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The New Biological Synthesis

By Clyde A. Hutchison III, Hamilton O. Smith, and J. Craig Venter FEATUREIs This Life? The New Biological Synthesis It's time to rewrite life's operating system Anything beyond the minimal gene set can be viewed as add on functions to improve adaptability and metabolic versatility. From top to bottom: Clyde A. Hutchinson is a distinguished investigator, Hamilton Smith is scientific director, and J. Craig Venter is

By | January 1, 2006

FEATURE
Is This Life?
The New Biological Synthesis

It's time to rewrite life's operating system



Anything beyond the minimal gene set can be viewed as add on functions to improve adaptability and metabolic versatility.
From top to bottom:
Clyde A. Hutchinson is a distinguished investigator, Hamilton Smith is scientific director, and J. Craig Venter is president of the J. Craig Venter Institute in Rockville, Md.

Synthetic biologist views the genome as the cell's operating system. The hardware, including ribosomes and other parts of the translational and transcriptional apparatus, carry out the instructions contained within this OS. Traditional genetic techniques have allowed us to alter the code and alter the cell in useful and informative ways, but these are limited to manipulation of existing sequence. With a synthetic genome, this limitation disappears. Dramatic alterations of genetic content and arrangement become possible, and totally novel designer genes can be included. Designing and building synthetic genomes that function properly will be a true test of our understanding of cellular molecular biology.

At the Venter Institute we are designing and building a synthetic version of the Mycoplasma genitalium genome. With only 482 protein-coding genes and 43 RNA genes, this bacterium is the simplest known cell capable of independent growth and replication. Importantly, its 580-kilobase circular chromosome is small enough to be manipulated in vitro. We have divided the chromosome into gene cassettes, each of which is being made from chemically synthesized oligonucleotides. We are designing several versions of each cassette such that combinatorial assembly into a complete chromosome would result in millions of different genomes. These genomes can be tested for functionality by "genome transplantation," replacement of a cell's resident chromosome by a new one.

We are also working toward the construction of synthetic cells pieced together from various subcellular into a complete chromosome would result in millions of different genomes. These genomes can be tested for functionality by "genome transplantation," replacement of a cell's resident chromosome by a new one.

We are also working toward the construction of synthetic cells pieced together from various subcellular components. It may be possible to "boot up" a genome in a cell-free environment, if it contains the necessary transcriptional and translational machinery to express genes. Once other parts of the cell are manufactured, enclosure in lipid vesicles in an appropriate nutrient environment may allow the formation of truly synthetic cells.

One of our initial goals is to build a minimal cell. What is the least number of gene functions for a viable cell, in a defined laboratory environment? The question is of fundamental importance because practically every cell must have those minimal functions. When we fully understand this minimal set it should be possible to build a computer model that accurately predicts cellular behavior. Our studies indicate that about 100 genes from M. genitalium are dispensable, one at a time. But we don't know if a cell would be viable when all 100 are removed. Using the synthetic approach we are building reduced genomes lacking subsets of the identified dispensable genes. The genomes will be tested by genome transplantation.

Anything beyond the minimal gene set can be viewed as add on functions to improve adaptability and metabolic versatility. Once obtained, the minimal cell could serve as a platform for adding on useful functions. These would include gene pathways for production of industrial organics, biofuels, and pharmaceutical compounds that are difficult to synthesize in the laboratory. The genomics age has given us an unprecedented view of life's underlying code. Synthetic biology will give us the power to rewrite it.

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