Science Literature

It took 20 skilled people working for a decade, and an estimated $40 million of funding, but the outcome is spectacular. It is described as "a defining moment in the history of biology and biotechnology" by Mark Bedau, editor of the journal Artificial Life. The BBC News headline was succinct: 'Artificial life' breakthrough announced by scientists. The Economist declared: "Artificial life, the stuff of dreams and nightmares, has arrived". The research paper claims to have made a synthetic cell, and uses the word "creation" in the title.

"We refer to such a cell controlled by a genome assembled from chemically synthesized pieces of DNA as a "synthetic cell", even though the cytoplasm of the recipient cell is not synthetic. Phenotypic effects of the recipient cytoplasm are diluted with protein turnover and as cells carrying only the transplanted genome replicate. Following transplantation and replication on a plate to form a colony (>30 divisions or >10^9 fold dilution), progeny will not contain any protein molecules that were present in the original recipient cell."

"Interesting creatures will be bubbling out of the Venter Institute's labs" (image source here)

It seems obvious that the research team should be congratulated, but we do need to ask - what exactly is it that they are being congratulated for? In a news article in Science, Pennisi wisely puts the word "synthetic" in quotation marks when referring to the whole organism, but is happy with "synthetic genome" in her title. So let's look at the genome and clarify what was done. The exercise was based on the bacterium with the smallest genome: Mycoplasma mycoides. In the past, the team has published a series of papers on constructing building blocks and assembling them. They have learned how to make changes to the code so they could trace progress. Pennisi summarises as follows:

"The researchers started building their synthetic chromosome by going DNA shopping. They bought from a company more than 1000 1080-base sequences that covered the whole M. mycoides genome; to facilitate their assembly in the correct order, the ends of each sequence had 80 bases that overlapped with its neighbors. So that the assembled genome would be recognizable as synthetic, four of the ordered DNA sequences contained strings of bases that, in code, spell out an e-mail address, the names of many of the people involved in the project, and a few famous quotations. Using yeast to assemble the synthetic DNA in stages, the researchers first stitched together 10,000-base sequences, then 100,000-base sequences, and finally the complete genome."

In view of the complexities experienced, the successful assembly was a magnificent achievement. The researchers then embedded their new genome in the cytoplasm of a recipient cell - the related bacterium Mycoplasma capricolum. Unfortunately, the cell died. It took three months to find the problem. The team systematically replaced stretches of the assembled genome with the natural genome until they identified the cause: a single-base mistake in the synthetic code. The research moved on to check the functioning of the replicating bacterium.

"They sequenced the DNA in this colony, confirming that the bacteria had the synthetic genome, and checked that the microbes were indeed making proteins characteristic of M. mycoides rather than M. capricolum. The colony grew like a typical M. mycoides as well. "We clearly transformed one cell into another," says Venter."

The research has long-term practical goals. Will it be possible to design bacteria that have novel functionalities? Clearly, many are working towards that goal. According to one expert, "One thing is sure, interesting creatures will be bubbling out of the Venter Institute's labs". The authors write:

"This work provides a proof of principle for producing cells based upon genome sequences designed in the computer. DNA sequencing of a cellular genome allows storage of the genetic instructions for life as a digital file. The synthetic genome described in this paper has only limited modifications from the naturally occurring M. mycoides genome. However, the approach we have developed should be applicable to the synthesis and transplantation of more novel genomes as genome design progresses."

One of the greatest concerns we should all have is the idea that because we can copy the processes found in living things, we can engineer those processes. The reality continues to be that we are ignorant of so much that is going on in the cell. The incident with the single-base mistake in the coding is just the tip of the iceberg! The information content of cells is such that we are continually out of our depth in understanding even the most basic functions. A specific concern is the way the research team describe the role of the recipient cell: a vessel that can be reprogrammed by the novel genome. This may be feasible with close relatives, but the danger is that information embedded in the recipient cell may be overlooked. The comments of Mae-Wan Ho are pertinent:

"Clearly the scientists have not created life or the bacterial cell. There is a yawning chasm in the physics and chemistry of the living state that the team hasn't even begun to address, let alone bridge. They did not create the genome that was used to transform the bacteria cell, only copied it from another species of the genus, adding a "water mark" for identification, and no doubt, for staking their claim to the synthetic genome. This synthetic genome was not even made from scratch, but cobbled together from pieces found in a catalogue, and then 'transplanted' into cells of the recipient bacterium species (a close relative of the donor) using an antibiotic to select for cells that have accepted the artificial chromosome and allow them to grow."

In his Muse column, Philip Ball also discusses reasons for caution. If we are going to research life, we must not reduce it to engineering the genome, where "the membranes, the cytoplasm - everything except the genes - are mere peripherals to the hard drive of life, whose algorithmic instructions need only be rejigged to produce new organisms."

"Attempts to make a genuinely 'designed' genome, rather than one based on a naturally evolved bacterium, will remind us how sketchy our understanding is of the rules that govern the crucial interactions among genes and with other elements of living cells. In the post-genomics era, our ideas of where the real business of life resides are shifting again. We are moving away from a linear 'code' and towards something altogether more abstract, emergent and entangled. So in marking yet another deepening appreciation of how life operates, the latest 'synthesis of life' seems likely to repeat the historical template."

Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome
Daniel G. Gibson, John I. Glass, Carole Lartigue, Vladimir N. Noskov, Ray-Yuan Chuang, Mikkel A. Algire, Gwynedd A. Benders, Michael G. Montague, Li Ma, Monzia M. Moodie, Chuck Merryman, Sanjay Vashee, Radha Krishnakumar, Nacyra Assad-Garcia, Cynthia Andrews-Pfannkoch, Evgeniya A. Denisova, Lei Young, Zhi-Qing Qi, Thomas H. Segall-Shapiro, Christopher H. Calvey, Prashanth P. Parmar, Clyde A. Hutchison III, Hamilton O. Smith & J. Craig Venter.
Science Express (May 20, 2010), doi 10.1126/science.1190719

Abstract: We report the design, synthesis, and assembly of the 1.08-Mbp Mycoplasma mycoides JCVI-syn1.0 genome starting from digitized genome sequence information and its transplantation into a Mycoplasma capricolum recipient cell to create new Mycoplasma mycoides cells that are controlled only by the synthetic chromosome. The only DNA in the cells is the designed synthetic DNA sequence, including "watermark" sequences and other designed gene deletions and polymorphisms, and mutations acquired during the building process. The new cells have expected phenotypic properties and are capable of continuous self-replication.

See also:

Ball, P. A synthetic creation story, Nature online 24 May 2010 | doi:10.1038/news.2010.261

Ho, M-W., Synthetic Life? Not By a Long Shot, ISIS Report 24/05/10

Life after the synthetic cell, Nature, 465, 422-424, (27 May 2010) |doi:10.1038/465422a

Pennisi, E. Synthetic Genome Brings New Life to Bacterium, Science 328, 21 May 2010, 958-959.

Wells, J. Has Craig Venter Produced Artificial Life? Evolution News & Views (May 24, 2010)

Kaebnick, G., Is the "Synthetic Cell" about Life? The Scientist, 24(7), July 2010, 27. [need to register for access]