Systems approaches for synthetic biology: a pathway toward mammalian design

Abstract

We review methods of understanding cellular interactions through computation in order to guide the synthetic design of mammalian cells for translational applications, such as regenerative medicine and cancer therapies. In doing so, we argue that the challenges of engineering mammalian cells provide a prime opportunity to leverage advances in computational systems biology. We support this claim systematically, by addressing each of the principal challenges to existing synthetic bioengineering approaches—stochasticity, complexity, and scale—with specific methods and paradigms in systems biology. Moreover, we characterize a key set of diverse computational techniques, including agent-based modeling, Bayesian network analysis, graph theory, and Gillespie simulations, with specific utility toward synthetic biology. Lastly, we examine the mammalian applications of synthetic biology for medicine and health, and how computational systems biology can aid in the continued development of these applications.

Using synthetic biology to explore principles of development

“…It should be noted, however, that there is a tendency in the field of synthetic biology to exaggerate the ease with which systems can be constructed by combining simple modules to perform a new function predictably (see Kwok, 2010, for a review of this exaggeration, and Pasotti et al, 2012;Ang et al, 2013;Rekhi and Qutub, 2013;Beal, 2015;Carbonell-Ballestero et al, 2016 for recent analysis of specific challenges to predictability and potential strategies for their mitigation). There is also a tendency to assess the success of a project according to the simple question 'does it work as expected?'.…”

The Billion Cell Construct: Will Three-Dimensional Printing Get Us There?

“…For example, models of angiogenesis, the sprouting of new blood vessels from pre-existing ones, are transitioning into 3D [46] and are backed by multiscale models [68]. When coupled with readouts that can measure cellular activity with spatiotemporal perspective, we might be able to better direct cellular motions and tissue deformations and stresses [69]–[71].…”

“…To understand morphogenesis and cooperativity in large-scale tissues, we need techniques which can pattern cell populations to focus and understand their behavior [65] , [66] in all three dimensions [67] . For example, models of angiogenesis, the sprouting of new blood vessels from pre-existing ones, are transitioning into 3D [46] and are backed by multiscale models [68] . When coupled with readouts that can measure cellular activity with spatiotemporal perspective, we might be able to better direct cellular motions and tissue deformations and stresses [69] – [71] .…”

Modeling Genetic Circuit Behavior in Transiently Transfected Mammalian Cells

“…Modern synthetic biology is inseparable from the computational models that guide the construction of synthetic networks 12 . One challenge in building such models for mammalian cells arises from the need for a more comprehensive understanding of the cellular mechanisms underlying the transfection system 12,13 .…”

“…Modern synthetic biology is inseparable from the computational models that guide the construction of synthetic networks 12 . One challenge in building such models for mammalian cells arises from the need for a more comprehensive understanding of the cellular mechanisms underlying the transfection system 12,13 . Another challenge is predicting the behavior of genetic circuits based on the behavior of the building blocks of the circuits [14][15][16][17][18][19][20] .…”