Membrane protein biogenesis by the EMC

Recent cryo‐EM‐based models reveal how the ER membrane protein complex may accomplish insertion of protein transmembrane domains with limited hydrophobicity.

Insertion of strongly hydrophobic TMDs into the ER membrane is mediated by the Sec61 complex for co‐translational insertion and the GET complex for post‐translational insertion of tail‐anchors (Volkmar & Christianson, 2020). By contrast, the EMC inserts TMDs of limited hydrophobicity, frequently located at the N‐ or C‐termini of proteins, and is involved in biogenesis of multi‐spanning membrane proteins (Volkmar & Christianson, 2020).The EMC is highly conserved (Wideman, 2015). In vertebrates, ten subunits have been identified (EMC1‐10), two of which, EMC8 and EMC9, are homologous and the result of a vertebrate‐specific gene duplication (Wideman, 2015). In Saccharomyces cerevisiae, EMC8 has been lost (Wideman, 2015). Only EMC3 displays clear homology to other membrane protein insertases, the Oxa1 family (Wideman, 2015; Volkmar & Christianson, 2020). This family includes YidC, which inserts TMDs into the bacterial cytoplasmic membrane, usually in cooperation with the Sec61‐homologous SecYEG channel (Volkmar & Christianson, 2020). Their association, along with the SecDF ancillary complex, forms a holo‐translocon capable of protein secretion and TMD insertion, with striking similarities to the EMC complex (Martin et al, 2019).Recent work by Pleiner et al (2020) presented a 3.4 Å cryo‐EM structure of the human EMC purified via a GFP‐tag on EMC2 and incorporated into a phospholipid nanodisc. The complex is formed by nine proteins (EMC1‐8, EMC10) (Pleiner et al, 2020). EMC8 and EMC9 are structurally similar, and their association with EMC2 is mutually exclusive (O''Donnell et al, 2020). Of the 12 TMDs, nine constitute the pseudosymmetric central ordered core, with a basket‐shaped cytosolic vestibule formed primarily by alpha‐helices of the EMC3 and EMC6 TMDs and cytosolic EMC2 (Fig 1A; Pleiner et al, 2020). The L‐shaped lumenal domain of the EMC consists mostly of beta‐sheets (Fig 1A; Pleiner et al, 2020), flanked by a conspicuous and conserved amphipathic alpha‐helix of EMC1 sealing the vestibule at the interface between the membrane and the ER lumen, together with another smaller amphipathic helix contributed by EMC3 (Fig 1A; Pleiner et al, 2020). In the ER lumen, the two 8‐bladed propellers of EMC1 contact six of the eight other subunits and stabilize the entire complex (Fig 1A; Pleiner et al, 2020). Beta‐sandwiches of EMC7 and EMC10 are anchored to the EMC1 lumenal domain (Fig 1A; Pleiner et al, 2020). In the cytosol, the tetratricopeptide repeat (TPR) spiral of EMC2 forms a cup underneath the partially hydrophilic vestibule in the membrane between the TMDs of EMC3 and EMC6, bridging the cytosolic ends of TMDs of EMC1, 3 and 5 (Fig 1A; Pleiner et al, 2020). Cytosolic EMC8 is bound to the opposite face of EMC2 (Fig 1A).Open in a separate windowFigure 1Comparison of the structures of human and yeast EMC(A) Cryo‐EM 3D map of the human (emdb‐21929) and yeast (emdb‐21587) EMC, showing front and back views with individual subunits coloured. Membrane position, obtained from the OPM database, is shown by grey discs. (B) Close‐up view of the EMC cavity formed by EMC3 and EMC6. Left, shown in a hydrophobicity surface pattern. Right, surface representation overlapped with the TMDs of EMC3 and EMC6. EMC4, flexible and with a gate function at the substrate‐binding place, is shown in pink in the yeast representation. EMC4 is not visible at the atomic EMC human structure, although is observed as a weak density at the human model, accompanied by TMs of EMC7 and EMC10 (Pleiner et al, 2020). (C) The yeast EMC following > 5 µs of CG‐MD simulation. The protein is shown as surface and coloured as per Pleiner et al (2020). The computed densities of waters and phospholipid tails and phosphates are shown as blue, yellow and lime green densities, sliced to bisect the cavity for clarity. Right, inset of the EMC cavity. Methods: CG‐MD simulations were built using PDB 6WB9 in a solvated symmetric POPC/POPE/cholesterol membrane and run in the Martini forcefield as described in Martin et al (2019). 3 µs unrestrained simulations were run, followed by 2.5 µs backbone restrained simulation for density calculation, done using VolMap in VMD (Humphrey et al, 1996).The 3.0 Å cryo‐EM structure of the yeast EMC presented by Bai and colleagues shows a very similar overall organization (Bai et al, 2020). Here, purification was via a 3xFLAG‐tag on EMC5, and the structure of the 8‐subunit complex (without EMC8/9) was visualized in detergent solution (Bai et al, 2020). The yeast complex has twelve TMDs like the human EMC, but unlike the human structure, EMC4 in yeast has three TMDs that are clearly visible (Bai et al, 2020). They are angled in the membrane pointing away from the complex at the cytosolic end (Fig 1A), and Bai et al (2020) propose that TMDs of EMC4, EMC3 and EMC6 form a substrate‐binding pocket similar to that of YidC. As in the human EMC, there are two amphipathic helices (EMC1 and EMC3) at the membrane/lumen interface (Fig 1A; Bai et al, 2020). In the ER lumen, yeast EMC1 only has one 8‐bladed beta‐propeller, to which the beta‐sandwiches of EMC7 and EMC10 are anchored (Fig 1A; Bai et al, 2020). In the cytosol, EMC2 bridges EMC3, 4 and 5, and its TPR repeats form a cup underneath the vestibule similar to human EMC2 (Fig 1A; Bai et al, 2020).The authors propose that insertion of a partially hydrophilic TMD by the yeast EMC is mechanistically similar to insertion by bacterial YidC (Bai et al, 2020). Yeast EMC is proposed to bind substrate between TMD2 of EMC3 and TMD2 of EMC4 in a pocket with polar and positively charged amino acids at either end and hydrophobic amino acids in the centre (Fig 1B; Bai et al, 2020). Much has been made of a conserved positive region within the EMC complex here, present in an equivalent position also in YidC (Kumazaki et al, 2014): It is claimed to be important for the incorporation of more‐hydrophilic TMDs and perhaps responsible for the “positive‐inside” orientation rule (von Heijne, 1992). Yeast and human EMC3 contain a specific R31 and R26 residue, respectively, conserved also in YidC and important for function of the EMC, as well as for YidC in Gram‐positive, but interestingly not Gram‐negative, bacteria (Chen et al, 2014; Pleiner et al, 2020; Bai et al, 2020). Another interesting feature, also conserved with YidC, is the flexibility of the TMDs flanking the substrate‐binding pocket, critical for EMC entry of substrates (Bai et al, 2020).In the human EMC, methionine residues in a cytosolic loop of EMC3 act as a substrate bait (Pleiner et al, 2020). Polar and charged residues within the substrate‐binding groove guide the lumenal domain across the membrane, facilitated by local membrane thinning (Pleiner et al, 2020; Fig 1B). The positive charges within the substrate‐binding site exclude signal peptides and enforce the “positive‐inside rule” (von Heijne, 1992; Pleiner et al, 2020). Flexible TMDs of EMC4, EMC7 and EMC10 forming a “lateral gate” of the substrate‐binding groove allow sampling of the bilayer by the substrate TMD (Pleiner et al, 2020). As the shortened TMDs of EMC3 and EMC6 cannot stably bind the substrate TMD, they favour its release into the bilayer (Pleiner et al, 2020). The EMC1 beta‐propeller(s) may recruit additional protein maturation factors in the ER lumen (Pleiner et al, 2020; Bai et al, 2020) or bind the Sec61 channel to allow cooperation between the two insertases (Bai et al, 2020).Arguably, the most interesting feature of the EMC complex is the location of a large interior cavity with distinctive hydrophilic character, which likely aids TMD insertion (Fig 1B). We ran a coarse‐grained molecular dynamics (CG‐MD) simulation of the yeast EMC structure, which highlights a profound perturbation of the phospholipid bilayer in the EMC interior cavity (Fig 1C). Here, a deep gorge forms in the cytoplasmic leaflet of the bilayer, allowing the cavity to become flooded with water (Fig 1C). Note the location of the lipid head groups here (lime green), which presumably define the site of amphipathic TMD insertion. The incursion of phospholipids into the centre of the EMC complex is a feature shared by the bacterial holo‐translocon (Martin et al, 2019) and perhaps by all membrane protein insertases. The shape and character of the EMC cavity presumably dictate its predisposition for less hydrophobic TMDs; it would be interesting to see whether the cavities of different insertases are similarly tailored to suit their substrates.     

Restraining CDK1–cyclin B activation: PP2A on the cUSP(7)

USP7 inhibitors are gaining momentum as a therapeutic strategy to stabilize p53 through their ability to induce MDM2 degradation. However, these inhibitors come with an unexpected p53‐independent toxicity, via an unknown mechanism. In this issue of The EMBO Journal, Galarreta et al report how inhibition of USP7 leads to re‐distribution of PP2A from cytoplasm to nucleus and an increase of deleterious CDK1‐dependent phosphorylation throughout the cell cycle, revealing a new regulatory mechanism for the progression of S‐phase cells toward mitosis to maintain genomic integrity.Subject Categories: Cell Cycle, Post-translational Modifications, Proteolysis & Proteomics

Recent work reveals untimely activation of mitotic cyclin‐dependent kinase as a molecular basis for p53‐independent cell toxicity of USP7 deubiquitinase inhibitors.

The G2‐M transition in the eukaryotic cell cycle is a critical point to ensure that cells with damaged DNA are unable to enter the mitotic phase. This checkpoint is highly regulated by a number of kinases, including ATR, ATM and WEE1, and ends upon activation of the CDK1–cyclin B1 kinase complex (Visconti et al, 2016). Since premature activation of CDK1–cyclin B1 causes replication fork collapse, DNA damage, apoptosis, and mitotic catastrophe (Szmyd et al, 2019 and references therein), restricting CDK1–cyclin B1 activity prior to mitosis is key to maintaining genomic integrity.A body of recent work has suggested that the deubiquitinase USP7 is a master regulator of genomic integrity; it is required for DNA replication in numerous ways, including indirect regulation of cyclin A2 during the S‐phase, origin firing, and replication fork progression. USP7 also regulates mitotic entry by stabilizing PLK1, another kinase which is highly active in the M phase and ensures proper alignment of chromatids prior to segregation. Notably, USP7 inhibitors have become an attractive cancer therapeutic strategy based on their ability to trigger degradation of MDM2, and thereby stabilize p53 (Valles et al, 2020). However, there is growing evidence of USP7 inhibitor‐related toxicity that is not mediated through p53 (Lecona et al, 2016; Agathanggelou et al, 2017), indicating that USP7 inhibitors impact other cellular processes. Therefore, Galarreta et al (2021) investigated the potential functional relationship between USP7 and CDK1, given the role of both factors in regulating the cell cycle.Through a series of in vitro experiments, the authors confirmed that five USP7 inhibitors induce premature mitotic kinase activity, including increased MPM2 signal (indicative of mitosis‐specific phosphorylation events) and phosphorylation of histone H3 Ser10 (H3S10P) in all cells, regardless of where they are in the cell cycle. To determine whether USP7 affects CDK1 during the cell cycle, Galarreta et al (2021) demonstrate that cell lines treated with USP7 inhibitors exhibit reduced levels of inhibitory Tyr‐15 phosphorylation on CDK1 and increased cyclin B1 presence in the nucleus, suggesting activation of the CDK1–cyclin B1 complex. Furthermore, treatment with the CDK1 inhibitor RO3306 rescues the USP7 inhibitor‐dependent increase of mitotic activity.These observations suggest that CDK1 has the potential to catalyze mitosis‐specific phosphorylation irrespective of cell cycle phase and that cells rely on USP7‐specific deubiquitination to suppress or reverse premature CDK1 activity. Surprisingly, despite the nuclear localization of cyclin B and decrease in inhibitory CDK1 Tyr‐15 phosphorylation, USP7 inhibitors failed to drive cells into mitosis. How might this be? Nuclear localization of cyclin B normally occurs just minutes before the onset of mitosis and nuclear envelope breakdown (Santos et al, 2012), yet the nucleus remains intact following USP7 inhibition. Moreover, the decrease in Tyr‐15 phosphorylation suggests the ATR‐ and WEE1‐dependent G2/M checkpoint is inactivated by USP7 inhibition. Do these data hint at the presence of an additional, unknown regulatory mechanism controlling mitotic entry independent of the G2/M checkpoint and nuclear localization of the CDK1–cyclin B complex?To determine whether CDK1 is the driver of USP7 inhibitor toxicity, Galarreta et al exposed cells to CDK1 inhibitors and observed a reduction in apoptosis. Furthermore, CDK1 inhibitors promote cell survival in cells treated with three structurally unrelated USP7 inhibitors. Finally, CDC25A‐deficient mouse embryonic stem cells, which constitutively express low levels of CDK1, resist USP7 inhibition. Together, these data suggest that the USP7 inhibitor‐dependent toxicity is the result of CDK1‐mediated cell death. The authors note that the phosphatase PP2A is an antagonist for CDK1 in addition to being a candidate USP7 substrate (Lecona et al, 2016; Wlodarchak & Xing, 2016), and thus, they turned their attention to elucidating the connection between USP7 and PP2A. Combining biochemical and immunofluorescence studies, Galarreta et al (2021) demonstrate that USP7 interacts with two subunits of PP2A, and this interaction increases in response to USP7 inhibition. Inhibiting USP7 furthermore triggers PP2A re‐localization from the cytoplasm to the nucleus and increases the phosphorylation levels of PP2A substrates, such as AKT and PRC1. DT‐061, a chemical activator of PP2A, reduces CDK1 phosphorylation events, suggesting that PP2A deregulation is a key mediator of USP7 inhibitor‐related toxicity. Using phosphoproteomics to analyze cells treated with a USP7 inhibitor or PP2A‐inhibiting okadaic acid, the authors reveal that both treatments share a significant number of altered phosphorylated targets—especially those related to mitosis, the cell cycle, and epitopes with a CDK‐dependent motif. Thus, the effects of USP7 inhibitors on CDK1 appear to be mediated through PP2A localization to the nucleus.These unexpected findings raise several questions that potentially impact the current view of cell cycle regulation. For example, how does USP7 regulate PP2A localization and is this important for reversing CDK1‐dependent phosphorylation of mitotic substrates prior to mitosis? Does PP2A accumulation in the nucleus explain the failure of USP7‐inhibited cells to enter mitosis despite cyclin B1 nuclear localization? A role for ubiquitin signaling as a regulator of CDK1 in interphase cells has not been reported, and accordingly, new investigations will be needed to unravel the mechanisms by which USP7 controls PP2A localization.Another important question that arises is whether or not CDK1 has sufficient basal activity to phosphorylate numerous mitotic proteins independent of cell cycle phase. The observation that USP7 and PP2A act to prevent the improper accumulation of CDK1‐dependent phosphorylation even in G1 phase cells suggests this to be the case. Alternatively, USP7 activity may be required to prevent abnormal pairing of CDK1 with a cyclin that is ubiquitously expressed across the cell cycle. If so, more research will be needed to uncover how ubiquitin signaling ensures CDK1 only pairs with cyclin A and cyclin B once they accumulate later in the cell cycle.Interestingly, USP7 inhibition also causes a rapid loss in DNA synthesis of S‐phase cells, prompting the authors to perform a time course experiment to decipher the order of events following treatment (i.e., does CDK1 activation precede or follow termination of DNA replication?). High‐throughput microscopy and flow cytometry analysis reveal an immediate reduction of DNA replication, an increase of CDK1 activity, and elevated DNA damage before a detectable increase in H3S10P. Long‐term exposure of USP7 inhibitors leads to DNA damage restricted only to cells with corresponding high levels of H3S10P and MPM2. Overall, these results illustrate how inhibition of USP7 activates CDK1, disrupting DNA replication and inducing DNA damage (Fig 1).Open in a separate windowFigure 1USP7 regulates CDK1In untreated cells, CDK1 is suppressed by USP7 and PP2A, and CDK1‐cyclin B is only active during the G2/M transition. In response to treatment, USP7 facilitates PP2A localization to the nucleus. This allows CDK1 to initiate premature mitotic activity throughout the cell cycle, resulting in increased DNA damage and cellular toxicity.The finding that USP7 inhibitors caused a rapid shutdown of DNA replication brings to mind the recent findings by several groups, that CDK1 activation occurs concomitantly with the S/G2 transition and that premature CDK1 activation in S‐phase terminates replication (Akopyan et al, 2014; Lemmens et al, 2018; Saldivar et al, 2018; Deng et al, 2019; Branigan et al, 2021). According to these studies, coupling of CDK1 activation to the S/G2 transition is regulated by ATR‐CHK1 signaling, a pathway activated by DNA replication to restrain CDK1 through Tyr‐15 phosphorylation. Galarreta et al''s observation that USP7 inhibition overrides ATR‐CHK1 (i.e., Tyr‐15 phosphorylation) highlights the fundamental importance of ubiquitin signaling, and potentially PP2A localization, for ensuring proper S‐to‐M progression and genome maintenance. Ultimately, the mechanistic details of Galarreta et al''s observations remain to be elucidated, and undoubtedly, their findings will inspire future investigations. Moreover, their discovery may lead to a new strategy targeting CDK1 to mitigate unwanted toxicities in the clinic.     

Mycobiota dysbiosis: a new nexus in intestinal tumorigenesis

While there is growing evidence that perturbation of the gut microbiota can result in a variety of pathologies including gut tumorigenesis, the influence of commensal fungi remains less clear. In this issue, Zhu et al (2021) show that mycobiota dysbiosis stimulates energy metabolism changes in subepithelial macrophages promoting colon cancer via enhancing innate lymphoid cell activity. These findings provide insights into a role of the gut flora in intestinal carcinogenesis and suggest opportunities for adjunctive antifungal or immunotherapeutic strategies to prevent colorectal cancer.Subject Categories: Cancer, Immunology, Metabolism

Recent work reports a role for the commensal gut flora in driving aberrant host immunity and malignant cytokine signaling.

There is growing evidence for an important role for the microbiota in influencing tumorigenesis (Helmink et al, 2019). It is now well documented that gut microbiota represents a highly diverse polymicrobial population of bacteria, fungi, viruses, and protozoa. Recent evidence highlights involvement of the bacterial component of the gut microbiota in protection or enhancement of colorectal tumorigenesis. In contrast, the importance of the mycobiota is less well understood although recently suggested to promote pancreatic oncogenesis and colitis‐associated colon cancer (CAC) (Wang et al, 2018; Aykut et al, 2019). Therefore, gut fungi may play a role in the development of other gastro‐intestinal cancer types, such as CRC. Notably, there is emerging evidence suggesting that mycobiota imbalance modulates immune cells and can trigger inflammatory bowel disease (IBD) (Richard & Sokol, 2019).Here, Zhu et al (2021) provide new insight into the association between mycobiota dysbiosis, immunomodulation, and tumorigenesis in the mouse gut (Fig 1).Open in a separate windowFigure 1Dectin‐3 deficiency induces fungal dysbiosis and tumorigenesis in mice by orchestrating immune cell metabolism and cytokine signalingIn the gut of wild‐type mice, the natural population of the commensal yeast Candida albicans is detected by the Dectin‐3 receptor located on the subepithelial macrophage cell surface. This recognition allows macrophages to maintain gut homeostasis by exerting an antifungal activity. In Dectin‐3‐deficient mice, the mycobiota becomes disrupted and aberrantly increased populations of C. albicans emerge. Elevated C. albicans load triggers increased glycolysis in macrophages and interleukin‐7 (IL‐7) secretion. Macrophage‐derived IL‐7 finally induces IL‐22 secretion by group‐3 innate lymphoid cells that in turn promote tumor cell proliferation in the gut epithelium.The current study (Zhu et al, 2021) is based on previous observations suggesting that human pathogenic fungi are recognized by the C‐type lectin receptor Dectin‐3. This led Zhu et al (2021) to test whether the mycobiota influenced gut tumor formation and is linked to immune recognition mediated by Dectin‐3. First, the authors demonstrated that mice lacking the Dectin‐3 receptor had increased colonic tumorigenesis in response to the azoxymethane (AOM) and dextran sodium sulfate (DSS). This was evident histologically in marked differences in tumor number, size, and burden in Dectin‐3‐deficient mice. Of note, immunohistochemical staining revealed that the lack of Dectin‐3 induced gut tumor formation by triggering epithelial cell proliferation rather than preventing cell apoptosis. In fact, first insight into the impact of microbes in CAC was suggested by the observation that co‐housed WT and Dectin‐3‐deficient mice displayed no difference in tumorigenesis. The pivotal role of the microbiota was then underlined in fecal transplantation experiments. Chemically induced germ‐free mice that received feces from Dectin‐3 tumor‐bearing mice displayed exacerbated tumor development compared to wild‐type controls. In addition, the fungal burden was specifically increased in tumor‐bearing Dectin‐3‐deficient animals. Deep profiling of the mycobiota alterations demonstrated an increase in a single yeast species, i.e., Candida albicans, that normally behaves as commensal in the gut (Papon et al, 2013; Wilson, 2019). Preliminary experiments suggested that the increased burden of C. albicans in Dectin‐3‐deficient tumor‐bearing mice is due to impaired antifungal killing by macrophages. Consistently, elevated C. albicans populations triggered glycolysis and inflammatory IL‐7 secretion from lamina propria macrophages, suggesting that Dectin‐3 deficiency‐induced fungal dysbiosis resulted in modulation of gut macrophage metabolism, promoting tumorigenesis. Exploring the molecular and cellular mechanisms that linked macrophage‐derived IL‐7 secretion and CRC development, Zhu et al (2021) showed in vitro that IL‐7 produced by subepithelial macrophages induced IL‐22 secretion by group‐3 innate lymphoid cells (ILC3s). In turn, up‐regulation of IL‐22 in Dectin‐3‐deficient mice contributed to the oncogenesis seen in these animals. Finally, a detailed analysis of tumor tissues collected from 172 patients with CRC showed correlation and poorer clinical outcome in patients with decreased expression of Dectin‐3, but increased expression of IL‐22 and mycobiota burden, although they did not directly link this to the presence of C. albicans in these patients.Overall, Zhu et al (2021) define a new cell paradigm linking mycobiota dysbiosis, macrophage energy metabolism, and innate lymphoid cell function to tumor development in the mouse gut. In this context, this study also sheds additional light on a new role of ILC3s, a recently described type of lymphoid effectors (Serafini et al, 2015). Indeed, ILC3s have been shown in the present article to act as cornerstone cells orchestrating cytokine‐regulated tumorigenesis in the gut. Beyond these pathophysiological considerations, the study opens up new opportunities for developing adjunctive antifungal or immunotherapeutic strategies for the prevention of high morbidity in CRC. Importantly, this enlightening article provides firm evidence that colonic C. albicans populations promote metabolic reprogramming in lamina propria macrophages and tumor cell formation. Metabolic reprogramming has been observed with other fungi, such as Aspergillus fumigatus, which induces metabolic rewiring of alveolar macrophages in the lung epithelium (Gonçalves et al, 2020). In line, the report by Zhu et al (2021) adds to previous work suggesting that mycobiota promotes pancreatic oncogenesis via activation of mannose‐binding lectins (Aykut et al, 2019). Mycobiota dysbiosis therefore stands out as an important new field of investigation in cancer research that is ripe for future exploration.     

Glycolysis regulates Hedgehog signalling via the plasma membrane potential

The authors regret omitting the citation of a bioRxiv preprint study by preprint: Emmons‐Bell et al (2020), who independently discovered the role of ion channel‐dependent membrane depolarization for Smo membrane accumulation in the fly wing disc. This study used a different methodological approach and did not describe the mechanism of how membrane potential affects hedgehog signaling. The reference is herewith added.     

The challenge of removing waste from wastewater: let technology use nature!

Tertiary treatments capable of removing chemical and biological contaminants of emerging concern have been successfully developed and implemented at full scale, opening the possibility of using wastewater treatment plants as recycling units, capable of producing wastewater that can be reused in various activities, such as agriculture irrigation; However, tertiary treatments remove only part of the wastewater microbiota, leaving the opportunity for regrowth and/or reactivation of potentially hazardous microorganisms, facilitated by the poor competition among the surviving microorganisms; Under the motto ‘added by technology, lead by nature’, the treatment and storage of treated wastewater must find the balance to develop a protection shield against the impoverishment the microbial quality and the development of potentially hazardous bacteria.

No man ever steps in the same river twice, for it''s not the same river and he''s not the same man. Heraclitus

Access to wholesome drinking water is not only a major ambition but also a basic human right that since antiquity has called scientists, engineers and politicians for action. The recognition that human excreta compromise the quality of the sources of drinking water triggered the development of sewage drainage systems as far as 3500–2500 BC, in cities such as Ur and Babylon (Lofrano and Brown, 2010). Among these ancient cities, Rome, where the largest known ancient sewer (Cloaca Maxima) and the first roman aqueduct (Aqua Appia) were built (600–312 BC), stands up (Lofrano and Brown, 2010). Despite the unexpected regression observed during the Middle Ages, the rising of urban and industrial agglomerations, matched by a growing production of wastewater, has been triggering the development of wastewater treatment technologies since the industrial revolution (Lofrano and Brown, 2010).Unlike other industrial activities, whose high added value products enable high‐profit margins, wastewater treatment may be not prioritized, at least in world regions with limited income and capacity to invest in both infrastructure and operation systems. Consequently, most of the urban wastewater treatment plants (UWWTP) operating worldwide rely upon biological‐based low‐cost technologies. The conventional activated sludge (CAS) technology is one of the most commonly applied worldwide (Orhon, 2014). With a long development history itself, this aerobic biologic process, in full‐scale operation since 1914, is regarded as the conventional norm for wastewater treatment (Alleman and Prakasam, 1983; Orhon, 2014).A century ago the major challenge of environmental engineers was to develop a treatment system able to reduce the load of readily degradable organic matter and pathogens from sewage. CAS‐based treatment systems fully achieve these goals (Tchobanoglous et al., 2003). But more than one century of industrial innovation and development changed dramatically our lifestyle, and consequently, the type of pollutants discharged in wastewater. Nowadays, UWWTPs are also expected to remove excess of inorganic nitrogen (N) and phosphorus (P) nutrients, responsible for the eutrophication of the receptor water bodies, and a myriad of (potentially) hazardous chemical micropollutants, which may pose risk to the aquatic ecosystems and human health given their acute and chronic toxicity. These chemical micropollutants of emerging concern, which are found at very low concentrations (up to μg l⁻¹), include both natural and xenobiotic compounds such as pharmaceuticals, personal care products, steroid hormones, drugs of abuse, and pesticides, among others (European Commission, 2013; Ribeiro et al., 2015). In addition to the chemical micropollutants, UWWTPs are now also challenged to impede the release of high loads of biological contaminants of emerging concern, such as some pathogenic virus, protozoa, or bacteria in particular antibiotic‐resistant (ARB) harbouring antibiotic resistance genes (ARG), into the receptor water bodies (Dulio et al., 2018; European Commission, 2020).Effective wastewater treatment systems are indeed the primary and major barrier between human activities and the environment, with a pivotal role on the prevention of contamination of surface‐ and groundwater. Inevitably, water bodies such as rivers, lakes and aquifers bridge sectors of activity and geographies, for instance when used as sources of agriculture irrigation water, drinking water production or habitat and fountain for wildlife or food‐producing animals. Pressures to implement technologies able to efficiently remove both chemical and biological contaminants within the urban water cycle are exacerbated under the climate change scenario. Massive withdrawal and consumption coupled with unpredictable weather conditions, such as drought and flood events, has been leading not only to freshwater scarcity but also to the deterioration of water quality (WWAP, 2019; European Commission, 2020).Freshwater scarcity brought the new concept of UWWTPs as recycling units, capable of producing final effluents that can be safely and sustainably reused for different purposes, namely in agriculture, the sector with the largest consumption of freshwater (WWAP, 2019). But to be reused, treated wastewater must be safe. This means that the concentration of eventual chemical and/or biological pollutants in treated wastewater must not put at risk the environmental and human health. Hence, the degree of contamination of the treated wastewater determines its end use or site of discharge (European Commission, 1991, 2020; Becerra‐Castro et al., 2015).Upgrading technologies capable of removal of N and P nutrients from wastewater have been successfully developed and implemented. Nowadays, full‐scale UWWTP with trains favouring the recirculation of the mixed liquor between aerobic and anoxic tanks, where ammonification of organic‐N, nitrification and denitrification occur according to the oxygen availability in each compartment are commonly found; and an increasing number of UWWTP where, in addition to the trains referred to above, recirculation includes anaerobic reactors favouring P granules accumulation are also operating worldwide (Tchobanoglous et al., 2003). More recently, the simultaneous C, N, and P removal is assured through the aerobic granular sludge technology, given the spatial distribution of the microorganisms of the different metabolic groups in the different micro‐environments of the granules (Nancharaiah and Reddy, 2018).In contrast with the C, N and P removal, the biological removal of chemical micropollutants seems to be less efficient. Despite the ability of a vast number of microorganisms to degrade a wide diversity of micropollutants, the low concentration of these compounds in wastewater may contribute for their low bioavailability in the biological reactors. Consequently, the secondary final effluents of CAS‐based UWWTPs still contain numerous micropollutants at environmental worrisome concentrations (McEachran et al., 2018).Advanced Oxidation Technologies (AOTs) have been recommended among the best solutions for the removal of chemical micropollutants from the secondary effluents of CAS‐based UWWTPs. A vast number of scientific studies has been conducted in this area, in order to develop and optimize tertiary processes capable of the efficient removal of these contaminants from the effluents before discharge into the receptor water bodies (Ribeiro et al., 2015). Among these technologies, ozonation has high visibility, being implemented in full‐scale UWWTPs, for instance in Switzerland, a country that recently implemented legislation recommending advanced treatment of wastewater aiming at protecting the environment (Rizzo et al., 2019).One of the advantages of AOTs is their capacity to disinfect water (Rizzo et al., 2020). Hence, besides degrading undesirable chemical micropollutants, numerous scientific bench studies demonstrated that the mechanisms for microbial inactivation used by AOTs, such as the oxidative stress as it is generated by ozonation, are also capable of reducing the microbial load of wastewater, including ARB&ARGs (e.g. Rizzo et al., 2020). Such promising results opened the possibility of upgrading CAS‐based UWWTPs with a final AOT polishing step and using the facilities as recycling units of urban wastewater. Additional treatment may be required in a reuse scenario, and in that cases, the final treated wastewater may need to undergo an adsorption post‐AOT treatment step to eventually remove toxic degradation products (Rizzo et al., 2019) and to be stored for periods that may vary between few hours to some days, depending on the needs. Hence, some bench and full‐scale studies have been conducted to assess the microbiological quality of the wastewater after the final AOT treatment.Consistently, studies focused on the effect of AOTs conclude that the microbiota, including ARB&ARGs, surviving AOT treatment is capable of re‐regrowth during the storage period, sometimes to values reaching or surpassing those measured in the untreated secondary effluent (Zimmermann et al., 2011; Becerra‐Castro et al., 2016; Czekalski et al., 2016; Sousa et al., 2017; Moreira et al., 2018; Biancullo et al., 2019; Iakovides et al., 2019). Moreover, re‐regrowth is accompanied by the disturbance of the microbial community, with possible implications on the decrease of diversity, and the overgrowth of Proteobacteria (Becerra‐Castro et al., 2016; Moreira et al., 2018). Among these, bacterial groups described as potential vectors of antibiotic resistance, such as Pseudomonas, have been detected at high relative abundance (Alexander et al., 2016; Jäger et al., 2018; Moreira et al., 2018).The same phenomena occur when other technologies are applied in the wastewater treatment. Comparatively milder processes such as UV_{254 nm} irradiation or even coagulation lead to similar disturbances (Becerra‐Castro et al., 2016; Grehs et al., 2019). When comparing different technologies, a positive correlation between disinfection efficacy and the predominance of ubiquitous, potentially hazardous, bacteria in the treated stored wastewater seems to occur (Becerra‐Castro et al., 2016). Interestingly, clean built environments, where asepsis and frequent disinfection are the rule, are characterized by the predominance of Proteobacteria (Mahnert et al., 2019). Moreover, cleaning with aggressive agents seems to favour microbiomes encoding functions related with virulence, multi‐drug efflux, oxidative stress, as well as membrane transport and secretion, which empower cells to acquire nutrients in highly competitive nutrient‐poor environments (Mahnert et al., 2019).Such results are not unexpected. Any process reducing the diversity and abundance of microorganisms in a given ecosystem, through physical removal of the cells or physical and/or chemical inactivation of macromolecules or cellular processes, is expected to generate a habitat where intercellular competition for space and nutrients is reduced, offering the opportunity for those that randomly survived the process and that are most versatile and fast to grow, to proliferate. Therefore, among the survivors, those with high capacity to grow under the conditions prevailing in the disinfected or cleaned system will thrive. Conversely, the microorganisms with specific requirements (e.g. nutritional) or with slower grow rates will be outcompeted. Proteobacteria are well known for their genomic plasticity. Some proteobacterial species, such as Pseudomonas aeruginosa, colonize a wide diversity of environmental compartments, including mineral water, chlorinated drinking water, surface water and soils, and even human bodies (Grobe et al., 2001; Naze et al., 2010; Palleroni, 2015). Part of the success of this ubiquitous opportunistic pathogenic species rely upon its capacity to exchange genetic information through horizontal gene transfer (Kung et al., 2010). Hence, Pseudomonas aeruginosa harbour genetic information which allows cell development in a wide diversity of environmental conditions, including in the presence of a vast array of antimicrobial compounds. Therefore, besides carrying intrinsic antimicrobial resistance, P. aeruginosa strains are excellent vectors of ARG dissemination (Manaia, 2017). The predominance of microorganisms with these type of features in treated wastewater is thus not desirable, mainly if its further use in agriculture irrigation is envisaged, given the possibility of contamination of the food chain.In this context, it may be argued that the upgrading UWWTPs with a final disinfection step is not enough to transform these facilities into wastewater recycling units, and more studies should be carried out to design and implement storage systems capable of attenuating the imbalance of the bacterial community before reuse of the stored treated wastewater.Measures to restore the microbial richness and diversity of the disinfected wastewater would prevent the overgrowth of hazardous bacteria fitted to couple with very clean oligotrophic environments, such as P. aeruginosa, through competition. Such measures might include the inoculation of the disinfected wastewater with balanced natural microbial communities, with a rich and diverse phylogenetic and functional assembly of microorganisms (van Bruggen et al., 2019). In these communities, organisms belonging to a wide variety of species interact through complex relationships (mutualism, commensalism, competition, predation, parasitism) assuring metabolic redundancy and the integrity of nutrient cycles and energy flows (van Bruggen et al., 2019). Such communities are stable and resilient, that is, show little disturbance and restore rapidly upon alteration of the environmental conditions or invasion (van Bruggen et al., 2019). Hence, procedures such as diluting disinfected wastewater with non‐polluted surface water, mixing with pristine sediments or soils or discharge in wetlands would introduce a healthy microbiome in the treated wastewater. Under this circumstance, the exogenous microbiome would act as a protection shield for the proliferation of the hazardous microorganism surviving the disinfection process, in a similar way of the natural human microbiota, our first line of defence against the invasion of pathogens.Definitely, microbes must have a say on removing waste from wastewater. The next research steps should be oriented towards a better understanding of the biotic relationships occurring in the treated wastewater and technological implementation of systems that are able to nurture these important artisan communities.     

Reply to Bronstein and Vinogradov

The response by the author. Subject Categories: S&S: Economics & Business, S&S: Ethics

I thank Michael Bronstein and Sophia Vinogradov for their interest and comments. I would like to respond to a few of their points.First, I agree with the authors that empirical studies should be conducted to validate any approaches to prevent the spread of misinformation before their implementation. Nonetheless, I think that the ideas I have proposed may be worth further discussion and inspire empirical studies to test their effectiveness.Second, the authors warn that informing about the imperfections of scientific research may undermine trust in science and scientists, which could result in higher vulnerability to online health misinformation (Roozenbeek et al, 2020; Bronstein & Vinogradov, 2021). I believe that transparency about limitations and problems in research does not necessarily have to diminish trust in science and scientists. On the contrary, as Veit et al put it, “such honesty… is a prerequisite for maintaining a trusting relationship between medical institutions (and practitioners) and the public” (Veit et al, 2021). Importantly, to give an honest picture of scientific research, information about its limitations should be put in adequate context. In particular, the public also should be aware that “good science” is being done by many researchers; we do have solid evidence of effectiveness of many medical interventions; and efforts are being taken to address the problems related to quality of research.Third, Bronstein and Vinogradov suggest that false and dangerous information should be censored. I agree with the authors that “[c]ensorship can prevent individuals from being exposed to false and potentially dangerous ideas” (Bronstein & Vinogradov, 2021). I also recognize that some information is false beyond any doubt and its spread may be harmful. What I am concerned about are, among others, the challenges related to defining what is dangerous and false information and limiting censorship only to this kind of information. For example, on what sources should decisions to censor be based and who should make such decisions? Anyone, whether an individual or an organization, with a responsibility to censor information will likely not only be prone to mistakes, but also to abuses of power to foster their interests. Do the benefits we want to achieve by censorship outweigh the potential risks?Fourth, we need rigorous empirical studies examining the actual impact of medical misinformation. What exactly are the harms we try to protect against and what is their scale? This information is necessary to choose proportionte and effective measures to reduce the harms. Bronstein and Vinogradov give an example of a harm which may be caused by misinformation—an increase in methanol poisoning in Iran. Yet, as noticed by the authors, misinformation is not the sole factor in this case; there are also cultural and other contexts (Arasteh et al, 2020; Bronstein & Vinogradov, 2021). Importantly, the methods of studies exploring the effects of misinformation should be carefully elaborated, especially when study participants are asked to self‐report. A recent study suggests that some claims about the prevalence of dangerous behaviors, such as drinking bleach, which may have been caused by misinformation are largely exaggerated due to the presence of problematic respondents in surveys (preprint: Litman et al, 2021).Last but not least, I would like to call attention to the importance of how veracity of information is determined in empirical studies on misinformation. For example, in a study of Roozenbeek et al, cited by Bronstein and Vinogradov, the World Health Organization (WHO) was used as reliable source of information, which raises questions. For instance, Roozenbeek et al (2020) used a statement “the coronavirus was bioengineered in a military lab in Wuhan” as an example of false information, relying on the judgment of the WHO found on its “mythbusters” website (Roozenbeek et al, 2020). Yet, is there a solid evidence to claim that this statement is false? At present, at least some scientists declare that we cannot rule out that the virus was genetically manipulated in a laboratory (Relman, 2020; Segreto & Deigin, 2020). Interestingly, the WHO also no longer excludes such a possibility and has launched an investigation on this issue (https://www.who.int/health‐topics/coronavirus/origins‐of‐the‐virus, https://www.who.int/emergencies/diseases/novel‐coronavirus‐2019/media‐resources/science‐in‐5/episode‐21‐‐‐covid‐19‐‐‐origins‐of‐the‐sars‐cov‐2‐virus); the information about the laboratory origin of the virus being false is no longer present on the WHO “mythbusters” website (https://www.who.int/emergencies/diseases/novel‐coronavirus‐2019/advice‐for‐public/myth‐busters). Against this backdrop, some results of the study by Roozenbeek et al (2020) seem misleading. In particular, the perception of the reliability of the statement about bioengineered virus by study participants in Roozenbeek et al (2020) does not reflect the susceptibility to misinformation, as intended by the researchers, but rather how the respondents perceive reliability of uncertain information.I hope that discussion and research on these and related issues will continue.     

Discussions on the quality of antibodies are no reason to ban animal immunization

Debates about the source of antibodies and their use are confusing two different issues. A ban on life immunization would have no repercussions on the quality of antibodies. Subject Categories: S&S: Economics & Business, Methods & Resources, Chemical Biology

There is an ongoing debate on how antibodies are being generated, produced and used (Gray, 2020; Marx, 2020). Or rather, there are two debates, which are not necessarily related to each other. The first one concerns the quality of antibodies used in scientific research and the repercussions for the validity of results (Bradbury & Pluckthun, 2015). The second debate is about the use of animals to generate and produce antibodies. Although these are two different issues, we observe that the debates have become entangled with arguments for one topic incorrectly being used to motivate the other and vice versa. This is not helpful, and we should disentangle the knot.Polyclonal antibodies are being criticized because they suffer from cross‐reactivity, high background and batch‐to‐batch variation (Bradbury & Pluckthun, 2015). Monoclonal antibodies produced from hybridomas are criticized because they often lack specificity owing to genetic heterogeneity introduced during hybridoma generation that impairs the quality of the monoclonals (Bradbury et al, 2018). These are valid criticisms and producing antibodies in a recombinant manner will, indeed, help to improve quality and specificity. But a mediocre antibody will remain a mediocre antibody, no matter how it is produced. Recombinant methods will just produce a mediocre antibody more consistently.Getting a good antibody is not easy and much depends on the nature and complexity of the antigen. And low‐quality antibodies are often the result of poor screening, poor quality control, incomplete characterization and the lack of international standards. Nevertheless, the technologies to ensure good selection and to guarantee consistent quality are much more advanced than a decade ago, and scientists and antibody producers should implement these to deliver high‐quality antibodies. Whether antibodies are generated by animal immunization or from naïve or synthetic antibody libraries is less relevant; they can all be produced recombinantly, and screening and characterization are needed in all cases to determine quality, and if the antibody is fit for purpose.But criticisms on the quality of many antibodies and pleas for switching to recombinant production of antibodies cannot be mixed up with a call to ban animal immunization. The EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) recently published a recommendation to stop using animals for generating and producing antibodies for scientific, diagnostic and even therapeutic applications (EURL ECVAM, 2020). This recommendation is mainly supported by scientists who seem to be biased towards synthetic antibody technology for various reasons. Their main argument is that antibodies derived from naïve or synthetic libraries are a valid (and exclusive) alternative. But are they?One can certainly select antibodies from non‐immune libraries, and, depending on the antigen and the type of application, these antibodies can be fit for purpose. In fact, a few of such antibodies have made it to the market as therapeutics, Adalimumab (Humira®) being a well‐known example. But up to now, the vast majority of antibodies continues to come from animal immunization (Lu et al, 2020). And there is a good reason for that. It is generally possible to generate a few positive hits in a naïve/synthetic library; and the more diverse the library, the more hits one is likely to get. But many decades of experience with immunization of animals—especially when they are outbred—shows that they generate larger amounts of antibodies with superior properties. And the more complex your antigen is, the more the balance swings towards animal immunization if you want to have a guarantee for success.There are different factors at work here. First, the immune system of mammals has evolved over millions of years to efficiently produce excellent antibodies against a very diverse range of antigens. Second, presenting the antigen multiple times in its desired (native) conformation to the animal immune system exploits the natural maturation process to fine‐tune the immune response against particular qualities. Another factor is that in vivo maturation seems to select against negative properties such as self‐recognition and aggregation. It also helps to select for important properties that go beyond mere molecular recognition (Jain et al, 2017). In industrial parlance, antibodies from animal immunization are more “developable” and have favourable biophysical properties (Lonberg, 2005). Indeed, the failure rate for antibodies selected from naïve or synthetic libraries is significantly higher.Of course, the properties of synthetic antibodies selected from non‐immune libraries can be further matured in vitro, for example by light chain shuffling or targeted mutagenesis of the complementarity determining region (CDR). While this method has become more sophisticated over the years, it remains a very complex and iterative process without guarantee that it produces a high‐quality antibody.Antibodies are an ever more important tool in scientific research and a growing area in human and veterinary therapeutics. Major therapeutic breakthroughs in immunology and oncology in the past decades are based on antibodies (Lu et al, 2020). The vast majority of these therapeutic antibodies were derived from animals. An identical picture appears when you look at the antibodies in fast‐track development to combat the current COVID‐19 crisis: again, the vast majority are either derived from patients or from animal immunizations. The same holds true for antibodies that are used in diagnostics and epidemiologic studies for COVID‐19.It is for that reason that we need the tools and methods that guarantee antibodies of the highest quality and provide the best chance for success. The COVID‐19 pandemic is only one illustration of this need. If we block access to these tools, both scientific research and society at large will be negatively impacted. We therefore should not limit ourselves to naïve and synthetic libraries. Animal immunization remains an inevitable method that needs to stay. But we all agree that these immunizations must be performed under best practice to further reduce the harm to animals.     

Molecular basis of cross‐species ACE2 interactions with SARS‐CoV‐2‐like viruses of pangolin origin

Correction to: The EMBO Journal (2021) 40: e107786. DOI 10.15252/embj.2021107786 | Published online 8 June 2021The authors would like to add three references to the paper: Starr et al and Zahradník et al also reported that the Q498H or Q498R mutation has enhanced binding affinity to ACE2; and Liu et al reported on the binding of bat coronavirus to ACE2.Starr et al and Zahradník et al have now been cited in the Discussion section, and the following sentence has been corrected from:“According to our data, the SARS‐CoV‐2 RBD with Q498H increases the binding strength to hACE2 by 5‐fold, suggesting the Q498H mutant is more ready to interact with human receptor than the wildtype and highlighting the necessity for more strict control of virus and virus‐infected animals”.to“Here, according to our data and two recently published papers, the SARS‐CoV‐2 RBD with Q498H or Q498R increases the binding strength to hACE2 (Starr et al, 2020; Zahradník et al, 2021), suggesting the mutant with Q498H or Q498R is more ready to interact with human receptor than the wild type and highlighting the necessity for more strict control of virus and virus‐infected animals”.The Liu et al citation has been added to the following sentence:“In another paper published by our group recently, RaTG13 RBD was found to bind to hACE2 with much lower binding affinity than SARS‐CoV‐2 though RaTG13 displays the highest whole‐genome sequence identity (96.2%) with the SARS‐CoV‐2 (Liu et al, 2021)”.Additionally, the authors have added the GISAID accession IDs to the sequence names of the SARS‐CoV‐2 in two human samples (Discussion section). To make identification unambiguous, the sequence names have been updated from “SA‐lsf‐27 and SA‐lsf‐37” to “GISAID accession ID: EPI_ISL_672581 and EPI_ISL_672589”.Lastly, the authors declare in the Materials and Methods section that all experiments employed SARS‐CoV‐2 pseudovirus in cultured cells. These experiments were performed in a BSL‐2‐level laboratory and approved by Science and Technology Conditions Platform Office, Institute of Microbiology, Chinese Academy of Sciences.These changes are herewith incorporated into the paper.     

Deconstructing PML‐induced premature senescence

The authors contacted the journal after being alerted to errors in Fig 6C. The authors provided the source data, which show that the panel had been assembled and presented incorrectly. Fig 6C is herewith corrected. The authors note that the corrected panel shows similar results, although less pronounced for the induction of p53 acetylation by PMLIV, consistent with what had been reported previously in PML+/+ MEFs (Fig 3C in Pearson et al, 2000). PMLIV‐induced increase in p53 acetylation is also shown in human fibroblasts (Fig 5B). The authors state that this correction does not affect the message of Fig 6, nor does it impact the overall conclusions of the article.The authors apologize for this oversight and any confusion it may have caused. The source data are available with this notice together with the corrected figure. Figure 6C. Original. Figure 6C. Corrected.. Source data are available online for this figure      

A CRISPR response to pandemics?: Exploring the ethics of genetically engineering the human immune system

Ethical challenges should be addressed before gene editing is made available to improve the immune response against emerging viruses. Subject Categories: S&S: Economics & Business, Genetics, Gene Therapy & Genetic Disease, Immunology

In 1881, Louis Pasteur proved the “germ theory of disease”, namely that microorganisms are responsible for causing a range of diseases. Following Pasteur’s and Robert Koch’s groundbreaking work on pathogens, further research during the 20^th century elucidated how the immune system fends off disease‐causing microorganisms from a molecular perspective.The COVID‐19 pandemic has again focused scientific and public attention on immunology not the least owing to the race of employing vaccines to halt the spread of the virus. Although most countries have now started vaccination programs to immunize a large part of the world''s population, the process will take time, vaccines may not be available to everyone, and a number of unresolved issues remain including the potential contagiousness of vaccinated individuals and the duration of protection (Polack et al, 2020).It would therefore be extremely helpful from a public health perspective—and indeed lifesaving for those with elevated risk of developing severe course of the disease—if we could boost the human immune system by other means to better fight off SARS‐CoV‐2 and possibly other viruses. Recent studies showing that some individuals may be less susceptible to contract severe COVID‐19 depending on their genetic status support such visions (COVID‐19 Host Genetics Initiative, 2020). This could eventually inspire research projects on gene therapy with the aim of generally enhancing immunity against viral infections.

It would therefore be extremely helpful from a public health perspective […] if we could boost the human immune system by other means to better fight off SARS‐CoV‐2 …

The idea of genetically enhancing the human immune response is not new and spread from academic circles to policymakers and the general public even before the pandemic, when He Jiankui announced in November 2018 the birth of genetically edited twins who, he claimed, were resistant to HIV. The public outcry was massive, not only because He violated standards of methodological rigor and research ethics, but also because of fundamental doubts about the wisdom and legitimacy of human germline manipulation (Schleidgen et al, 2020).Somatic gene therapy has been met with a less categorical rejection, but it has also been confronted with skepticism when major setbacks or untoward events occurred, such as the death of Jesse Gelsinger during an early clinical trial for gene therapy in 1999. Nonetheless, given the drastic impact the current pandemic has on so many lives, there may be a motivation to put concerns aside. In fact, even if we managed to get rid of COVID‐19 owing to vaccines—or at least to keep its infectiousness and mortality low—another virus will appear sooner or later; an improved resistance to viral pathogens—including coronaviruses—would be an important asset.Interventions to boost the immune system could in fact make use of either germline gene editing, as has been the case of the Chinese twins, or through somatic gene editing. The first requires time and only the next generation would potentially benefit while the latter could be immediately applied and theoretically used to deal with the ongoing COVID‐19 pandemic.

Interventions to boost the immune system could in fact make use of either germline gene editing, as has been the case of the Chinese twins, or through somatic gene editing.

     

Syncytia formation by SARS‐CoV‐2‐infected cells

In the supporting information of the article, the authors noticed that there was an error in Movie EV1. The right panel (SARS‐CoV‐2 + IFITM1) showed the same PI channel data (red) as the middle panel (SARS‐CoV‐2). This mistake occurred during the assembly of the merged movie file and does not change the interpretation of the data. A corrected version of the movie is herewith updated.