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Making Life from Scratch

Artificial intelligence is not human intelligence, nor is synthetic life the same as life with evolutionary history.

Robert L. Dorit

Brewing a New Genetics

2013-09MargDoritF2.jpgClick to Enlarge ImageTrading on the multiple meanings of the word synthetic, two radically different approaches to synthetic biology have emerged, each of which embodies different assumptions about the living world and about the goals of the field.

The first of these approaches, sometimes called bottom-up or de novo, seeks to synthesize new kinds of cells from scratch. This strategy addresses a profound—literally, a fundamental—question in biology: To what extent is the history of life on this or any other planet constrained by the chemistry of the building blocks of life?

For a long time, questions about alternative unfoldings of the history of life were no more than the stuff of late-night musings at scientific meetings. But my colleagues and I knew the questions to be profound and not merely abstract. Over the past two decades, scientists have begun seriously investigating alternative chemistries and organizations for living systems on other planets. This effort has gained importance as astronomers have intensified the search for life on Mars, and as the estimate of potentially habitable planets in the Solar System and beyond continues to expand. If the only life known (that on Earth) is but one of many conceivable ways of building what is called a cell—a system capable of evolving—th

en scientists risk overlooking life forms that do not exhibit the signatures of Earthlike life.

2013-09MargDoritF3.jpgClick to Enlarge ImageIn the past, my colleagues were confined to raising such issues without being able to address them experimentally. After all, life reflects its single common origin by relying on nucleic acids (RNA and DNA) for the preservation and transmission of information and on proteins for most of its essential molecular functions. Everything, in every cell of every organism on this planet, evolved in response to these fundamentals. There were quite literally no alternatives on Earth to study.

The lack of points of comparison did not daunt us, however. Instead, a number of labs decided to address the question by chemically synthesizing novel building blocks—modified amino acids and new nucleotides—and exploring how these new chemistries might throw open previously closed evolutionary pathways. This synthesis approach proved to be no simple undertaking: Aberra

nt amino acids and nucleotides occasionally arise spontaneously in living cells, but they are always bad news for a healthy cell because they can cause misfolding of proteins or stop replication in its tracks. As a result, multiple systems have evolved in all organisms precisely to guard against the incorporation of such novel building blocks into the cell’s nucleic acids and proteins. But over the past decade, experimental imagination and persistence have enabled investigators to select variants of existing molecular machinery that can work with these new building blocks. In so doing, my colleagues have succeeded in adding new text to that Rosetta Stone of living systems, the genetic code. New or modified nucleotides expand the canonical A–T and G–C DNA pairings, thus increasing the potential number and nuance of hereditary information. For instance, two novel nucleotides, called NaM and 5SICS, have recently been shown to pair (albeit in an unusual way) within the DNA double helix and can be replicated by the cell’s machinery. These novel nucleotides have novel geometries and hence differ slightly in how they pair with their counterparts across the DNA double helix. Similarly, the expansion of the amino acid vocabulary beyond the 20 or so amino acids normally encountered in living organisms, in turn, makes possible the synthesis of proteins with novel stabilities, architectures, and functions. 2013-09MargDoritF4.jpgClick to Enlarge Image

These are early days still, but new building blocks with unique properties continue to be synthesized. At the same time, they remain compatible with the roles played by existing nucleic acids and proteins. These results already make one thing clear: Th

e world of naturally occurring genetics here on Earth is certainly not the only possible world.

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