FLAWED CODE
Landmark study prompts rethink of genetic code
By Richard Ingham, Agence France-Presse
PARIS
The most detailed probe yet into the workings of the human genome has led scientists to conclude that a cornerstone concept about the chemical code for life is badly flawed.
The groundbreaking study, published in more than two dozen papers in journals on both sides of the Atlantic, takes a small percentage of the genome to pieces to draw up a "parts list," identifying the biological role of every component.
For the international team of investigators, the four-year project was the computer-equivalent of passing a fine-toothed comb through a mountain of raw data. Reporting in Nature and Genome Research in June, they suggest that an established theory about the genome should be consigned to history.
Under this view, the genome is rather like a ribbon studded with some 22,000 "nuggets" in the form of genes, which make proteins, the essential stuff of life. Genes-deemed so valuable that some discoverers of them have been prompted to file patents over them for commercial gain-amount to only around a 20th, or even less, of the genetic code.
In between the genes and the sequences known to regulate their activity are long, tedious stretches that appear to do nothing. The term for them is "junk" DNA, reflecting the presumption that they are merely driftwood from our evolutionary past and have no biological function.
But the work by the ENCODE (Encyclopedia of DNA Elements) consortium implies that this nuggets-and-dross concept of DNA should be, well, junked. The genome turns out to a highly complex, interwoven machine with very few inactive stretches, the researchers report.
Genes, are just one of many types of DNA sequences that have a functional role. And "junk" DNA turns out to have an essential role in regulating the protein-making business. Previously written off as silent, it emerges as a singer with its own discreet voice, part of a vast, interacting molecular choir.
"The majority of the genome is copied, or transcribed, into RNA, which is the active molecule in our cells, relaying information from the archival DNA to the cellular machinery," said Tim Hubbard of the Wellcome Trust Sanger Institute, a British research group that was part of the team. "This is a remarkable finding, since most prior research suggested only a fraction of the genome was transcribed."
Francis Collins, director of the US National Human Genome Research Institute, which gathered 35 scientific groups from around the world into the ENCODE project, said the scientific community "will need to rethink some long-held views about what genes are and what they do." He said this "could have significant implications for efforts to identify the DNA sequences involved in many human diseases."
Another rethink is in the offing about how the genome has evolved, said Collins.
Until now, researchers thought that the pressure to survive would relentlessly sculpt the human genome, leaving it with a slim, efficient core of genes that are essential for biological function.
But the ENCODE consortium was surprised to find that the genome appears to be stuffed with functional elements that offer no identifiable benefits in terms of survival or reproduction.
The researchers speculate that there is a point behind this survival of the evolutionary cull. Humans could share with other animals a large pool of functional elements-a "warehouse" stuffed with a variety of tools on which each species can draw, enabling it to adapt according to its environmental niche.
The ENCODE endeavor flows from the Human Genome Project, which concluded in April 2003 with the publication of a polished draft of the human genetic code. But having the draft is not the same as knowing what is in it or how it works. And this is essential for unlocking knowledge about our evolutionary odyssey, just as it is needed for engineering new treatments for inherited disease.
The collaborative study focused on 44 strategically chosen targets that together account for about one percent of the genome, or about 30 million of the three billion "rungs" in the DNA double-helix ladder.
The data is being placed in the public domain to help medical and other research.
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GENE TRANSPLANTATION
Pioneering experiment shows its possible to engineer bacterial transformation by swapping genomes, boosting the race to develop designer bugs
CHICAGO
Researchers transformed one bacterial species into another by swapping their genomes, a move that will accelerate the race to develop custom-built synthetic bugs.
Craig Venter, who had a hand in mapping the human genome, said a team of his researchers had transplanted the entire genetic code of one bacterial organism into another closely related species.
The experiment marks the most ambitious attempt yet to reengineer a living cell with a view to one day developing microorganisms that could be used for biofuels, cleaning up toxic waste, sequestering carbon, or other applications.
For decades, molecular biologists have genetically modified microbes and other kinds of cells by adding short DNA sequences, whole genes and even large pieces of chromosomes in their quest to fashion synthetic bugs that can make antimalaria drugs or novel biofuels.
But this is the first time that researchers have transplanted an entire genome into a living organism and shown that the cell can express the foreign DNA.
"This is equivalent to changing a Macintosh computer to a PC by inserting a new piece of software," Venter said.
It "is a landmark in biological engineering taking us from moving one gene or a set of genes to the ability to move an intact genome," said Barbara Jasny, deputy editor of Science, which first reported the experiment.
The experiment shows for the first time that it is possible to insert an intact genome into a host organism and have that organism express the foreign DNA. The next step is to create a synthetic genome and transplant that into a host organism.
"It's a key enabling step," said Venter. "Synthetic biology still remains to be proven, but now we are much closer to knowing it's absolutely theoretically possible."
In this experiment, the scientists at the J. Craig Venter Institute in Rockville, Maryland, used naturally occurring DNA from a living organism, but they believe the transplantation techniques could be used on artificial, or man-made genomes, once they are developed.
To that end, they are seeking patents on the methods they used in this study.
The researchers took the genome of a simple, one-celled organism, Mycoplasma mycoides, and transplanted it into a close relative, M. capricolum. Both of these bacteria, which are innocuous goat pathogens, lack an outer membrane, facilitating genome transfer.
Before transplantation, the researchers modified the DNA of the donor bacteria, adding two genes that would provide proof if the transfer had worked. One gene conferred antibiotic resistance, the other caused bacteria expressing it to turn blue.
The enhanced Mycoplasma mycoides genome was added to a test tube of M. capricolum, and the contents of the tube were exposed to an antibiotic. Within four days blue colonies appeared, indicating that the host organisms had taken up the foreign DNA.
When the team analyzed the blue bacteria for DNA sequences specific to either mycoplasma, it found no evidence of the host bacteria's genetic material. Many questions still remain. The researchers acknowledged that they were not sure how the one genome displaced the other.
"We don't know for certain how the donor genome takes over," Hamilton Smith, a lead author on the paper, said.
The process is also "extremely inefficient" with a success rate of one in 150,000, said John Glass, a lead author on the paper.
Still, Venter said this proof of concept is likely to speed research in this emerging discipline, yielding new developments in months, instead of years as was previously the case.
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