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MARGINALIA

Making Life from Scratch

Artificial intelligence is not human intelligence, nor is synthetic life the same as life with evolutionary history.

Robert L. Dorit

The Cell with No Past

Despite our growing knowledge of cellular circuitry, engineering novel organisms from existing genetic elements with the use of the top-down strategy has proven surprisingly hard. Individual genes drawn from one bacterium do not always behave as expected when placed in a different host. The more heterogeneous the collection of novel elements introduced, the less likely they are to perform as expected. Regulation, synchronization, and feedback collapse as the subtle conversation underlying all the networks in living systems degenerates into babble.

My colleagues and I wrestle with the seeming contradiction between the apparent modularity of genetic information and the maddeningly difficult task of designing a new organism from preexisting and well-characterized genetic information. The explanation, I suspect, lies in one of the fundamental differences between biology and engineering: the importance of history.

When researchers combine genetic information from disparate sources into a single genome, they are by definition dismissing history. In so doing, they are foolishly expecting genetic elements to behave predictably independent of their surroundings. But virtually no gene is an island, and all genetic information has been shaped by evolution in the context of an entire genome, itself harbored within an organism. As a result, only a handful of genetic elements really do behave independent of their location. Antibiotic resistance genes may be an example: Actively traded among species in the microbial world, they seem strangely impervious to their surroundings—but only because they have evolved to be so.

Evolution is a blind, brute-force experiment, testing innumerable solutions, much like Deep Blue’s playing chess by methodically examining virtually every possible move. This natural experiment, ongoing for more than three billion years, is constantly placing functional genetic elements in novel contexts. Sometimes this relocation is the result of an orderly evolved mechanism (such as recombination during cell division), sometimes it is the consequence of unexpected random events (such as breaks in a chromosome or translocation of genes across species barriers).

In evolution’s natural experiment every movement of genetic information into a new neighborhood is carefully scrutinized by selection. Genetic elements placed in new contexts coevolve with their neighbors into higher-order networks that contribute to the survival and reproduction of the organism. Those that do not are quickly weeded out by selection. This history of coevolution—of genetic elements having evolved together in the same genetic neighborhood—is what synthetic biology will need to incorporate into its approach if it hopes to realize its stated ambitions.

Similarly, practitioners of the bottom-up strategy have to contend with the myriad ways organisms have evolved to operate with the amino acids and nucleotides that were exploited—in what may have been only a fortunate accident—early in the origins of life. The entire history of life—from its beginnings as organized chemistry—has given rise to enzymes and organelles that are exquisitely dependent on the chemistry and architecture of the existing nucleotide and amino acid building blocks. The complex interlocking cellular machinery of life evolved around this small subset of available (or easily produced) building blocks and simultaneously learned to discriminate against variants and alternatives. As a result, synthetic biologists seeking to expand the size and meaning of the genetic alphabet are constantly contending with history. Other chemical beginnings can be envisioned and synthesized, but the contingent history of life as it has actually unfolded cannot be so easily overcome, and it constrains what synthetic biology can hope to achieve with new fundamental blocks.

Our efforts in synthetic biology have already taught us a great deal. By confirming the fact that life as it exists today is but one realized embodiment amid many possible and by reminding us yet again that contingency matters, the research agenda of synthetic biology has already borne fruit. I suspect that we may eventually succeed in creating an artificial cell from novel starting materials. This truly new synthetic cell may be able to sustain a complex network of coupled metabolic reactions and may even be capable of reproducing and evolving. But I would wager that it will do so in ways radically different from existing living cells.

Deep Blue taught us a great deal about the power of the human mind precisely because it could not reproduce the intuitive and logical leaps of Kasparov’s mind. A truly synthetic cell, built from scratch or even from preexisting components, will be a cell without ancestry, and it, too, will teach us a great deal about the underlying complexities of life without actually reproducing them. In so doing, it will remind us yet again that biology is not just engineering, that organisms are not just machines assembled from preexisting parts, and that history matters to living systems in profound and inescapable ways.

Bibliography

  • Benner, S. A., and A. M. Sismour. 2005. Synthetic biology. Nature Reviews Genetics 6:533–543.
  • Collins, J. 2012. Synthetic biology: Bits and pieces come to life. Nature 483:S8–S10.
  • Gibson, D. G., et al. 2010. Creation of a bacterial cell controlled by a chemically synthesized genome. Science 329:52–56.
  • Khalil, A. S., and J. J. Collins. 2010. Synthetic biology: Applications come of age. Nature Reviews Genetics 11:367–379.
  • Schwille, P. 2011. Bottom-up synthetic biology: Engineering in a tinkerer’s world. Science 333:1252–1254.
  • Young, T. S., and P. G. Schultz. 2010. Beyond the canonical 20 amino acids: Expanding the genetic lexicon. Journal of Biological Chemistry 285:11039–11044.




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