Appreciation of the Machinations of the Blind Watchmaker

One danger in using the language of engineering to describe the patterns and operations of the evident products of natural selection is that invoking principles of design runs the risk of invoking a designer. But as we analyze the increasing amount of data on the genome and its organization across a wide array of organisms, we are discovering there are patterns and dynamics reminiscent of designs that we, as imperfect human designers, recognize as serving an engineering purpose, including the purpose to be designable and evolvable. There is no doubt that biological artifacts are the product of Dawkins’ Blind Watchmaker, natural selection. But natural selection has at its heart one of engineering’s most prized principles, optimization. Survival of the fittest, while not directly specifying an objective function that an organism must meet, nonetheless provides a clear figure of merit for long term biological success, persistence of lineages through reproduction of organisms, and is a well-formed if ever-changing specification. The mechanisms which provide the optimization algorithm for an organism to meet the demands of this changeable requirement, composed of a program subject to operations of mutation and interorganismal transfer and inheritance, are themselves under selection. Repeated rounds of this process leads, some argue, to architectures that facilitate evolution itself, the evolving of evolvability

Contextualizing context for synthetic biology--identifying causes of failure of synthetic biological systems.

Despite the efforts that bioengineers have exerted in designing and constructing biological processes that function according to a predetermined set of rules, their operation remains fundamentally circumstantial. The contextual situation in which molecules and single-celled or multi-cellular organisms find themselves shapes the way they interact, respond to the environment and process external information. Since the birth of the field, synthetic biologists have had to grapple with contextual issues, particularly when the molecular and genetic devices inexplicably fail to function as designed when tested in vivo. In this review, we set out to identify and classify the sources of the unexpected divergences between design and actual function of synthetic systems and analyze possible methodologies aimed at controlling, if not preventing, unwanted contextual issues

Detailed simulations of cell biology with Smoldyn 2.1.

Most cellular processes depend on intracellular locations and random collisions of individual protein molecules. To model these processes, we developed algorithms to simulate the diffusion, membrane interactions, and reactions of individual molecules, and implemented these in the Smoldyn program. Compared to the popular MCell and ChemCell simulators, we found that Smoldyn was in many cases more accurate, more computationally efficient, and easier to use. Using Smoldyn, we modeled pheromone response system signaling among yeast cells of opposite mating type. This model showed that secreted Bar1 protease might help a cell identify the fittest mating partner by sharpening the pheromone concentration gradient. This model involved about 200,000 protein molecules, about 7000 cubic microns of volume, and about 75 minutes of simulated time; it took about 10 hours to run. Over the next several years, as faster computers become available, Smoldyn will allow researchers to model and explore systems the size of entire bacterial and smaller eukaryotic cells

A Standard Parts List for Biological Circuitry

One of the hallmarks of biochemical circuits found in nature is analog, asymmetric, asynchronous design. That is, there is little standardization of parts, e.g. all the promoters have different strengths and kinetics, transcription factors are designed to have different effects at different loci, and each enzymatic reaction has its own idiosyncratic mechanism and rates. In addition, all of the heterogeneous circuit elements are executing their functions concurrently and asynchronously. Biological circuits are seemingly designed to deal with the fluctuating delays, different time-scales and energy requirements associated with each component process of the overall network. These factors also make design of novel biochemical circuitry from existent parts difficult to achieve. Without standardization, the qualitative design methods used in other engineering fields are simply inapplicable. The de facto design methodology for biological circuitry is natural selection. Rational design of biological systems by humans has remained restricted to rather small or hit-or-miss efforts and has often relied on the ability to "select" for biochemical parts that fulfill some criteria. In practice however biological-designers are rare, and solutions are usually realized through an expensive stepwise trial and error approach or through mutation and selection. Furthermore, these otherwise practical approaches are limited in terms of the problems they can solve. We believe that implementation of designed biological circuitry is limited by issues of practice

Fundamental Limits to Position Determination by Concentration Gradients

Position determination in biological systems is often achieved through protein concentration gradients. Measuring the local concentration of such a protein with a spatially-varying distribution allows the measurement of position within the system. In order for these systems to work effectively, position determination must be robust to noise. Here, we calculate fundamental limits to the precision of position determination by concentration gradients due to unavoidable biochemical noise perturbing the gradients. We focus on gradient proteins with first order reaction kinetics. Systems of this type have been experimentally characterised in both developmental and cell biology settings. For a single gradient we show that, through time-averaging, great precision can potentially be achieved even with very low protein copy numbers. As a second example, we investigate the ability of a system with oppositely directed gradients to find its centre. With this mechanism, positional precision close to the centre improves more slowly with increasing averaging time, and so longer averaging times or higher copy numbers are required for high precision. For both single and double gradients, we demonstrate the existence of optimal length scales for the gradients, where precision is maximized, as well as analyzing how precision depends on the size of the concentration measuring apparatus. Our results provide fundamental constraints on the positional precision supplied by concentration gradients in various contexts, including both in developmental biology and also within a single cell.Comment: 24 pages, 2 figure

Towards synthetic biological approaches to resource utilization on space missions.

This paper demonstrates the significant utility of deploying non-traditional biological techniques to harness available volatiles and waste resources on manned missions to explore the Moon and Mars. Compared with anticipated non-biological approaches, it is determined that for 916 day Martian missions: 205 days of high-quality methane and oxygen Mars bioproduction with Methanobacterium thermoautotrophicum can reduce the mass of a Martian fuel-manufacture plant by 56%; 496 days of biomass generation with Arthrospira platensis and Arthrospira maxima on Mars can decrease the shipped wet-food mixed-menu mass for a Mars stay and a one-way voyage by 38%; 202 days of Mars polyhydroxybutyrate synthesis with Cupriavidus necator can lower the shipped mass to three-dimensional print a 120 m(3) six-person habitat by 85% and a few days of acetaminophen production with engineered Synechocystis sp. PCC 6803 can completely replenish expired or irradiated stocks of the pharmaceutical, thereby providing independence from unmanned resupply spacecraft that take up to 210 days to arrive. Analogous outcomes are included for lunar missions. Because of the benign assumptions involved, the results provide a glimpse of the intriguing potential of 'space synthetic biology', and help focus related efforts for immediate, near-term impact

Pattern Formation with a Compartmental Lateral Inhibition System

We propose a compartmental lateral inhibition system that generates contrasting patterns of gene expression between neighboring compartments. The system consists of a set of compartments interconnected by channels. Each compartment contains a colony of cells that produce diffusible molecules to be detected by the neighboring colony, and each cell is equipped with an inhibitory circuit that reduces its production when the detected signal is stronger. We develop a technique to analyze the steady-state patterns emerging from this lateral inhibition system and apply it to a specific implementation. The analysis shows that the proposed system indeed exhibits contrasting patterns within realistic parameter ranges.Comment: 9 pages, 6 figure

Fast, cheap and somewhat in control

Efforts to manipulate living organisms have raised the question of whether engineering principles of hierarchy, abstraction and design can be applied to biological systems. Here, we consider the practical challenges to controlling living organisms that must be surmounted, or at least managed, if synthetic biology and cellular bioengineering are to be productive