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Stanford Report, February 21, 2001
Minimal genome research raises thorny questions

BY KRISTA CONGER

As more and more organisms yield their genetic sequences for scientific scrutiny, researchers are coming ever closer to a tantalizing goal: creating a fully functional bacterium from scratch with the smallest number of genes necessary to maintain life. Along with such an endeavor, however, come some thorny questions: Is life defined by genes? Is it ethical for scientists to create new, unique forms of life in a test tube? And perhaps even more importantly, what research paths lie ahead once this task is accomplished?

Biologists, religious leaders, and ethicists grappled with these and other issues in a symposium hosted by Stanford University Medical Center researcher Mildred Cho. The symposium, "Ethical and Policy Implications of Synthesizing 'Minimal Genomes'," was held Tuesday in San Francisco at the annual meeting of the American Association for the Advancement of Science.

"We're hoping this symposium will be part of a continuous forum for public dialog about this research and will stimulate the discussion of new issues," said Cho, PhD, a senior research scholar at Stanford's Center for Biomedical Ethics.

Cho has been involved in ongoing discussions about minimal genome research since scientists studying the bacteria Mycoplasma genitalium first sought the help of bioethicists three years ago. M genitalium has the smallest genome -- encoding 517 genes -- of any known free-living organism. By inserting pieces of nonsense DNA into each gene, scientists inferred that only about 300 are absolutely required for the bacteria to live under laboratory conditions. The discovery makes it theoretically possible to create life in a test tube by mixing these genes with synthetic components that mimic the architecture and machinery of a cell.

When the paper about the minimal requirements of the M genitalium genome was published in the Dec. 10, 1999, issue of Science, it was accompanied by an article authored by Cho and other members of the multi-institutional Ethics of Genomics Group. The article concluded there were no fundamental moral or religious reasons against synthesizing minimal or new genomes, but cautioned that the work raises questions that must be carefully considered as research progresses. "The article's intent was not to answer all the ethical questions involved but to raise the issues for public discussion," Cho said. "I don't think we have all the answers. We're still just figuring out what the questions are, or should be."

Cho said the implications of synthesizing a minimal genome extend beyond the immediate, "What is life?" question. To create life from scratch, scientists would have to know exactly what each gene contributes to the new organism. When combined with the ongoing study of the human genome, such knowledge could spur the development of deadly germs for biowarfare or blur the lines between species.

"For example, researchers are finding differences among humans in their reaction to microorganisms. Sometimes these differences can appear to be racially based," said Cho. This raises the possibility that a unique microorganism could be synthesized to selectively target certain populations while leaving others unscathed, she noted.

Cho also cautioned that scientists could unintentionally create a dangerous organism. She cited the example of a group of Australian scientists who recently attempted to modify the mousepox virus by adding the gene for mouse interleukin-4. The scientists, surprised when a previously resistant strain of mice began dying from the engineered virus, discovered that previous vaccination against the virus was only partially protective. Concerned that the unexpected results could provide a blueprint for terrorist groups seeking to create a deadly biological weapon, the researchers debated whether to release their findings before publishing the results.

Such results make it especially important for both scientists and the public to carefully consider the implications of mixing and matching genes between organisms, Cho said. "Even if you try your best not to do harm, sometimes -- by accident -- you do."

Safety issues aside, mixing genes between species can lead to other ethical quandaries.

"A related question is what makes certain organisms different from other organisms," Cho said. "Right now classification is based on rather primitive physical and metabolical characteristics. But if life is more accurately defined by an organism's genes, how should one classify a hybrid of two species? How many human genes can you add to a monkey before it becomes something you would call human?"