Exciting Boring Big Small News

Headline writers are going to have a field day with this, and I am going to spend the next week wincing at the weird ways it will get portrayed in the news. Anyway, it’s finally happened: Craig Venter’s group has finally made an organism with a completely synthetic genome. Or, as the headlines will have it, “SCIENTISTS MAKE ARTIFICIAL LIFE!!1!” “OMG! FRANKENSTEIN!! RUN!!!”

Now, this is exciting, in that it represents an incredible technical tour de force. This is a project that Venter has been working on for several years now, and his group has overcome some formidable technical hurdles. He has taken raw, non-living ingredients, and made an entire genome out of them. This is easy to do for a single gene, or for a few thousand bases of DNA. Venter’s group has made DNA molecules of 1,077,947 bases, encoding about a thousand genes. His group has also figured out how to move this artificial genome into a cell, and have it displace the genome that was already there. To use Venter’s analogy, he has wiped the cell’s operating system and re-booted it with a new operating system.

However, this is also kind of boring. Venter’s group solved each of these technical problems, in isolation, over the last few years (see here for making a synthetic genome (which was not transplanted) and the reboot of a cell (with “natural,” not synthetic DNA)). Today’s news is simply that they have managed to do these things together. Most people who keep tabs on this kind of expected it to happen sooner, almost a year ago, and Venter himself has expressed some surprise that it’s taken so long.

This is big news, since it does open up a couple of cans of worms. There will be a bunch of hand-wringing, especially among those who have not been paying attention. (Half an hour after hearing the news, I heard the first wild conjectures about terrorists making killer superbugs. The commentator was apparently unaware of the tons—literally, thousands of kilograms—of genetically modified anthrax that the Soviet Union made, and thought that some schlub in a cave can do what Venter did.) Those who have been paying attention, including Venter, have been chewing on the ethical implications of this work for over a decade. The real big thing will be down the road. This is one step in the business plan of Venter’s company, Synthetic Genomics, which is to use purpose-built microorganisms to do all manner of useful things. They envision using these custom organisms to do everything from making hydrocarbons to, well, cleaning up oil spills.

And finally, it’s small news. This is a small step in Synthetic Genomics’ plan, and the organism that they’ve made is about as simple as possible. Its genes are the barest essentials. The cells are tiny, simple, and require a lot of help to grow. The only genetic material that these cells carry that is not about mere survival is a handful of genetic “watermarks,” regions of DNA that don’t encode anything, but have a distinctive sequence—a maker’s mark.

So, be excited, but try to be calmer than the headlines. More later.

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 (2010). Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome. Science DOI: 10.1126

Neadertals and Lateral Gene Transfer

The big buzz in the science news the last few days has been the finding that the genomes of modern European and Asian humans are actually between 1 and 4% Neandertal in origin. We share a common ancestor, but evolved separately. Most genes found in our last common ancestor evolved one way in us, but a different way in Neandertals. What really surprised the folks who did this study is that they found that while most humans have one version some genes (that evolved in the human lineage after humans and Neandertals diverged), the Eurasians have a different version—and that version is identical to the gene found in the Neandertal genome. This could have happened if these genes randomly changed in exactly the same way in both lineages, or if the genes evolved in Neandertals, then somehow moved into the human genome.

How did Neandertal genes get into the human genome? Humorists have jumped all over this with scenarios of beetle-browed Neandertals gettin’ it on with some modern types. But to a humorless biologist, this is an example of what is called “lateral gene transfer”, or the movement of genes between two distinct species. Lateral gene transfer doesn’t seem to have had that big an effect on human evolution—the Neandertal contribution to modern humanity is trivial—but lateral gene transfer can be of huge significance to Bacteria and Archaea. In some Bacteria, almost of a quarter of the genome got there by lateral gene transfer.

Lateral gene transfer changes prokaryotic evolution from a slow and linear process to a lightning fast and jumpy process. Prokaryotic genomes evolve slowly without lateral gene transfer. Evolving in isolation and relying on modification of existing genes, it is difficult to acquire radically new traits such as the ability to use light for energy. However, lateral gene transfer makes such changes possible and rapid. A small number of genes acquired by lateral gene transfer—a few thousand bases of DNA encoding a simple light-gathering machine—can change an organism into a phototroph. In the Bacteria and Archaea, lateral gene transfer seems almost free of constraints both in scale and effect. However, there are limits, and some of these were described in a clever study from Edward Rubin of the Joint Genome Institute.

I’ll preserve the modesty of the Bacteria involved, and refrain from discussing the mechanics of lateral gene transfer. Suffice it to say that it’s very easy to take a piece of DNA out of one bacterial cell and pop it into another cell—especially if the cell receiving the DNA is that workhorse of the lab, E. coli. In fact, because E. coli is so easy to transform with foreign DNA and grow, it has become the standard procedure to study genes from other organisms by moving them into E. coli. If you’re working on the genes of some eccentric bug that grows extremely slowly, and only in a growth medium of sheep’s guts, then you’ll want to move those genes into E. coli. In the last few years, entire genomes of other organisms have been put into E. coli. They’re not put in complete—there’s only room in the E. coli cell for a couple of dozen extra genes at a time—but one can make a “library” of E. coli cells carrying the entire genome of organism X. So, we laterally transfer genes one through 10 from organism X into this cell of E. coli; we laterally transfer genes five through 15 from organism X into that cell of E. coli; and so on until we have our library, each volume of which is an E. coli cell.

Nearly a hundred such “genomic libraries” have been made in E. coli, almost two million different individual volumes. This represents a lot of work by lots of different people over many years. The clever thing that Ed Rubin did was to analyze the results of all that work after other people did it.

Every so often, it’s impossible to make one of the volumes in a genomic library. Some genes simply can’t be transferred into E. coli. The DNA can be moved into the cell without difficulties, but the presence of that DNA in E. coli kills the cell. Rubin collected these failures in library-making help to establish the limits of lateral gene transfer.

How could a piece of DNA kill a cell? In some cases, the laterally-transferred DNA can encode a toxin; the “antitoxin” is on another piece of DNA that didn’t get transferred. Rubin’s group found very few examples of this. More often, the DNA that got transferred contained “safe” genes, but the expression of these genes was no longer controlled properly. So, the E. coli cell was essentially killed by too much of a good thing. The problem with these genes was not what they encoded, but how they were regulated. So, neither of these classes of genes is inherently untransferrable. The library-makers were simply unlucky.

The genes most difficult to transfer into E. coli were those encoding the basic machinery of the cell. In automotive terms, it was OK to transfer trim, paint, and upholstery. However, tinkering with the engine and the transmission was forbidden. So, there was no problem transferring genes for metabolizing different types of sugars—adding the ability to digest melibiose to E. coli is like adding a spoiler to your VW. However, transferring genes for ribosomes (the part of the cell that actually makes proteins) was difficult—a Lamborghini piston just won’t work in a VW.

Interestingly, successful lateral gene transfer was more difficult if the source of the DNA was closely related to E. coli. These genes could be similar enough to the E. coli genes that it will try to use their products, but different enough that the product doesn’t quite work. To return to our automotive analogy, if you’re building an engine and you need a 3/8 inch bolt, you’re likely to have a problem if the 3/8 bolt is mixed in with a bunch of 7/16 bolts. However, if the 3/8 inch bolt is mixed in with a bunch of wood screws, you won’t have any problems finding the right thing. Rubin’s group found that close relatives of E. coli typically had over a dozen genes that couldn’t be horizontally transferred into E. coli, while distant relatives often had no untransferrable genes. It’s as if Bacteria evolve by two different clocks. There is a slowly ticking clock for their “core” life functions, evolving by the stately march of mutation and selection and drift, and a rapidly buzzing timer for everything else, evolving by lateral gene transfer.

It’s interesting to compare lateral gene transfer in human evolution and microbial evolution. As we study more animal genomes, we’ll probably see a few more examples (Nancy Moran just reported that aphids have genes acquired from a fungus), but these will be oddities in the flow of animal evolution. On the other hand, in Bacteria, it’s news when we find that there are limits to what lateral gene transfer can do.

Rotem Sorek, Yiwen Zhu, Christopher J. Creevey, M. Pilar Francino, Peer Bork, Edward M. Rubin (2007). Genome-Wide Experimental Determination of Barriers to Horizontal Gene Transfer. Science 318, 1449-1452.

A. Martinez, A. S. Bradley, J. R. Waldbauer , R. E. Summons, E. F. DeLong (2007). Proteorhodopsin photosystem gene expression enables photophosphorylation in a heterologous host. Proceedings of the National Academy of Sciences (USA) 104(13):5590-5595