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      Functional biology in its natural context: A search for emergent simplicity

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          Abstract

          The immeasurable complexity at every level of biological organization creates a daunting task for understanding biological function. Here, we highlight the risks of stripping it away at the outset and discuss a possible path toward arriving at emergent simplicity of understanding while still embracing the ever-changing complexity of biotic interactions that we see in nature.

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          CDK4/6 inhibition triggers anti-tumor immunity

          Shom Goel, Molly DeCristo, April Watt … (2017)
          Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies 1,2 . Pharmacologic inhibitors of CDK4/6 have shown significant activity against several solid tumors 3,4 . Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma (RB) tumor suppressor, inducing G1 cell cycle arrest in tumor cells 5 . Here, we use murine models of breast carcinoma and other solid tumors to show that selective CDK4/6 inhibitors not only induce tumor cell cycle arrest, but also promote anti-tumor immunity. We confirm this phenomenon through transcriptomic analysis of serial biopsies from a clinical trial of CDK4/6 inhibitor treatment for breast cancer. The enhanced anti-tumor immune response has two underpinnings. First, CDK4/6 inhibitors activate tumor cell expression of endogenous retroviral elements, thus increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and hence enhances tumor antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells (Tregs). Mechanistically, the effects of CDK4/6 inhibitors on both tumor cells and Tregs are associated with reduced activity of the E2F target, DNA methyltransferase 1. Ultimately, these events promote cytotoxic T cell-mediated clearance of tumor cells, which is further enhanced by the addition of immune checkpoint blockade. Our findings indicate that CDK4/6 inhibitors increase tumor immunogenicity and provide rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti-cancer treatment.
          Article 0 comments Cited 482 times – based on 0 reviews     Review now
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            Ecological and evolutionary forces shaping microbial diversity in the human intestine.

            Ruth E Ley, Daniel A Peterson, Jeffrey Gordon (2006)
            The human gut is populated with as many as 100 trillion cells, whose collective genome, the microbiome, is a reflection of evolutionary selection pressures acting at the level of the host and at the level of the microbial cell. The ecological rules that govern the shape of microbial diversity in the gut apply to mutualists and pathogens alike.
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              Emergent simplicity in microbial community assembly

              Daniel Segrè, Pankaj D. Mehta, Alvaro Sanchez … (2018)
              A major unresolved question in microbiome research is whether the complex taxonomic architectures observed in surveys of natural communities can be explained and predicted by fundamental, quantitative principles. Bridging theory and experiment is hampered by the multiplicity of ecological processes that simultaneously affect community assembly in natural ecosystems. We addressed this challenge by monitoring the assembly of hundreds of soil- and plant-derived microbiomes in well-controlled minimal synthetic media. Both the community-level function and the coarse-grained taxonomy of the resulting communities are highly predictable and governed by nutrient availability, despite substantial species variability. By generalizing classical ecological models to include widespread nonspecific cross-feeding, we show that these features are all emergent properties of the assembly of large microbial communities, explaining their ubiquity in natural microbiomes.
              Article 0 comments Cited 339 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Joy Bergelson:
                ORCID: https://orcid.org/0000-0001-7893-7387
                Christian R Landry: Role: Reviewing Editor
                George H Perry: Role: Senior Editor
                Journal
                Journal ID (nlm-ta): eLife
                Journal ID (iso-abbrev): Elife
                Journal ID (publisher-id): eLife
                Title: eLife
                Publisher: eLife Sciences Publications, Ltd
                ISSN (Electronic): 2050-084X
                Publication date (Electronic, pub): 07 June 2021
                Publication date Collection: 2021
                Volume: 10
                Electronic Location Identifier: e67646
                Affiliations
                [1 ]Department of Ecology & Evolution, University of Chicago ChicagoUnited States
                [2 ]Department of Biology, Stanford University StanfordUnited States
                [3 ]Department of Ecology & Evolutionary Biology, Yale University New HavenUnited States
                [4 ]Department of Physics, Washington University in St Louis St. LouisUnited States
                Université Laval Canada
                Pennsylvania State University United States
                Author notes
                [‡]

                Department of Biology, NYU, NY, United States.

                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-7893-7387
                http://orcid.org/0000-0002-3664-9130
                https://orcid.org/0000-0002-2292-5608
                https://orcid.org/0000-0002-9558-1121
                Article
                Publisher ID: 67646
                DOI: 10.7554/eLife.67646
                PMC ID: 8184206
                PubMed ID: 34096867
                SO-VID: 91c34515-2b9f-4053-be23-d36ecc461144
                Copyright © © 2021, Bergelson et al
                License:

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                Date received : 19 February 2021
                Date accepted : 28 May 2021
                Funding
                No external funding was received for this work.
                Categories
                Subject: Review Article
                Subject: Evolutionary Biology
                Subject: Physics of Living Systems
                Custom metadata
                Author impact statement The time is right to study biological function without stripping systems of their essential eco-evolutionary context.

                ScienceOpen disciplines: Life sciences
                Keywords: eco-evolutionary dynamics,functional biology,ecological context,systems biology
                Data availability:
                ScienceOpen disciplines: Life sciences
                Keywords: eco-evolutionary dynamics, functional biology, ecological context, systems biology

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