Lifeboat Foundation

What happens when humans begin combining biology with technology, harnessing the power to recode life itself.

What does the future of biotechnology look like? How will humans program biology to create organ farm technology and bio-robots. And what happens when companies begin investing in advanced bio-printing, artificial wombs, and cybernetic prosthetic limbs.

Continue reading “GENETIC ENGINEERING & BIOTECHNOLOGY in the Future (2077 & Beyond)” »

Several factors contribute to the development of inflamm-aging, including genetic susceptibility, visceral obesity, microbiota and gut permeability, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by mitochondrial dysfunction, immune cells dysregulation, and chronic infection (Ferrucci & Fabbri, 2018). The immune system becomes gradually dysregulated during aging, leading to elevated blood levels of pro-inflammatory mediators, such as TNFα, IL6, and C-reactive protein (Harris et al., 1999 ; Mooradian et al., 1991). Energy homeostasis also becomes dysregulated with aging, which results in the redistribution of subcutaneous fat to visceral regions and contributes to inflammation (Bouchard et al., 1993 ; Chumlea et al., 1989 ; Curtis et al., 2005). Metabolism-induced inflammation, also known as metaflammation, shares similarities with inflamm-aging, including the elevation of certain circulating pro-inflammatory cytokines (Prattichizzo et al., 2018). Therefore, the molecules that play a key role in the regulation of metabolic homeostasis potentially mediate the development of chronic inflammation during aging.

Forkhead box O1 (FOXO1) transcription factor has been indicated to be involved in the regulation of nutrient metabolism and energy homeostasis (Cheng et al., 2009 ; InSug et al., 2015 ; Matsumoto et al., 2007 ; Yang et al., 2019 ; Zhang et al., 2012). Deletion of hepatic Foxo1 improves glucose homeostasis in insulin resistant mice (Dong et al., 2008). FOXO1 inhibition by AS1842856 attenuates hepatic steatosis in diet-induced obesity mice (Ding et al., 2020). In mature macrophages, FOXO1 promotes inflammation through the activation of TLR4-and STAT6-mediated signaling pathways (Fan et al., 2010 ; Lee et al., 2022). In invertebrates, DAF-16, the Foxo homolog gene, mediates the effect of insulin/IGF signaling on lifespan (Ogg et al., 1997). Overexpression of FOXO in Drosophila and C.elegans increases their lifespan (Giannakou et al., 2004 ; Henderson & Johnson, 2001). However, studies in mammalians show that FOXO1 does not have a significant correlation with longevity (Chiba et al., 2009 ; Kleindorp et al., 2011). Considering the role of FOXO1 in regulating glucose metabolism and inflammation, we hypothesize that FOXO1 plays an important role in the regulation of aging-induced inflammation and dysregulation of glucose homeostasis.

Liver is an important metabolic organ that plays a key role in maintaining whole-body nutrient homeostasis by regulating energy metabolism, clearing xenobiotic and endobiotic, and synthesizing necessary molecules (Rui, 2014). As a result, aging-induced changes in liver contribute to systemic susceptibility to aging-related diseases. Different types of liver cells, including hepatocytes, endothelial cells, hepatic stellate cells (HSC), and macrophages, are all affected by the aging process (Hunt et al., 2019). However, most studies on liver aging focused on whole-liver tissue, which is mainly composed of parenchymal cells, hepatocytes. Thus, the effects of aging on liver nonparenchymal cells (NPCs) are less understood. In this study, we used bulk RNA-Seq and single-cell RNA (scRNA)-Seq technologies to analyze aging-induced changes, and the role of FOXO1 in aging-related processes in both whole-liver and individual liver cells, particularly liver macrophages. We found that insulin resistance, liver fat accumulation, liver inflammation, and systemic inflammation were significantly aggravated in old mice. Additionally, aging significantly increased pro-inflammatory response in Kupffer cells (KCs) and induced a functional quiescence in monocyte-derived macrophages (MDMs). FOXO1 activity was significantly enhanced in the livers of old mice and FOXO1 inhibition improved insulin resistance, hepatic steatosis, and inflammation in old mice. Furthermore, we found that FOXO1 inhibition attenuated aging-induced pro-inflammation in KCs and had a limited effect on aging-induced functional quiescence in MDMs. Taken together, this study indicates that FOXO1 plays an important role in the liver aging processes and suggests that FOXO1 is a potential therapeutic target for the treatment of aging-induced chronic diseases.

Researchers at Washington University School of Medicine in St. Louis have transformed stem cells into insulin-producing cells. They used the CRISPR gene-editing tool to correct a defect that caused a form of diabetes, and implanted the cells into mice to reverse diabetes in the animals. Shown is a microscopic image of insulin-secreting beta cells (insulin is green) that were made from stem cells produced from the skin of a patient with Wolfram syndrome.

CRISPR corrects genetic defect so cells can normalize blood sugar.

More than 20 years ago, the human genome was first sequenced. While the first version was full of “holes” representing missing DNA sequences, the genome has been gradually improved in successive rounds. Each has increased the quality of the genome and, in so doing, resolved most of the blank spaces that prevented us from having a complete reading of our genetic material.

The fundamental difficulty researchers faced in reading the genome from end to end is the enormous number of repeated sequences that populate it. The 20,000 or so genes we humans have occupy barely 2% of the entire genome. The remaining 98% is essentially made up of these families of repeated sequences, mobile elements known as transposons and retrotransposons, and—to a lesser but functionally important extent— gene expression regulatory sequences. These function as switches that determine when and where genes are turned on and off.

In March 2022, a major revision of the genome was published in the journal Science. An international consortium of researchers known as “T2T” (telomere to telomere, which are the ends of chromosomes) used a novel strategy based a type of cell (CHM13) that retains only one copy of each chromosome.

Scientists already have their ways of coaxing human cells into new forms, using a special concoction of chemicals to nudge humble skin cells into malleable tissues known as induced pluripotent stem cells.

In spite of this new lease on life, these particular cells still retain a few genetic reminders of their time as a fully developed tissue, affecting their use as a blank slate.

Now an international team of researchers has gone one better: finding a new way of wiping a cell’s memory clean so it can be better reprogrammed as a stem cell.

Stem cells in organoids self-organize into tissue patterns with unknown mechanisms. Here, we use skin organoids to analyze this process. Cell behavior videos show that the morphological transformation from multiple spheroidal units with morphogenesis competence (CMU) to planar skin is characterized by two abrupt cell motility–increasing events before calming down. The self-organizing processes are controlled by a morphogenetic module composed of molecular sensors, modulators, and executers. Increasing dermal stiffness provides the initial driving force (driver) which activates Yap1 (sensor) in epidermal cysts. Notch signaling (modulator 1) in epidermal cyst tunes the threshold of Yap1 activation. Activated Yap1 induces Wnts and MMPs (epidermal executers) in basal cells to facilitate cellular flows, allowing epidermal cells to protrude out from the CMU. Dermal cell–expressed Rock (dermal executer) generates a stiff force bridge between two CMU and accelerates tissue mixing via activating Laminin and β1-integrin. Thus, this self-organizing coalescence process is controlled by a mechano-chemical circuit. Beyond skin, self-organization in organoids may use similar mechano-chemical circuit structures.

Life runs on ribosomes. Every cell across the globe requires ribosomes to convert genetic data into the vital proteins required for the organism’s operation, and, subsequently, for the production of more ribosomes. However, scientists still lack a clear understanding of how these essential nanomachines are assembled.

Now, new high-resolution images of the large ribosomal subunit are shedding light on how arguably nature’s most fundamental molecule coalesces in human cells. The findings, published in Science, bring us one step closer to a complete picture of ribosome assembly.

“We now have a pretty good idea of how the large ribosomal subunit is assembled in humans,” says Rockefeller’s Sebastian Klinge. “We still have quite a few gaps in our understanding, but we certainly now have a much better idea than we had before.”

Scientists have recently reviewed the available literature to examine the critical roles played by mitochondria in maintaining homeostasis. The review summarized the involvement of mitochondria in age-related disease progression and highlighted its potential as a therapeutic target of these diseases. This review has been published in Experimental & Molecular Medicine.

Mitochondria is a cytoplasmic organelle in most eukaryotic cells and is enclosed by two phospholipid membranes: the inner mitochondrial membrane (IMM) and outer mitochondrial membrane (OMM). These membranes separate functionally compartmentalized structures, i.e., matrix and intermembrane space. Mitochondria contain a unique genetic code, mitochondrial DNA (mtDNA).

During evolution, most mitochondrial genes were lost or translocated to nuclei. However, genes that remained in mtDNA encode for essential translational apparatus, i.e., ribosomal RNAs and transfer RNAs. In addition, these genes also encode proteins that are key components of oxidative phosphorylation system (OXPHOS) complexes embedded in the IMM.

The findings suggest that adenosine base editing raised the expression of fetal hemoglobin to higher, more stable, and more uniform levels than other genome editing technologies that use CRISPR/Cas9 nuclease in human hematopoietic stem cells.

“Ultimately, we showed that not all genetic approaches are equal,” said Jonathan Yen, PhD, genome engineering group director at St. Jude Children’s Research Hospital. “Base editors may be able to create more potent and precise edits than other technologies. But we must do more safety testing and optimization.”

SCD and beta-thalassemia are blood disorders caused by mutations in the gene encoding hemoglobin affecting millions of people. Restoring gene expression of an alternative hemoglobin subunit active in a developing fetus has previously shown therapeutic benefit in SCD and beta-thalassemia patients. The researchers wanted to find and optimize genomic technology to edit the fetal hemoglobin gene.

Continue reading “Base Editing Beats Other Genome Editing Strategies for Treating Sickle Cell Disease” »