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    251 | Rosemary Braun on Uncovering Patterns in Biological Complexity

    enSeptember 25, 2023

    Podcast Summary

    • Leveraging Platforms for Hiring and Managing FinancesIndeed streamlines hiring with features like scheduling, screening, and messaging, while Rocket Money helps manage finances by identifying and canceling unwanted subscriptions and monitoring spending.

      For hiring, instead of actively searching for candidates, utilizing a platform like Indeed can help streamline the process and provide high-quality matches. Indeed, with over 350 million monthly visitors, offers features like scheduling, screening, and messaging to help connect with candidates quickly and efficiently. The platform is trusted by 93% of employers for delivering the highest quality matches compared to other job sites. On the other hand, when it comes to managing personal finances, Rocket Money serves as a valuable tool to help identify and cancel unwanted subscriptions, monitor spending, and lower bills. With over 5 million users, Rocket Money has helped save its members an average of $720 a year and over $500 billion in canceled subscriptions. In the realm of science, specifically biology, it's fascinating to learn that every cell in our body has its own circadian clock, influencing the cell's behavior based on the time of day. This intricate system, which includes the nervous and metabolic systems, is a testament to the complexity of biological organisms and the potential for discoveries through advanced data analysis, computational power, and innovative research.

    • Understanding complex systems in biologyBiology is shifting towards understanding complex systems and networks instead of individual organisms or species, requiring a systems perspective to identify key interactions and variables

      In the field of biology, there has been a shift towards understanding complex systems and networks instead of focusing solely on individual organisms or species. This change has been driven by advancements in molecular biology profiling technologies, which have made it possible to assay gene expression and genetic variations in great detail. However, making sense of this vast amount of data requires a systems perspective. Researchers are trying to identify the key interactions between microscopic elements that produce macroscopic features. More data is not always useful by itself, and it's essential to identify the state variables that the system actually cares about. This process is referred to as coarse graining and emergence, where we focus on a small number of variables to understand the overall behavior of the system. For example, in physics, we don't need to know the exact position and velocity of every atom to understand how the Earth orbits the sun. Instead, we focus on the center of mass and velocity. Similarly, in biology, it's crucial to identify the essential interactions and variables that govern the behavior of cells and organisms. The Mindscape Big Picture Scholarship, offered by Bold.org, aims to support young students who are interested in thinking deeply about these fundamental concepts.

    • A biology professor's perspective on self-organization in living systems through computational omics researchA biology professor uses computational methods to study self-organization in living systems, collaborating with experimentalists and running an in silico 'dry lab'. She acknowledges skepticism towards theoretical research but believes interdisciplinary approaches are key to understanding complex biological systems.

      The speaker, a biology professor with a background in theoretical physics, is passionate about understanding how living systems self-organize at various scales, from molecular complexes to ecological networks. She approaches this problem from a computational perspective and collaborates extensively with experimentalists to test her models. Despite being a theorist, she runs a "dry lab" where all experiments are in silico. She acknowledges that there's still skepticism towards theoretical or non-experimental research in biology, but she believes that this is changing as the importance of interdisciplinary approaches in understanding complex biological systems becomes more recognized. The term "omics" refers to various fields of study that focus on large-scale analysis of biological data, such as genomics, proteomics, and metabolomics.

    • From Genomics to Transcriptomics and ProteomicsGenetic research has evolved from DNA sequencing to analyzing mRNA and protein abundances, providing a more comprehensive understanding of gene function and regulation.

      The study of genetics and gene expression has evolved significantly over the past few decades, moving beyond the sequencing of DNA to the analysis of mRNA and protein abundances. This progression, from genomics to transcriptomics and proteomics, has given scientists an unprecedented understanding of gene function and regulation. Initially, the focus was on understanding the DNA sequence and its variations between individuals or species. However, the development of microarray technology allowed for the simultaneous measurement of mRNA abundances across thousands of genes, providing insights into gene expression and function. This period was referred to as genomics and transcriptomics. Now, with next-generation sequencing technologies, scientists can analyze the entire genome, mRNA, and protein levels of a sample, gaining a comprehensive understanding of a given sample's biological state. This high-throughput approach has led to a more nuanced understanding of genes and their functions, revealing that a single gene can produce different isoforms under various conditions, leading to distinct proteins or regulatory properties. In summary, the study of genetics and gene expression has progressed from the sequencing of DNA to the analysis of mRNA and protein abundances, providing a more comprehensive understanding of gene function and regulation. This evolution has led to a more nuanced view of genes, revealing their complex and dynamic nature.

    • Biology challenges the lock-and-key model of protein functionIn biology, proteins and regulatory molecules can bind to multiple targets, challenging the assumption of a one-to-one relationship and offering new insights into systems-level control

      The binding of proteins to one another and the targeting of regulatory elements by regulatory proteins is not as specific as once thought. The assumption of a lock-and-key mechanism, where each protein has a clear and distinct function, may limit discoveries in biology. This concept is challenging to grasp because we often think of designed systems where each part has a specific purpose. However, in biology, the boundaries are not always clear, and evolution through natural selection results in complex systems where multiple functions can be served by a single protein or regulatory molecule. MicroRNAs, small noncoding RNA molecules, serve as an example of this concept. They are very short, 6 to 8 bases long, and can bind to multiple mRNA molecules, leading to a many-to-many relationship between microRNAs and their targets. This flies in the face of the one-to-one assumption that we are taught early on in biology. The evolution of such a nonspecific binding mechanism may serve a purpose in exerting systems-level control over entire processes by redundantly targeting different elements of that system. Gary Wilk and I investigated this concept using data from TCGA, a repository of genomic data, and found statistical evidence of systems-level control through redundant targeting of microRNAs and their targets. In this way, the biological world challenges our assumptions and offers new insights into the complex and interconnected nature of living organisms.

    • Understanding complex biological systems through gene interconnectedness and microRNA pathwaysResearchers analyze gene expression levels and microRNA interactions to measure pathway activity and infer network structure, ultimately aiming to understand individual node effects on system behavior.

      Researchers are working on understanding complex biological systems by analyzing the interconnectedness of genes and their pathways, as well as the potential interactions between them. This involves summarizing the expression levels of genes in a particular pathway to measure its activity and identifying microRNA pathway pairs where microRNA levels correlate with decreased pathway activity. However, researchers are now also considering the "wiring diagrams" or networks of putative interactions between genes, acknowledging that these diagrams are incomplete and subject to ongoing discovery. The ultimate goal is to understand the causal effects of individual nodes on the behavior of the system as a whole, but this is a challenging problem due to the vast amount of omics data available and the underdetermined nature of the problem. Researchers are making progress by looking for patterns of correlation in the data to infer network structure, but it's not yet at the level where everyone agrees on the circuits in the same way they agree on the organs in the body. This work is reminiscent of causal networks in other fields, such as social science and medicine, and the ultimate goal is to understand the causal effects of individual nodes on the behavior of the system as a whole.

    • Understanding biological networks requires detailed information beyond statistical propertiesBiological networks are complex, adaptive systems that require a nuanced approach combining domain expertise and computational analysis for accurate understanding and prediction

      While statistical properties of complex biological networks can provide some insights into their functionality, recovering every node and edge in detail is crucial for fully understanding their behavior. Biological networks, as rich and complex systems, are unique due to their adaptability, non-equilibrium state, and reliability despite environmental and genetic variations. These networks are not fine-tuned and exhibit a wide basin of attraction, meaning their systems-level effects are important. Machine learning and AI play significant roles in analyzing these networks, but a naive application of these techniques may not yield valuable results without prior knowledge of the biological context. The complex nature of biological systems requires a nuanced approach that combines computational analysis with domain expertise.

    • Understanding the geometry of biological data to identify meaningful variationsBiological data analysis benefits from integrating old and new data, but understanding the geometry of low-dimensional manifolds within high-dimensional feature spaces can help identify meaningful variations and insights into complex biological systems.

      In the field of biology, particularly in the area of machine learning and data analysis, there's a growing interest in integrating existing, albeit incomplete or erroneous, data with new discoveries. This approach contrasts with the strategy used in games like chess or Go, where it's better for the computer to learn on its own without human intervention. However, given the complexity of biological systems, with approximately 20,000 genes or mRNAs to consider, it might be beneficial to constrain the search space. This can be achieved by understanding the geometry of the low-dimensional manifold within the high-dimensional feature space of biological data. This geometry can help identify meaningful variations and deviations, providing insights into the behavior of biological systems as a whole. While significant progress has been made in this area through techniques like nonlinear dimension reduction and manifold learning, challenges remain. These include the vast amount of data and the need to accurately model the complex, non-linear relationships within biological systems.

    • Exploring gene-protein relationships for improved healthcareBy analyzing gene expression and circadian rhythms, researchers can develop better diagnostics and therapeutics, potentially improving overall health outcomes. Understanding the influence of feeding behaviors on circadian rhythms could lead to more effective jet lag recovery.

      Understanding the complex relationships between genes, proteins, and their respective roles in the body, particularly in the context of circadian rhythms, can lead to significant advancements in healthcare. By measuring physiological time through multi-gene expression profiles, researchers can potentially develop better diagnostics and therapeutic interventions. For instance, the circadian rhythm, a self-sustained 24-hour oscillation, can be influenced by feeding behaviors, with high calorie intake in the morning acting as a more effective phase resetting signal than other times of the day. This knowledge could help individuals recover from jet lag more efficiently and potentially improve overall health outcomes. However, the challenge lies in determining the appropriate scale for analyzing this vast, 20,000-dimensional data space. Future research will focus on adapting this scale to different regions of the data, enabling the discovery of new hypotheses and ultimately, better health outcomes.

    • Discovery of a molecular clock in every cellThe molecular clock, present in nearly every cell, regulates processes through a temperature-compensated transcription-translation feedback loop, enabling efficient coordination and orchestration of functions across the body.

      Our bodies have a molecular clock, nearly present in every cell, with an approximate 24-hour period. This discovery was surprising as it was initially thought that only the brain would require such a clock. This core clock circuit is a transcription-translation feedback loop, involving genes that regulate each other's transcription, creating negative feedback oscillations. These oscillations are temperature-compensated, allowing for consistent rhythms across a wide range of temperatures. This molecular clock system enables processes to be coordinated and orchestrated across the body without direct communication between cells. The discovery of peripheral clocks in every tissue raises questions about its purpose, one hypothesis being that it allows for efficient coordination and orchestration of processes in a spatially extended system. The clock's robust 24-hour period, despite varying temperatures, highlights its importance in anticipating daily changes. However, the exact mechanisms behind temperature compensation and its sensitivity to environmental temperature fluctuations are still not well understood.

    • Understanding the intricacies of biological clocksBiological clocks are complex systems that regulate various biological processes and function through chemical oscillators, temperature communication, and gene control. Their study has significant implications for health and therapeutic interventions.

      Our bodies have intricate biological clocks, which function through chemical oscillators, and these oscillators are connected to each other and to the environment through various signaling molecules and physical interactions. These clocks are crucial for various biological processes, including metabolism, lifespan, and reproduction. The design of these biological clocks is a complex challenge, as they need to function accurately under different temperature conditions and communicate with other cells and systems. The study of these clocks is ongoing, and many fundamental questions remain unanswered. For instance, the exact mechanism of communication between different oscillators and cells is not yet fully understood. The oscillators are not isolated entities but are part of larger networks, with many genes under circadian control. The discovery of these biological clocks and their functions has significant implications for understanding various health conditions and developing therapeutic interventions.

    • The circadian rhythm's impact on biological processesUnderstanding the circadian rhythm's role in regulating metabolism, gene expression, and other processes could lead to insights into healthy aging and extending lifespans.

      The circadian rhythm plays a crucial role in regulating various biological processes in organisms, including fruit flies and humans. These processes, such as metabolism and gene expression, can differ significantly depending on the time of day. Knocking out certain genes associated with the circadian rhythm can lead to arrhythmic behavior and similar lifespans, regardless of caloric intake. This suggests that the specific genes under circadian control have a significant impact on macroscopic outcomes, including lifespan. Furthermore, disruptions in sleep and circadian rhythms have been linked to neurodegenerative diseases like Alzheimer's. Research is ongoing to understand the connections between circadian rhythms and healthy aging. In essence, the circadian rhythm acts as a complex system that regulates various biological processes, and understanding this system could potentially lead to insights into extending healthy human lifespans. The study of complex systems, including biological networks, offers a common approach to investigating these phenomena. While each system may have unique features, the methods used to study them can provide valuable insights.

    • Identifying minimal changes in networks to recover normal propertiesNetwork analysis can help identify statistical differences between normal and cancer samples, allowing researchers to target a smaller number of nodes and edges experimentally, while considering whether leading eigenvalues fully explain network function.

      While it's tempting to focus on specific genes or molecules when studying biological systems, it's important to remember that complex outcomes result from systems-level properties. However, to make interventions or produce desired outcomes, we need to narrow down our focus. One approach is to use network analysis to identify statistical differences between normal and cancer samples at the whole network level, and then identify the minimal number of edges that need to be altered to recover the statistical properties of the normal sample. This can help researchers target a smaller number of nodes and edges experimentally. Additionally, while coarse-grained statistical properties can provide valuable insights, it's important to consider whether recovering the leading eigenvalues of the graph is enough to understand the function of the network fully. Overall, this approach can help bridge the gap between understanding complex systems at a systems level and making targeted interventions.

    • Focusing on smooth patterns in complex networks and exploring 'rules of life' can lead to deeper insightsExploring smooth patterns and 'rules of life' in complex networks can simplify understanding, reveal underlying constraints, and bridge microscopic and macroscopic observations

      When analyzing complex networks, focusing on the smoothest patterns may provide valuable insights into the flow of information in a biologically meaningful way. The graph's coarse features can be mathematically characterized, potentially simplifying the understanding of the system without requiring extensive detail. Furthermore, the concept of "rules of life" is a useful one for understanding the relationship between microscopic and macroscopic observations. This concept refers to the constraints or organizing principles that enable us to move from microscopic descriptions, such as omics data, to macroscopic observations, like whether a cell is cancerous or an organism is a mouse or a frog. Discovering these rules can help us gain insight into the system and better understand the underlying constraints. In summary, focusing on the smooth patterns in complex networks and exploring the rules of life can lead to a deeper understanding of complex systems, allowing us to make connections between microscopic and macroscopic observations.

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    RELEVANT LINKS 

    From Our Conversation with Elizabeth Jeffries PhD

     

    THANK YOU - ELIZABETH JEFFRIES PhD

    A big thank you to Elizabeth Jeffries PhD for being on the show this week.  Make sure to keep up to date on all her work on her website http://www.elizabethjeffrieswrites.com.  Also follow her on Instagram and Twitter.  And of course make sure to get your copy of Through the Kaleidoscope: How Exploring Cell Biology Transforms My Relationship with God

     

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    IRENCAST HOSTS

    Rev. Allen O’Brien, MAT | co-founder & co-host | allen@irenicast.com

    Allen is a venerator of emotionality. He thrives on education, peace, and interconnectedness— passions which permeate his work as pastor, writer, lover of all the things, and occasional vegan.

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    CREDITS

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    67 | Kate Jeffery on Entropy, Complexity, and Evolution

    67 | Kate Jeffery on Entropy, Complexity, and Evolution

    Our observable universe started out in a highly non-generic state, one of very low entropy, and disorderliness has been growing ever since. How, then, can we account for the appearance of complex systems such as organisms and biospheres? The answer is that very low-entropy states typically appear simple, and high-entropy states also appear simple, and complexity can emerge along the road in between. Today’s podcast is more of a discussion than an interview, in which behavioral neuroscientist Kate Jeffery and I discuss how complexity emerges through cosmological and biological evolution. As someone on the biological side of things, Kate is especially interested in how complexity can build up and then catastrophically disappear, as in mass extinction events.

    There were some audio-quality issues with the remote recording of this episode, but loyal listeners David Gennaro and Ben Cordell were able to help repair it. I think it sounds pretty good!

    Support Mindscape on Patreon.

    Kate Jeffery received her Ph.D. in behavioural neuroscience from the University of Edinburgh. She is currently a professor in the Department of Behavioural Neuroscience at University College, London. She is the founder and Director of the Institute of Behavioural Neuroscience at UCL.


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