Sabine Eming (virtual), Immunological checkpoints in wound healing and misregulated reparative responses

Dr. Sabine Eming is Professor of Dermatology at the University of Cologne. She received her MD and her training in Dermatology at the University of Cologne. She was research fellow at The Scripps Research Institute and Harvard Medical School.
Dr. Eming’s research interest has focused on the mechanisms how the skin senses damage and how these events translate into a regenerative response or disease. Her research team has extensively studied mechanisms of induction and regulation of the immune response during skin wound healing. Her findings aim to develop novel strategies for pharmacological interventions in pathological healing conditions associated with diabetes mellitus, inflammatory diseases or ageing. (More detailed description below).
Poor wound healing and its consequences on health and morbidity are one of the major unresolved medical problems today. Therefore, pharmaceutical advances to boost endogenous regenerative responses and to prevent misregulated reparative responses as e.g. tissue fibrosis are milestones in medicine. Yet, any therapeutic intervention would have to be carefully designed to accommodate the spatial-temporal complexity of intercellular metabolic interactions in the wound environment and to prevent neoplastic growth.
Frequently, impaired wound healing is associated with immune dysfunction leading to prolonged inflammation and tissue damage with a spectrum of pathological outcomes. An ulcerative healing defect in barrier organs (e.g. chronic wounds in the skin, mucosa, or cornea) and the excessive formation of ECM with perturbed architecture leading to organ fibrosis (e.g. hypertrophic scarring of the skin, keloid formation, or scleroderma) represent extremes on this spectrum. The underlying molecular pathology is not resolved and requires deeper mechanistic investigation. Findings generated in the Eming group demonstrate that metabolic pathways in immune cells or stromal cells control the outcome of a tissue damage response and that metabolic dysbalance in these cell types provides an explanation for the spectrum of pathological repair phenotypes. Specifically, using a combination of gene-modified mouse models and transcriptome profiling, the Eming group showed that metabolic reprogramming in macrophages coordinates critical stage-specific repair processes during wound healing. These findings may unravel useful targets for therapeutic innovation, which will be presented and discussed.
More detailed description of research done in Eming’s group
The skin is constantly exposed to environmental stress factors such as injury, microbes, UV light and toxic substances. Therefore, by nature the skin is explicitly well furnished to restore tissue integrity and homeostasis following tissue damage. Cellular and molecular mechanisms that control tissue repair are complex and involve cell-cell and cell-matrix interactions directed by a network of soluble mediators. Furthermore, wound healing mechanisms are not unique to the tissue repair response. In fact, postnatal wound healing in part recapitulates processes in developmental biology and organogenesis. Signals controlling cell growth, migration and differentiation during tissue repair have also emerged as central mediators in cancer biology and other inflammatory disease processes.
Professor Eming leads a programme of work in tissue damage and repair that encompasses the range from basic structure-function analysis, through in vivo models, to human disease. The group is aiming at a deeper understanding on how the skin senses tissue damage and how these events translate into a regenerative response or disease. Our findings might provide the possibility to manipulate the healing response in order to readjust postnatal repair into regeneration and to develop novel strategies for pharmacological interventions in pathological healing conditions associated with diabetes mellitus, inflammatory diseases or ageing. In addition, we are interested to study the interrelation between tissue repair, mechanisms of cancer development and inflammatory skin diseases.

Andrew Ewald (Johns Hopkins), Cellular strategies and molecular mechanisms driving breast cancer metastasis

Andrew J. Ewald, Ph.D.
Virginia DeAcetis Professor and Director, Department of Cell Biology
Director, Giovanis Institute for Translational Cell Biology
Johns Hopkins Medical School

Video of the event:

Cancer mortality is driven by metastasis, the process by which cells escape from the primary tumor and colonize distant organs. We have shown that luminal breast cancer cells can initiate invasion by expressing basal genes, such as keratin 14 (K14). K14+ luminal breast cancer cells collectively invade and intravasate as adherent clusters. Upon arrival at the distant site, K14+ clusters transition to K14- growing metastases. RNA-seq analysis revealed that K14+ cancer cells exhibit high expression of adhesion proteins (e.g. E-cadherin) and low expression of major histocompatibility complex class I (MHC I). We demonstrated genetically that E-cadherin represses invasion and promotes metastasis by acting as a survival factor. We next demonstrated that loss of MHC I expression sensitized K14+ cancer cells to natural killer (NK) cell attack and that cancer cells can induce NK cells to enter a novel metastasis-promoting cell state. We next tested how metastasis mechanisms differ in triple negative breast cancer (TNBC). We found that TNBC tumors express and require both epithelial and mesenchymal markers, as both E-cadherin and vimentin are required for metastasis. We are currently using genetic, multi-omic, and proteomic techniques to identify molecular regulators of metastatic cell states. We also develop and apply co-culture models to test the constraints imposed by intercellular interactions with both cancer and stromal cells.

Tyler Brunet (University of Exeter, UK), Constructive Neutral Evolution and its Close Relatives 

Tyler Brunet (University of Exeter, UK) is a Leverhulme Postdoctoral fellow working with John Dupré at Egenis. He is a reformed biologist who turned to philosophy of biology. Among several other topics, he works on constructive neutral evolution (CNE).
Constructive Neutral Evolution (CNE) is a theory for explaining the origin and maintenance of complexity in biological systems without the necessary input of adaptive Evolution by Natural Selection (ENS). CNE was originally developed to explain a few comparatively obscure cases of complexity in molecular biology, including spliceosomal splicing, trypansomal  gene editing, scrambled genes in ciliates, and duplicate gene retention. However, since its conception, CNE has been extended and applied to a number of other cases – both novel molecular cases, and cases at cellular, organismal and ecological levels of organization. At the same time, CNE is not the only theory for explaining biological complexity that differs from ENS. For example, prior to the coinage of CNE the theory of Generative Entrenchment (GE) was also used to explain complexity without reliance on ENS alone; many authors in molecular evolution have since deployed a related, similar theory, here called Contingency and Entrenchment (CE). This talk will define and examine cases of CNE, using examples from molecular, cell and organismal biology, then compare it to other theories of complexity. I present CNE as a more general theory of the evolution of complexity which, alongside traditional adaptive explanations employing ENS, can account for a wide range of complex structures and relationships in biology.
Tyler’s publications:
Brunet TDP (2022). Higher level constructive neutral evolution. Biology & Philosophy, 37(4). Abstract. DOI.
Erasmus A, Brunet TDP (2022). Interpretability and Unification. Philosophy & Technology, 35(2). DOI.
Brunet TDP (2021). Local causation. Synthese, 199(3-4), 10885-10908. Abstract. DOI.
Brunet TDP, Doolittle WF, Bielawski JP (2021). The role of purifying selection in the origin and maintenance of complex function. Studies in History and Philosophy of Science Part A, 87, 125-135. DOI.
Brunet TDP, Fisher E (2020). Reasoning Continuously: a Formal Construction of Continuous Proofs. Studia Logica, 108(6), 1145-1160. Abstract. DOI.
Erasmus A, Brunet TDP, Fisher E (2020). What is Interpretability?. Philosophy & Technology, 34(4), 833-862. Abstract. DOI.
Brunet TDP (2019). On Purpose. ISIS, 110(3), 580-581. Author URL. DOI.
Brunet TDP, Doolittle WF (2018). The generality of Constructive Neutral Evolution. Biology & Philosophy, 33(1-2). DOI.
Doolittle WF, Brunet TDP (2017). On causal roles and selected effects: our genome is mostly junk. BMC BIOLOGY, 15 Author URL. DOI.
Inkpen SA, Douglas GM, Brunet TDP, Leuschen K, Doolittle WF, Langille MGI (2017). The coupling of taxonomy and function in microbiomes. BIOLOGY & PHILOSOPHY, 32(6), 1225-1243. Author URL. DOI.
Brunet TDP (2016). Aims and methods of biosteganography. JOURNAL OF BIOTECHNOLOGY, 226, 56-64. Author URL. DOI.
Doolittle WF, Brunet TDP (2016). What is the Tree of Life?. PLOS GENETICS, 12(4). Author URL. DOI.
Brunet TDP, Doolittle WF (2015). Multilevel Selection Theory and the Evolutionary Functions of Transposable Elements. GENOME BIOLOGY AND EVOLUTION, 7(8), 2445-2457. Author URL. DOI.
Doolittle WF, Brunet TDP, Linquist S, Gregory TR (2014). Distinguishing between “Function” and “Effect” in Genome Biology. GENOME BIOLOGY AND EVOLUTION, 6(5), 1234-1237. Author URL. DOI.
Brunet TDP, Doolittle WF (2014). Getting “function” right. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111(33), E3365-E3365. Author URL. DOI.

Uri Alon (Weizmann Institute of Science, Israel), Simplifying inflammation and fibrosis

Uri Alon is Professor, Department of Molecular Cell Biology, Weizmann Institute, Israel. His lab studies biological circuits using a combined experimental and theoretical approach, aiming to uncover general underlying principles that govern their functioning and evolution.
Video of the talk:

Fibrosis -excess scarring- is a condition that cuts across medicine, causes many diseases, and has no cure. It is a complex process with many cell types and molecules. We will show how a minimal mathematical model can form concepts that explain the basic features of fibrosis. These concepts led to experiments that provide new drug candidates that reduce fibrosis in mice for heart attacks and liver fibrosis. No knowledge of either fibrosis or math is needed to understand this talk.

Steven Frank (Univ. of California Irvine, USA) (Zoom only), Robustness and complexity: how evolution builds precise traits from sloppy components

Steven Frank is Donald Bren Professor & Distinguished Professor, Ecology & Evolutionary Biology
School of Biological Sciences at University of California Irvine (USA)
His main research interests concern evolutionary genetics and host-parasite interactions.
Video of the talk:

Academic Distinctions
Fellow, American Academy of Arts and Sciences, Elected 2012
Fellow, American Association for the Advancement of Science, Elected 2009
John Simon Guggenheim Fellowship, 1995
Theodosius Dobzhansky Prize, Society for the Study of Evolution, 1988
Young Investigator Prize, American Society of Naturalists, 1986

The first part of the talk describes the paradox of robustness. When a system robustly corrects errors in its components, the direct selective pressure on those components declines. Weakened selection on components causes them to become less reliable, maintain more genetic variability, or change in design. Loosened constraint on component-level design allows complexity to creep in arbitrarily, without natural selection to remove unnecessary elaboration. New forms of organismal complexity appear, seemingly without any clear logic. In the second part, I link the paradox of robustness to similar ideas developed by others, such as the theory of constructive neutral evolution. In the third part, I unify previous ideas into a more general perspective. I then link the paradox of robustness to the observation that, in evolution, intermediate stages in development tend to be more strongly constrained than earlier or later stages. This leads us to John Doyle’s discussion of the universal architecture of complex robustly designed systems in engineering and in biology, in which there is an important distinction between hardware and software layers. I link the observations about evolutionary constraints in development to Doyle’s hardware vs software distinction. Finally, I argue that constructive neutral evolution is mainly about genomic hardware, in which neutrality likely dominates, whereas the broader paradox of robustness also includes functional components in the software layer, in which nonneutral economic costs and benefits likely dominate.
This talk will be given via Zoom. Please contact Thomas Pradeu if you’d like to join us for this seminar.

Deborah Gordon (Professor of Biology, Stanford University, USA), The ecology of collective behavior

Deborah Gordon is Professor of Biology at University of Stanford (USA).
Deborah Gordon is a world-leading specialist of ant colonies and collective behaviors. With her group, she uses ant colonies to investigate systems that operate without central control, and explore analogies with other systems, such as the internet, the immune system, and the brain. She is interested in collective behavior, which can take many forms, such as emergence, self-organization, superorganism, quorum sensing, artificial intelligence, and dynamical networks.
Collective behavior operates without central control, using local interactions among participants to allow groups to respond to changing conditions. It is widespread in nature, not only producing the coordinated movement of bird flocks or fish schools, but also regulating activity in natural systems from cells, as in cancer metastasis or embryonic development, to the social groups of many vertebrates. An ecological perspective on collective behavior examines how collective behavior adjusts to changing environments. Ant colonies function collectively, and the enormous diversity of more than 14K species of ants, in different habitats, provides opportunities to look for general ecological patterns. The collective foraging behavior of harvester ants in the desert adjusts activity to manage water loss, while the trail networks of turtle ants in the canopy of the  tropical forest adjust to rapidly changing resources and vegetation. These examples suggests how systems with similar dynamics in their surroundings have evolved to show similar dynamics in the regulation of collective behavior. An ecological perspective can contribute to new insights in medical research.
See here Deborah Gordon’s TED talk: “What ants teach us about the brain, cancer and the Internet”

Publications of Deborah Gordon.

Ned Block (Silver Professor of Philosophy and Psychology, New York University, USA), Perception is non-conceptual

Ned Block is Silver Professor in the Departments of Philosophy, Psychology and Center for Neural Science at New York University (NYU), NY, USA.

This talk will argue that the reason that perception is fundamentally different from cognition is that perception is non-conceptual whereas cognition is conceptual.  I will review evidence that infants between the ages of 6 and 11 months can see colors but cannot accomplish even the simplest kinds of cognition involving colors.  Children of the same ages can see shapes and also exhibit cognition with shape concepts.  I will argue that the upshot is that color perception of these infants is non-conceptual and that one can extrapolate from this finding to all of perception.

David Bilder (Univ. Berkeley, USA), Ancient origins of tumor-host interactions: insights from the Drosophila model

The Bilder Lab (University of Berkeley, USA) studies the molecules and mechanisms that govern the polarity, growth, and morphogenesis of epithelia, the fundamental tissue of all animals and the major constituent of human organs. They also use Drosophila cancer models as a simple system to understand both how epithelial organization prevents tumor formation and how tumors actually kill their hosts.
Example of recent work:
Bilder et al., Tumour-host interactions through the lens of Drosophila, Nature Reviews Cancer (2021)
There is a large gap between the deep understanding of mechanisms driving tumour growth and the reasons why patients ultimately die of cancer. It is now appreciated that interactions between the tumour and surrounding non-tumour (sometimes referred to as host) cells play critical roles in mortality as well as tumour progression, but much remains unknown about the underlying molecular mechanisms, especially those that act beyond the tumour microenvironment. Drosophila has a track record of high-impact discoveries about cell-autonomous growth regulation, and is well suited to now probe mysteries of tumour – host interactions. Here, we review current knowledge about how fly tumours interact with microenvironmental stroma, circulating innate immune cells and distant organs to influence disease progression. We also discuss reciprocal regulation between tumours and host physiology, with a particular focus on paraneoplasias. The fly’s simplicity along with the ability to study lethality directly provide an opportunity to shed new light on how cancer actually kills.

Sarah-Maria Fendt (Professor of Oncology, KU Leuven, Belgium), Nutrient dependencies of metastasis formation

Sarah-Maria Fendt is since 2013 a Principal Investigator at the VIB Center for Cancer Biology and Professor of Oncology at KU Leuven, Belgium. Sarah’s lab is specifically interested in elucidating general regulatory principles in metabolism, and understanding cancer metabolism during metastasis formation as well as during altered whole body physiology. To perform novel research in her fields of interest her group exploits their expertise in metabolomics and fluxomics. The research of Sarah’s lab is currently funded by multiple (inter)national grants and industry, which include an ERC consolidator grant. Sarah received several awards such as the EMBO Gold Medal.
This talk will be given by Zoom. (Please contact Thomas Pradeu for the link).
Metastasis formation is the leading cause of death in cancer patients. We find that metabolic rewiring is a liability of metastasizing cancer cells. For example, we discovered that extracellular remodeling of the metastatic niche, a process essential to metastasis formation, requires a transcriptional- independent regulation via the metabolites. Moreover, we provide knowledge on intratumor heterogeneity of metabolism and its role in metastasis formation. Specifically, we discovered that heterogeneity in the metabolic enzyme phosphoglycerate dehydrogenase (PHGDH) predicts in cancer patients the risk for metastasis formation. Strikingly, loss of PHGDH protein expression drives early dissemination of cancer cells due to a novel mechanism leading to the posttranslational modification of cell surface integrins. More recently, we have investigated the nutrient dependencies of metastasis and find a strong organ specific pattern. Thus, we study the metabolism of metastasizing cancer cells with the goal to define novel therapeutic strategies.

Stephen M. Downes (Utah), An Early History of the Heritability Coefficient Applied to Humans (1918–1960)

Stephen M. Downes is a Full Professor in the Philosophy Department at the University of Utah (USA). Most of his work is in philosophy of science with special focus on philosophy of biology, philosophy of social science and models and modeling across the sciences. He is also an Adjunct Professor in the School of Biological Sciences at the University of Utah, and a member of the PhilInBioMed network.
Detailed CV.

An Early History of the Heritability Coefficient Applied to Humans (1918–1960)

Stephen M. Downes (in collaboration with Eric Turkheimer)
(See full paper here)
Fisher’s 1918 paper accomplished two distinct goals: unifying discrete Mendelian genetics with continuous biometric phe- notypes and quantifying the variance components of variation in complex human characteristics. The former contributed to the foundation of modern quantitative genetics; the latter was adopted by social scientists interested in the pursuit of Gal- tonian nature-nurture questions about the biological and social origins of human behavior, especially human intelligence. This historical divergence has produced competing notions of the estimation of variance ratios referred to as heritability. Jay Lush showed that they could be applied to selective breeding on the farm, while the early twin geneticists used them as a descriptive statistic to describe the degree of genetic determination in complex human traits. Here we trace the early history (1918 to 1960) of the heritability coefficient now used by social scientists.
Behavior genetics · Heritability · Heritability coefficient · Human behavior genetics