on the other hand, try to alter the basic biochemical building blocks of life, such as the nucleic acids or the bases used to encode genetic information.
What the origin of life research community, exobiologists, system chemists and synthetic biologists have in common, is the view that unusual life forms – in other words: xenobiology – could either be found on or beyond Earth, or be deliberately created in the laboratory (Fig. 1). The most obvious difference between them, however, is that the origin of life community and astrobiologists are more interested in “understanding” why life has evolved as it is, while most synthetic biologists are interested in “applying” engineering principles to create unnatural life forms for useful purposes. This paper deals with SB and its attempt to create orthogonal biological systems based on a biochemistry not found in nature.