Lifeboat Foundation

Year 2023 😗

Data from patients with AMD, retinal dystrophies, and diabetic retinopathy indicate an important role of immune cells, including microglia, in the pathogenesis of these retinal diseases¹. The accumulation of drusen components provides an environment rich in chemoattractants for microglia and leads to their translocation to the subretinal space in AMD^2,4. The involvement of microglia in the activation of the NLRP3 inflammasome and the promotion of proinflammatory cytokine secretion has been confirmed in in vitro and animal studies^11,12,14. In patients with retinal dystrophies like retinitis pigmentosa, it has been shown that microglia become activated in response to signals from degenerating rod photoreceptors and migrate to the outer retinal layers⁴. There, they participate in the phagocytosis of debris and dying cells and secrete proinflammatory factors. Mouse models of retinal degeneration (e.g. rd1, rd7, rd8, and rd10 models) confirm many of these conclusions^9,10,13,15, but make it clear that the role of microglia may also be homeostatic, depending on both stimuli and anatomical location within the retina^7,20. Activated microglia are observed at all the stages of human diabetic retinopathy^3,8 and also feature prominently in many animal models of the disease^44,45. Finally, accumulations of activated microglia are also seen in a variety of animal models of retinal degeneration, including light-induced retinal degeneration and models based on complement dysregulation^34,46,47.

The pathways regulating immune surveillance, cell trafficking, and neuroinflammation in the retina are not well understood. A large number of molecules and processes have been implicated, ranging from chemokines involved in chemotaxis, cytokines involved in activation, factors that regulate oxidative stress and complement activation, and immunoregulatory proteins. In such a complex biological system, the unbiased nature of a forward genetics approach is particularly valuable in identifying genes affecting these immune cell processes. Furthermore, the accumulation of subretinal microglia, visible as or correlated with the accumulation of fundus spots, can serve as a marker for retinal pathology and thus as a screen for genes essential to retinal homeostasis. Our approach here has two important advantages relative to all prior forward genetics studies of the retina: 1. We are systematically applying a semiquantitative fundus spot scale to fundus photographs, and 2. Our pipeline is the only one in which all mice screened are G3 mice that have been pre-genotyped at all mutant loci. Our unbiased identification of 6 gene-phenotype associations to retinal pathology with strong literature support using our fundus spot scale screen is proof of concept supporting the efficacy of our approach. We identified other associations that had not been reported in the literature at the time of the screening. From those, we first concentrated our efforts on the gene Lipe, partly because the fundus spot scale was the only parameter leading to its identification.

Continue reading “Forward genetic screening using fundus spot scale identifies an essential role for Lipe in murine retinal homeostasis” »

Commercial platforms for protein therapeutics are being built on academic research that has expanded the genetic code behind cell-based translation.

Antibiotic resistance is a major danger to public health that threatens to claim the lives of millions of people per year within the next few decades. Years of necessary administration and excessive application of antibiotics have selected for strains that are resistant to many of our currently available treatments. Due to the high costs and difficulty of developing new antibiotics, the emergence of resistant bacteria is outpacing the introduction of new drugs to fight them. To overcome this problem, many researchers are focusing on developing antibacterial therapeutic strategies that are “resistance-resistant”—regimens that slow or stall resistance development in the targeted pathogens. In this mini review, we outline major examples of novel resistance-resistant therapeutic strategies. We discuss the use of compounds that reduce mutagenesis and thereby decrease the likelihood of resistance emergence. Then, we examine the effectiveness of antibiotic cycling and evolutionary steering, in which a bacterial population is forced by one antibiotic toward susceptibility to another antibiotic. We also consider combination therapies that aim to sabotage defensive mechanisms and eliminate potentially resistant pathogens by combining two antibiotics or combining an antibiotic with other therapeutics, such as antibodies or phages. Finally, we highlight promising future directions in this field, including the potential of applying machine learning and personalized medicine to fight antibiotic resistance emergence and out-maneuver adaptive pathogens.

The use of antibiotics is central to the practice of modern medicine but is threatened by widespread antibiotic resistance (Centers for Disease Control and Prevention (U.S.), 2019). Antibiotics are a selective evolutionary pressure—they inhibit bacterial growth and viability, and antibiotic-treated bacteria are forced to either adapt and survive or succumb to treatment. The stress of antibiotic treatment can enhance bacterial mutagenesis leading to de novo resistance mutations (Figure 1A), promote the acquisition of horizontally transferred genetic elements that confer resistance, or trigger phenotypic responses that increase tolerance to drugs (Davies and Davies, 2010; Levin-Reisman et al., 2017; Bakkeren et al., 2019; Darby et al., 2022;). Additionally, antibiotic treatment can select for the proliferation of pre-existing mutants already in the population (Figure 1B).

Serious Science — http://serious-science.org.

Behavioral geneticist Robert Plomin on twin studies, genetic influence of parents on their children, and 1% of DNA that makes people different.

Continue reading “DNA and Behavioral Genetics — Robert Plomin” »

Ecologists have shown that the genetic material that species.

A species is a group of living organisms that share a set of common characteristics and are able to breed and produce fertile offspring. The concept of a species is important in biology as it is used to classify and organize the diversity of life. There are different ways to define a species, but the most widely accepted one is the biological species concept, which defines a species as a group of organisms that can interbreed and produce viable offspring in nature. This definition is widely used in evolutionary biology and ecology to identify and classify living organisms.

According to recent research published in the Journal of Experimental Medicine, equipping cancer-infecting viruses with tumor-inhibiting genetic cargo boosts the immune system and supports immunotherapy in reducing or totally eradicating aggressive tumours in mice. The findings pave the path for clinical studies combining oncolytic viruses with immunotherapy.

The study states that cancer-infecting viruses can boost immunity of the body and support immunotherapy.

As salt encroaches on productive agricultural land, a handful of startups are finding ways to make crops grow in seawater with genetic modification and transforming solar saltwork.

Cool paper that adds a useful tool to the gene therapist’s toolbox! Young et al. utilize an in vivo screening method to develop adeno-associated viruses (AAVs) which target microglia. They show that their AAVs transduce central nervous system microglia as well as tissue macrophages after intravenous injection. #biotechnology

Tissue macrophages, including microglia, are notoriously resistant to genetic manipulation. Here, we report the creation of Adeno-associated viruses (AAV) variants that efficiently and widely transduce microglia and tissue macrophages in vivo following intravenous delivery, with transgene expression of up to 80%. We use this technology to demonstrate manipulation of microglia gene expression and microglial ablation, thereby providing invaluable research tools for the study of these important cells.

This genetically engineered microorganism has the ability to break down a type of plastic known as polyethylene terephthalate (PET).

Various bacterial species have demonstrated an extraordinary ability to degrade plastics, which are synthetic polymers known for their long-lasting and non-biodegradable characteristics.

Research in this area continues to advance to create viable and sustainable solutions to combat the growing menace of plastic waste in terrestrial and marine environments.