Last, if the global features of terran life reflect nothing more than the common ancestry of the life that we know, we could infer little from a study of life on Earth about the nature of alien life that does not share an ancestry. Indeed, as Cleland and Copley have recently discussed,1 it is conceivable that Earth harbors yet undiscovered forms of life that are not related by common ancestry to the life that we know, have quite different biochemistry, and may have been overlooked for precisely that reason.


The goal of synthetic biology is to create a more comprehensive understanding of life by integrating different areas of research, such as engineering, physics, and chemistry, so as to design and construct novel biological and biochemical functional systems. Since biological systems are composed of organic compounds, synthetic biology has become more connected to synthetic chemistry (the shift from studying nature’s chemistry to the design and synthesis of new chemistry). The result is novel biochemistry. One area of current emphasis in synthetic biology that is germane to this report is the design and synthesis of new biochemicals that can lead to the synthesis of novel but functional structural, informational, and catalytic biochemical systems. Significant progress has also been made using synthetic biology approaches to origin of life studies and particularly in designing biochemical systems that might better reflect early stages in the synthesis of information macromolecules, replicators, and cell-like structures. One of the goals is to find alternative biochemical systems that undergo evolution.

The committee considered a variety of approaches to determine whether the biochemical structures found in terran life are unique. One was derived from synthetic organic chemistry and is sometimes referred to as synthetic biology.2,3 Much of contemporary biological research deconstructs living systems, but the ability of chemists to synthesize new forms of matter (i.e., new arrangements of atoms in new molecules) offers an alternative approach, especially if the aim is to ask whether alternative chemistries can support biomolecular function. It is possible for chemists to synthesize alternative chemistries, to ask Why not? and What if? questions about biomolecular structure, and to determine whether the alternative structures might function as alternative genetic molecules, membrane components, catalytic species, or metabolites. That is directly related to the question, Are the biomolecular structures that we know in terran life the only structures that can possibly meet the functional demands of living systems?

Terran Nucleic Acids Are Not the Only Structures That Can Support Genetic-like Behavior

In some cases, direct experimental evidence shows that the molecules found globally in terran biochemistry are not the only structures that can perform the functions that they perform in the life that we know. For example, in terran DNA, the Watson-Crick nucleobase pairs obey two rules of complementarity: size complementarity (large purines pair with small pyrimidines) and hydrogen-bonding complementarity (hydrogen-bond donors from one nucleobase pair with hydrogen-bond acceptors from the other). Those rules enable the specificity that gives rise to the simple rules for base pairing (A pairs with T, G pairs with C) that underlie terran genetics and molecular biology.

It is possible through synthesis to show that the DNA alphabet is not limited to the four standard nucleotides known in terran DNA.4,5 Rather, 12 nucleobases forming six base pairs joined by mutually exclusive hydrogen-bonding patterns are within the geometry of the Watson-Crick base pair. Figure 4.1 shows some of the standard and nonstandard nucleobase pairs and the nomenclature to designate them. Those nucleobase analogues presenting nonstandard hydrogen-bonding patterns are part of an artificially expanded genetic information system (AEGIS).

On the basis of simple binding studies, it is clear that the AEGIS components work as well as the natural nucleotides. Each nucleotide pairs with its partner, and mismatches between the 12 destabilize the duplex about as much as mismatches between the standard four nucleotides. Indeed, the specificity of the synthetic biological genetic molecules is so good that they are incorporated into diagnostic tools that first received Food and Drug Administration approval in 2002. Each year, artificial genetic molecules exploiting an expanded genetic alphabet improve the health care of some 400,000 patients infected with HIV or the hepatitis B or hepatitis C virus.

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