Just as the Institute for Genomic Research (TIGR)'s decade-long Human Genome Project, and its rival Celera Genomics, slide into home plate with their efforts to sequence the human genome, other genome research is heating up. In March, Celera and its collaborators finished sequencing the Drosophila genome. Some scientists have commented that this work represents "a landmark achievement that marks the end of a century of gene hunting and heralds a new era of exploration and analysis" [1].

The project has two parts: in the first phase, scientists are taking a "top-down" approach to determine how many and which of the 517 genes of Mycoplasma genitalium (the smallest gene complement of any independently replicating organism) are necessary for life. To date, analyzing about 2,000 transposons, they have found that only 265 to 350 of the 480 protein-coding genes in the organism are essential for growth in the lab. Next, researchers plan to retest the genome, this time analyzing 10,000 transposon insertions to derive a more precise list of the necessary genes, said Scott Peterson, associate investigator at TIGR and one of the authors of the paper.

But the most unique and challenging part to the research is still to come: the second major phase. Still in the planning stages, TIGR currently is seeking funding: scientists will take a "bottom up" approach, using data gleaned in the first phase, to synthesize a live organism from the ground up.

Acknowledging the sensitive and controversial nature of this phase - creating an altogether new, minimal genome organism - TIGR decided to ask for guidance, and brought a bioethics working group on board to help delve into the ethical, societal, and legal implications of the work. The 15-member multidisciplinary Ethics of Genomics Group represents thinkers, not only in bioethics, but also in sociology, theology, science, anthropology, and philosophy. The group has received an unrestricted grant from TIGR to meet several times a year and work together to write their views about the research. The group's first paper was published in December in Science [3] concurrently with TIGR's account of its research.

"This is an effort to do proactive bioethics, to think through issues before the science is done," says Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania and a member of the Ethics of Genomics Group. The group's mandate is to help present the issues to the public and also to try to respond to some of the questions this work engenders, such as:

(1) Is creating a minimal genome tantamount to playing God?

(2) Should scientists attempt to create life in a test tube?

(3) Might a totally new organism, if developed, harm the environment or be used to create bioweapons?

Whether or not the research moves forward - TIGR is currently seeking funding to continue the project - the fact that scientists engaged in controversial research are willing and, indeed, anxious to receive input from society and some of its best thinkers is more than a first, more than noteworthy - it is revolutionary. Perhaps it marks the beginning of the end to past paternalism in science, in which scientists kept their own counsel and then presented society with the "fruits" of their work, asking questions later or, as in the case of the atomic bomb, too late.

"We are approaching our work differently from the way Dolly was introduced to the public - before it's a done deal," said Scott Peterson. The Ethics of Genomics Group's partnership with TIGR could serve as a model for other efforts that reflect a partnership between science and society, in which implications of the research are examined and evaluated before the work is done.

This partnership is a first and may well serve as a model. In publishing its first article at the same time the preliminary research is published, the ethics group and TIGR hope to create public reflection and discussion about the scope and use of the technology long before it is too late. If the second phase does move ahead, estimates are that it could take 10-15 years to complete the research.

"The great difficulty for truly proactive bioethics is that it requires that scientists recognize their research may have profound implications for society and be willing to invite discussion, reflection, and commentary before their work has progressed very far," said David Magnus, committee member and professor of bioethics at the University of Pennsylvania. "In order for these questions to be of value, they must be based on facts and grounded in a detailed understanding of the cutting-edge science."

The idea behind the group's discussions and publications is that "it is better that the work be done in the context of an open dialog, rather than in secret, without discussion," said theologian Daniel McGee, professor of religion at Baylor University.

If it decides the work should be halted, can the group end it, and will scientists listen? "Possibly," says Art Caplan. "Or we might be able to slow it down some." The group concluded that creating a minimal genome does not transgress religious or moral precepts and that the work "would represent an important step forward in genetic engineering . . ." A newly created genome could be used as a basis for "designer" bacteria that could break down environmental toxins.

The group's most pressing concern is that the research will be interpreted to mean that life can be reduced simply to an organism's genetic components. "Reducing life to genes has profound implications for several critical societal debates, including what constitutes human life and when life begins," the group writes. Implicit in the scientific research itself is a reductionist view, stresses lead author Mildred Cho, senior research scholar, Stanford University Center for Biomedical Ethics. "TIGR's work itself is a culmination of hundreds of years of scientific inquiry about what is the smallest component of life, what makes something alive?" said Cho.

"We are not critical of making reductionist assumptions as a starting point to do the science itself," Magnus agrees. "However, we do believe that it's a mistake to believe you've shown that life is nothing but a bunch of genes." When scientists discuss their work, they should be careful in the public setting not to speak as if their work defines life in its totality, adds Cho. What is life's most defining component - reproduction, metabolism, or genes? Scientists continue this debate.

It is important to note that while many scientists hold reductionistic views, such as reducing life to a number of physical components, some, like Peterson, do not. "Regarding the project's second phase, I'm quite certain that I'm not creating life," Peterson said. "It is vital that the media do not transmit the message that we are 'creating life in a test tube.'"

TIGR hopes to avoid the problems that occurred with other controversial science conducted intentionally out of the public's eye. TIGR hopes that the public will view its research favorably and believes it is necessary to work with the ethics group to receive its input and to take it seriously. "After all, I am not perfectly capable of being objective about my own work," Peterson said.

Most scientific research does not have what Peterson dubs "the double-edged sword" - the potential for extreme good and extreme destruction, which makes outside input into the research even more important. However, he believes that a critique of the science on the basis that it could further the creation of new bioweapons is not persuasive. "Anyone who wants to wreak biological destruction doesn't have to go to these lengths to do it," said Peterson. That said, "It doesn't get us off the hook from worrying about it."

"We need to understand that science is moving fast," Peterson concludes. Bringing this work to the public's eye will encourage legislation to be enacted to limit the research or its application - and that is a good thing," he acknowledged. Similarly, at the end of March, Francis Collins announced that the human genome sequence is close to completion. "The time to implement protection for the public is now," said Peterson. "If our work helps wake people up to this reality, that is a good thing."