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Speakers and Abstracts

We have brought together researchers who have the potential to take the lead in quantitative biology as next-generation leaders.
次世代のリーダーとして定量生物学を牽引していくポテンシャルを有する研究者が揃っています。大御所を並べただけではない、定量生物学の会ならではの講演者のラインナップになっております。

Session: Quantity - FORCE -

Date and Time: Jan. 9th 13:10-15:25

Otger Campàs ( University of California, Santa Barbara, USA )

油滴を利用して、生体組織の力学を"その場で"測る。

Quantifying tissue mechanics in vivo and in situ

Mechanical cues play a critical role during tissue morphogenesis and organ formation in the embryo. Despite their relevance in sculpting functional embryonic structures, very little is known about the mechanisms by which tissue mechanics affects/controls developmental processes, mainly because it has not been possible to quantify tissue mechanics within developing tissues in vivo. In this talk, I will present two new techniques that permit direct quantification of (1) cell-generated mechanical forces and (2) the mechanical properties of the cellular microenvironment, in situ within living tissues and developing organs. Using these novel techniques, we quantify the cell-generated mechanical stresses and the local mechanical properties within cell aggregates, living mouse mandibles and live zebrafish embryos.

Selected refs: Campàs et al. Nat. Methods (2014); Campàs et al. BPJ (2012); Campàs et al. PNAS (2010)

Kaoru Sugimura ( Kyoto University, Japan )

ベイズ統計学をつかって、見えない力を見る。アクチン結合タンパク質の力生成能と力感知能に注目して、形態形成の力学制御の分子メカニズムに迫る。

Dissecting the mechanical control of Drosophila wing shape determination

Tissues acquire their unique shape and size through a series of deformations. Tissue deformation consists of changes in cell shape, number, and position, which are triggered by forces acting between cells and by biochemical signaling. Reciprocal feedback is present at and among the molecular, cellular, and tissue scales. We sought to clarify the emergence of the Drosophila wing shape from these multi-scale feedback regulations. In the symposium, I shall discuss our ongoing research on the unified quantification of epithelial tissue development and molecular dissection of force sensing/generation by F-actin during directional cell rearrangement.
1. Quantifying tissue mechanics and kinematics in an integrated way We have developed and validated key techniques to quantify the multi-scale dynamics underlying wing shape determination, including Bayesian force inference, whole-wing imaging, and texture tensor formalism (Ishihara and Sugimura, 2012; Ishihara et al., 2013; Sugimura et al., 2013; Guirao et al., 2015). By analyzing space-time maps of tissue deformation, tissue stress, and cell dynamics in control and mutant tissues, we evidenced unexpected interplays between patterns of tissue elongation, cell division and stress. Our methods provide a basis for comprehensive analyses of mechanical control of epithelial tissue development (this work is done in collaboration with F. Graner, Y. Bellaïche, B. Guirao, S. Rigaud, P. Marcq, and S. Ishihara).
2. Dissecting molecular mechanism of extrinsic force-driven cell rearrangement During tissue morphogenesis, cells change their relative positions along the tissue axis by remodeling cell contact surfaces. This process, called directional cell rearrangement, shapes a tissue and develops its multi-cellular pattern. In the Drosophila pupal wing, anterior-posterior cell contact surfaces shrink and are remodeled to form new proximal-distal cell contact surfaces from 21 hr APF onwards. We previously reported that the extrinsic stretching force provides directional information for assignment of the orientation of cell rearrangement, leading to tissue elongation and hexagonal cell packing (Sugimura and Ishihara, 2013). However, the mechanisms by which cells sense the extrinsic forces and transmit the information to the molecular machinery for cell rearrangement remain unknown. To answer these questions, we performed screening of actin-binding proteins. Our results suggest that AIP1, cofilin, and coronin-1 regulate F-actin to trigger the extrinsic force-driven cell rearrangement (this work is done in collaboration with K. Ikawa).

Selected refs: Guirao et al. eLife (2015); Sugimura and Ishihara. Development (2013); Ishihara and Sugimura. J. Theor. Biol. (2012)

Emmanuel Farge ( Institut Curie, France )

原腸形成過程は進化的に広くみられるが、コアとなる誘導シグナルははっきりしていなかった。それがなんと機械的応力である可能性が示された。

From mesoderm mechanotransductive evolutionary origins to tumourigenic mechanical induction

Bilaterians are complex organisms, characterized by the existence of a mesoderm tissue from which most of animal complex organs develop. Mesoderm emerged 570 millions years ago from cnidarians that are characterized by and ectoderm and an endoderm only. The lack of conservation of biochemical signalling proteins upstream of early embryonic mesoderm differentiation across bilaterians prevents to answer the question of the signal having been at the origin evolutionary origin of mesoderm emergence and complex animals. Here we found the mechano-transductive phosphorylation of the Y654 site of β-catenin by the first morphogenetic movements of embryogenesis, leading to its release into the cytoplasm and nucleus, as involved and conserved in earliest mesoderm differentiation in the vertebrate zebrafish and un-vertebrate Drosophila, two species having directly diverged from the last common ancestor of bilaterians. We proposed mechanical activation of β-catenin signalling as having initiated the evolutionary transition to mesoderm differentiation and complex animals evolutionary emergence[1].
We additionally find mechanical activation of β-catenin as involved in the mechanical activation of tumorogenic biochemical pathways, in the healthy epithelium compressed by the neighbouring tumour, in response to tumour growth pressure in vivo [2-4].

1 Brunet, T. et al. Evolutionary conservation of early mesoderm specification by mechanotransduction in Bilateria. Nature communications 4, doi:10.1038/ncomms3821 (2013).
2 Whitehead, J. et al. Mechanical factors activate beta-catenin-dependent oncogene expression in APC mouse colon. HFSP journal 2, 286-294, doi:10.2976/1.2955566 (2008).
3 Fernandez-Sanchez, M. E., Barbier, S. & al., e. Mechanical induction of the tumorogenic β-catenin pathway by tumour growth pressure. Nature, 10.1038/nature14329 (2015).
4 Fernandez-Sanchez, M. E., Brunet, T., Roper, J. C. & Farge, E. Mechanotransduction's Impact in Animal Development, Evolution, and Tumorigenesis. Annu Rev Cell Dev Biol, doi:10.1146/annurev-cellbio-102314-112441 (2015).

Background : soft matter biophysics, developmental biology Websites : http://cvscience.aviesan.fr/cv/818/emmanuel-farge, http://umr168.curie.fr/en/Farge-group

Selected refs: Fernández-Sánchez et al. Nature (2015); Brunet et al. Nat. Commun. (2013); Farge. Curr. Biol. (2003)

Session: Quantity - SYMMETRY I -

Date and Time: Jan. 10th 9:00-12:00

Noriko Hiroi ( Keio University, Japan )

Anisotropy shaped by and for the dynamic distribution of heat

In this talk, we demonstrate how to detect the temperature increase after the mitochondrial stimulation with the sequential observation of single quantum dot, and for the first time the temperature difference within a neuronal cell by using multiple quantum dot imaging, and suggest the cause of heterogeneity of temperature by using the characteristic shape of neuronal cells based on the actual 3D observation.

Nicolas D Plachta ( IMCB, Singapore )

マウス初期胚の対称性の破れに定量イメージングで迫る

Seeing how mammalian life starts: Quantitative imaging in live mouse embryos

We have established imaging tools to study how the early mammalian embryo forms. We combine photoactivation with fluorescence correlation spectroscopy techniques to show how transcription factors change their DNA binding dynamics to control cell fate, as the mouse embryo establishes its first cell lineages. We then show that as they decide their fates, cells use a new class of filopodia to pull their neighbor cells closer and achieve compaction of the embryo. Finally, we develop membrane segmentation methods to show how mechanical forces form the pluripotent inner mass of the embryo. Unlike classic models based on highly orientated cell divisions, we show that the prime mechanism forming the pluripotent inner mass is apical constriction. Using laser ablations, we discover that anisotropies in tensile forces produced by actomyosin networks control the first spatial separation of cells during development. Our findings reveal mechanisms explaining how mammalian cells choose their fate, shape and position during mammalian development.

Selected refs: Samarage et al. Dev. Cell (2015); Fierro-González et al. Nat. Cell Biol. (2013); Plachta et al. Nat. Cell Biol. (2011)

Yusuke Maeda ( Kyushu University, Japan )

構成的手法から探る生命システムの構築原理:生命の起源と人工細胞のダイナミクス

A physicist’s approach to the origin of life: Non-equilibrium entropic force

Temperature differences at large scales, kilometers or more, are present in our planet and essential for plate tectonics and meteorological phenomena. As the earth is blessed with temperature, it has revolutionized our life: Carnot showed the operation of the heat engine in two temperature systems at the industrial revolution, which led to the second law of thermodynamics. On a smaller scale, millimeters or less, temperature differences are also present in the pores of hydrothermal vents. The motion of molecules under such temperature gradients, called thermophoresis or the Soret effect, where thermal convection is suppressed could be relevant to the inhomogeneous distribution of chemical species. Thermophoresis depletes a polymer such as polyethylene glycol (PEG) from the hot region and builds a concentration gradient. In such a solution, solutes of small concentration experience thermophoresis and the restoring force dependent on PEG gradient of large concentration. Under focused laser heating, DNA and RNA as solutes localize as a ring-like structure which diameter monotonically decreases with their size following a behavior analogous to gel electrophoresis [1]. Trapping and selection of molecules could be physically feasible in a simple way relying on temperature gradient. Thermophoresis of RNA enzyme might be relevant to primitive life: Separation of RNA from the large library of RNA world might occur at the thermal vent of the deep ocean where large temperature gradient is present [2]. Moreover, because this effect relies on the entropic force in solute contrasts, trapping with little material dependence is feasible. It allows us to optically control the density of living cells and proteins [3,4].

[1] YT Maeda, A Buguin, A Libchaber. Phys. Rev. Lett. 107, 038301 (2011).
[2] YT Maeda, T Tlusty, A Libchaber. Proc. Natl. Acad. Sci. USA 109, 17972 (2012).
[3] YT Maeda. Appl. Phys. Lett. 103, 243704 (2013).
[4] T Fukuyama, et al. Langmuir 31, 12567 (2015).

Zoher Gueroui ( École Normale Supérieure, France )

マグネトジェネティクス:情報流れの時空間制御が明らかにする自己組織化の原理

Studying cytoskeleton symmetry breakings using cellular reconstitution of cytoplasmic extracts and biophysical tools

Studying cytoskeleton symmetry breakings using cellular reconstitution of cytoplasmic extracts and biophysical tools.
The cytoskeleton is essential for the function of cellular processes such as cell division and cell migration. Cytoskeleton fibers participate in the maintenance of cell internal organization and play essential roles in breaking symmetry and establishing cell polarity. We have developed an in vitro system capturing the spatial organization of cytoskeleton filaments within a geometry that mimic the cellular environment. This system, based on the cellular reconstitution by confinement of Xenopus cytoplasmic extracts, is used to examine simple aspects of symmetry breaking.
(1) We will first discuss how geometrical confinement and mechanical properties influence the self-organization of microtubules and molecular motors.
(2) In most physiological situations, the asymmetric fate of a system follow from certain “cues” that pre-exist before symmetry is broken. These cues are either localized signals often encoded in protein concentration gradients, or “landmarks” inherited from the system’s history. For instance, gradients of signaling proteins and protein localization can be key for cell-fate decision and asymmetric cell division. In order to control the spatiotemporal localizations of these cues, we are using magnetic nanoparticles to spatially localize signaling proteins within confined extracts. This system is used to examine how the spatial localization and clustering of RCC1/RanGTP proteins feedbacks on microtubule spatial organization.

Selected refs: Hoffmann et al. Nat. Nanotech. (2013); Pinot et al. PNAS (2012).

Session: Quantity - SYMMETRY II -

Date and Time: Jan. 10th 13:30-15:45

Cliff Brangwynne ( Princeton University, USA )

Cliff Brangwynne博士は物理学の視点から細胞生物学に新しいコンセプトを導入し、近年、大きなインパクトを与えて続けている新進気鋭の研究者です。「相転移/phase transition」は、例えば水分子が沸点や融点をまたぐと固体、液体、気体と急激に状態を変化させるような物理学のコンセプトです。Brangwynne博士は、細胞内で核小体や生殖顆粒が形成・消滅する過程を、この相転移現象として理解できることを明らかにしています。

Measuring the Intracellular Dew Point: The Physics and Biology of Membrane-less Organelles

RNP bodies are RNA and Protein-rich, membraneless organelles that play important roles in regulating gene expression. The largest and most well-known nuclear RNP body is the nucleolus, whose primary function in ribosome biogenesis makes it key for cell growth and size homeostasis. The nucleolus and other nuclear bodies behave like liquid-phase droplets. Increasing evidence suggests they condense from the nucleoplasm by concentration-dependent phase separation. However, nucleoli actively consume chemical energy, and it is unclear how such nonequilibrium activity might impact classical liquid–liquid phase separation. We combine in vivo and in vitro experiments with theory and simulation to characterize the assembly and disassembly dynamics of nucleoli in early Caenorhabditis elegans embryos. In addition to classical nucleoli that assemble at the transcriptionally active nucleolar organizing regions, we observe dozens of “extranucleolar droplets” (ENDs) that condense in the nucleoplasm in a transcription-independent manner. We show that growth of nucleoli and ENDs is consistent with a first-order phase transition in which late-stage coarsening dynamics are mediated by Brownian coalescence and, to a lesser degree, Ostwald ripening. By manipulating C.elegans cell size, we change nucleolar component concentration and confirm several key model predictions. Our results show that rRNA transcription and other nonequilibrium biological activity can modulate the effective thermodynamic parameters governing nucleolar and END assembly, but do not appear to fundamentally alter the passive phase separation mechanism.

selected refs: Berry et al. PNAS (2015); Feric and Brangwynne. Nat. Cell Biol. (2013); Brangwynne et al. Science (2009)

Akatsuki Kimura ( National Insititute of Genetics, Japan )

多数の小さな分子たちによってどのように細胞レベルでの空間的な秩序ができるのかを研究しています。本発表では、線虫C. elegansの細胞質流動を例に、流れの方向が定まらない(不安定)流動が、必ず(安定的に)生じるメカニズムについて発表します。

How a cell-wide cytoplasmic flow with unstable direction emerges reproducibly?

In this presentation, I will present our recent research on a symmetry breaking event observed in the early embryo of Caenorhabditis elegans. Cytoplasmic streaming is a cell-wide flow occurring in various plants and animals. In C. elegans, the streaming of ooplasm is observed upon fertilization. As the polarity of the zygote is not established at this stage, the direction of the cell-wide flow is not pre-determined, but determined in a self-organized manner. Interestingly, the direction of the flow changes during the streaming. Using a quantitative live-cell imaging, we characterized the dynamics of the flow, and proposed a mechanism for the self-organization of the flow. The proposed mechanism was tested using a theoretical modeling. I will discuss the applicability of our model on cytoplasmic streaming in general.

selected refs: Kimura and Kimura. J. Cell Sci. (2012); Niwayama et al. PNAS (2011); Kimura and Kimura. PNAS (2011)

Brian Stramer ( King's College London, UK )

細胞のミクロとマクロを定量的 in vivo イメージングでつなぐ:細胞内アクチン動態・張力から細胞の巨視的挙動へ

Intercellular forces orchestrate contact inhibition of locomotion

Contact Inhibition of locomotion (CIL), a process where migrating cells repel upon collision, was first observed in cultured cells more than 60 years ago. We have recently revealed that Drosophila hemocytes have precise CIL interactions in vivo, which lead to their subsequent developmental patterning. To quantify the dynamics of collisions we have recently developed techniques to analyze the exact velocity and acceleration changes surrounding the contact inhibition process. This analysis has revealed rapid and synchronous kinematic changes (over second timescales) during collisions, which further highlight the precision of the CIL response.
To examine the cause of such intriguing CIL kinematics we have examined the actin network dynamics surrounding collisions. We adapted a pseudo-speckle microscopy technique to track the retrograde flow dynamics of the actin cytoskeleton during hemocyte developmental dispersal. Non-colliding cells show rapid retrograde flow (3-4μm/min), which moves centripetally towards the cell body where actin flow significantly decreases. Analysis of collisions reveals that the actin flow undergoes significant temporal and spatial reorganization across the entire lamella, which occurs simultaneously in colliding partners. A region of low retrograde flow develops perpendicular to the leading edge spanning colliding cells, and upon repulsion, retrograde flow simultaneously spikes in both lamellae. These dynamics suggest that hemocytes are becoming transiently coupled during CIL via a clutch-like mechanism, analogous to the integrin clutch encountered in migrating cells.
Exploiting the precise retrograde flow displacements, we subsequently modelled the cytoskeletal stresses in freely moving and colliding cells using a linear viscoelastic model. Preliminary results show that non-colliding cells have high regions of network stress surrounding the cell body, explaining the convergence of the retrograde flow within this region. Upon collision, forces are redistributed from the cell body to the leading edge along the region of low retrograde flow. This region of stress becomes decorated with myosin II suggesting the development of a transient stress fiber as colliding cells pull on each other during the collision. We speculate that this “haptic feedback” mechanism, and subsequent release of lamellar tension, explains the precise and synchronous nature of the contact inhibition response.

Selected refs: Davis et al. Cell (2015); Davis et al. Development (2012); Stramer et al. J. Cell Biol. (2010)

Session: Quantity - INFORMATION -

Date and Time: Jan. 10th 16:00-19:00

Satoshi Sawai ( the University of Tokyo, Japan )

Revisiting cell migration mechanisms of crawling cells

In the social amoebae Dictyostelium discoideum, stimulation by chemoattractant cAMP invokes a transient rise in cytosolic cAMP that is secreted to excite other cells in the neighborhood. Aggregation of Dictyostelium cells is dictated by chemotaxis towards traveling waves of cAMP that self-organize in the cell monolayer. Because reversal of spatial gradient occurs after every passage of wavefronts, it is unclear why the cells do not fall into a futile cycle of back and forth movement. This is the so-called ‘chemotactic wave paradox’. By employing a microfluidics-based flow focusing, we have recently demonstrated that small guanosine triphosphatase (GTPase) Ras activation at the leading edge is suppressed when the chemoattractant concentration is decreasing over time. This ‘rectification’ of directional sensing is optimal for wave passage time of ~6min and the overall features can be fully recapitulated by a mathematical model that describes an adaptive leading edge response that is localized in space by a global inhibitory signal. In the talk, we will present some of our recent findings in the related collective migratory behaviors as well as some of the common features found in immune cells.

Selected refs: Nakajima et al. Nat. Commun. (2014); Taniguchi et al. PNAS (2013); Gregor et al. Science (2010)

David Umulis ( Purdue University, USA )

Quantification and modeling of BMP signaling during zebrafish embryo development

Bone Morphogenetic Proteins (BMPs) act in developmental pattern formation as a paradigm of extracellular information that is passed from an extracellular morphogen to cells that process the information and differentiate into distinct cell types based on the morphogen level. In addition to their role in development, BMPs play an important role in tissue homeostasis and mutations in the BMP family are associated with a number of human cancers. Numerous extracellular modulators and feedback regulators establish and control the BMP signaling distribution along the dorsal-ventral (DV) embryonic axis in vertebrates to induce space and time-dependent patterns of gene expression. To identify how the dynamic pattern is regulated during development, we have developed a seamless data-to-model integration and optimization strategy. First, the nuclear intensities of fluorescent stained Phosphorylated-Smad5 (P-Smad) are acquired for each nuclei in each embryo from staged populations to provide a quantitative time-course for the BMP signaling gradient. Next, the nuclei are segmented to yield quantitative point-clouds of P-Smad level at each nuclei. The individual point clouds are registered to similarly staged embryos using a process called Coherent Point Drift (CPD) and the registered populations provide rigorous quantification and comparison of phenotype. To delineate the mechanism of BMP signal inhibition by the secreted binding proteins Chordin (Chd), Noggin (Nog), and Follistatin (Flst), a mathematical model was developed and optimized against the population data for wild type and combinations of the Chd mutants with and without morpholino knockdown of Noggin and Follistatin. We found a model that reproduced the experimentally observed reliability of the patterning network for Chd LOF, and for Nog/Flst morpholino knockdown that was also consistent with the dramatic increase in signaling observed in Chd LOF, Nog/Flst knockdown. Models consistent with experimental behavior require that Chordin has a greater range than Noggin, that Noggin is not freely diffusible, and that Noggin rapidly binds available BMP ligands in the organizer region. We are continuing to experimentally test the model predictions and isolate the roles of Noggin and Follistatin to determine the extent of dorsal enrichment under different conditions.

Selected refs: Pargett et al. PLoS Comp. Biol. (2014); Umulis et al. Dev. Cell (2010)

Yuki Tsukada ( Nagoya University, Japan )

定量と再構築から理解する感覚神経細胞の環境認識

Quantification and reconstruction of thermosensory neuronal processing in C. elegans

How do neural circuits encode environmental information? During navigation, animals process temporal sequences of sensory inputs to evaluate their surrounding environment. An encoding mechanism of the temporal sensory signals to grasp environmental landscape is a fundamental operation for navigating animals. To elucidate how a sensory system transforms the environmental information to temporal neural activity, we focused on a thermosensory neuron AFD in a nematode Caenorhabditis elegans, which plays a major role in a temperature dependent navigational behavior called thermotaxis. Thermotaxis is observed when we cultivate worms in a constant temperature with plenty of food, and then locate them on a thermal gradient without food: the worms migrate to the conditioned temperature region. A pair of AFD thermosensory neurons is essential for the animals to migrate toward the memorized temperature region on a thermal gradient, and is known to show calcium increase in response to temperature stimulus of the memorized temperature. However, encoding mechanisms of the temporal AFD activity during navigation remains to be elucidated. We developed simultaneous calcium imaging and tracking system for a freely-moving animal on a thermal gradient, and characterized the response property of AFD neuron to the thermal stimulus during thermotaxis. Our data of AFD neuronal activities in freely moving animals show that the AFD responds to shallow temperature increases as intermittent calcium pulses and detects temperature differential with critical time window of 20 seconds, which is similar to the time scale of behavioral elements of C. elegans such as turning. We constructed a model for AFD activity based on the identified response kernel, and reconstructed the AFD activity from a time course of observed thermal stimulus. Conversely, deconvolution of the identified response kernel and AFD activity accurately reconstructs the shallow thermal gradient with migration trajectory, indicating that AFD activity and the migration trajectory are sufficient as the encoded signals for thermal environment. Our study demonstrates bidirectional transformation between environmental thermal information and encoded neural activity.

Selected refs:Tsukada et al. J Neurosci. in press; Tsukada and Hashimoto Develop Growth Differ. (2013); Miyara et al. PLoS Genetics (2011)

Damon Clark ( Yale University, USA )

ショウジョウバエの視覚神経回路:動きを読みだす情報処理に迫る定量生物学

Dissecting neural circuits for motion estimation in Drosophila

Many sighted animals use visual signals to estimate motion. In order to estimate visual motion, animals must use nonlinear processing to integrate visual information over time and space, making visual motion estimation a paradigm of neural computation. In insects, including the fruit fly Drosophila, the neural and behavioral responses to visual motion have historically been well predicted by a model known as the Hassenstein-Reichardt correlator (HRC). To detect motion, this model correlates two inputs by delaying one before multiplying them together. However, the operations that implement the neuronal motion detector have yet to be quantified. We have used calcium imaging to measure the response properties of single local motion detectors in Drosophila’s visual circuits. We have used these measurements to characterize the timescales and lengthscales on which visual correlations are computed, as well as the types of correlations computed by different cell types. We find that the fly’s motion estimators are most sensitive to correlations on the ~20 ms timescale. Strikingly, these cell types respond to specific correlations in a manner not predicted by the HRC. Our results show that fly direction-selective cells are responsive to a spatially-structured and complementary set of fast timescale correlations.

Selected refs: Fitzgerald and Clark. eLife (2015); Clark et al. Nat. Neurosci. (2014); Clark et al. Neuron (2011);

Session: Quantities and Beyond -

Date and Time: Jan. 11th 9:00-11:00

Naoki Irie( the University of Tokto, Japan )

胚発生と進化の法則性として近年支持された砂時計モデル。この法則性を生み出すメカニズムの有力候補がみえてきた。

Double bladed aspect of gene recruitment to morphological evolution.

What makes animal body plans to be conserved over 550 million years of evolution? Recently supported, the developmental hourglass model provided attractive explanation for this; Developmental system in mid-embryonic organogenesis stage has less flexibility (fragile, constrained), and thus become evolutionarily conserved. However, no quantitative, empirical evidence has been provided for this assumption. To test the above hypothesis, we have investigated the fragility of mid-embryonic developmental systems by adding fluctuations and mutations to vertebrate embryos. Our results indicated that mid-embryonic stages are not necessarily fragile, suggesting lethality of certain embryonic stage is not sufficient to explain the hourglass-like divergence. To further investigate molecular characteristics of developmental system at mid-embyonic stages, we have collected and analyzed transcriptome data obtained from early to late embryos of 8 chordate species, and found that developmental program at vertebrate mid-embryonic stages have common characteristics such as regulatory quiescence and higher pleiotropy. Based on these findings, here we propose potential mechanism that made chordate body plan conserved. Ideas for potential collaborations are welcomed, and I also appreciate critical feedback on our proposals.

Selected refs: Wang et al. Nat. Genetics (2013); Irie and Kuratani. Nat. Commun. (2011)

Yuichi Wakamoto ( the University of Tokyo, Japan )

1細胞ヒストリーの観点から適応度と遺伝子発現を捉え直す

Fitness and gene expression from the viewpoint of single-cell histories

Growth and division of cells require interplay of large numbers of intracellular molecular species. An amount of each molecular species in a single cell such as protein and RNA is variable among different individual cells and in time-course, which results in cellular growth noise. In this talk, we address two important questions regarding cellular growth noise both theoretically and experimentally: (1) How does growth noise at the cellular level affect population growth properties? (2) How can we quantitatively reveal the effect of noise at the molecular level on cellular reproduction ability? To answer the first question, we carried out large-scale single-cell time-lapse measurements on clonal proliferation processes of Escherichia coli in constant environments with a custom microfluidic device. The results show that clonal population of E. coli grow faster than the constituent single cells under diverse balanced-growth conditions. We reveal that the observed growth rate gain at the population level is strongly correlated with cellular growth noise strength and quantitatively predictable from the equation that connects generation time distribution and population growth rate. Furthermore, we prove that growth rate gain is directly linked to statistical deviation between two types of generation time distribution along chronological and retrospective cell histories. To address the second question, we developed a statistical method that allows us to measure fitness landscape and selection strength for heterogeneous phenotypic states, employing a conceptual framework to regard cell history as a unit of proliferation. We analyzed single-cell time-lapse data of E. coli that expresses streptomycin resistance gene (smR) in the presence of sub-inhibitory concentration of streptomycin. The result suggests that the role of smR against drug exposure is better represented by protein production rate than protein concentration. These measurements demonstrate the utility of cell history-based viewpoint in single-cell analysis, and raise a question as to the interpretation on the role of gene expression level at the cellular level.

Selected refs: Wakamoto et al. Science (2013); Wakamoto et al. Evolution (2012); Tomita et al. Langmuir (2011)

Tetsuya J Kobayashi( the University of Tokyo, Japan )

「量」をつなぐ:情報から適応度まで

Integrating Fitness and Information in Biological Adaptation

A cell can adapt to fluctuating environment by actively controlling its state based on the information on the environment obtained by sensing the environment.
Information and associated information measures are fundamental notion and quantities to characterize such active adaptation of cells and its efficiency. Even without sensing, however, the cells as a population can also adapt to the changing environment passively by natural selection if the population has sufficient diversity in genetic and phenotypic states. Such passive adaptation by selection is characterized by fitness that quantifies the success of the population. In real biological systems, however, both mechanisms of the adaptation are mixed, and therefore linking information and fitness, two apparently different quantities, is crucial to understand biological adaptation.
In this work, by introducing a retrospective view of single-cell histories, we show that information and fitness can be unified theoretically in the problem of biological adaptations as is the case with the unification of entropy and information in information thermodynamics (Maxwell’s demon problem). The integrated theory shows that not only average but also the fluctuation of fitness and information are mutually constrained via fluctuation relations. We also would like to discuss how we can unify various quantities (X-factors) that associates with different biological phenomena.

Selected refs: Kobayashi and Sughiyama. PRL (2015); Kobayashi. PRL (2011); Kobayashi. PRL (2010)


Tokyo Symposium: Force, Information and Dynamics: X factors shaping living systems
NIG International Symposium 2016 satellite workshop
Toyota Physical & Chemical Research Institute Workshop
Mishima Symposium: Quantitative Biology - force, information and dynamics