Microbiologists have long thought of themselves as gods; now some among them have created life: J. Craig Venter, Hamilton Smith, Clyde Hutchison III, Daniel Gibson and a dedicated team at the J Craig Venter Institute (JCVI) in Rockville Maryland just announced that they’ve made a living creature using only a computer, a chemical synthesizer and four bottles of off-the-shelf chemicals.
The creature is a bacterium named Mycoplasma mycoides JCVI-syn 1.0 and importantly, it reproduces on its own. “To me the most remarkable thing about our synthetic cell,” says Dr. Hutchison “is that its genome was designed in the computer and brought to life through chemical synthesis, without using any pieces of natural DNA. This involved developing many new and useful methods along the way.”
What Does it Take to Construct a Synthetic Microbe? Time, Talent, Patience and a Lot of Money.
This achievement is certainly momentous however it is not unexpected. The Venter group has been trying to build a genome from scratch, put it into a gutted bacterium and boot it up for 15 years, spending an estimated of $40 million in the process. Funding for the research came from Synthetic Genomics Inc., a company in San Diego, California co-founded by Drs. Venter and Smith.
The original plan was to find the smallest living thing possible and make it even smaller; Mycoplasma genitalium, with only 485 genes got the job. In the early 1990s, Venter, Smith and Hutchison sequenced its genome and began knocking out genes to see how few M. genitalium needed to stay alive. “Easy to say,”. Venter stresses, but extremely hard and frustrating to carry out.” Fortunately, technology came to the rescue with better and cheaper DNA sequencing.
The team decided to speed things up by switching to a faster-growing relative of M. genitalium called Mycoplasma mycoides which has more DNA than its predecessor, but that was no longer important. The actual synthesis and assembly of bacterial genes had been a “formidable technical challenge because as the strands get longer they get increasingly brittle,” says Dr. Gibson. But the Venter team had solved this problem by dividing the synthesized genome into manageable cassettes and enlisting the help of a yeast called Saccharomyces cerevisiae to piece them together in the correct order.
The Final Hurdle - Getting the Laboratory-made Genome to Boot Up a Bacterial Cadaver
The last step was to implant the synthetic genomes, patterned after those of M. mycoides, into gutted recipient cells made from M. capricolum and see if the newly-created organisms - those controlled only by the synthetic chromosomes - grew normally. However, bacteria are exceptionally innovative and used to chopping up foreign DNA, generally in the form of invading viruses. To do this these crafty microbes use chemicals called restriction enzymes, the identification of which earned Hamilton Smith a Noble Prize in 1978. It seemed donor and recipient mycoplasmas share a common restriction system and the team had to overcome this obstacle before the new genome could be booted up.
Success was then thwarted for many weeks because one wrong base in over a million in an essential gene, dnaA, rendered the synthetic genome inactive. However, after months of frustration the researchers walked into their laboratory one Monday morning and discovered a blue colony of bacteria –blue showed the microbes were using the new genome. Like any proud parents, they immediately filmed the new babies. Then the scientists sequenced the colony’s DNA and checked to make certain all the growing bacteria were typical M. mycoides. They were. The team had clearly transformed one cell into another with a man-made genome and devised methods along the way which will enable scientists to turn bacteria into made-to-order drug, vaccine and fuel-making factories.
The next challenge for the JCVI scientists is to try the same thing with single-celled algae, creatures much more like ourselves and far more complicated than bacteria.
For research details see:
Gibson DG, Glass JI, Lartigue C, et al. "Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome." Science Express 20 May 2010; pp. 1-7.
Gibson DG, Benders GA, Andrews-Pfannkoch C, et al. "Complete Chemical Synthesis, Assembly, and Cloning of a Mycoplasma genitalium Genome." Science Express 24 January 2008; pp.1-7.
Lartigue C, Glass JI, Alperovich N, et al. "Genome Transplantation in Bacteria: Changing One Species to Another." Science Express 28 June 2006; pp. 1-7.
Glass JI, Assad-Garcia N, Alperovich N, et al "Essential genes of a minimal bacterium." PNAS 10 January 2006; 103 (2) pp. 425-430.
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