If you thought that designing life was the sole domain of nature or a divine power, think again.
A team of U.S. scientists is reporting that it has constructed the genome of a bacterium for the first time. Assembling bits of lab-made DNA, researchers at the J. Craig Venter Institute in Maryland say they have built the full genetic structure of the living organism from scratch.
The feat marks a historic and controversial milestone in the fledgling field known as synthetic biology. It uses chunks of synthetic DNA like Lego blocks to create life forms that can be genetically programmed to perform useful tasks.
Its proponents envision making micro-organisms that gobble up pollution, produce hard-to-make drugs, pump out clean energy, or, at the whimsical end, flowers designed to bloom on your birthday.
The field has raised profound ethical questions about human control of creation and the potential to produce new weapons of bioterror. But the Venter project is also drawing criticism of a different kind.
Bioethicists and some scientists allege the researchers have applied for such broad patents on their human-made genome that, if granted, they might give the group a monopoly on all synthetic life forms - which some believe will fuel the next industrial revolution.
Until now, researchers had not crossed the technical barriers of putting together the whole DNA sequence of a single living organism, or even stretches of genetic code nearly 20 times smaller. But in a paper published online by the journal Science yesterday, the Venter group says it has done that with Mycoplasma genitalium, a bacterium common to the human reproductive tract.
"It's the largest molecule made by humans. ... We don't know if there is an upper limit now," said co-author J. Craig Venter, the U.S. biologist and businessman who heads the not-for-profit institute. "The broader implications of this work have not been missed by us - we could enter into a new design phase of biology."
The lab-made genome has not so far resulted in a living microbe that functions or replicates. But Dr. Venter said it is just a matter of time before they figure out how "to boot it up" by inserting the synthetic DNA into the shell of another bacterium. (The team showed last year that transplanting the genome of one bacterium inside the casing of another could bring it to life.)
With advances in computer technology, making bits of DNA from scratch has become relatively easy and cheap. Even amateurs can type up genetic code with keystrokes, e-mail it to a commercial lab that spits it out as chemical dots on a glass sheet, synthesizes it, tucks it into a bacterium for transport and returns a live version to the customer.
After the Venter group announcement, the ETC Group, a Canadian-based bioethics watchdog, dubbed the lab-made genome "Synthia" and distributed a statement calling the work "unacceptable."
"While synthetic biology is speeding ahead in the lab and in the marketplace ... there has been no meaningful or inclusive discussion on how to govern synthetic biology in a safe and just way," group member Jim Thomas said.
Dr. Venter, who mapped a private version of the human genome in 2000 and last fall became the first person to have his DNA fully sequenced, is no stranger to controversy and rejected the notion that social debate has been skimpy.
Before his group published the assembly of a viral genome in 2003, Dr. Venter said there were extensive discussions and reviews with bioethicists, the National Academy of Sciences and "every branch of the (U.S.) government." Given fears that the work could be misused to build novel pathogens, Dr. Venter said the government thought about blocking its publication, but decided to move the research forward and keep the technology in the public domain.
Groups and corporations have used synthetic biology to construct new genes that do not exist in nature. But the longer the stretch of genetic code they try to assemble, the more brittle DNA becomes.
The Venter group, which began its work in 1995, opted to assemble a small bug, initially to build the leanest genome possible and determine which genes are essential for life. M. genitalium contains just one circular-shaped chromosome, 517 genes and about 583,000 nucleotides, the chemical units that make up DNA. During a news conference yesterday, the researchers, led by Nobel laureate Hamilton Smith, described the assembly as though it were a laborious jigsaw puzzle that "started with four bottles." Those bottles refer to the four nucleotide chemicals contained in DNA - adenine, cytosine, guanine and thymine.
The genome - the natural version of which the group had already sequenced - was then divided into 101 pieces, Dr. Smith said. Those pieces were then synthesized at three commercial labs before the group figured out a multistep process for putting them all together. Dr. Venter noted that having commercial labs synthesize the pieces cost less than a dollar for each base pair of nucleotides.
Robert Holt, a scientist at the Genome Science Centre of the B.C. Cancer Agency and a former collaborator with the Venter group, called the report "an important technical accomplishment" because the size of the DNA molecule constructed dwarfs previous efforts.
"While they haven't yet shown that their synthetic mycoplasma genome is functional ... it is now feasible to activate a genome by inserting it into an existing cell of the same or closely related organism."
Stephen Davies, an assistant professor of biomaterials and biomedical engineering at the University of Toronto, said the work could be a template for others. "It's not rocket science that they have done. Rather, their achievement is to be the first to build something this large," said Prof. Davies, who works in the synthetic biology field. "Their work clearly demonstrates a way to make whole genomes with good yields ... it would make sense for others to follow this process."
But the ETC Group has likened the Venter group's patent applications to "a bid for extreme monopoly" that could stymie the field.
Prof. Davies said the controversy stems in part from the fact that pioneers of synthetic biology have pushed the new science as an "open-source" technology, with genetic code freely available online. But, he added, it is essentially an engineering field, where patenting is commonplace.
It could be, Prof. Davies said, that the methods of making synthetic organisms should not be patented, only their commercial applications.
Dr. Venter dismissed the allegation of a monopoly grab yesterday, arguing that protecting intellectual property is the norm and lifeblood of most other industries. He said his group would be willing to license its technologies and that there could be other methods to do the work.
He said their accomplishment "paves the way for some exciting next steps."
How they did it
Sequencing
In 1995, the Venter group sequenced the entire genome of Mycoplasma genitalium, a bacterium of the reproductive tract
Breaking into pieces
To produce a synthetic version of the genome, the researchers first broke this sequence into 101 pieces and added a few of their own designs. They disrupted the gene that gives the bacterium its ability to infect and encoded a "watermark" so that they could identify their synthetic version.
Synthesizing
The Venter group relied on three commercial labs to synthesize the 101 DNA pieces, each one between 5,000 and 7,000 base pairs in length.
Connecting ends
Each piece was designed to overlap at the ends where they could connect without leaving gaps in the code. This way the pieces could be combined in a test tube with particular chemicals and "the overlapping pieces came together spontaneously," said Nobel laureate Hamilton Smith, senior author of the report.
Making copies
The plan was to piece together ever larger fractions of the genome this way, and then insert them into an E. coli bacterium to make copies for assembly. (E. coli can handily duplicate copies of genetic material inserted into it.)
Hitting obstacle
The team discovered the DNA pieces eventually became too large for the E. coli to handle.
Switching to yeast
The breakthrough came when the team decided to assemble the pieces in yeast, an organism that can accept much larger pieces of DNA without integrating it into its own genome. Lead author Daniel Gibson said the yeast acts "like a factory making more of the synthetic molecule."
Completed genome
The synthetic genome that they have made is a circular chromosome of 582,970 base pairs.
Now what?
The next step will be to insert the synthetic genome into the shell of a host organism to see whether it will come to life. J. Craig Venter expects this will happen this year.
Carolyn Abraham
Genetic inventions
In genetic engineering, researchers tinker with an organism's genetic instructions by knocking pieces out or rearranging them. They can also add in genes from another organism. But in synthetic biology, researchers use lab-made DNA to invent new genes and add them to an organism to perform novel functions.
Among the projects under way:
Make new fibre
Scientists at DuPont have redesigned the genome of E. coli, the intestinal bacterium, to produce a new, spandex-like fibre.
Mass produce drug
The Bill and Melinda Gates Foundation awarded researchers at the University of California at Berkeley $42.6-million (U.S.) to reconstruct the genome of E. coli so it can mass produce the malaria drug artemisinin.
Alter release of drug
Researchers at Boston University have developed synthetic genetic components to alter the way drugs are released in the body and to screen the effects of experimental drugs on a cell.
Carolyn Abraham