Scientists Find Smallest Number Of Genes Needed For Organism's Survival

Using a technique known as global transposon mutagenesis, Dr. Clyde A. Hutchison III, professor of microbiology at the UNC-CH School of Medicine, and colleagues at The Institute for Genomic Research (TIGR) in Rockville, Md., found that roughly a third of the genes in the disease-causing Mycoplasma genitalium were unnecessary for the bacterium's survival.

The technique -- a process of elimination -- involved randomly inserting bits of unrelated DNA into the middle of genes to disrupt their function and see if the organism thrived anyway.

Such research is a significant step forward in creating minimal, tailor-made life forms that can be further altered for such purposes as making biologically active agents for treating illness, Hutchison said. More immediately, it boosts scientists' basic understanding of the question, "What is life?"

"Cells that grow and divide after this procedure can have such disruptive insertions only in non-essential genes," he said. "Surprisingly, the minimal set of genes we found included about 100 whose function we don't yet understand. This finding calls into question the prevailing assumption that the basic molecular mechanisms underlying cellular life are understood, at least broadly."

Further work will explain those functions and create a more exact number of the minimal genes required to create life in the laboratory, the scientist said. New organisms bearing only the fewest genes needed to survive could have major commercial, social and ethical implications.

A report on the research appears in the Dec. 10 issue of the journal Science. Besides Hutchison, authors are Drs. Scott Peterson (Hutchison's former student), Steve Gill, Robin Cline, Owen White, Claire Fraser and Hamilton Smith, all of the institute, and Craig Venter, who founded TIGR and now heads Celera Genomics.

"Defining the minimal genome is a very fundamental problem, and no one else seems to be approaching it experimentally," said Nobel Prize winner Hamilton Smith, who was a TIGR investigator when the work began.

A genome is the complete set of genes, or genetic blueprints, an organism contains in each of its cells. The human genome is about 5,000 times larger than that of Mycoplasma genitalium, which causes gonorrhea-like symptoms in humans. Scientists study it in part because it contains only 517 cellular genes, the fewest known in single-celled organisms.

"The prospect of constructing minimal and new genomes does not violate any fundamental moral precepts or boundaries, but does raise questions that are essential to consider before the technology advances further," wrote Dr. Mildred K. Cho of the Stanford University Center for Biomedical Ethics and colleagues in an accompanying Science editorial.

"How does work on minimal genomes and the creation of new free-living organisms change how we frame ideas of life and our relationship to it?" Cho said. "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 demonize this fundamental research may be irresistible," she said. "However, the scientific community and the public can begin to understand what is at stake if efforts are made now to identify the nature of the science involved and to pinpoint key ethical, religious and metaphysical questions..."

Hutchison was co-inventor of a technique known as site-directed mutagenesis, which is now used by researchers around the world for introducing designed changes into genes. His friend and colleague Dr. Michael Smith of the University of British Columbia won a Nobel Prize for the work in 1993.

TIGR is non-profit research institute founded in 1992. Its researchers conduct structural, functional and comparative analyses of genomes and gene products in viruses, bacteria, other microorganisms, plants, animals and humans and has pioneered determining the sequences, or structures, of genomes.