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Scientists try to discover how many genes are necessary to build a living organism

Deborah Josefson San Francisco

Scientists from the Institute of Genomics Research, in Rockville, Maryland, have taken a significant step towards answering the age old question, "What is life?" by defining the minimal genomic sequence essential for a functional organism.

The research sets the stage for creating a living organism in the laboratory and opens up a host of ethical, legal, biomedical, and environmental considerations.

The researchers, led by Clyde Hutchinson III, Scott Peterson, and Craig Venter from the institute, and colleagues at the University of North Carolina at Chapel Hill tried to define the minimal DNA sequence necessary to maintain cellular function for an organism under laboratory conditions (Science 1999;December 10;286:2165-9).

To do so, they started with the bacterium Mycoplasma genitalium, a bacterium which has the smallest known fully sequenced genome and is only 580 kilobase (kb) pairs long. A total of 517 genes are encoded in these base pairs, of which 480 encode proteins and an additional 37 represent genes for RNA species.

The researchers sought to determine which of these genes were essential for life by a knockout approach and through genomic comparison to a related species, Mycoplasma pneumonia. M pneumonia is 816 kb long and shares about 65% of its coding sequences with M genitalium. The investigators hoped to test whether the 480 genes shared by the two organisms represented the minimal genome essential for life.

The scientists estimated that only about 300 of the 517 genes in M genitalium were essential for life. Intriguingly, nothing is known about the function of 111 of these essential genes.

There were also some surprises in that some genes thought to be essential, such as those coding for some transfer RNA’s, were found to be dispensable.

This raises the question of functional redundancies among remaining genes and challenges us to re-examine what we think of as essential function and known roles for certain elements. The scientists note that the "essential gene set is not the same as the minimal genome and that it is clear that genes that are individually dispensable may not be simultaneously dispensable."

One should also keep in mind that the minimal genome defined by the team was one that could exist in laboratory conditions, but not necessarily independently in a "wild type" environment.

Commenting on the work, Dr Venter and Dr Claire Fraser said that "it was very humbling to find out that as a scientific community we do not understand even the basic elements essential for cellular life and nothing is known about the function of a third of the genes thought to be essential."

The researchers intend to further the study by creating an artificial chromosome, which would contain the minimal gene set, and seeing whether a self replicating organism would result. Such an endeavour, if successful, would be tantamount to creating life artificially from scratch, from its genetic blueprints. Because of the controversial nature of such a process, before proceeding with this experiment, the institute team sought guidance from a biomedical ethics council, which they funded through a grant.

In a related editorial, the ethics committee, dubbed the Ethics of Genomics Group, found no principal reason for not proceeding with such research and found that tampering with nature has been a historic human activity and there was nothing inherently wrong with it.

The team, led by Mildred Cho of Stanford University and Arthur Caplan of the University of Pennsylvania, however, cautioned against a reductionist view of life that a minimal genome might imply, and emphasised safety as well as beneficial utility issues.

The committee found that the research could provide insight into the origins of life, as well as providing advances in microbial and genetic engineering that have important health consequences.

For instance, antibiotic resistance may be avoided and bacteria constructed to clean up environmental hazards based on a better understanding of genomic function. They dismiss concerns of "playing God" as unethical.

The committee further found that law and ethics unfortunately lag behind technological advances and called for a coalition of theologians, religious leaders, scientists, and legal experts to be proactive about constructing a social policy regarding such research.

They conclude: "How does the work on minimal genomes and the creation of new free living organisms change how we frame ideas of life and our relationship to it? How can the technology be used for the benefit of all and what can be done in law and social policy to ensure that outcome.

"The temptation to demonise this fundamental research may be irresistible…efforts must be made now to identify the nature of the science involved and to pinpoint key ethical, religious and metaphysical questions so that debate can proceed apace with science. The only reason for ethics to lag behind this line of research is if we choose to allow it to do so."  
 

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