Is the bottom-up approach enough to understand a whole system?

An opinion piece by IBEC group leader Xavier Trepat has appeared in the News and Views section of the current issue of Nature, which is devoted to ‘Bottom-up biology’.

In his piece ‘Bottom does not explain top’, Xavier argues that understanding how complex biological structures – or even entire cells – are built can only provide a certain amount of insight into how biological systems function at higher levels of organization. There are many variables such as density, or even pathologies suffered by the subject, that affect cell behavior at the mesoscale – that is, at the longer, more ‘system-level’ scale than that of the individual components of an organism. Cells in a group, for example, can sense or respond to external stimuli that an individual cell cannot identify.

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In Xavier’s opinion, to determine how complex living systems work, it’s better to try to understand the principles and variables that govern processes at the mesoscale. While reconstituting molecular-scale processes is useful in certain cases – engineering the genetic circuits responsible for cell communication is sufficient to control 3D tissue shape, for example – he believes that in order to shed light on what happens at the level of the biological system, experiments should probe tissues at multiple length- and timescales through both mechanical and biochemical manipulation.

Bottom-up approaches have attracted much interest recently among other researchers, including Matthew Good, a biologist at the University of Pennsylvania, who penned a companion piece in the same article, ‘Understanding by building’. He argues for bottom-up approaches, saying that engineering biological structures and behaviours  from their constituent parts reduces a complex living system to a more manageable set of components. In this way, the minimal set of proteins and interactions needed for the emergence of complex phenomena such as cell division can be defined. “Bottom-up approaches are useful, and we use them all the time in the lab, but it’s important to bear in mind that mechanisms in living systems do not originate at the bottom, but rather at intermediate scales,” he says. In fact, in the same issue of Nature, his group published another article using bottom-up approaches to engineer epithelial tissues.

Good M, Trepat X. (2018). Cell parts to complex processes, from the bottom up. Nature, 563(7730):188-189