EXPLORATORY MECHANISMS IN BIOLOGY

Kim Cooper (University of California, San Diego)
Title: "What big feet you have!" The complex control of limb skeletal proportion
Abstract: Our long arm bones allow us to reach for objects that our short fingers grasp and manipulate with remarkable dexterity. Since skeletal proportion is integral to vertebrate animal form and function, the variety of limb proportions is also a striking aspect of species diversity. Although the relative lengths of skeletal elements differ by an order of magnitude within and between species, little is known of the molecular mechanisms that determine the different lengths of individual limb bones in any species. To identify genes that give skeletons their characteristic shapes, we took advantage of the extreme hindlimb proportion of the bipedal jerboa (Jaculus jaculus) and its close evolutionary relationship to the laboratory mouse (Mus musculus). Although expression levels diverged throughout the genome over approximately 55 million years since the last common ancestor of the two species, only 10% of genes are associated with skeletal growth rate differences that contribute to limb proportion. Among these, we were surprised to find evidence suggesting that the disproportionate elongation of the jerboa foot occurred in part by releasing growth potential that is restricted in the mouse.

Together with the phylogenetic complexity of skeletal proportion, these data predict that skeletal scaling involved multiple mutations that may have additively or collectively amplified differential growth. A holistic understanding of the genetics of skeletal proportion therefore requires assembly of complex genotypes that are currently impossible to achieve in mice by Mendelian inheritance. To overcome this obstacle, we recently demonstrated feasibility of a “gene drive” approach that biases the inheritance of one of two copies of a gene in mice. Using genetically encoded CRISPR/Cas9 components to convert a heterozygous genotype to homozygosity, we increased the frequency of transmitting a desired allele from 50% to as high as 90% of offspring. If applied to multiple genes at once, this approach will accelerate efforts to understand how evolution shaped complex differences between species. Additionally, this powerful approach will advance efforts to develop rodent models to understand the complex genetic causes of many of the most prevalent human diseases that include heart disease, diabetes, arthritis, and cancer.
 

Deborah Gordon (Stanford University)
Title: The ecology of collective behavior
Abstract: Collective behavior operates without central control, through interactions among individuals. Like any phenotypic trait, the process that regulates collective behavior evolves in relation with a dynamic environment. Similar ecological constraints, in many natural systems from cells to ants, may correspond to similar algorithms that regulate collective outcomes. Some important aspects of the dynamics of the environment include stability, the threat of rupture or disturbance, the ratio of inflow and outflow of resources or energy, and the distribution of resources. These correspond to the dynamics of collective behavior, including the rate of amplification, how feedback instigates and inhibits activity, and whether information is spatially centralized. The collective behavior of ant colonies is based on simple olfactory interactions. Ant species differ enormously in the algorithms that regulate collective behavior, reflecting diversity in ecology. An example is the contrast between the regulation of foraging by harvester ants in the desert, where life is tough but stable, and by arboreal turtle ants in the tropical forest, where life is easy but unpredictable.
 

DYNAMICS OF DEVELOPMENTAL SYSTEMS

Angelike Stathopoulos (California Institute of Technology)
Title: Developmental programs acting in embryos to temporally regulate cell signaling
Abstract: no abstract 

Angela DePace (Harvard Medical School)
Title: Precision and plasticity in animal transcription
Abstract: To Be Announced
 

HOW CELLS AND ORGANISMS COMPUTE

Uri Alon (Weizmann Institute of Science)
Title: Senescent cells and the dynamics of ageing
Abstract: A major driver of aging are senescent cells, cells that stop dividing, accumulate with age, and cause inflammation, lack of regeneration and tissue damage. Experimental removal of senescent cells from old mice delays ageing-related decline, including the onset of cancer. Despite the importance of senescent cell accumulation, it is unclear whether they passively accumulate or instead are continually produced and removed. This talk will present recent data and mathematical modelling which clarifies senescent cell dynamics. We will discuss how senescent cell dynamics offer a picture that can unify many hallmarks of ageing into an understandable framework.

Lea Goentoro (California Institute of Technology)
Title: Inducing regeneration in moon jellyfish
Abstract: While many studies focus on animals that highly regenerate, less understood is how or whether we can induce regeneration in animals with limited regeneration. We pursue this question in the moon jellyfish, Aurelia aurita. As we showed in previous work, Aurelia readily reorganize existing arms to regain body symmetry, rather than regenerate lost arms. Now, after 3.5 years of screening various chemical and physical factors, we have discovered that we can induce Aurelia to regenerate arms. Further, rather than a specific stimulus, our findings suggest that multiple broad stimuli could work in inducing regeneration. Finally, rather than modulating specific genes or patterning pathways, our findings suggest that inducing regeneration may involve broad energetic reprogramming of the organism.

Daniel Colón-Ramos (Yale University)
Title: Building a brain: systematic examination of the logic of brain connectivity in C. elegans
Abstract: How is a brain wired during development?  While molecular genetic studies have contributed significantly to the identification of conserved signaling pathways that regulate distinct steps during neurodevelopment, we lack a systematic understanding of the logic governing the coordinated decisions of the system as it self assembles into a functional brain.  We have decided to take an orthogonal approach to understand how, during the development of the C. elegans brain, system’s level neurodevelopmental decisions influence precise and stereotyped connectivity by restricting the degrees of freedom of single neurons within circuits. Using probabilistic network models to analyze connectomics data, we provide evidence that the nematode brain is composed of domains of nerve bundles with related functional connectivity.  We then use light-sheet microscopy in C. elegans embryos to identify pioneer neurons and elucidate a hierarchical ordering of neurodevelopmental decisions that underlie the functional circuits identified. By linking connectomic data, probabilistic network models and developmental studies, our approaches allow us to dissect the top-down logic of brain neurodevelopment in a simple nervous system.

CELL STATE DECISIONS

Ben Simons (University of Cambridge)
Title: Competition for fate determinants as a mechanism of stem cell homeostasis
Abstract: The maintenance of cycling tissues relies on the activity of adult stem cell populations. To replenish cells lost through damage or exhaustion, stem cells must achieve a perfect balance between cell duplication and differentiation. To resolve the factors that control such fate asymmetry, emphasis is placed on short-range signals from an anatomically-defined niche, a specialized microenvironment to which stem cells anchor. However, in some tissues, such as vertebrate testis and blood, stem cell maintenance takes place in a “facultative” niche environment, where cells actively migrate among their differentiating progeny. Using mouse spermatogenesis as a model system, we argue that stem cell density regulation is achieved through competition for a limited supply of fate determinants (FGFs) released by somatic (lymphatic endothelial) cells. We show that the quantitative dependence of stem cell density on Fgf dose and its structured dynamics during regeneration can be predicted within the framework of a minimal model. We propose that such a model provides a conserved mechanism of self-organization, allowing stem cells to regulate their density in a facultative niche. We discuss the implications of these findings on fate priming, cell state flexibility and disease propagation.

Johan Paulsson (Harvard Medical School)
Title: Life-changing single-molecule events
Abstract: To Be Announced