Ethics and science
On the borders of DNA

Something Left out in the Recipe for life
Is it possible to speak of “artificial life”? It might seem so, after biologist Craig Venter recently announced the results of  his work on the first self-replicating “synthetic” bacterial cell. Jane Hubbard, Associate Professor of Pathology, clarifying the scientist’s accomplishments, suggests that science s still far from creating life de novo.

by Jane Hubbard

Last month, what was hailed in the media scuttlebutt as “creation” should be understood as more like “imitation.” What makes this “imitation” special is that, unlike art imitating nature, the outcome is a live organism. Why bother? What was “created”? How was it done? How is it different from what was done before? And why did it create (no pun intended) such a stir?
I have a friend who calls a meal prepared without a recipe “a creation,” giving credit to the cook’s inspiration by invoking the “something from nothing” connotation of the word “creation.” However, while the cook’s idea took form as a specific mixture of ingredients and seasonings, the substance of the meal is not a matter of bringing the ingredients into being, as would a true “creation.”
So too with the new Venter bacteria: DNA, the chemical currency of heredity and of the reproductive capacity of organisms from viruses to humans, was synthesized from its constituent building blocks–adenine (A), cytosine (C), guanine (G), and thymine (T)–in the specific sequence that codes for the functional genes of a specific bacterium (with some minor differences) and inserted into a closely related host cell.

First, why bother? According to the companion “news” article by Elizabeth Pennisi in Science magazine, the effort required ~$40 million and 20 people working for over 10 years. The idea is that with the ability to design a bacterial genome and the technology to successfully place it into a host cell, one could coax the cell to produce useful products such as drugs or biofuels. The fact is, we can do this already without synthesizing the entire genome de novo. People have been altering the biosynthetic output of bacteria for over 60 years. In fact, some of the early evidence that DNA is the genetic material was precisely the type of experiment that took DNA from one bacteria and put it into another, changing the features of the host cells (O. T. Avery, C. M. MacLeod, M. McCarty, J. [1944] Exp. Med). Since then, we  have learned to do this far more efficiently using recombinant DNA technology. Combining nucleic acid (RNA and DNA) chemistry and the biology of microorganisms, we routinely modify the genomes of organisms such as yeast, plants, worms, fruit flies, and mice to answer specific biological questions. For example, specific human genes can be inserted into the genomes of other organisms where their cellular function can be more easily investigated, or jellyfish genes that encode fluorescent proteins can be used to tag a protein of interest and determine its localization in vivo. These are day-to-day activities in laboratories all over the world. When this technology was first introduced, the scientific community stopped work for a time to determine safe conditions for its utilization. Following self-imposed restrictions and now standard practice, these feats of DNA manipulation are performed using strains of microorganisms dependent on laboratory conditions for survival, or under other containment conditions. Using the same technologies, people have engineered work-horse bacteria (by introducing appropriate DNA) to facilitate the large-scale production of vaccines and drugs, such as insulin for diabetics.

Not so new. If people can already manipulate genes and DNA at will, what was different about Venter’s recent work? In a series of papers published over the past several years, Venter’s group worked out several technological advances. First, building on previous technology, they devised techniques to manipulate and concatenate very large pieces of DNA, eventually as large as an entire bacterial genome (~1 million base pairs or 1 Mb, compared to ~3 billion base pairs in the human genome). They first accomplished these tasks using non-synthetic DNA, that is, DNA extracted from one bacterium and put back into another such that the host would use the donor DNA as its sole genetic information.
With the ability to manipulate and transplant bacterial-genome-sized pieces of DNA, they set about to do the same thing starting with chemically synthesized DNA. That is, rather than starting from DNA extracted from an organism, they started with chemically synthesized stretches of DNA that were ultimately assembled–with the further engineering facilitated by bacteria and yeast–into one large piece of DNA. The sequence of DNA used to design the starting fragments was based on a known bacterial genome sequence chosen for its relatively small size and fast replication time. The designed sequence contained traceable “watermarks” or unique sequences (some of which whimsically spell out quotes from famous scientists). They then introduced the DNA into a closely related bacterial species using their genome “transplantation” technique, replacing the host genome with that of the donor. Soon the host produced proteins characteristic of the donor species, rather than its own.

A new owner. Was this “creation”?  No. Is it artificial life? No. Venter’s group designed the chromosome to closely match a known sequence from a pre-existing bacteria species. Natalie Angier, writing in the New York Times, described it as an “otherwise plagiarized” genome. The new DNA was transplanted into a related species’ cell that was already stuffed with all the proteins, membranes, and molecular machines necessary to decode and use the DNA sequence as if it were its own. This process essentially changed one bacterial species into something much like another related species, but with additional design features inserted in the genome to distinguish it. Imagine a house with a new owner who, in addition to evicting the old owner, sets about to replace each nail, plank, wall and shingle, piece by piece over time according to his own plans. Because the new DNA encodes new proteins, as the bacteria goes through its usual routine of replication, and the building, destruction, and recycling of new molecules, eventually all the cellular material will be turned over and will resemble the new species.

Why the fuss?  We can already cut and paste genes in and out of bacteria to get them to produce substances that are beneficial. Indeed, such technology can also be used for harm–this is the familiar double-edged sword of many technologies. In fact, the usual way of using existing DNA as a template for modification is a lot easier and cheaper than starting from scratch as the Venter group did. But what they did was prove the principle that with the right information, the right technology, and the right environment, one can design a new genome de novo and get it to work.