Perspective Modeling Planarian Regeneration: A Primer for Reverse- Engineering the Worm Daniel Lobo, Wendy S. Beane, Michael Levin* Center for Regenerative and Developmental Biology, and Department of Biology, Tufts University, Medford, Massachusetts, United States of America chines and fault-tolerant, robust systems. Abstract: A mechanistic under- the cellular mechanisms that are A medical treatment that would enable a standing of robust self-assembly and thought to underlie them. By es- person to regenerate a completely new repair capabilities of complex systems tablishing an engineering-like style head, or a robotic system that could would have enormous implications for reviews of the molecular devel- automatically recover its proper structure for basic evolutionary developmental opmental biology of biomedically and function after losing more than 99% biology as well as for transformative important model systems, signifi- of its constitutive parts, is still only a applications in regenerative biomed- cant fresh insights and quantitative dream. However, there does exist a icine and the engineering of highly computational models will be de- natural system capable of performing these fault-tolerant cybernetic systems. Mo- veloped by new collaborations amazing feats: the planaria. lecular biologists are working to between biology and the informa- Planarians are nonparasitic flatworms identify the pathways underlying the tion sciences. remarkable regenerative abilities of that have bilateral symmetry, a true brain model species that perfectly regener- driving a complex behavioral repertoire ate limbs, brains, and other complex [2], and an extraordinary capacity to body parts. However, a profound regenerate due to the presence of a large disconnect remains between the adult stem cell population [3]. Individual deluge of high-resolution genetic Possibly the people who are trying to planarians are practically immortal—able and protein data on pathways re- discover how to set up a computer to to regenerate aging, as well as severely quired for regeneration, and the learn to play good chess, or bridge, damaged or lost, tissues [4]. A trunk desired spatial, algorithmic models are among those most likely to make fragment cut from the middle of an adult that show how self-monitoring and a major contribution to the funda- planarian will regenerate into a whole growth control arise from the synthe- worm, always growing a new head and sis of cellular activities. This barrier to mental theory of evolution. — C. H. Waddington [1] new tail in the same orientation as the progress in the understanding of original worm. As little as 1/279th of a morphogenetic controls may be planarian [5], or a fragment with as few as breached by powerful techniques 10,000 cells [6], can regenerate into a new from the computational sciences— Introduction using non-traditional modeling ap- worm within 1–2 weeks. Planaria are a proaches to reverse-engineer systems The ability to control the pattern popular model for molecular-genetic and such as planaria: flatworms with a formation of organs and appendages is a biophysical dissection of pathways that complex bodyplan and nervous sys- key aim of regenerative medicine. Trans- underlie regenerative patterning [4,7,8], tem that are able to regenerate any formative impact in areas such as birth having more genes in common with body part after traumatic injury. defects, traumatic injury, cancer, and humans than with the fruit fly Drosophila. Currently, the involvement of experts degenerative disease requires that we A mechanistic understanding of the com- from outside of molecular genetics is understand the molecular mechanisms munication and control networks that hampered by the specialist literature that allow living beings to detect and maintain complex shape against radical of molecular developmental biology: repair damage to complex biological perturbations will revolutionize our ability impactful collaborations across such structures. A similar goal is pursued by to regulate stem cell behavior in the different fields require that review engineers seeking to build resilient ma- context of the host organism. Thus, literature be available that presents the key functional capabilities of important biological model systems Citation: Lobo D, Beane WS, Levin M (2012) Modeling Planarian Regeneration: A Primer for Reverse- while abstracting away from the Engineering the Worm. PLoS Comput Biol 8(4): e1002481. doi:10.1371/journal.pcbi.1002481 often irrelevant and confusing details Editor: Takashi Gojobori, National Institute of Genetics, Japan of specific genes and proteins. To Published April 26, 2012 facilitate modeling efforts by comput- Copyright: ß 2012 Lobo et al. This is an open-access article distributed under the terms of the Creative er scientists, physicists, engineers, and Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, mathematicians, we present a differ- provided the original author and source are credited. ent kind of review of planarian Funding: This work was supported by the Telemedicine and Advanced Technology Research Center (TATRC) regeneration. Focusing on the main at the U.S. Army Medical Research and Materiel Command (USAMRMC) through award W81XWH-10-2-0058. ML patterning properties of this system, is also grateful for the support of the G. Harold and Leila Y. Mathers Charitable Foundation, and NSF CDI grant - EF-1124651. WSB gratefully acknowledges the support of the NIH Kirschstein-NRSA grant F32 GM08354. The we review what is known about the funders had no role in the preparation of the manuscript. signal exchanges that occur during regenerative repair in planaria and Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] PLoS Computational Biology | www.ploscompbiol.org 1 April 2012 | Volume 8 | Issue 4 | e1002481 reverse-engineering the remarkable system processes [14,15] (for excellent introduc- In this review, we hope to close the gap that is planarian regeneration would have tions to biological pattern formation mod- between regenerative biology and the profound impacts on regenerative medi- eling see [16–19]). Unlike bare gene or fields of mathematics, computer science, cine, bioengineering, synthetic biology, protein networks, such models are con- and engineering and lower the barrier for and robotics. structive in the sense that they make experts from the information and systems Regeneration in planarians involves a explicit the events that need to occur to engineering sciences to apply their knowl- truly complex interaction of several sys- create a specific shape. Only a handful of edge to unraveling the mechanisms of tems at the organismal level. After an algorithmic models have been proposed large-scale regeneration. Here we provide injury, the stem cells in the worm over the years to explain regeneration in an overview of the planarian regeneration proliferate and migrate to form a protec- planarians [20–23] (see ‘‘Existing Models’’ system, explain what is known about the tive mass of new cells (blastema) at the section below and Supplemental Text S1), signaling mechanisms, summarize the wound site. This cell proliferation is tightly and none of them successfully integrate proposed partial models in the literature, coordinated with the selective destruction more than one or two key features of and frame the specific issues that must be of some old cells (apoptosis), effectively regeneration. addressed to bring the power of interdis- remodeling both the new and old tissues to There is a gap between the success of ciplinary investigation to fruition. Our recreate exactly those regions and organs high-resolution genetic analysis and the goal is to present the basic features of this the worm is missing, adjust the propor- needed level of insight into systems-level system from an engineering perspective to tions of the remaining regions and organs mechanisms that enable adaptive control facilitate modeling approaches [35–38]. If to the new smaller worm size, and of pattern formation. A fresh set of ideas the modeling and engineering communi- maintain the original patterning orienta- may be helpful, from areas of science that ties can be engaged to produce algorith- tion of the worm with the new tissues. have developed techniques for reverse- mic models that can accurately explain These complex interactions are controlled engineering complex systems, utilizing the regeneration process, the application by a diverse set of signals, including analytical methods and types of models of biologically inspired computational molecular pathways, gap junctional com- that are distinct from those familiar to ideas will feed back into biology and aid munication, ion fluxes, and nervous sys- most cell biologists today. Construction of our understanding of complex biological tem signals. Although essential for regen- in silico implementations is especially systems [39]. Conversely, the insights eration, the mechanisms by which these crucial; for any but the most trivial set of gained from the construction and appli- signals integrate to maintain and restore relationships among subunits, running a cation of these regenerative models will the correct geometry of the animal are still simulation on a computer is the only way equally benefit computer science, artificial not well understood. to determine the predictions of a given life, robotics, and many areas of engi- After more than 100