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## Section: Research Program

### Research program

The recent advent of an increasing number of new microscopy techniques giving access to high throughput screenings and micro or nano-metric resolutions provides a means for quantitative imaging of biological structures and phenomena. To conduct quantitative biological studies based on these new data, it is necessary to develop non-standard specific tools. This requires using a multi-disciplinary approach. We need biologists to define experiment protocols and interpret the results, but also physicists to model the sensors, computer scientists to develop algorithms and mathematicians to model the resulting information. These different expertises are combined within the Morpheme team. This generates a fecund frame for exchanging expertise, knowledge, leading to an optimal framework for the different tasks (imaging, image analysis, classification, modeling). We thus aim at providing adapted and robust tools required to describe, explain and model fundamental phenomena underlying the morphogenesis of cellular and supra-cellular biological structures. Combining experimental manipulations, in vivo imaging, image processing and computational modeling, we plan to provide methods for the quantitative analysis of the morphological changes that occur during development. This is of key importance as the morphology and topology of mesoscopic structures govern organ and cell function. Alterations in the genetic programs underlying cellular morphogenesis have been linked to a range of pathologies.

Biological questions we will focus on include:

1. what are the parameters and the factors controlling the establishment of ramified structures? (Are they really organize to ensure maximal coverage? How are genetic and physical constraints limiting their morphology?),

2. how are newly generated cells incorporated into reorganizing tissues during development? (is the relative position of cells governed by the lineage they belong to?)

Our goal is to characterize different populations or development conditions based on the shape of cellular and supra-cellular structures, e.g. micro-vascular networks, dendrite/axon networks, tissues from 2D, 2D+t, 3D or 3D+t images (obtained with confocal microscopy, video-microscopy, photon-microscopy or micro-tomography). We plan to extract shapes or quantitative parameters to characterize the morphometric properties of different samples. On the one hand, we will propose numerical and biological models explaining the temporal evolution of the sample, and on the other hand, we will statistically analyze shapes and complex structures to identify relevant markers for classification purposes. This should contribute to a better understanding of the development of normal tissues but also to a characterization at the supra-cellular scale of different pathologies such as Alzheimer, cancer, diabetes, or the Fragile X Syndrome. In this multidisciplinary context, several challenges have to be faced. The expertise of biologists concerning sample generation, as well as optimization of experimental protocols and imaging conditions, is of course crucial. However, the imaging protocols optimized for a qualitative analysis may be sub-optimal for quantitative biology. Second, sample imaging is only a first step, as we need to extract quantitative information. Achieving quantitative imaging remains an open issue in biology, and requires close interactions between biologists, computer scientists and applied mathematicians. On the one hand, experimental and imaging protocols should integrate constraints from the downstream computer-assisted analysis, yielding to a trade-off between qualitative optimized and quantitative optimized protocols. On the other hand, computer analysis should integrate constraints specific to the biological problem, from acquisition to quantitative information extraction. There is therefore a need of specificity for embedding precise biological information for a given task. Besides, a level of generality is also desirable for addressing data from different teams acquired with different protocols and/or sensors. The mathematical modeling of the physics of the acquisition system will yield higher performance reconstruction/restoration algorithms in terms of accuracy. Therefore, physicists and computer scientists have to work together. Quantitative information extraction also has to deal with both the complexity of the structures of interest (e.g., very dense network, small structure detection in a volume, multiscale behavior, $...$) and the unavoidable defects of in vivo imaging (artifacts, missing data, $...$). Incorporating biological expertise in model-based segmentation methods provides the required specificity while robustness gained from a methodological analysis increases the generality. Finally, beyond image processing, we aim at quantifying and then statistically analyzing shapes and complex structures (e.g., neuronal or vascular networks), static or in evolution, taking into account variability. In this context, learning methods will be developed for determining (dis)similarity measures between two samples or for determining directly a classification rule using discriminative models, generative models, or hybrid models. Besides, some metrics for comparing, classifying and characterizing objects under study are necessary. We will construct such metrics for biological structures such as neuronal or vascular networks. Attention will be paid to computational cost and scalability of the developed algorithms: biological experimentations generally yield huge data sets resulting from high throughput screenings. The research of Morpheme will be developed along the following axes:

• Imaging: this includes i) definition of the studied populations (experimental conditions) and preparation of samples, ii) definition of relevant quantitative characteristics and optimized acquisition protocol (staining, imaging, $...$) for the specific biological question, and iii) reconstruction/restoration of native data to improve the image readability and interpretation.

• Feature extraction: this consists in detecting and delineating the biological structures of interest from images. Embedding biological properties in the algorithms and models is a key issue. Two main challenges are the variability, both in shape and scale, of biological structures and the huge size of data sets. Following features along time will allow to address morphogenesis and structure development.

• Classification/Interpretation: considering a database of images containing different populations, we can infer the parameters associated with a given model on each dataset from which the biological structure under study has been extracted. We plan to define classification schemes for characterizing the different populations based either on the model parameters, or on some specific metric between the extracted structures.

• Modeling: two aspects will be considered. This first one consists in modeling biological phenomena such as axon growing or network topology in different contexts. One main advantage of our team is the possibility to use the image information for calibrating and/or validating the biological models. Calibration induces parameter inference as a main challenge. The second aspect consists in using a prior based on biological properties for extracting relevant information from images. Here again, combining biology and computer science expertise is a key point.