Lifeboat Foundation

Life’s evolutionary timescale is typically calibrated to the oldest fossil occurrences. However, the veracity of fossil discoveries from the early Archaean period has been contested^11,12. Relaxed Bayesian node-calibrated molecular clock approaches provide a means of integrating the sparse fossil and geochemical record of early life with the information provided by molecular data; however, constraining LUCA’s age is challenging due to limited prokaryote fossil calibrations and the uncertainty in their placement on the phylogeny. Molecular clock estimates of LUCA^13,14,15 have relied on conserved universal single-copy marker genes within phylogenies for which LUCA represented the root. Dating the root of a tree is difficult because errors propagate from the tips to the root of the dated phylogeny and information is not available to estimate the rate of evolution for the branch incident on the root node. Therefore, we analysed genes that duplicated before LUCA with two (or more) copies in LUCA’s genome¹⁶. The root in these gene trees represents this duplication preceding LUCA, whereas LUCA is represented by two descendant nodes. Use of these universal paralogues also has the advantage that the same calibrations can be applied at least twice. After duplication, the same species divergences are represented on both sides of the gene tree^17,18 and thus can be assumed to have the same age. This considerably reduces the uncertainty when genetic distance (branch length) is resolved into absolute time and rate. When a shared node is assigned a fossil calibration, such cross-bracing also serves to double the number of calibrations on the phylogeny, improving divergence time estimates. We calibrated our molecular clock analyses using 13 calibrations (see ‘Fossil calibrations’ in Supplementary Information). The calibration on the root of the tree of life is of particular importance. Some previous studies have placed a younger maximum constraint on the age of LUCA based on the assumption that life could not have survived Late Heavy Bombardment (LHB) (~3.7–3.9 billion years ago (Ga))¹⁹. However, the LHB hypothesis is extrapolated and scaled from the Moon’s impact record, the interpretation of which has been questioned in terms of the intensity, duration and even the veracity of an LHB episode^20,21,22,23. Thus, the LHB hypothesis should not be considered a credible maximum constraint on the age of LUCA. We used soft-uniform bounds, with the maximum-age bound based on the time of the Moon-forming impact (4,510 million years ago (Ma) ± 10 Myr), which would have effectively sterilized Earth’s precursors, Tellus and Theia¹³. Our minimum bound on the age of LUCA is based on low δ⁹⁸ Mo isotope values indicative of Mn oxidation compatible with oxygenic photosynthesis and, therefore, total-group Oxyphotobacteria in the Mozaan Group, Pongola Supergroup, South Africa^24,25, dated minimally to 2,954 Ma ± 9 Myr (ref. ²⁶).

Our estimates for the age of LUCA are inferred with a concatenated and a partitioned dataset, both consisting of five pre-LUCA paralogues: catalytic and non-catalytic subunits from ATP synthases, elongation factor Tu and G, signal recognition protein and signal recognition particle receptor, tyrosyl-tRNA and tryptophanyl-tRNA synthetases, and leucyl-and valyl-tRNA synthetases²⁷. Marginal densities (commonly referred to as effective priors) fall within calibration densities (that is, user-specified priors) when topologically adjacent calibrations do not overlap temporally, but may differ when they overlap, to ensure the relative age relationships between ancestor-descendant nodes. We consider the marginal densities a reasonable interpretation of the calibration evidence given the phylogeny; we are not attempting to test the hypothesis that the fossil record is an accurate temporal archive of evolutionary history because it is not²⁸.

Increased frailty, higher incidence of diseases, and death. As the population grows older, there is a need to reveal mechanisms associated with aging that could spearhead treatments to postpone the onset of age-associated decline, extend both healthspan and lifespan. One possibility is targeting the sirtuin SIRT1, the founding member of the sirtuin family, a highly conserved family of histone deacetylases that have been linked to metabolism, stress response, protein synthesis, genomic instability, neurodegeneration, DNA damage repair, and inflammation. Importantly, sirtuins have also been implicated to promote health and lifespan extension, while their dysregulation has been linked to cancer, neurological processes, and heart disorders. SIRT1 is one of seven members of sirtuin family; each requiring nicotinamide adenine dinucleotide (NAD⁺) as co-substrate for their catalytic activity. Overexpression of yeast, worm, fly, and mice SIRT1 homologs extend lifespan in each animal, respectively. Moreover, lifespan extension due to calorie restriction are associated with increased sirtuin activity. These findings led to the search for a calorie restriction mimetic, which revealed the compound resveratrol; (3, 5, 4′-trihydroxy-trans-stilbene) belonging to the stilbenoids group of polyphenols. Following this finding, resveratrol and other sirtuin-activating compounds have been extensively studied for their ability to affect health and lifespan in a variety of species, including humans via clinical studies.

Aging is associated with a progressive metabolic, physiological decline and can be genetically and environmentally modified (Helfand and Rogina, 2000). The search for the molecular basis of aging led to the identification of several pathways associated with longevity including insulin/IGF-1, target of rapamycin (TOR) and the Sirtuins (Kenyon, 2010; Chen et al., 2022). The sirtuins are a family of nicotinamide adenine dinucleotide (NAD⁺)-dependent histone deacetylases (Haigis and Sinclair, 2010; Hall et al., 2013; Bonkowski and Sinclair, 2016; Dai et al., 2018; Singh et al., 2018). Sirtuins are also categorized as deacetylases because they catalyze the post-translational modification of signaling molecules including decrotonylation, ADP-ribosylation, diacylation, desuccinylation, demalonylation, depropynylation, delipoamidation, and deglutarylation, and other long-chain fatty acid deacylations (Feldman, Baeza, and Denu, 2013; Choudhary et al., 2014; Fiorentino et al., 2022).

In mammals, there are seven members (SIRT1-SIRT7) including SIRT1, SIRT6 and SIRT7, which are localized to the nucleus, and SIRT3, SIRT4, and SIRT5 localized to the mitochondria, SIRT2 localized to the cytosol, and SIRT1 also localized to cytosol in some cell types (Bonkowski and Sinclair, 2016). As histone deacetylases, sirtuins function by removing acetyl groups from the target proteins resulting in either inhibition or activation. SIRT1, SIRT6 and SIRT7 have many functions including: regulators of transcription, control of cellular metabolism, DNA repair, cell survival, tissue regeneration, inflammation, circadian rhythms and neuronal signaling (Haigis and Sinclair, 2010). SIRT3-5 are important for switching to mitochondrial oxidative metabolism during CR and modulate stress tolerance (Verdin et al., 2010).

The genetically modified lymphocytes were then multiplied into the hundreds of millions in the laboratory and infused back into the patients, where they expressed the tumor-specific T-cell receptors and continued to multiply.

“By taking the natural T-cell receptors that are present in a very small number of cells and putting them into normal lymphocytes for which we have enormous numbers—a million in every thimbleful of blood—we can generate as many cancer-fighting cells as we want,” Dr. Rosenberg explained.

As part of a larger phase 2 trial, seven patients with metastatic colon cancer were treated with the experimental personalized cellular immunotherapy. All seven received several doses of the immunotherapy drug pembrolizumab (Keytruda) before the cell therapy and another immunotherapy drug called IL-2 afterward. Three patients had substantial shrinkage of metastatic tumors in the liver, lung, and lymph nodes that lasted for four to seven months. The median time to disease progression was 4.6 months.

A global collaboration involving University of Manchester scientists has discovered a gene whose variants potentially cause neurodevelopmental disorders (NDDs) in hundreds of thousands of people across the world.

The findings of the University of Oxford led study, published in Nature, are an exciting first step towards the development of future treatments for the disorders which have devastating impacts on learning, behavior, speech, and movement.

While most NDDs are thought to be genetic and caused by changes to DNA, to date around 60% of individuals with the conditions do not know the specific DNA change that causes their disorder.

To create one-time cures for Alzheimer’s disease, researchers are investigating the application of CRISPR-Cas9 gene-editing for novel therapies. Cutting and pasting genes is difficult with current technology, but CRISPR gene editing may help later stages or those individuals with hereditary mutations. Variants in the lipid transport protein apolipoprotein E (APOE4) have been associated with late-onset Alzheimer’s disease, with a three-to twelve-fold increase in risk.

Researchers engineered the Christchurch gene variation into mice bearing human APOE4 using CRISPR. After that, these mice were crossed, resulting in progeny that carried one or two copies of the modified variation.

The group discovered that mice bearing a single copy of the APOE4-Christchurch variation exhibited a partial defense against Alzheimer’s disease. The disease did not exhibit typical symptoms in mice carrying two copies. The work mimics the advantageous effects of the Christchurch mutation to propose possible treatment strategies for Alzheimer’s disease associated with APOE4.

In 2006, just a few years after the fruit fly genome had been sequenced, geneticists at the University of California, Davis, made a startling discovery: Several new genes had cropped up, seemingly out of nowhere.

These “de novo genes” weren’t simply new variants of existing ones; they had sprung forth from the supposedly inert spaces in between the coding sections of DNA—regions long dismissed as the junkyards of the double helix. Since the days of Darwin, such sprightly biological change agents had never before been seen.

A young graduate student at the time, Li Zhao was so intrigued that upon graduating in 2011, she set out to join the lab of David Begun, where the discovery was first made. She soon revealed that these little genetic big bangs happen all the time­­—over the past decade, she and her team have identified more than 500 de novo genes in the Drosophila lineage alone.

Over the recent decades, comprehensive genome-wide association studies (GWAS) have indicated the potential influence of genetic factors on one’s alcohol consumption volume and identified over 100 related variants^6,7. However, a predominant proportion of the identified variants are localized within noncoding regions, and their effect sizes tend to be small, making interpretation and identification of the causal gene challenging⁸. In addition, previous GWAS mainly utilized imputed genotype data, which only cover limited regions of the genome, and thus may have missed many potential genes. Furthermore, GWAS studies focused mainly on common variants, and few studies have investigated rare variants associated with alcohol consumption, which yield greater potential to interpret biological function and elucidate mechanisms⁹. Although there are studies that have attempted to leverage exome chip data to identify rare variants contributing to alcohol consumption, the sample size was small and limited regions of the whole exome were examined¹⁰.

The introduction of whole exome sequencing (WES) provides a great chance to overcome the limitations of previous genetic studies on alcohol consumption with a substantially larger amount of rare and ultra-rare protein-coding variants^11,12,13. Collapsing of loss-of-function (LOF) variants helps estimate the effect direction of associated genes^13,14. When combined with large-scale population cohorts with multi-modal phenotypic data, WES would greatly facilitate our understanding of the genetic underpinnings of alcohol consumption as well as its implication on physical and mental health⁶. However, to our knowledge, there have been few large-scale WES studies on alcohol consumption, let alone elucidating the potential implications of the identified genes^10,15. Meanwhile, as indicated by a previous genome-wide association study, significant genetic associations existed between alcohol consumption and several body health phenotypes⁷. The application of phenome-wide analysis for alcohol-related genes can help extend and deepen our current comprehension of the association between alcohol consumption and human health.

Hence, aiming to refine the genetic architecture of alcohol consumption, we conduct an exome-wide association study (ExWAS) for alcohol consumption among 304,119 individuals from the UK Biobank (UKB). We also examine the rare-variant associations with genes reported by previous GWAS^6,7,16,17. Finally, we provide biological insights into the identified genes via bioinformatics analyses and phenome-wide association analysis (PheWAS).

Genome editing stands as one of the most transformative scientific breakthroughs of our time. It allows us to dive into the very code of life and make precise modifications. Imagine being able to rewrite the genetic instructions that determine almost everything about an organism—how it looks, behaves, interacts with its environment, and its unique characteristics. This is the power of genome editing.

We use genome editing tools to tweak the genetic sequences of microbes, animals, and plants. Our goal? To develop desired traits and eliminate unwanted ones. This technology’s impact has been felt across biotechnology, human therapeutics, and agriculture, bringing rapid advancements and solutions.

The most widely used proteins in genome editing are Cas9 and Cas12a. These proteins are like the scissors of the genetic world, allowing us to cut and edit DNA. However, they are quite bulky, consisting of 1,000–1,350 amino acids. Advanced editing technologies like base editing and prime editing require the fusion of additional proteins with Cas9 and Cas12a, making them even bulkier. This bulkiness poses a challenge to delivering these proteins efficiently into cells, where the genetic material resides.

Scientists have connected two organoids together with an axon bundle, to study how brain areas communicate. They sent signals back and forth and responded to external stimulation. This could be a step toward biocomputing.

Learn about: axons, white matter, re-entry, optogenetics, myelination, entrainment, short-term potentiation.

Continue reading “Brain Organoids Communicate: A Step Toward ‘Organoid Intelligence’” »