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Scientists a step closer to creating designer organisms, superbugs

Scientists a step closer to creating designer organisms, superbugs

Bangalore: Taking scientists’ ambition of creating designer organisms one step closer to the end goal, US researchers have synthesized the complete genome of a bacterium, proving that it’s possible to create microorganisms that can be used for cleaning up toxic waste, producing pharmaceuticals and biofuels, sequestering carbon and other applications.

In Friday’s issue of the journal Science, researchers from the J. Craig Venter Institute (JCVI) in Rockville, Madison, report that they have synthesized the entire genome of Mycoplasma genitalium, a parasitic bacterium known to have the smallest genome. In the event, they have developed a method that can be easily used by others to create much larger DNA molecules than they could before.

“The work appears to be a technological tour de force, and demonstrates that a microbial genome can, in principle, be assembled from chemical synthesis," said Pamela Silver, professor of systems biology at Harvard Medical School in Massachusetts, US. Although the chemical synthesis of genes is now routine this is the first time that such a large genome (582,970 base pairs or complementary DNA or RNA strands connected by hydrogen bonds), has been assembled and cloned exactly the way researchers had designed the sequence.

Some Indian researchers who are exploring the field of synthetic biology (a new discipline that applies engineering to biology to build biological systems) believe the study will create a lot of excitement in the scientific community as parts of the technology developed by the JCVI group are applicable to molecular research at large. “We all knew it was coming. Craig Venter’s achievement lies in using the proven technologies to build something new and disruptive," said Mukund Thattai, a researcher at National Centre for Biological Science in Bangalore.

“It’s a tool waiting for applications," he added. “More than the complete genome, the fact that Venter has shown making of plasmids a routine affair, gives us a piece of technology that would change the way we all do molecular biology," Thattai noted. A plasmid is a circular, double stranded piece of DNA, which exists independent of the chromosomal DNA and is used in research for transferring genes between cells. It takes anywhere between 4-6 weeks to design and make a new plasmid, which seriously limits the rate of research. If Venter’s technology can bring down the time it takes to construct a plasmid to a day or so, molecular biologists can design, validate, measure and predict outcomes of research on computers much faster, argues Thattai.

As for the technological breakthrough, JCVI researchers chemically synthesized large chunks of the genome sequence, ranging from one-fourth or one-eighth of the full genome in test tubes. The copies were stored in artificial chromosomes within E. coli bacteria. The large pieces were then assembled in yeast, where some of the yeast cell’s own cellular machinery was used.

“It does not take much foresight to see that much bigger genomes will be artificially tailored in future. This may just be the beginning of the next revolution in synthetic biology," said Guhan Jayaraman, professor of biochemical and bioprocess engineering at IIT Madras, who intends to send an IIT team to iGEM 2008.

Jayaraman believes such designer microorganisms have very obvious potential for industrial biotechnology. Until now, industrial biotechnology has been isolating microorganisms having a unique genetic property for over-producing a certain product, and then fine tuning that property by random and directed mutations or even metabolic engineering. But now the entire genetic makeup can be altered. However, it’ll be a while before scientists could actually use such microorganisms.

“It is one thing to assemble the so-called ‘essential genome’ of a bacterium (this group removed 100 ‘non-essential’ genes out of 485 genes), but quite another to predict how the bacterium with ‘essential genome’ will behave under laboratory conditions," cautioned Jayaraman.

JCVI researchers are aware of this challenge. “Our next step is to place it in a cell cytoplasm so that it can ‘boot up’ and produce a living synthetic cell," said lead researcher Hamilton O. Smith over telephone.

J. Craig Venter, who shot into fame in 1995 after developing a new ‘shotgun’ technique for sequencing the genome which significantly contributed in expediting the Human Genome Project and has since been widely used, is a strong proponent of creating new life forms for solving global problems. His own goals are to target bacterial engineering for energy and environment (see box).

Thattai believes the country should begin using pieces of this research to suit its needs. “We should be seriously bio-prospecting soil for novel enzymes, characterize and categorize them and look for those that might be useful in biofuels," he said.

Initial steps have already been undertaken. The Department of Biotechnology (DBT), under its bioprospecting programme, has identified some enzymes that can convert plant material first into sugar and then ethanol. “We are still far away from any pilot or commercial scale application, though," said R.C. Kuhad, professor of microbiology, University of Delhi, South Campus, who leads the DBT program. However, Kuhad has managed to isolate an enzyme xylanase from a wild organism that will soon enter pilot study for bleaching paper pulp.

Organisms engineered for industrial use:

• Jay Keasling at the University of California, Berkeley, has engineered microbes to produce artemisinin, the most potent ingredient in anti-malarial drugs today, which is normally derived from plants. His strategy has helped increase artemisinin production 10-million-fold. Keasling is now attempting to use his microbes to produce transportation fuel.

• J. Craig Venter Institute (JCVI) has used naturally occurring bacteria to develop microbial fuel cells, which can process human and animal waste to produce electricity or clean water.

• At its plant in Tennessee, agrochemical company DuPont is using engineered bacteria to convert sugar into a new polymer called propanediol, which imparts stain resistance to carpets and clothing.

• JCVI has also made a new fuel chemical from sugar that has the potential to be one of the first green jet fuels.

• The US National Institutes of Health funds research that is trying to produce the expensive cancer drug Taxol (and related taxoids) in yeast.

• Synthetic Genomics, a company founded by Craig Venter, is collaborating with British Petroleum to test if naturally occurring microorganisms can metabolize coal into methane, to be harvested later as natural gas. The company has also developed organisms that can covert carbon dioxide into methane, a renewable source of fuel.

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