Editorial: Venter: The implications of our synthetic cell
MAKE a genome 鈥 check. Transplant it into an emptied cell to create the world鈥檚 first synthetic life form 鈥 check. Frenzied media coverage accusing the researchers concerned of 鈥減laying God鈥 鈥 check.
Craig Venter and his teams at the in Rockville, Maryland, and San Diego, California, have shown themselves to be technical wizards by synthesising a genome from code contained on a computer, and using it to start a cell line of the resulting synthetic organism (see 鈥淗ow the synthetic bacterium was made鈥). If demonstration was needed that there is no such thing as the 鈥渕ystery of life鈥, they have provided it in stunning style. The new life form they have made is derived from information, pure and simple.
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Other synthetic biology researchers, while impressed by Venter鈥檚 technical achievement, are restrained about its implications, both practical and philosophical. They were already well aware that there is no magical Wizard of Oz behind life鈥檚 curtain, and they feel the first fruits of synthetic biology 鈥 organisms designed to make clean fuels and cheap pharmaceuticals, for example 鈥 are more likely to come through less ambitious approaches.
鈥淚t鈥檚 cool and has taken a lot of effort,鈥 says at the University of Edinburgh, UK. 鈥淏ut it doesn鈥檛 take us that much further scientifically.鈥 He and many other researchers in the field say they are unlikely to synthesise whole bacterial genomes themselves.
鈥淚t鈥檚 cool and has taken a lot of effort, but it doesn鈥檛 take us that much further scientifically鈥
鈥淭his is a marvellous advance, but it doesn鈥檛 immediately open up or enable new studies for the broad community,鈥 says of Boston University, who notes that Venter鈥檚 team spent about $40 million to create the synthetic cell. 鈥淲e don鈥檛 have that kind of money in academic research.鈥
The costs of making long stretches of DNA 鈥 currently about $1 per letter 鈥 will almost certainly fall. But even if synthetic genomes become dramatically cheaper to make, there is still the question of how to write one. 鈥淲e have a long way to go to really develop sufficient understanding to build an operational genome from scratch,鈥 Collins says.
Genomes are too much of a black box for deliberate and predictable tinkering, says at the University of Cambridge. 鈥淚t鈥檚 like trying to build a car engine when you don鈥檛 understand what the individual parts do.鈥
Even if biologists learn how to write novel genomes fluently, they face another huge hurdle: getting the enormous molecules to 鈥渂oot up鈥 in a foreign cell. Venter鈥檚 genome was modelled on that of a mycobacterium, and was implanted into the cytoplasm of a closely related species. It remains to be seen whether these vessels will accept the genome of drug-making Escherichia coli or, more difficult still, a biofuel-producing alga. 鈥淚t will be very challenging to jump between very different species,鈥 Collins says.
These criticisms may be unfair to Venter and his team, as their stated goal was to synthesise a bacterial genome that existed as data and implant it into a cell. As Venter is fond of saying: 鈥淭his is the first self-replicating species that we鈥檝e had on the planet whose parent is a computer.鈥
More than anything, the guarded reception from Venter鈥檚 peers demonstrates how far synthetic biology has come via other routes. In recent years, it has yielded the once costly anti-malarial drug artemisinin, a valuable polymer, and even biofuels. 鈥淭hose didn鈥檛 involve millions of genetic changes, those involved a dozen,鈥 says at Harvard Medical School in Boston.
The chemical company DuPont has spent the better part of a decade and hundreds of millions of dollars identifying about 20 genetic changes that enable E. coli to produce a chemical building block, used in the production of polymers, called 1,3-propanediol. Church and his team have come up with a way of introducing multiple genetic changes into bacteria more quickly and cheaply, called multiplex automated genome engineering or MAGE.
Church is now working on improving the technique. 鈥淚t鈥檚 an order of magnitude less expensive to do partial genomes than to do the whole ones, and there are really amazing things that can be done,鈥 he says.
For now the preferred approach 鈥 and one that is acknowledged by Venter 鈥 is to create a 鈥渢oolbox鈥 of genetic components or 鈥淏ioBricks鈥 that act in a predictable way, ready for assembly into combinations with whatever properties are desired. These genes or circuits of genes are kept ready and available for assembly into bio-devices that actually have a function.
The Massachusetts Institute of Technology keeps a registry of 2500 BioBricks. Many of these have come from students competing in an annual event called the International Genetically Engineered Machine competition, or iGEM, but according to at Imperial College London, only about 10 per cent work properly.
So Kitney, in collaboration with the University of California, Berkeley, and Stanford University in California, is creating a professional BioBrick registry. 鈥淭here are now about 300 parts that are fully understood and characterised,鈥 he says. 鈥淵ou can use them to make professionally engineered biological devices.鈥
In contrast to Venter鈥檚 latest achievement, which demonstrates a proof of principle but has no immediate practical use, everyone involved in BioBrick projects is using biological tools to try and solve practical problems, Kitney says. 鈥淎ll of us are focused on applications鈥 producing devices and systems that spawn new industries.鈥
Kitney and his colleagues have made a biological sensor which detects a protein from bacteria that cause urinary tract infections. The device has three BioBrick components: a detector; an amplifier that increases the signal; and an indicator. The three components form a bio-device which is then placed into E. coli.
Going one step further, the team is developing a version that doesn鈥檛 need an E. coli cell. Instead, the three genes are added to a broth and produce a response equivalent to that of a live cell. 鈥淲e鈥檙e working on a new version that detects the superbug MRSA, with a red fluorescent protein,鈥 Kitney says.
Elfick and his colleagues are tinkering with six enzymes that together can break down cellulose, the normally indigestible polymer in waste plant matter, with the aim of turning plant waste into biofuel.
Venter has the same goals. He just envisions a different way of achieving them, and perhaps it is this ambition that sets him apart from his peers. 鈥淭here鈥檚 zero doubt in my mind that being able to control the whole thing from scratch is orders of magnitude more powerful than changing a genome,鈥 Venter says. 鈥淭he unknown is how long it will take us.鈥
Editorial: Venter: The implications of our synthetic cell
How the synthetic Bacterium was made
What has Craig Venter actually produced, and what might he be planning to do with it?
What are the basics?
Craig Venter鈥檚 team at the J. Craig Venter Institute (JCVI) in Rockville, Maryland, and San Diego, California, made a synthetic cell by stitching together the genome of a goat pathogen called Mycoplasma mycoides from smaller stretches of DNA synthesised in the lab. They then inserted the genome into the empty cytoplasm of a related bacterium, Mycoplasma capricolum. The transplanted genome booted up in its host cell, and then divided over and over to make billions of M. mycoides cells (Science, ). The new strain has been named JCVI-syn1.0.
Cool. But it sounds familiar.
Venter and his team, which includes geneticists Hamilton Smith and Clyde Hutchison, have previously accomplished both feats 鈥 creating a synthetic genome and transplanting a genome from one bacterium into another 鈥 but this time they have combined the two.
To trick the M. capricolum host into accepting an artificial genome from another species, the team added chemical markers called methyl groups to the synthetic DNA 鈥 making it appear to be natural 鈥 and knocked out an 鈥渁nti-invader鈥 enzyme in the host cell. Achieving this trick was the breakthrough 鈥 and Venter has not published all the details on how it was achieved.
Why not 鈥 do they want to patent the technique?
Yes. JCVI鈥檚 main funder, a company also headed by Venter called , has exclusive access to all the technology JCVI produces, and has applied for 13 patents on unique synthetic genomes invented by the JCVI team. The JCVI applied in 2006 for a patent on the 鈥渕inimal bacterial genome鈥 that Venter now hopes to assemble. Entire, customised synthetic genomes with industrially useful capabilities may be easier than natural genes to patent as they do not face the objections raised by attempts at 鈥減atenting nature鈥.
Can Venter expect to become mega-rich?
Very likely. The JCVI is a not-for-profit foundation but Venter is hoping that the huge range of potentially useful applications of customised bugs will eventually produce rich dividends for him and for society. Venter is collaborating with Exxon Mobil to produce biofuels from algae and with Novartis to create vaccines. 鈥淎s soon as next year, the flu vaccine you get could be made synthetically,鈥 he says.
What are the pure science applications?
Synthetic cells have potential as a scientific tool. For example, bacteria could be created that produce new amino acids, the chemical units that make up proteins. Geneticists could then see how these 鈥渃yborg鈥 bacteria evolve, compared with bacteria that produce the usual suite of amino acids.
How can they be sure that the new bacteria are what they intended?
The bugs鈥 genomes are 鈥渨atermarked鈥 with distinctive markers, all of which were found in the synthetic cell when it was sequenced. The watermarks contain the names of 46 scientists on the project, several quotations written out in a secret code, and a website address. As a hint to the code, Venter has revealed the quotations, which include: 鈥淭o live, to err, to fall, to triumph, to recreate life out of life,鈥 from A Portrait of the Artist as a Young Man by James Joyce.
Does this mean they created life?
No. The team made the new genome out of DNA sequences that had initially been made by a machine, but bacteria and yeast cells were used to stitch it together and duplicate it. The cell into which the synthetic genome was then transplanted contained its own proteins, lipids and other molecules. Until the host cell is itself built artificially from scratch it cannot be said that life has been created.
Bioterror, kill switches and hara-kiri
Now that synthetic life has been made in the lab, how do we make sure it stays there?
For Venter and his team, bio-containment was simple: the cells they created require a broth of nutrients unlikely to be found outside the lab. Their genome also lacks the harmful genes from the goat pathogen on which it was based. 鈥淲e don鈥檛 work with goats, so we think we have pretty good containment systems,鈥 Venter says.
Future synthetic cells, though, will require extra measures. One approach would be to make cells that incorporate a synthetic amino acid into their proteins, so no proteins could be made without the supplement. James Collins at Boston University envisions a killer genetic circuit that is shut off by a lab chemical, and switched on outside the lab. 鈥淚f they are not in their happy lab environment they would commit cellular hara-kiri,鈥 he says. Bacteria could also be programmed to stop dividing after a certain number of generations.
George Church of Harvard Medical School has called for all synthetic biology labs and their suppliers to be registered, an idea the US National Institutes of Health is looking into. 鈥淓verybody in the synthetic biology ecosystem should be licensed,鈥 Church says.
Some companies that make stretches of DNA to order have begun scanning requests to see if they match genes for known toxins, but these measures are only voluntary, and therefore patchy.
at the University of Texas in Austin says fears of synthetic bioterrorism are in any case overhyped, and probably unrealistic given the $40 million and thousands of person- hours it took Venter鈥檚 team. 鈥淚t鈥檚 not a real threat,鈥 he says.
