Re-membering the body: applications of computational neuroscience to the top-down control of regeneration of limbs and other complex organs

Abstract

A major goal of regenerative medicine and bioengineering is the regeneration of complex organs, such as limbs, and the capability to create artificial constructs (so-called biobots) with defined morphologies and robust self-repair capabilities. Developmental biology presents remarkable examples of systems that self-assemble and regenerate complex structures toward their correct shape despite significant perturbations. A fundamental challenge is to translate progress in molecular genetics into control of large-scale organismal anatomy, and the field is still searching for an appropriate theoretical paradigm for facilitating control of pattern homeostasis. However, computational neuroscience provides many examples in which cell networks (brains) store memories of geometrical states and coordinate their activity towards proximal and distant goals. In this Perspective, we propose that programming large-scale morphogenesis requires exploiting the information processing by which cellular structures work toward specific shapes. In non-neural cells, as in the brain, bioelectric signaling implements information processing, decision-making, and memory in regulating pattern and its remodeling. Thus, approaches used in computational neuroscience to understand goal-seeking neural systems offer a toolbox of techniques to model and control regenerative pattern formation. Here, we review recent data on developmental bioelectricity as a regulator of patterning, and propose that target morphology could be encoded within tissues as a kind of memory, using the same molecular mechanisms and algorithms so successfully exploited by the brain. We highlight the next steps of an unconventional research program, which may allow top-down control of growth and form for numerous applications in regenerative medicine and synthetic bioengineering.

Mechanisms of urodele limb regeneration

“…In a series of papers, Levin and colleagues have described the bioelectric code and provided extensive evidence for its existence and function. In addition, they have provided many examples of manipulation of the code that result in the rearrangement of large‐scale pattern (Levin, 2011, 2013; Mustard & Levin, 2014; Pezzulo & Levin, 2015). For example, a number of cell membrane channels associated with eye formation in Xenopus embryos induced eye formation in the gut, tail, or lateral plate mesoderm when misexpressed in these regions.…”

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

“…Much like organisms maintaining morphostasis, tumors maintain their identity during massive cell turnover during selection for founder cells resistant to chemotherapy drugs [455]. Recent work describes the highly malignant brain tumor as an 'opportunistic, self-organizing, and adaptive complex dynamic biosystem' [456], which is also a great description of an embryo; proper characterization of the essential principles predictive of the properties of tumor invasion makes uses of concepts such as least resistance, most permission, and highest attractionthese are systems-level, goal-directed elements that are very compatible with the conceptual modeling techniques suggested for understanding embryogenesis and regeneration of whole organisms [20,182]. Much analysis and experimentation will be needed to reveal whether a tumor and its activity in the body is best modeled as the activity of unicellular organisms, emergent swarm dynamics of the tumor 'colony', or a cognitive structure embodied in a kind of group cognition of the tumor 'organoid' [457][458][459][460].…”

“…Most importantly, the known ability of bioelectric networks to process global information and implement networks with multiple causal layers (e.g. goal-directed activity mediated by brain bioelectric circuits) make it an ideal nexus from which to understand and manipulate cancer as an error of global organization [20,182]. Thus, in prelude to the discussion of mathematical theory germane to topdown approaches to cancer, we first review a set of important emerging mechanisms that provide plentiful fodder-both quantitative and conceptual datafor computational analyses to the control of cancer as a defection from normal developmental cues.…”

“…Inter-regional information transfer has, for example, been measured in neural fMRI data [428] to infer the informational structure of visuo-motor tracking in the brain. Importantly, metrics from computational neuroscience have begun to be applied to the problem of developmental/regenerative patterning [65,182,429], and the emerging field of primitive cognition suggests a research program to understand the information processing/computational capacity of tumor cells versus normal cells, and tumors versus normal organs.…”

From cytoskeletal dynamics to organ asymmetry: a nonlinear, regulative pathway underlies left–right patterning

“…A dynamical system view of these repair pathways, as a network rather than a linear pathway with 'necessary and sufficient' master regulators, is necessary, as has already been noted in the field of cancer and the search for driver genes [215][216][217][218][219][220]. The future is likely to involve not only molecular-genetic picture of these repair pathways, but a cybernetic, systems-control view of the information processed by these closed-loop, shape-homeostatic capabilities of embryogenesis [221][222][223][224][225]. It thus becomes clear that checking immediate downstream consequences of gene misexpression is not sufficient for functional analyses; a subtler strategy targeting further upstream of a gene of interest, which gives the embryo more time to recognize errors, is required to form a full picture of regulatory networks and 'necessary and sufficient' claims for an explanation of what gene product determines expression of some other gene product.…”