Synthetic Biology Interdisciplinary Challenge 5
Why are human-designed biological circuits and devices fragile and inaccurate relative to their natural counterparts?
Challenge Summary
Three characteristic features of natural biological systems are robustness, adaptability, and redundancy. Natural systems are remarkably resistant to failure induced by changes in component abundance or activity (robustness), yet they maintain an underlying flexibility required to allow them to adjust to new environments (adaptability and redundancy). By contrast, many synthetic systems lack robustness, especially when compared to their natural counterparts that perform a similar task. Adaptability and redundancy are typically not considered. Two examples of synthetic systems that lack certain aspects of robustness are:
(1) Ajo-Franklin et al (see reading references) designed and characterized an elegant memory device in yeast that is based on a synthetic transcriptional cascade. This device does exhibit memory, but is sensitive to dilution of the autoactivator component during growth and requires “tuning” of growth rate by changes in media to maintain bistability.
(2) Elowitz and Leibler (see reading references) constructed an oscillator based on a transcriptional cascade and found that only a fraction of cells exhibited oscillations; additionally, they observed significant variation in the period and amplitude between cells in a population. In comparison, the transcriptional oscillations associated with the circadian clock are far more robust.
What can we learn from comparisons of designed systems and their natural counterparts?
Comparison of synthetic systems with those of their natural counterparts can be extremely informative -- such studies sometimes provide insights that can be used to improve the function and design of engineered systems. Additionally, these comparisons can reveal the presence of previously unappreciated complexity and phenomena. Such an example comes from the Elowitz and Leibler study mentioned above, where these authors recognized that the oscillator was “noisy” and speculated that such noise might arise from stochastic fluctuations in transcription in cells. This observation was the motivation for the development of what turned out to be a highly influential method for quantifying stochastic fluctuations in gene expression, and the demonstration that transcription in E. coli is indeed noisy.
Can we harness the power of evolution to shape and design more robust systems?
The forces of evolution shape natural systems. In the process of natural selection, a population of cells or organisms effectively explores parameter space in a manner that allows for the discovery of biological circuits that are robust, adaptable and redundant. In contrast, many efforts in synthetic biology are engineering-based and exploit the modular nature of biology to assemble functioning circuits from sets of well-characterized component parts. It will be interesting to see if it is possible to use experimental evolution to discover or tune synthetic circuits that exhibit robustness, adaptability, and the redundancy seen in natural systems.
Key Questions
The challenge to this interdisciplinary team is to identify reasons why human designed biological circuits and devices are fragile and inaccurate relative to their natural counterparts. As a framing for the discussion, the team is encouraged to consider the following key questions:
- What are “design principles” observed in natural circuits that have not been implemented in synthetic circuits and that may increase the reliability and robustness of engineered circuits?
- How can these new design principles be most effectively implemented into human-designed circuits?
- Are new tools required?
- Are new characterization methods and strategies required in order to measure properties such as robustness and adaptability?
- How can evolution be effectively integrated as a design principle into synthetic circuits
Reading
Ajo-Franklin CM, Drubin DA, Eskin JA, Gee E, Landgraf D, Phillips I, Silver PA. Rational design of memory in eukaryotic cells. Genes Dev 2007;21:2271: http://genesdev.cshlp.org/content/21/18/2271.full. Accessed online 28 July 2009.
Elowitz MB and Leibler S. A synthetic oscillatory network of transcriptional regulators. Nature 2000;403:335:http://www.nature.com/nature/journal/v403/n6767/full/403335a0.html Accessed online 28 July 2009.
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