A Complexity Science Approach to Plant Tissue Regeneration

Tissue regeneration in multi-cellular organisms is a topic of great interest both from a basic scientific point of view and from an applied one. In the attempt to shed new light on the fundamental nature of the mechanisms underlying tissue regeneration, this project intends to test experimentally a quite technical but intriguing hypothesis on the way cellular divisions are organized during regeneration.

The experimental case studied is that of a plant's root that completely regenerates its tip when this is excised by mechanical means, and a multi-disciplinary approach combining live imaging and advanced statistical analysis is followed.
From the experimental point of view, the main challenge is to develop a type of microscope that allows very frequent observations of the internal organisation of a regenerating root, without of course killing the root. The idea is to be able to collect data about when and where cell divisions occur during the tissue re-growth and reorganization, and this can be achieved through a non-invasive technique that detects fluorescent proteins in the sample. The trick is to genetically engineer a fluorescent protein that is expressed in a cell only at the moment of its division, and this has been done, already.

The initial part of this project is dedicated to the optimisation of a microscope - starting from existing prototypes - specifically redesigned to image for many days a regenerating root, quite often and at cellular resolution. Time-lapse sequences will be then systematically collected with this instrument, to capture in great details the regeneration of the root tip.
The more advanced part of the project is aimed at the statistical analysis of such data, to test the hypothesis that the dynamics of cellular divisions guiding root regeneration shares common features with a wide class of complex phenomena found in physics and biology, as different from each other as sand piles, earthquakes, flying birds or neural networks. This class is sometimes called Self-Organizing Critical (SOC) systems, and is characterized by the ideas that (i) global patterns emerge simply from interactions among all the system's elements and without the need of a central director (self-organization) and that (ii) the system exhibits a spontaneous convergence towards a special (critical) state. At the critical state the system is said to be scale-free, which means that there is no typical length or duration in the underlying dynamics. Moreover, at the critical state some statistical distributions that describe the system's dynamics take a universal shape (power law distributions). It is a bit technical, but it turns out that these statistical distributions can be measured from the data collected with the microscope used in this project, and therefore it becomes possible to test whether a regenerating root behaves like a SOC system or not. We will then be able to test more in details the causal link between cellular interactions and global tissue behavior by developing a mathematical model designed to give a simplified representation of all the key characteristics of the system. This will be based on previous experience gained by applied mathematicians in the field of complexity science, where SOC and similar phenomena are studied in great details.
Finally, it is understood that any major improvement of our understanding on how a root can regenerate its tip after a major injury opens the possibility to enhance growth and resistance of plants of economic interests in harsh conditions. Moreover, any new insight in natural mechanisms leading to tissue repair and regeneration is of major interest for the biomedical and biotech community.

The goal of this multi-disciplinary project is to study the phenomenon of tissue regeneration from the novel point of view of complex systems, focusing on an original quantitative analysis of the cell division dynamics. The working hypothesis is that the process of regeneration can be described as the emergent property of a complex dynamical system, and that the underlying statistics of cell division events carries crucial information on the fundamental mechanisms driving the process. One intriguing possibility is that such dynamics could exhibit some degree of scale-free behaviour as would be indicated by (approximate) power-law distributions, suggesting a parallel with a very broad category of natural phenomena which operates at or near a state of self-organised criticality. Such a result would have a wide impact, well beyond developmental biology.

The approach proposed is multi-disciplinary in its essence, generating novel experimental data within developmental biology and analyzing it with mathematical tools adopted from current studies in complex systems. The methods will include novel high spatial and temporal-resolution live imaging, statistical analysis of response distributions in time series of cell division events, and mathematical modelling of effective cell-cell interactions leading to intermittent activity.

In synthesis, we propose to look for classic signs of scale-free behaviour in the temporal distribution of cell divisions during root tip regeneration. A scale-free dynamics, one where no characteristic scale length or duration can be identified, is a classic hallmark of criticality observed, at least to some degree, in a variety of phenomena ranging from earthquake events to brain neuronal activity. The main question here addressed is whether this notion can be extended to complex phenomena in developmental biology.

The proposed project takes fully advantage of a typical systems biology approach. It naturally falls within the Exploiting New Ways of Working theme identified by BBSRC as integral part of its strategic priority Systems Approaches to Biosciences. The project promotes a combination of mathematical modelling imported from complexity science and novel live imaging, bringing together integrative systems biology and quantitative developmental biology. The case study is plant root regeneration, but the actual questions addressed are much more general and refer to the essence of multi-cellularity itself.
Due to the multi-disciplinary nature of the proposed approach, this project is likely to impact more than one scientific community and group of interest.

- Academic communities.
The project intersects topics in developmental biology, regenerative biology and root biology, together with generating mathematical and computational tools. This makes it likely to impact the work of developmental biologists, plant biologists, bio-physicists and applied mathematicians interested in complexity and self-organization, and computer scientists involved in automated image processing.

-Training the next generation.
The PDRA involved in this project will receive a unique training in developing ad hoc imaging tools, in taking a quantitative approach to developmental biology - particularly in complex morphological dynamics - and in developing original mathematical models. The proposed line of work will induce a strong multidisciplinary and out-of-the-box attitude within the lab and the department, without any doubts a critical skill to reach new achievements in world-class bioscience.

- Translations to agronomy and other industrial applications.
Since the exploration proposed in this application is mainly grounded in basic science, any potential practical application must be viewed with a long-term perspective.
Among these, the topic of plant root regeneration is of clear relevance for the agronomy industry, interested in translating mechanisms regulating plant growth and robustness into enhanced crop cultivations. This proposal is based on the model organisms Arabidopsis, but it is well understood that basic knowledge gained in this system often translates into agricultural or horticultural applications involving economically relevant crop species such as rice and corn. More specifically, the project presented here has the potential to significantly advance our understanding of tissue repair in roots, a crucial organ for plants. This would open the possibility to improve root resistance to harsh soil conditions, a topic very much pursued in the agronomy industry.
Other industry-related fields that will be interested in applying the results emerging from this project are the new and rapidly expanding area soft robotics and the more established bio-inspired engineering. At the core of the proposed study is the desire to expose new fundamental mechanisms driving tissue self-repair. This topic is highly relevant for anybody interested in either enhancing existing organisms, or producing completely artificial systems taking inspiration by solutions already successful in nature. The potentials for impact are vast.

- General public
We will seek opportunities to engage the general public by promoting and discussing the notion of multidisciplinary approaches to gain understanding of natural phenomena. Any potential for contributing to the "knowledge economy" will be considered and pursued. In particular, expanding on the idea that cross-pollination between disciplines has the potential to deliver truly innovative solutions to old problems and inspiration for new applications. This project and its results will be presented to the public as a clear example of that strategy.