In March 2010, a team of genetic researchers at the J. Craig Venter Institute (JCVI) in Maryland, USA, heralded the success of their 15-year-old project to create artificial life. The Mycoplasma mycoides bacterium, christened JCVI-syn 1.0 and nicknamed “Synthia”, contains the first entirely synthetic, functional genome: a major step forward in creating life in the lab. The achievement, as with any radical scientific breakthrough, made international headlines and raised questions about the ethics and future potential uses of this technology. So how was this feat of genetic engineering achieved, and what was the rationale behind it? In creating JCVI-syn 1.0, are Craig Venter and his colleagues playing God, 2.0?
Making a functional bacterial genome, able to orchestrate survival and self-replication of the cell, is a challenging and precise business. Starting with a computerised DNA sequence of the M. mycoides genome, the JCVI team divided the sequence into short fragments with overlapping ends. Using these as a blueprint, short sequences of DNA called cassettes were synthesised from scratch. The cassettes were gradually joined together like puzzle pieces into increasingly larger stretches of DNA, the overlapping regions indicating where they should fit in relation to one another, until the 1.08 million base pair genome was complete.
But that was only the chemical side of the process — what had yet to be done was the more biological task of transferring the genome into M. capricolum, a sister species of M. mycoides, to eventually produce cells entirely under the control of synthetic DNA. Bacterial genomes usually contain genes coding for proteins called restriction enzymes, which destroy foreign genetic material; they were removed in M. capricolum before the synthetic genome was introduced. The first division of the cells separated the wild-type and JVCI-syn 1.0 genomes. The synthetic DNA contained antibiotic resistance genes, which allowed the JCVI-syn 1.0 cells to survive antibiotic treatment, while wild-type cells were killed. As the artificial genome was booted up in the cells, its restriction enzymes destroyed any residual M. capricolum DNA, the remainder of occasionally uneven divisions. Colonies of living synthetic cells resulted; the project was a success.
The process wasn’t without flaws, however; the first attempts to make viable cells failed as the genome seemingly refused to function. After a lengthy troubleshooting session, Venter’s team found the genomic culprit — a single base deletion, testament to the magnitude of the task. As a flourishing signature of their achievement, and to identify synthetic cells, the JVCI team used the DNA and protein codes as an alphabet to “watermark” their genome with messages. Amongst them were three quotations: “To live, to err, to fall, to triumph, to recreate life out of life” (James Joyce); “See things not as they are, but how they might be” (‘American Prometheus’); and “What I cannot build, I cannot understand” (Richard Feynman).
As it turns out, these inspirational genomic trademarks fit the ethos of the project — and of Venter’s organisation as a whole. The quotations are a reminder of the wider societal impact that this advancement will have.
“As this is as much a philosophical as a technical advancement in science, we’ve tried to deal with both the philosophical and the technical side,” Venter explains.
In a broad sense, the potential uses of synthetic genomes are great: vaccine and drug production, and carbon dioxide conversion into biofuels are just two of the possible applications that are currently being investigated by JCVI. With beneficial uses, however, comes the potential to cause harm — for example, through a new means of creating biological weapons. Media representation tends to focus on the bigger picture rather than the technological details, pointing out its “dual use”— in one case, even extrapolating it to the “destruction of humanity”. In a more philosophical vein, the research has sparked debate about what we can define as “alive”. For example, biologists widely accept that the process of Darwinian evolution by natural selection is an important, all-encompassing property of life. Human crafting of genomes for specific purposes clearly flouts that rule, indicating that the way we think about life may have to change. Venter acknowledges that the philosophical step forward may be a large one, and works in close collaboration with bioethicists in every step of the institute’s progress.
But for Venter, the creation of JCVI-syn 1.0 is just a “baby-step” in terms of what the institute hopes to achieve. Now that the hurdle of synthesising a genome from scratch has been cleared, the next is to create a “universal recipient cell” — a blank cell in which the function of future synthetic genomes can be tested — instead of converting a cell that already has an identity, like M. capricolum. Another goal is to pare down the genome until it contains no other genes but those essential to life. These accomplishments would provide a blank slate for creating genomes with weird and wonderful properties that may alter life as we know it — as long as careful consideration is given to the scope and ethics of the project, that change will be for the greater good.