Lifeboat Foundation

Half a century after its foundation, the neutral theory of molecular evolution continues to attract controversy. The debate has been hampered by the coexistence of different interpretations of the core proposition of the neutral theory, the ‘neutral mutation–random drift’ hypothesis. In this review, we trace the origins of these ambiguities and suggest potential solutions. We highlight the difference between the original, the revised and the nearly neutral hypothesis, and re-emphasise that none of them equates to the null hypothesis of strict neutrality. We distinguish the neutral hypothesis of protein evolution, the main focus of the ongoing debate, from the neutral hypotheses of genomic and functional DNA evolution, which for many species are generally accepted. We advocate a further distinction between a narrow and an extended neutral hypothesis (of which the latter posits that random non-conservative amino acid substitutions can cause non-ecological phenotypic divergence), and we discuss the implications for evolutionary biology beyond the domain of molecular evolution. We furthermore point out that the debate has widened from its initial focus on point mutations, and also concerns the fitness effects of large-scale mutations, which can alter the dosage of genes and regulatory sequences. We evaluate the validity of neutralist and selectionist arguments and find that the tested predictions, apart from being sensitive to violation of underlying assumptions, are often derived from the null hypothesis of strict neutrality, or equally consistent with the opposing selectionist hypothesis, except when assuming molecular panselectionism. Our review aims to facilitate a constructive neutralist–selectionist debate, and thereby to contribute to answering a key question of evolutionary biology: what proportions of amino acid and nucleotide substitutions and polymorphisms are adaptive?

COVER STORY: The epigenetic clock uses DNA methylation to calculate the metric of “epigenetic age”. Epigenetic age acceleration (epigenetic > chronological age) has been repeatedly linked to pediatric asthma and allergic disease, demonstrating its potential as a diagnostic biomarker. However, questions remain about the accuracy and utility of epigenetic clocks in children.

This review by researchers at University of British Columbia examines the most used current epigenetic clocks and details the associations between epigenetic age acceleration and asthma/allergic disease. They explore the potential of the epigenetic clock as a biomarker for asthma and discuss the need for a pediatric epigenetic clock that is accurate in blood samples in order to maximize the utility of this powerful tool.

In a new study, Abudayyeh and Gootenberg led a team of scientists on a quest to identify and characterize Fanzor enyzmes in large-scale genetic databases. Their genetic mining venture, published in Science Advances, outlines the discovery of over 3,600 Fanzors in eukaryotes, including algae, snails, amoebas and the viruses that infect them.

Fanzors evolved new features to survive and thrive in eukaryotes

Five distinct families of Fanzors could be identified from the study data. By comparing the biological makeup of these families, Abudayyeh and colleagues could track their evolutionary history. Fanzors most likely evolved from proteins called TnpB, which are encoded in transposons – mobile genetic elements often nicknamed “jumping genes”. In Nature, the McGovern team hypothesized that the TnpB gene may have “jumped” from bacteria to eukaryotes in a genetic “shuffling” many years ago. Abudayyeh and Gootenburg’s new study and genetic tracing implies that this event likely occurred several times, with Fanzors “jumping” from viruses and symbiotic bacteria. Their analyses also suggest that once these genes had made their way into eukaryotes, they evolved new features that promoted their survival, including the ability to enter a cell’s nucleus and access its DNA.

Scientists have successfully gene-edited chickens to make them partially resistant to the bird flu and believe full immunity may be within reach.

Scientists from the University of Edinburgh’s Roslin Institute have successfully gene-edited chickens to make them partially resistant to the bird flu but experts argue that only full immunity can see the danger of the virus eradicated.

This is according to a report by BBC News published this week.

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The Collective Intelligence of Cells During Morphogenesis: What Bioelectricity Outside the Brain Means for Understanding our Multiscale Nature with Michael Levin — Incredible Minds.

Recorded: April 29, 2023.

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The most common screening test for prostate cancer — a measure of prostate-specific antigen, or PSA, levels — so often suggests cancer where there is none that clinical guidelines no longer recommend the test for men over 70 and leave the decision up to younger patients.

Scientists at Stanford Medicine and their collaborators aim to make PSA screening more accurate — by calibrating PSA levels to each man’s genetics. Applying this type of personalization could significantly reduce overdiagnosis and better predict aggressive disease. Their research was published June 1 in Nature Medicine.

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In this webinar, three experts will discuss how Precision NanoSystems’ modular microfluidic platform technologies and analytics can help scientists successfully design, develop, test, and scale-up promising mRNA-LNP vaccines and therapeutics from concept to clinic. Don’t miss this webinar, now available on demand.

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Nucleic acids (e.g., siRNA, mRNA and saRNA) can be designed and formulated to silence, express, and edit specific genes providing a flexible and powerful approach to preventing and treating diseases. The recent commercialization and widespread distribution of COVID-19 mRNA vaccines has exemplified the massive potential of this new class of genomic medicines and vaccines to effectively thwart emerging viral threats and treat a wide range of challenging diseases. Part of developing a successful mRNA therapeutic or vaccine is choosing a delivery mechanism that protects the nucleic acids on the way to their target tissue. Encapsulating mRNA in lipid nanoparticles has proven to be one of the best vehicles for overcoming extracellular and intracellular barriers and safely delivering the treatment. Several mRNA-LNP formulations that target things like viral infections and cancers are being evaluated clinically.

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Researchers at Columbia University have developed a probiotic-guided chimeric antigen receptor (CAR)-T platform that uses engineered bacteria to infiltrate and produce synthetic antigen targets, enabling CAR-T cells to find, identify, and destroy tumor cells in situ. The results of in vivo preclinical tests suggest that the combined ProCAR cell therapy platform could expand the scope of CAR-T cell therapy to include difficult-to-target solid tumors.

Tal Danino, PhD, and Rosa L. Vincent, PhD, at Columbia University’s department of biomedical engineering, and colleagues, reported on their developments in Science, in a paper titled “Probiotic-guided CAR-T cells for solid tumor targeting,” in which they concluded, “These findings highlight the potential of the ProCAR platform to address the roadblock of identifying suitable CAR targets by providing an antigen that is orthogonal to both healthy tissue and tumor genetics … Overall, combining the advantages of tumor-homing bacteria and CAR-T cells provides a new strategy for tumor recognition and, in turn, builds the foundation for engineered communities of living therapies.”

Immunotherapies using CAR-T cells have proven successful in treating some types of blood cancers, but their efficacy against solid tumors remains elusive. A key challenge facing tumor-antigen targeting immunotherapies like CAR-T is the identification of suitable targets that are specifically and uniformly expressed on solid tumors, the authors noted. “A key challenge of antigen-targeted cell therapies relates to the expression patterns of the antigen itself, which makes the identification of optimal targets for solid tumor cell therapies an obstacle for the development of new CARs.” Solid tumors express heterogeneous and nonspecific antigens and are poorly infiltrated by T cells. As a result, the approach carries a high risk of fatal on-target, off-tumor toxicity, wherein CAR-T cells attack the targeted antigen on healthy vital tissues with potentially fatal effects.