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Top-down models in biology: Explanation and control of complex living systems above the molecular level

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Journal of the Royal Society Interface
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Giovanni Pezzulo at Italian National Research Council
Giovanni Pezzulo
Michael Levin at Tufts University
Michael Levin
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Abstract

It is widely assumed in developmental biology and bioengineering that optimal understanding and control of complex living systems follows from models of molecular events. The success of reductionism has overshadowed attempts at top-down models and control policies in biological systems. However, other fields, including physics, engineering and neuroscience, have successfully used the explanations and models at higher levels of organization, including least-action principles in physics and controltheoretic models in computational neuroscience. Exploiting the dynamic regulation of pattern formation in embryogenesis and regeneration requires new approaches to understand how cells cooperate towards large-scale anatomical goal states. Here, we argue that top-down models of pattern homeostasis serve as proof of principle for extending the current paradigm beyond emergence and molecule-level rules. We define top-down control in a biological context, discuss the examples of how cognitive neuroscience and physics exploit these strategies, and illustrate areas in which they may offer significant advantages as complements to the mainstream paradigm. By targeting system controls at multiple levels of organization and demystifying goal-directed (cybernetic) processes, top-down strategies represent a roadmap for using the deep insights of other fields for transformative advances in regenerative medicine and systems bioengineering. © 2016 The Author(s) Published by the Royal Society. All rights reserved.
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Perspective
Cite this article: Pezzulo G, Levin M. 2016
Top-down models in biology: explanation and
control of complex living systems above the
molecular level. J. R. Soc. Interface 13:
20160555.
http://dx.doi.org/10.1098/rsif.2016.0555
Received: 12 July 2016
Accepted: 11 October 2016
Subject Category:
Life Sciences–Engineering interface
Subject Areas:
systems biology, synthetic biology, biophysics
Keywords:
top-down, integrative, cognitive modelling,
developmental biology, regeneration,
remodelling
Author for correspondence:
Michael Levin
e-mail: michael.levin@tufts.edu
Top-down models in biology: explanation
and control of complex living systems
above the molecular level
Giovanni Pezzulo2and Michael Levin1
1
Biology Department, Allen Discovery Center at Tufts, Tufts University, Medford, MA 02155, USA
2
Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy
GP, 0000-0001-6813-8282; ML, 0000-0001-7292-8084
It is widely assumed in developmental biology and bioengineering that opti-
mal understanding and control of complex living systems follows from
models of molecular events. The success of reductionism has overshadowed
attempts at top-down models and control policies in biological systems.
However, other fields, including physics, engineering and neuroscience,
have successfully used the explanations and models at higher levels
of organization, including least-action principles in physics and control-
theoretic models in computational neuroscience. Exploiting the dynamic
regulation of pattern formation in embryogenesis and regeneration requires
new approaches to understand how cells cooperate towards large-scale
anatomical goal states. Here, we argue that top-down models of pattern
homeostasis serve as proof of principle for extending the current paradigm
beyond emergence and molecule-level rules. We define top-down control
in a biological context, discuss the examples of how cognitive neuroscience
and physics exploit these strategies, and illustrate areas in which they may
offer significant advantages as complements to the mainstream paradigm.
By targeting system controls at multiple levels of organization and demysti-
fying goal-directed (cybernetic) processes, top-down strategies represent a
roadmap for using the deep insights of other fields for transformative
advances in regenerative medicine and systems bioengineering.
1. Introduction
If you want to build a ship, don’t herd people together to collect wood, and don’t
assign them tasks and work, but teach them to long for the endless immensity of
the sea.
—Antoine de Saint-Exupery, ‘Wisdom of the Sands’.
1.1. Levels of explanation: the example of pattern regulation
Most biological phenomena are complex—they depend on the interplay of many
factors and show adaptive self-organization under selection pressure [1]. One of
the most salient examples is the regulation of body anatomy. A single fertilized
egg gives rise to a cell mass that reliably self-assembles into the complex three-
dimensional structure of a body. Crucially, however, bioscience needs to understand
more than the feedforward progressive emergence of a stereotypical pattern. Some
animals have the remarkable ability to compensate for huge external perturbations
during embryogenesis, and as adults can regenerate amputated limbs or heads,
remodel whole organs into other organs if grafted to ectopic locations (figure 1a),
and reprogramme-induced tumours into normal structures (reviewed in [4,5]).
These capabilities reveal that biological structures implement closed-loop controls
that pursue shape homeostasis at many levels, from individual cells to the entire
body plan.
Biologists work towards two main goals: understanding the system to make
predictions and inferring manipulations that lead to desired changes. The
former is the province of developmental and evolutionary biology, whereas
&2016 The Author(s) Published by the Royal Society. All rights reserved.
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