doi:10.1038/nindia.2011.26 Published online 28 February 2011

Biology by design

Why is it a good idea to use the engineering approach rather than using equations to design biological systems? Pawan Kumar Dhar explores.

Biological systems are noisy and unpredictable. To create predictable systems in biology, one needs standards and rules.

Enter synthetic biology — an engineering inspired approach to design novel parts, devices and circuits for constructing biological systems. This stream is understandably also called by one of several other names — intentional biology, constructive biology, biological engineering, biological technology.

Traditionally, biology has been studied by decomposing systems one part at a time. In synthetic biology, one composes the system one part at a time. The idea is to document individual part behaviour and stitch parts together to design controllable systems and organisms.

Biology and engineering

Synthetic biology takes inspiration from engineering to design novel biological parts.

Upon first glance, one finds many things common between engineering and biological systems. Both are robust, multi-tasking, serial and parallel systems. Both show analog and digital behaviours. Moreover, a number of biological equivalents of 'logic gates' are found in organisms.

Some technical examples — an activator and an inducer that trigger a gene expression seem to represent the logic 'AND gate'. The lac operon seems represents a logic 'NOT gate' i.e., when the repressor is ON, the protein output is OFF. Thus, it is encouraging to use engineering approaches to construct biological systems de novo.

However, a closer look reveals several key differences between the disciplines. As opposed to engineering systems, organisms are predominately analog, have mobile parts (RNA and proteins) and show contextual behaviors. Unlike engineering systems, where laws of physics are used to build complex systems, biology is governed by the century-old laws of inheritance. The recent progress in metagenomics and epigenetics has made the search of new biological laws more difficult. It is clear that every organism is unique, uses methylation mechanisms, non-protein coding DNA and a large number of bacteria for survival. Even under constant culture conditions a cell line can evolve over time to acquire a different genetic composition.

Even so, it is good to use the engineering approach to design biological systems rather than copying and pasting equations from physics because absolute engineering solutions for biological problems do not exist. Probably engineers didn't face a problem as complex as biology!

Tackling the complexity

The complexity of biology is not in terms of numbers. It is in the uncertainty of interactions and expression, which cannot be reliably predicted in advance by just looking at the DNA or protein sequence. Also, cells exhibit micro to macro complexity, the space and time complexity and the structural complexity. From an atom to the cell level, information must travel at least six orders of magnitude in size! Moreover, biological data is incomplete and inaccurate.

The challenge is to build a reliable system using incomplete and sometimes inaccurate data.

The solution to this is probably to gather more data, develop a well characterized parts-inventory, with each part tagged to a data sheet of truth table, lag time, transfer function, best operating conditions and so on. Synthetic Biology work during the last decade delivers this key message of performing rich parts-characterization for rational biological engineering, . Recognizing the need to have more data around each part, the biobricks programme was started several years ago at the Massachusetts Institute of Technology (MIT). Simply put, a biobrick is a natural DNA sequence (such as a gene or a promoter) without certain restriction sites. For a normal part to be transformed into a biobrick, these sites must be removed from the part and included as prefix and suffix of a given DNA sequence. The hope is that complex systems can be easily assembled ground up.

Redoing a genetic part with slight modification and renaming it as biobrick does not address the underlying biological complexity. It's time that cell specific non-biobrick initiatives are started to construct parts-behavior inventory and understand their quantitative behaviour in natural settings.

Technically, it is less challenging to assemble devices from individual parts. However, it is more challenging to control what has been created,due to the fundamental non-linearity and analog nature of molecular interactions. A large number of examples point to the frustrations that people had to experience while constructing pre-designed circuits, a classic example being the repressilator — a three gene circuit developed and installed as oscillatory applet independent of cellular control.

The core issue often overlooked in synthetic biology is the fact that a cell is an evolving system. There will always be possibilities of mutations changing the properties of synthetic devices carefully designed in controlled environments. For biology to move completely into the realm of engineering, evolution must be stopped!


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