concepts

118 NATURE | VOL 421 | 9 JANUARY 2003 | www.nature.com/nature

Steven A. Benner

Over the past two centuries, organicchemists developed their discipline by purifying natural products from

biological systems and determining howthey are assembled from their constituentatoms. As their deconstructive powers grew,chemists targeted larger biomolecules, firstproteins and nucleic acids, and then supra-molecular structures such as the nucleosomeand the ribosome.

Sequencing the human genome repre-sents a culmination, of sorts, of this type ofchemical reductionism. After all, the humangenome is nothing more (and nothing less)than a statement about how carbon, hydro-gen, nitrogen, oxygen and phosphorusatoms are bonded together in the organicmolecules that we inherit.

Traditionally, however, chemists comple-mented deconstruction with a second theme:synthesis. After determining the structure of a new natural product, organic chemistsmade some more of it. At first, chemists usedsynthesis simply to prove that the structureproposed for their natural product was cor-rect. Over time, however, synthesis became astruggle that pits the wits of chemists againstincreasingly complex natural products. Thestruggle forced chemists to discover thingsabout molecules. Perhaps best known are theobservations made during the total synthesisof vitamin B12 that led to theWoodward–Hoffman rules of orbital sym-metry, recognized by the Nobel Prize in 1981.

Chemists next attempted to synthesizemolecular structures that were not identicalto natural products, but reproduced some of the behaviours that natural biomoleculesdisplay. ‘Biomimetic chemistry’, as thisendeavour came to be known,was more thanthe preparation of the plastics,pharmaceuti-cals and other synthetic materials of moderncivilization. The goal became to reproduceadvanced,

dynamic behaviours of biological systems,including genetics, inheritance and evolu-tion. These goals define synthetic biology as a field.

To a synthetic biologist, life is a specialkind of chemistry, one that combines a fre-quently encountered property of organicmolecules (the ability to undergo sponta-neous transformation) with an uncommonproperty (the ability to direct the synthesis ofself-copies), in a way that allows transformedmolecular structures themselves to becopied. Any chemical system that combinesthese properties will be able to undergo darwinian selection, evolving in structure to replicate more efficiently. In a word, ‘life’will have been created.

But what chemical structures combinethese properties? Computer models that simulate replication and evolution in silicoare relatively easy to come by. A computerprogram can suffer mutations and keep onticking.But real molecules often change theirbehaviour dramatically upon even a slightchange in structure. Chemists have in hand amodest number of chemical systems that canfunction as templates for their own synthesis.But those that can suffer mutation and stillhave ‘children’are proving harder to find.

The pursuit of synthetic biology hasalready identified some structural features of natural self-replicating biomolecules thatare crucial to their performance. For exam-ple, the repeating negative charges on DNA’sphosphate backbone allow it to survive mutation while continuing to act as a template for copies. These charges are moreimportant for evolution than the identity of the specific bases that carry the geneticinformation.

From such observations have comeentirely new, artificial genetic systems. Thefirst, created a decade ago, contains 12 basesrather than the four (A, T, G and C) found innatural DNA. The artificial genetic systemcan direct the synthesis of artificial RNA andproteins with extra amino acids. Chemistshave appended functional groups onto synthetic genetic systems, creating a hybrid

biomolecule that can be copied like DNA,but which also carries the functionality

of proteins.In parallel, molecular biologists

have recruited tools from natural systems to generate synthetic evolution inthe test tube. To identify new receptors andcatalysts, libraries of random nucleic-acid

sequences are generated and challenged inan artificial environment. Those that perform well are allowed to direct the synthesis of their copies. Those that fail

are discarded. Chemists and molecular

biologists are now set to merge the two,creating artificial evolution with artificialgenetic systems from synthetic biology.

Synthetic biology is not merely demiurgy.In September, for example, the US Food andDrug Administration approved a diagnostictest that uses artificial genetics to measurethe level of the HIV virus in infected individ-uals.The artificial genetic system allows highsensitivity and remarkable dynamic range,without interference from the natural DNAfound in patient samples, and represents aremarkable step forward in the managementof AIDS as a disease.

Synthetic biology should also help NASAto seek life in its probes of the Solar System.By asking what is possible in the chemistrythat supports life,we are more likely to recog-nize weird life should we encounter it.

Perhaps most important, however, is thevista that synthetic biology offers at the fron-tier between chemistry and biology. Biologyhas been limited by “poke and measure theresponse” research strategies. RecombinantDNA technology allowed biologists to takethe next step through synthesis of differentsequences of natural molecules.

But synthetic biology with ‘bottom-up’design may achieve much more. Building artificial genetic, regulatory and metabolicsystems should offer a new way to learn moreabout genetic, regulatory and metabolic systems in general (and, dare we say it,universally). Thus, in this century, syntheticbiology should aid the discovery of new, uni-versal ideas about biology, ideas that mighthave remained undiscovered using simplyreductionist analyses.Which is what synthesisdid for chemistry in the twentieth century. ■

Steven A. Benner is in the Departments ofChemistry, and Anatomy and Cell Biology,University of Florida, Gainesville, Florida 32611, USA.

FURTHER READINGWoodward, R. B. Pure Appl. Chem. 17, 519–547 (1968).http://www.genarts.com/karl/evolved-virtual-creatures.htmlBain, J. D., Chamberlin,A. R., Switzer, C. Y. & Benner, S. A. Nature 356, 537–539 (1992).http://www.alife.org/index.phpGee, H. Nature 409, 1079 (2001).http://xanadu.mgh.harvard.edu/szostakweb/web.2

Act natural SyntheticbiologyThis burgeoning field aims toreproduce advanced, dynamicbehaviours of biological systems,including genetics, inheritance and evolution.

© 2003 Nature Publishing Group