Get in the mood for this bit of news, the synthesis of an artificial organism by Craig Venter’s research team.
Here’s the equivalent of that twitching hand of Frankenstein’s monster:
Those are two colonies of Mycoplasma mycoides, their nucleoids containing entirely synthesized DNA. You can tell because the synthesized DNA contained a lacZ gene for beta-galactosidase, making the pretty blue product. That’s one of the indicators that the artificial chromosome is functioning inside the cell; the DNA was also encoded with recognizable watermarks, and they also used a cell of a different species, M. capricolum, as the host for the DNA.
The experiment involved creating a strand of DNA as specified by a computer in a sequencing machine, and inserting it into a dead cell of M. capricolum, and then watching it revivify and express the artificial markers and the M. mycoides proteins. It really is like bringing the dead back to life.
It was also a lot more difficult than stitching together corpses and zapping it with lightning bolts. The DNA in this cell is over one million bases long, and it all had to be assembled appropriately with a sequencing machine. That was the first tricky part; current machines can’t build DNA strands that long. They could coax sequences about a thousand nucleotides long out of the machines.
Then what they had to do was splice over a thousand of these short pieces into a complete bacterial chromosome. This was done with a combination of enzymatic reactions in a test tube, and in vivo assembly by recombination inside yeast cells. The end result is a circular bacterial chromosome that is, in its sequence, almost entirely the M. mycoides genome…but made from a sequence stored in a computer rather than a parental bacterium.
Finally, there was one more hurdle to overcome, getting this large loop of DNA into the husk of a cell. These techniques, at least, had been worked out last year in experiments in which they had transplanted natural M. mycoides chromosomes into bacteria.
The end result is a new, functioning, replicating cell. One could argue that it isn’t entirely artificial yet, since the artificial DNA is being placed in a cell of natural origin…but give it time. The turnover of lipids and proteins and such in the cytoplasm in the membrane means that within 30 generations all of the organism will have been effectively replaced, anyway.
It’s a very small cell that has been created — the mycoplasmas have the smallest genomes of any extant cells. It’s not much, but this is a breakthrough comparable to Wöhler’s synthesis of urea. That event was a revelation, because it broke the idea that organic chemicals were somehow special and incapable of synthesis from inorganic molecules. And that led to the establishment of the whole field of organic chemistry, and we all know how big and important that has become to our culture.
Venter’s synthesis of a simple life form is like the synthesis of urea in that it has the potential to lead to some huge new possibilities. Get ready for it.
If the methods described here can be generalized, design, synthesis, assembly, and transplantation of synthetic chromosomes will no longer be a barrier to the progress of synthetic biology. We expect that the cost of DNA synthesis will follow what has happened with DNA sequencing and continue to exponentially decrease. Lower synthesis costs combined with automation will enable broad applications for synthetic genomics.
We should be aware of the limitations right now, though. It was a large undertaking to assemble the 1 million base pair synthetic chromosome for a mycoplasma. If you’re dreaming of using the draft Neandertal sequence to make your own resynthesized caveman, you’re going to have to appreciate the fact that that is a job more than three orders of magnitude greater than building a bacterium. Also keep in mind that the sequence introduced into the bacterium was not exactly as intended, but contained expected small errors that had accumulated during the extended synthesis process.
A single transplant originating from the sMmYCp235 synthetic genome was sequenced. We refer to this strain as M. mycoides JCVI-syn1.0. The sequence matched the intended design with the exception of the known polymorphisms, 8 new single nucleotide polymorphisms, an E. coli transposon insertion, and an 85-bp duplication. The transposon insertion exactly matches the size and sequence of IS1, a transposon in E. coli. It is likely that IS1 infected the 10-kb sub-assembly following its transfer to E. coli. The IS1 insert is flanked by direct repeats of M. mycoides sequence suggesting that it was inserted by a transposition mechanism. The 85-bp duplication is a result of a non-homologous end joining event, which was not detected in our sequence analysis at the 10-kb stage. These two insertions disrupt two genes that are evidently non-essential.
So we aren’t quite at the stage of building novel new multicellular plants or animals — that’s going to be a long way down the road. But it does mean we can expect to be able to build custom bacteria within another generation, I would think, and that they will provide some major new industrial potential.
I know that there are some ethical concerns — Venter also mentions them in the paper — but I’m not personally too worried about them just yet. This cell created is not a monster with ten times the strength of an ordinary cell and the brain of a madman — it’s actually more fragile and contains only genes found in naturally occurring species (and a few harmless markers). When the techniques become economically practical, everyone will be building specialized bacteria to carry out very specific biochemical reactions, and again, they’re going to be poor generalists and aren’t going to be able to compete in survival with natural species that have been honed by a few billion years of selection for fecundity and survivability.
Give it a decade or two, though, and we’ll have all kinds of new capabilities in our hands. The ethical concerns now are a little premature, though, because we have no idea what our children and grandchildren will be able to do with this power. I don’t think Wöhler could have predicted plastics from his discovery, after all: we’re going to have to sit back, enjoy the ride, and watch carefully for new promises and perils as they emerge.
Gibson et al. (2010) Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome. Science Express.
Lartigue et al. (2009) Creating Bacterial Strains from Genomes That Have Been Cloned and Engineered in Yeast. Science 325:1693-1696.