Category Archives: Transhuman News

Against the backdrop of the cost-of-living crisis it is argued that the UK could bolster food security, combat climate change and lower food prices by relaxing the rules on and around genetic engineering. By designing more resistant crops which are less reliant on fertiliser and are more nutritious, progress could be made. On the other hand, this may be a short-sighted approach to deregulation and taking the risk could result in disastrous consequences.

The Genetic Technology (Precision Breeding) Bill 2022

The arguments are surfacing as The Genetic Technology (Precision Breeding) Bill (GT (PB) Bill) which is currently in the House of Commons at the report stage (allowing the House to consider further amendments) heading for its 3rd reading. Much of the debate centres around the understanding of the technology.

Genetically Modified Organisms (GMOs) are organisms in which the genetic material (DNA or RNA) has been altered in a way that does not occur naturally, and the modification can be replicated and/or transferred to other cells or organisms. This typically involves the removal of DNA, manipulation outside the cell and reinsertion into the same or other organism. Gene editing (GE) is arguably different as rather than inserting new DNA it edits the organisms own DNA - which could happen over time, but this essentially speeds up the natural process. Both plants and animals can be genetically manipulated.

Regulation (EC) No 1829/2003 provides the general framework for regulating genetically modified (GM) food in the EU with a centralised procedure for applications to place GM food on the EU market. It focusses on the traceability and labelling of GMO and the traceability of food and feed products to ensure a high level of protection of human life and health. GM foods can only be placed on the market after scientific risk assessment of the risks to human health and the environment.

The EU implemented these regulations back in 2001 which heavily restricted the use of GMOs and it has maintained that conservative position since. To continue not to allow GMOs is at odds with other countries, such as Australia, Japan and the US. As the technology developed several member states (including the UK) felt that a more relaxed approach to genetic editing would be beneficial. However, in 2018 the European Court of Justice in, Confederation Paysanne v Premier Minister (C-528/16) decided that there was no real distinction with gene editing (also described as Precision breeding) and they were to be treated as GMOs within the meaning of the GMO Release Directive 2001.

Nevertheless, in the UK in 2019 the then prime minister famously declared that he would liberate the U.K.s extraordinary bio science sector from anti-genetic modification rules. Consequently, since leaving the EU the UK has been working on moving away from the EUs stricter definition of a GMO as evidenced by the GT (PB) Bill.

The Bill defines precision bred to be, if any, or every feature of its genome results from the application of modern biotechnology and every feature of its genome could have resulted from either traditional processes or natural transformation.[1]

It is argued that this removes unnecessary barriers to innovation inherited from the EU to allow the development and marketing of precision bred plants and animals, which will drive economic growth and position the UK as a leading country in which to invest in agri-food research and innovation.

The main elements of the Genetic Technology (Precision Breeding) Bill are:

Creating a new, simpler regulatory regime for precision bred plants and animals that have genetic changes that could have arisen through traditional breeding or natural processes. No changes are proposed to the regulation of animals until animal welfare is safeguarded.

Introducing two notification systems for research and marketing purposes where breeders and researchers will need to notify Department for Environment, food and Rural Affairs (Defra) of precision bred organisms. The information collected on precision bred organisms will be published on a public register.

Establishing a new science-based authorisation process for food and feed products developed using precision bred organisms.

This is the result of an All-Party Parliamentary Group which called for amendments to be made in 2020 to the, at the time, forthcoming Agriculture Bill 2019-21 (now the Agriculture Act 2020) to allow precision breeding in the UK.

The amendments would require changes to the UK Environmental Protection Act 1990, including changing the use of the EU definition of a GMO which would allow UK scientists, farmers and both plant and animal breeders access to gene editing technologies that other countries outside the EU have.

The focus in the UK is to allow traditional breeding methods to alleviate some of the effects such as extreme weather, food shortages, the cost-of-living crisis and to encourage pest-resistance.

The Genetically Modified Organisms (Deliberate Release) (Amendment) (England) Regulations 2022

On 11th April 2022, the Genetically Modified Organisms (Deliberate Release) (Amendment) (England) Regulations 2022 implemented an alignment of GE with the regulation of plants using traditional breeding methods. The Regulations removed the need to submit a risk assessment and seek consent from the Secretary of State before releasing certain GE plants for non-marketing purposes. They apply to England only.

This will allow for the release and marketing of gene edited products under certain circumstances that has so far been prohibited by the EU. It will allow UK scientists to develop plant varieties and animals with beneficial traits that could also occur through traditional breeding and natural processes, while providing safeguards in both marketing and authorisations via regulation.

Taking a Risk?

Another consequence of leaving the EU is that the Food Standards authority (FSA) is now responsible for authorising Novel foods applications in the UK. The FSA points to this need for authorisation as a further check and balance on any risks that may arise from a divergence from EU regulation.

Although it is argued that the Bill may have been drafted a little hastily, any food developed using new technology is subject to the scientific scrutiny of a Novel foods application. If there is a risk of unintended consequences from GE (it is argued that there is a risk of unidentified and untested mutations resulting from gene editing) the role of regulatory authorities such as DEFRA and the FSA is to ensure that no unintended product gains approval.

The debate is becoming increasingly focussed as the cost-of-living crises deepens.

Co-Authored by Laura Hipwell, Trainee Solicitor at CMS.

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To modify or not to modify? Genetic Modification and Gene Editing - A divergence by the UK - Lexology

Gene therapy has a history of presenting possibilities that stay out of reach for a long time. The tantalizing idea of using exogenous good DNA to replace defective DNA was suggested by Stanfield Rogers in 1970. Then, in 1972, the idea was elaborated upon by Theodore Friedmann and Richard Roblin, who wrote that viruses could be tweaked to contain human genes and allowed to infect patients. Once copied into patients cells, the genes could start to function, compensating for defective and disease-causing genes.1

Despite these conceptual advances, clinical progress was slow. Indeed, there were dead ends and reversals. In 1971, Rogers deployed a naturally occurring virus in an attempt to treat an arginase deficiency. And in 1980, Martin J. Cline tried to treat b-thalassemia by using an ex vivo procedure in which bone marrow cells were transfected with a recombinant human globin gene and then reintroduced to patients. Both these efforts were, at best, inconclusive.

Finally, a partial and temporary gene therapy success was reported in 1990. Scientists led by William French Anderson used an ex vivo procedure to treat a four-year-old girl suffering adenosine deaminasedeficient severe combined immunodeficiency disease. They infected the patients own white blood cells with a virus that had been engineered to carry a gene encoding a functional variant of the adenosine deaminase gene. For two years, transfusions were administered that incorporated transfected white blood cells. The transfusions didnt bring about a cure, but they did help reduce the patients symptoms.

Then, in 1999, the field suffered a major setback when an 18-year-old patient with a metabolic disorder died after suffering an immune overreaction to an adenovirus designed to restore a missing liver enzyme. And a few years later, several patients with immunodeficiencies developed leukemias after receiving gene therapy, as the viruses caused insertions into cancer-related genome sites. The U.S. Food and Drug Administration (FDA) reacted swiftly, putting many gene trials on hold.2 The development of gene therapy stalled.

In subsequent years, however, researchers learned from these setbacks. For instance, safer viral vectors were identified, such as adeno-associated viruses (AAVs). The genes they deliver typically remain in the cell cytoplasm and are expressed there, rather than being integrated into human cells genomes, making them less likely than some earlier vectors to trigger cancer.

Since 2017, the FDA has approved several gene therapies for disorders caused by defects in single genes, including Luxturna for retinal dystrophy, Zolgensma for young children with spinal muscular atrophy, and Zynteglo for certain patients with b-thalassemia. The agency has also green-lighted several cell-based gene therapies which alter patients cells and reinfuse them into patients. For example, approvals have been granted to several therapies that use modified T cells, specifically, chimeric antigen receptor (CAR) T cells. They have proven effective in treating certain blood cancers.

Meanwhile, hundreds more gene therapy trials are underway. To get a sense of what these trials tell us about the current status and near-term future of gene therapy, GEN spoke with representatives of companies at various stages of clinical development. They took the opportunity to expand on the results they shared at the 25th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT), which was held last May in Washington, DC. They emphasized that for many diseaseshereditary monogenic disorders, complex diseases, and even cancersingle-dose gene therapies held disease-modifying potential.

The New York Citybased Lexeo Therapeutics has been developing a treatment for Friedreichs ataxia (FA), a rare condition that is currently incurable. Its caused by a mutation in the frataxin gene FXN which leads to progressive degeneration of the nervous system. Rather than targeting the diseases neurological pathology, which is tricky as the viruses fail to transduce efficiently and specifically in affected brain areas, Lexeo tackles the oft-fatal cardiac disease associated with FA, said Jay Barth, MD, Lexeos executive vice president and chief medical officer.

Lexeos therapeutic, LX2006, employs an AAV thats effective at infecting cardiac cells, introducing the FXN gene, increasing frataxin levels, and thereby restoring mitochondrial function. According to data presented at the ASGCT conference, mouse models of FA that received a single intravenous dose of LX2006 had improved heart function, general mobility, and survival compared with untreated rodents, even after they developed fairly advanced cardiac disease, Barth noted.3

Lexeo is planning a Phase I/II trial to assess safety of the therapy in 10 FA patients with cardiomyopathy. One of the goals is to identify the maximum safest dose for LX2006.4 Investigators are taking a cautious approach, Barth said, as overexpression of frataxin has been associated with safety issues.

The first study cohorts will receive the lowest dose thats shown efficacy in mice, and the dose will be incrementally increased in subsequent groups. Frataxin levels will be monitored through heart tissue biopsies. Patients will be followed for one year, and then for an additional four years as the FDA requires. In Barths view, the study could help find some way to prolong the lives of these patients beyond what the disease would give them.

While many gene therapy companies focus on restoring lost functions to normal cells, the Australia-based immuno-oncology company Imugene is employing the method to help kill cancer cells. In 2019, the company acquired an oncolytic virus called CF33, a chimeric vaccinia that infects and selectively replicates in malignant solid tumor cells.5

Imugene scientists have tinkered with CF33 in various ways that are already being tested in patients with specific cancer types. But according to Leslie Chong, the companys chief executive officer and managing director, the crown jewel of Imugene is a version of CF33 that contains a gene encoding the CD19 protein.

This surface protein is expressed on B cells and is the target of several CAR T-cell therapies. Using CF33 to induce uniform expression of CD19 across tumor cells could make CAR T-cell therapy work against solid tumors, which has proven a challenge as the tumors often express a heterogeneous mix of cell surface antigens. But with CF33, Chong explained, We line all your solid tumor [cells] with the CD19-directed targets, such that when you add a CD19-targeted therapy, you then obliterate the solid tumor where it hasnt had markers before.

In 2020, scientists at the City of Hope National Medical Center published data in support of this approach.6 Specifically, the scientists used mouse models of various cancer types to study the effects of administering the CD19-carrying CF33 virus followed by CD19-directed CAR T-cell therapy. Mice that received the antigen-matched therapy survived significantly longer than mice that received only mock T cells or CD19-CAR T cells.

Imugene looks forward to identifying indications that may benefit the most from this onCARlytics approach. The company is also planning a human trial. In our initial in-clinic study, we will be focused on certain indications, Chong noted. However, I think the application could be huge.

The North Carolinabased gene therapy company Asklepios BioPharmaceutical (AskBio) is also pursuing a target that falls outside the usual paradigm of monogenic disorders: congestive heart failure (CHF), a chronic and progressive condition in which the heart cannot pump blood sufficiently. Theres a high unmet medical need to develop additional medicines to reduce mortality and improve quality of life for the patients, said Canwen Jiang, MD, PhD, AskBios chief development officer and chief medical officer.

AskBios approach to tackling this complex disease has been to deliver a gene encoding the phosphatase-1 inhibitor-1, a key protein in regulating cardiac contractions. Introducing the gene via an AAV thats engineered to target cardiac cells could improve heart function as well as reverse and prevent the detrimental remodeling of cardiac muscle that occurs in CHF, Jiang said. The therapy, NAN-101, is delivered via a one-time injection into the hearts coronary arteries.

After collecting robust preclinical data, AskBio launched a Phase I study in 2019, enrolling eight individuals with Class III CHF. According to preliminary results presented at the ASGCT meeting, investigators observed efficient transduction of NAN-101 in heart cells of one trial participant from whom a tissue biopsy could be obtained.7 A cohort consisting of three patients who had completed their 12-month follow-up appeared to tolerate the treatment well and saw consistent improvements in heart function.8

If successful, such studies will not only motivate AskBio to expand into broader CHF indications, but also bolster the idea that gene therapy is useful beyond monogenic disorders. It would be a confidence-building example for the industry, for the academic community, as well as for the regulatory agencies, Jiang said.

One of the companies at the Phase III stage is Sarepta Therapeutics, a Cambridge, MAbased biotech firm specializing in rare diseases such as Duchenne muscular dystrophy (DMD), a monogenic disease that causes progressive muscle deterioration.

The gene therapy SRP9001 is based on an AAV virus subtype with an affinity for reaching muscle cells. It contains a gene encoding a form of the dystrophin protein, which is lacking in DMD patients tissues, coupled with a promoter that causes selective expression in skeletal and cardiac muscle cells, explained Jake Elkins, MD, Sareptas senior vice president of research and development and chief medical officer.

In a pilot study that tracked four DMD patients aged four to seven, data was collected four to five years after SRP9001 was taken. The treatment was well tolerated, and patients showed a 7-point improvement on a 17-step mobility scale (the North Star Ambulatory Assessment), despite being at an age where theyd typically experience rapid deterioration of mobility.9 A randomized Phase II study of 41 pediatric participants has so far bolstered these observations at one year of follow up, Elkins noted.10

Currently, Sarepta is closely tracking 120 boys with DMD aged four to seven in a Phase III study. The first half of patients are receiving gene therapy in the first year, during which the second half will receive a placebo until being rolled onto gene therapy after one year. At one year, were able to document clinically meaningful effects of the therapy, Elkins said. We view it as a confirmatory study of our early findings, but [it] will really expand our knowledge base of how this treatment works across the range of ambulatory patients with DMD.

Ultragenyx Pharmaceutical, a California-based rare disease-focused company, has also reached the Phase III stage with DTX401, which tackles glycogen storage disease type IA (GSDIa). This condition is caused by a genetic deficiency of the enzyme glucose-6-phosphatase, which breaks down glycogen reserves into glucose during fasting periods. GSDIa causes low blood sugar and accumulation of glycogen in the liver and kidneys, and patients need to regularly take cornstarch to maintain normal blood sugar levels, explained Eric Crombez, MD, Ultragenyxs chief medical officer for gene therapy and inborn errors of metabolism.

DTX401 is based on a liver-targeting AAV designed to restore glucose-6-phosphatase expression in patients hepatocytes. According to results presented at the ASGCT meeting, a Phase I/II study of DTX401 reported only mild adverse events in adult GSDIa patients.11 And all 12 participants were able to reduce their daily cornstarch intake by around 70% over three years. When interviewed at 52 weeks, most of the patients reported having more energy and better mental clarity.

If the transgene wasnt working, they would be having a lot of problems, Crombez asserted. [We can see that] they dont, [which] shows that weve established the normal breakdown of glycogen to produce glucose.

Motivated by these results, the company launched a Phase III study in 50 patients to compare the efficacy of DTX401 to that of a saline infusion. Primary endpointsincluding patients ability to taper cornstarch usewill be assessed after 48 weeks, but investigators hope to follow patients for as long as possible.

As the liver has high cell turnover, and the therapy doesnt integrate into the genome, the transgene will eventually be lost, Crombez said. Thats why he doesnt describe gene therapy as a cure in the strictest sense. However, he emphasizes that even if you need [another] dose 20 years down the road, [youve still] treated it for a very long period of time.

References1. Friedmann T, Roblin R. Gene Therapy for Human Genetic Disease? Proposals for genetic manipulation in humans raise difficult scientific and ethical problems. Science 1972; 175(4025): 9499552. Pollack A. FDA halts 27 gene therapy trials after illness. New York Times. Published January 15, 2003.3. Zuluaga CM, Gertz M, Yost-Bido M, et al. Identification of the Therapeutically Beneficial Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friederichss Ataxia. Paper presented at: 25th Annual Meeting of the American Society of Gene and Cell Therapy; May 1619, 2022; Washington, DC.4. Lexeo Therapeutics. LEXEO Therapeutics Announces FDA Clearance of Investigational New Drug Application for LX2006, an AAV-Based Gene Therapy Candidate for Friedreichs Ataxia Cardiomyopathy. Published February 16, 2022.5. Imugene. Today we enhanced our portfolio with a compelling oncolytic virus technology. Published July 15, 2019.6. Park AK, Fong Y, Yang SK, et al. Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors. Sci. Transl. Med. 2020; 12(559): eaaz1863.7. Tretiakova AP, Ozkan T, Sethna F, et al. Rationally designed cardiotropic AAV capsid demonstrates 30-fold higher efficiency in human vs. porcine heart. Paper presented at: 25th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT), Washington, D.C., May 16-19, 20228. Henry T, Chung ES, Egnaczyk GF, et al. A first in-human phase 1 clinical gene therapy trial for the treatment of heart failure using a novel re-engineered adeno-associated vector. Presented at: 25th Annual Meeting of the American Society of Gene and Cell Therapy; May 1619, 2022; Washington, DC.9. Sarepta Therapeutics. Sarepta Therapeutics Investigational Gene Therapy SRP-9001 for Duchenne Muscular Dystrophy Demonstrates Significant Functional Improvements Across Multiple Studies. Published July 6, 2022.10. Sarepta Therapeutics. Sarepta Therapeutics SRP-9001 Shows Sustained Functional Improvements in Multiple Studies of Patients with Duchenne. Published October 11, 2021.11. Ultragenyx Pharmaceutical. Ultragenyx Announces Positive Longer-Term Durability Data from Two Phase 1/2 Gene Therapy Studies at American Society of Gene & Cell Therapy (ASGCT) 2022 Annual Meeting. Published May 19, 2022.

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Gene Therapy Hits Its Stride in the Clinic - Genetic Engineering & Biotechnology News

GWAS identifies genetic variations associated with agronomic traits in foxtail millet

A total of 827 foxtail millet cultivars collected from China were sequenced and genotyped using common single-nucleotide polymorphisms (SNPs) based on a ~423Mb Setaria italica cv. Zhanggu reference genome (v.2.3)27. In total, 161,562 SNPs were detected after stringent steps of quality control, including population stratification and pedigree filtering, individual- and site-level call-rate filtering, and minor allele frequency (MAF) filtering. The SNPs were evenly distributed along chromosomes and the genetic distance for linkage disequilibrium (LD) decay to its half maximum was 9kb (Supplementary Fig.1A, B). Phylogenetic analysis based on the genetic SNPs revealed three main groups in the tested foxtail millet cultivars (Supplementary Fig.1C).

In addition, we planted these 827 foxtail millet cultivars for a field trial in Yangling, China, and measured their agronomic traits (Supplementary Data1). Twelve agronomic traits were used for further analysis, including six growth traits and six yield traits. The growth traits were mainly composed of top second leaf length (TSLL), top second leaf width (TSLW), main stem height (MSH), main stem width (MSW), panicle diameter of the main stem (MSPD) and fringe neck length (FNL) while the yield traits were represented by panicle length of the main stem (MSPL), per plant grain weight (PGW), main stem panicle weight (MSPW), hundred kernel weight (HKW), spikelet number of the main stem (MSSN) and grain number per spike (SGN). Genotypephenotype analysis showed that all 11 traits were significantly heritable except the trait HKW (H2=0.006, P=0.15). Growth traits exhibited higher heritability than yield traits, for example, MSPD showed the highest heritability (H2=0.46, the broad sense heritability) while PGW showed the lowest heritability (H2=0.16) (Supplementary Fig.2). GWAS on phenotypes was performed to identify the SNPs associated with the growth and yield traits. In total, 86 significant SNP loci and 91 associations for 10 traits (except MSPW and TSLW) were identified under suggestive P-value thresholds (P<2.01e5), some of which were for multiple traits (Fig.1, Supplementary Data2). Among these, 15, 16, 11, 10 and 16 significant SNPs co-located on chromosomes 2, 4, 6,7 and 9, respectively. The candidate genes located around the significant signal were analyzed for known molecular functions (Supplementary Data3). Firstly, several candidate genes responsible for growth and development regulation were observed such as ATG8C, ERF1B, PRR37 and Cyclin-like F-box. For example, the peak SNP signal si7:30050703 of MSW, located within the genic region of a homolog of ATG8C (autophagy-related protein 8C, Fig.1B), which functions in the early development of xylem and phloem tissues28. Additionally, SNP si2:6562955 was associated with MSW and near ERF1 (ethylene-responsive transcription factor) (Fig.1B and Supplementary Data3). ERF1 is implicated in cambium proliferation29, which might influence main stem width. Interestingly, the candidate gene PRR37 near the peak SNP si2:49328133 of the MSPL (Fig.1D), suppressed heading and showed shorter panicle length than its mutant in rice30, which might directly regulate the panicle length of foxtail millet. Besides, the peak SNP si2:6646016 of PGW was located within the genic region of Cyclin-like F-box (Fig.1C), which controls many crucial processes such as embryogenesis, hormonal responses, seedling development, floral organogenesis, senescence, and pathogen resistance31,32.

Manhattan plots showing the genome-wide associations between host genetic SNPs and A panicle diameter of the main stem (MSPD), B main stem width (MSW), C per plant grain weight (PGW) and D panicle length of the main stem (MSPL). The dotted line corresponds to a significance threshold of 2.01e5. Genes with significant SNPs are marked in red; genes near the significant SNPs are marked in green. NADKs: NAD+ kinase; PP2C:Phosphoinositide phospholipase C 2; WAT1:WAT1-related protein; ERF1: ethylene-responsive transcription factor 1; ATG8C:autophagy-related protein 8C; PRR37: two-component response regulator-like PRR37.

Secondly, numerous drought stress-responsive (PP2C, ARR12, NPF1.2, NPF4.6, WDR26, Plastocyanin-like protein, CPK2a, PIP5K1) and tolerant genes (APX, DTX12, bHLH3, Thioredoxin fold domain containing protein, SAPK9, Ca2+-transporting ATPase, InsP3, E3 ubiquitin-protein ligase, MIEL1) whose expression are frequently upregulated and contribute to drought resistance in drought-stressed seedlings, were found to be associated with the growth and yield traits (Supplementary Data3). For example, the SNP si2:49320133 that was associated with MSPD was located within the genetic region of PP2C (phosphatidylinositol-specific phospholipase C) (Fig.1A, Supplementary Data3), a stress and ABA-responsive gene that is involved in many physiological responses, including salt, drought and osmotic stress, carbon fixation in C4 plants, and inducible plant responses to pathogen33,34. In addition, NPF1.2 (protein NRT1/ PTR FAMILY 1.2) near the peak SNP (si4:27590764) of MSPD, which functioned as an ABA importer, is important for the regulation of stomatal aperture in inflorescence stems of Arabidopsis35. Another candidate gene SAPK9 (serine/threonine-protein kinase SAPK9) near the significant SNP (si3:44029863) of PGW improves drought tolerance and grain yield in rice by modulating cellular osmotic potential, stomatal closure and stress-responsive gene expression36 (Supplementary Data3).

Thirdly, a great number of plant immune responsive genes and pathogen defense genes were also found to be associated with traits, mainly including RPP13, RGA2, RPS2, LRR-RLKs, EF-Tu SYP22, NOG1, BBE, NB-ARC, and WAK2. Finally, several candidate genes responsible for nutrient uptakes such as iron transporter (IRT1, IRT2) and phosphate transporter (PT) were also observed (Supplementary Data3). Most of the candidate genes related to the significant SNPs were mainly involved in abiotic and biotic stress responses, implying that the host genotype and environment interaction might co-contribute to plant adaption and modulate the traits of foxtail millet.

To explore the contributions of genetic variations to plant performance, linear regression models were used to calculate the role of host genotypes on key growth (TSLW, MSPD, MSW)- and yield (MSPW, PGW, MSPL)-related traits of the 827 different foxtail millet cultivars. Considering no SNPs associations with phenotypes TSLW and MSPW under suggestive thresholds, we extended the candidate SNPs (adjusted P<1.0e4) as inputs of the linear regression models34,35 (Supplementary Data4). After performing thirty rounds of five-fold cross-validation, the genetic SNP markers in predicting model could explain an average of 32.82%, 28.55%, 47.27%, 15.02%, 38.89% and 64.60% of the variances in TSLW, MSPD, MSW, MSPW, PGW and MSPL in the testing data, respectively (Supplementary Fig.3).

Root associated microbiota are thought to promote resistance to pathogens and tolerance to specific environmental constraints, and also contribute to plant performance37,38. Firstly, linear regression models were performed to calculate the effect of the rhizoplane microbiota on growth- and yield-related traits of the 827 different foxtail millet cultivars. The 1004 rhizoplane operational taxonomic units (OTUs) with a 70% occurrence in all samples (here defined as common OTUs), covering an average of 61.30% of total abundances were used as the input data as these OTUs commonly exist in the root zone of foxtail millet cultivars. The common sub-community (1004 common OTUs) showed higher evenness and correlations with the growth traits than the whole microbial community (Kruskal-Wallis test (one-way analysis), Pevenness=2.58e30, Supplementary Fig.4AC). The average variation degree (AVD) index from the common sub-community, 0.5 and 0.3 sub-community (OTUs with 50 and 30% occurrence), were calculated to assess the microbiota stability. The common sub-community had a lower AVD value than the other two sub-communities, indicating that it has a more stable microbiota (Supplementary Fig.4D). In the common sub-communities, the moderate OTUs (covered 83.67% of OTU numbers) were abundant, followed by abundant OTUs (12.85%) and rare OTUs (3.48%) (Supplementary Table1). The network analysis was used to disentangle the ecological role and co-occurrence patterns of 1004 OTUs in the common sub-community. Abundant OTUs (ATs) had significantly higher values of the degree, closeness, betweenness centrality and hub scores than both rare (RTs) and moderate OTUs (MTs) in the network (Kruskal-Wallis test (one-way) with P<0.001, Supplementary Fig.4E), indicating their important roles in sustaining the stability of the microbial community. Thus, the candidate OTUs that were significantly correlated with the traits (adjusted P<0.05) were selected from the common sub-community and used as the input of the predicting models (Supplementary Data5). A five-fold cross-validation approach was repeated thirty times for each trait to reduce the noise in the estimated model performance. The candidate OTU markers in the OTU-predicting models explained an average of 32.47%, 17.43%, 56.06%, 30.36%, 35.17% and 12.61% of the variances in TSLW, MSPD, MSW, MSPW, PGW and MSPL in the testing data, respectively (Supplementary Fig.3).

To explore the contributions of genetic variations and environmental microbiota to plant performance, we used linear mixed models to calculate the role of host genotypes and rhizoplane microbiota on the aforementioned growth and yield traits. We used the candidate SNPs (adjusted P<1.0e4) as inputs of the linear regression models39,40 to predict phenotypic variations (Supplementary Data4). Then the candidate OTUs markers from the above models were also added to the linear regression model (Supplementary Data5). After performing thirty rounds of five-fold cross-validation, the genetic SNP and OTU markers in predicting model could explain an average of 46.50%, 59.08%, 65.69%, 38.45%, 43.04% and 44.31% of the variances in TSLW, MSPD, MSW, MSPW, PGW and MSPL in the testing data, respectively (Supplementary Fig.3). The correlation coefficients only using genotype as variables were obviously higher than that only using root microbiota as variables in several agronomic traits such as MSW and MSPL.However, in the trait MSPD and MSPW, the contribution of root microbiota to phenotypic plasticity was higher when root microbiota variables were used instead of genotype variables alone, indicating a different contribution of host genotype and root microbiota to phenotypic plasticity. The combination of host genotype and root microbiota significantly promoted the explanation of variations in all six traits than genotype and root microbiota alone (Wilcox rank test, P<0.001) except for the trait MSPL (Supplementary Fig.3). Consistently, the panicle length has been proven to be directly impacted by gene PRR3725, similar to our observed data. The predictive models with the best prediction accuracy for the phenotypes using the SNP and OTU variables were retained, which explained 53.42%, 63.73%, 70.54%, 50.16%, 55.88%, and 54.82% variations for TSLW, MSPD, MSW, MSPW, PGW and MSPL trait, respectively, resulting in a final set of 257 marker OTUs (Fig.2AF, Supplementary Data5). Network analysis of 257 marker OTUs showed that the abundant marker OTUs (AMTs) had a significantly higher value of the degree, closeness and betweenness centrality than both rare (RMTs) and moderate marker OTUs (MMTs), indicating the abundant marker OTUs have more important roles in community structure (Kruskal-Wallis test (one-way) with P<0.05, Supplementary Fig.5 and Supplementary Table1).

AF The variation of growth (TSLW, MSW, MSPD) and yield (MSPW, PGW, MSPL) traits explained by the genetic SNPs and microbial OTUs combined. Each panel shows observed values on the x-axis and model-predicted values on the y axis, with a fitted linear regression. Specifically, the predicted value of TSLW, MSW, MSPD, MSPW, PGW, and MSPL is calculated based on 136, 100, 117, 126, 110 and 106 samples in the testing dataset, respectively. The dark trend line illustrates the predicted effect in the linear model (LM). The gray shading around the line represents a confidence interval of 0.95. TSLW, top second leaf width; MSW, main stem width; MSPD, panicle diameter of the main stem; MSPW, main stem panicle weight; PGW, per plant grain weight; MSPL, panicle length of the main stem.

Among the 257 marker OTUs identified by MWAS, 145 and 128 marker OTUs were significantly correlated with growth and yield traits, respectively (Supplementary Data5). Taxonomic profiling of these marker OTUs revealed 86 genera distributed across 15 phyla. The top five abundant phyla were Proteobacteria (with 68 OTUs), Actinobacteria (54 OTUs), Bacteroidetes (36 OTUs), Acidobacteria (35 OTUs), and Firmicutes (33 OTUs) (Fig.3A). In particular,17 marker OTUs were shared by growth and yield traits. Unexpectedly, no marker OTU or genus was shared by all six traits (Supplementary Fig.6), suggesting that the microbial markers may function in different development stages or different processes of foxtail millet.

A Phylogenetic tree of the 257 microbial markers associated with agronomic traits of foxtail millet. The outer circle represents the phylum level. The beta estimates of the microbial OTUs to growth and yield traits are plotted in the inner circles, respectively. The arrows indicate the strains tested in planta (B, C), including strains responded to six positive marker OTUs: Acid550 to Acidovorax OTU_46, Baci299 to Bacillaceae OTU_22228, Kita594 to Kitasatospora OTU_8, Baci154 to Bacillus OTU_19414, Baci312 to Bacillus OTU_25704, Baci429 to Bacillales OTU_381, and strains responded to four negative marker OTUs: Shin228 to Shinella OTU_37, Baci81 to Bacillus OTU_54, Baci173 to Bacillaceae OTU_19835 and Baci554 to Bacillaceae OTU_28133. The strains predicted to affect growth traits are validated by plate (B) and sterilized soil (C). Significance is determined within each pair of treatment and control via one-tailed t-test and the P-values are adjusted by Benjamini-Hochberg (BH) method. n=41, 40, 38, 34, 43, 43, 44, 32, 21, 34 and 27 (from left to right) biological replicates in plate experiment. From Kita594 to Baci554, adjusted P(plant height)=8.68e07, 1.02e09, 0.07, 0.001, 0.49, 0.29, 0.03, 0.40, 0.001, 5.39e06, adjusted P(root length)=0.012, 0.10, 0.40, 0.18, 0.01, 0.11, 1.14e06, 0.02, 1.20e09, 5.68e12. n=20, 32, 31, 40, 23, 20 and 23 (from left to right) biological replicates in sterilized soil experiment. From Kita594 to Baci554, adjusted P(plant height)=1.6e07, 0.003, 0.018, 0.011, 0.98, 0.06, adjusted P(root length)=0.046, 4.4e04, 8.43e05, 0.016, 0.058, 0.15. *, ** and *** represented the adjusted P<0.05, 0.01 and 0.001, respectively. The box depicts the interquartile range (IQR) between the 25th and 75th percentiles, respectively and the line within the box represents the median. The whiskers extend 1.5 times the IQR from the top and bottom of the box, respectively.

To validate the predicted effects of these microbial markers on foxtail millet growth, we isolated a range of taxonomically different bacterial strains from root microbiota of the foxtail millet varieties grown in the field. A total of 644 bacterial strains were collected, and 257 bacterial isolates with complete 16S rRNA gene sequences were retained, representing four bacterial phyla and 25 genera (Supplementary Data6).

A cultured strain was considered a representative OTU if its 16S rRNA gene had 97% similarity with the rhizoplane microbiota OTU (Supplementary Data6). Representative cultivated strains of six positive marker OTUs (Acid550 to Acidovorax OTU_46, Baci299 to Bacillaceae OTU_22228, Kita594 to Kitasatospora OTU_8, Baci154 to Bacillus OTU_19414, Baci312 to Bacillus OTU_25704 and Baci429 to Bacillales OTU_381) and four negative marker OTUs (Shin228 to Shinella OTU_37, Baci81 to Bacillus OTU_54, Baci173 to Bacillaceae OTU_19835 and Baci554 to Bacillaceae OTU_28133) with top beta estimation in the regression model were selected for the validation experiments (Fig.3A and Supplementary Fig.7). We co-cultivated these 10 biomarker strains with foxtail millet Huagu12 (a bred cultivar of foxtail millet (Setaria italica) at Shenzhen, China) for 7-days in sterilized plates, and observed altered root lengths and plant heights compared with the control (Fig.3B and Supplementary Fig.7A). The positive biomarker strains representing OTUs with top beta estimation showed significant growth-promoting abilities. Specifically, positive biomarker strain Kita594 (Kitasatospora OTU_8) promoted both root and stem growth, whereas Baci299 (Bacillus OTU_22228) and Acid550 (Acidovorax OTU_46) only promoted shoot growth compared to the control (one-tailed t-test with adjusted P<0.05, Fig.3B and Supplementary Fig.7A). The negative marker strain Baci173 (Bacillaceae OTU_19835) and Baci554 (Bacillaceae OTU_28133) suppressed the shoot and root growth of Huagu12 (one-tailed t-test with adjusted P<0.05, Fig.3B and Supplementary Fig.7A). While the negative marker strains Shin228 (Shinella OTU 37) and Baci81 (Bacillus OTU 54) exhibited growth-promoting effects, they may only function in special root microbial flora in collaboration with other strains or be mistakenly identified as representative strains due to high 16S rDNA sequence similarities with negative marker OTU 37 and 54.

Next, we validated the effects of four positive marker strains (Kita594, Baci299, Baci154 and Acid550) and two negative marker strains (Baci173 and Baci554) with good promoting or suppressing performances on plant growth in plate experiment by watering millet seedlings grown in sterilized soil with these bacterial suspensions separately. Consistently, the seedlings watered with suspensions of the promoting bacterial strains Kita594, Baci299, Baci154 and Acid550 showed significantly increased plant height and root length compared with the control, whereas the seedlings watered with suspensions of the suppressing bacteria Baci173 showed shorter roots (one-tailed t-test with adjusted P<0.05, Fig.3C and Supplementary Fig.7B). These results validated the plant growth promoting (PGP) traits of marker microbes in foxtail millet.

To shed light on how bacterium regulates the growth of foxtail millet, we analyzed the transcriptomes of seedlings colonized for 14 days with the growth-promoting strains Baci299, Acid550, Kita594 or with the growth-suppressing strain Baci173. The differentially expressed genes from biomarker strain-inoculated versus non-inoculated samples were enriched in different pathways (Fishers exact test, q<0.05, Fig.4A). For example, the differentially expressed genes caused by growth-promoting strains were mainly enriched in the pathways such as Phenylalanine, tyrosine and tryptophan biosynthesis (ko00400), Biosynthesis of amino acids (ko01230), Phenylalanine metabolism (ko00360), Carbon fixation in photosynthetic organisms (ko00710), Photosynthesis-antenna proteins (ko00196), Photosynthesis (ko00195), MAPK signaling pathway-plant (ko04016), Plant-pathogen interaction (ko04626), Diterpenoid biosynthesis (ko00904), Monoterpenoid biosynthesis (ko00902), alphaLinolenic acid metabolism (ko00592) and Selenocompound metabolism(ko00450), while the differentially expressed genes caused by suppressing strain were mainly involved in the pathways such as Arginine and proline metabolism (ko00330) and Valine, leucine and isoleucine degradation (ko00280) (Fig.4A).

A KEGG enrichment analysis of differentially expressed genes in Baci173-, Baci299-, Acid550-, Kita594- inoculated seedlings. The differentially expressed genes represent the genes that were significantly upregulated or downregulated in seedlings inoculated with marker strain compared with control. Circle size represents the number of genes within the pathway and color represents the significance of the pathway. B Venn diagram showing the overlap of the significantly upregulated genes under different inoculations. C Transcript abundance of genes that were induced only in Baci173-, Baci299-, Acid550- and Kita594-inoculated seedlings, respectively.

Interestingly, the growth-promoting strains displayed strain-specific induction of genes involved in nutrient transformation, pathogen defense, anti-abiotic stresses and growth-promoting processes (Fig.4B, C, Supplementary Data7). For instance, the ammonia producing gene (K01455_fomamidase) and terpenoids synthase (K15803, germacrene D) were highly induced by strain 299; ethylene synthase (K05933, aminocyclopropanecarboxylate oxidase) and plant immunity responsive genes (K18834, WRKY1; K20538, MPK8; K00430, peroxidase; K13422, MYC2; and K04079, HSP90A) were abundantly induced by strain 550, and photosynthesis-related genes (K02692, psaD, K01092, IMPA; and K08916, LHCB5), anti-oxidant gene (K00434, Lascorbate peroxidase) and pterostilbene biosynthesis gene (K16040, ROMT) were highly induced by strain 594 (Fig.4C). Intriguingly, the expansin gene that mediates cell wall loosening and increased root and shoot growth in rice41, was induced by all of the growth-promoting strains.

Similarly, 39 genes were significantly induced only by the growth-suppressing strain Baci173, including auxin synthetase (K01426, amidase; K00128, aldehyde dehydrogenases ALDH), auxin-responsive protein IAA (K14484, auxin-responsive protein), L-glutamine synthetase (K01915) and branched-chain amino acid synthetase (BCAT, K00826) (Fig.4B, C, Supplementary Data7), which all have well-documented roles in inhibiting root growth42,43,44. Thus, the plant growth mechanisms mediated by microorganisms were strain-dependent.

To explore the relationship between the host genotype and rhizoplane microbial composition, Mantels test was used to evaluate the correlation between host phylogenetic distances and rhizoplane microbiota distance, exhibiting a significant Mantels correlations (r=0.06, P=0.0003, 9999 permutations). Subsequently, to investigate host genotype-dependent variation in the foxtail millet rhizoplane microbiota, the heritable microbes were identified based on a common rhizoplane OTUs data set, which covered 17 phylum and 52 orders. Using an SNP-based approach, the heritability for individual OTU was calculated. 281 OTUs with H2 (the broad sense heritability) more than 0.15 were defined as highly heritable and the others as lowly heritable (Supplementary Data8). Bacillales and Gp4 orders enriched greater numbers of highly heritable OTUs when compared with the lowly heritable fraction (Fishers exact test, q<0.05, Supplementary Fig.8A), implying that these bacterial orders were more easily impacted by host genotypes of foxtail millet. To explore whether there are similarities in heritable microbes across Poaceae family, we compared the top 100 most heritable OTUs from foxtail millet, sorghum45 and maize datasets46,47. After removing the order with a total number of OTUs less than 4, seven bacterial orders such as Bacillales, Actinomycetales, Burkholderiales, Rhizobiales, Myxococcales, Sphingobacteriales and Xanthomonadales were identified, which shared and covered more than half of the most heritable OTUs from foxtail millet, sorghum, and maize datasets, respectively (Supplementary Fig.8B, C). These results hence indicated that the microorganisms in these bacterial orders were more sensitive to genetic variations across both sorghum, maize and foxtail millet.

To further assess the association of host genetic variations and root microbial abundance, we ran mGWAS on 1004 common rhizoplane OTUs of foxtail millet. We identified significant associations of 2108 SNP loci with 838 microbial OTUs (here called SNPs-associated OTUs) at the genome-wide suggestive significance threshold of P<2.01e5 (Supplementary Data9). To identify how the host genetic variations drove abundance variations of the specific microbial taxonomies, especially the bacterial orders that were more sensitive to genetic variations, the SNP-associated genes for each order were enriched into pathways (Supplementary Fig.9). However, only four bacterial orders associated genes were significantly enriched into different pathways. Taking Bacillales for example, the associated genes were mainly enriched in the monoterpenoid biosynthesis pathway (Fishers exact test, q=0.05, Supplementary Fig.9). The GP4 associated genes were significantly enriched in producing D-galacturonic acid (Fishers exact test, q=0.08, Supplementary Fig.9). GP4 from Acidobacteria phylum, which has been reported with the capability of utilizing galacturonic acid, a characteristic component of the cell wall in higher plant48, might be recruited to rhizoplane by plant-secreted galacturonic acid. The genes associated with plant pathogen-containing order Xanthomonadales were significantly enriched into the pathway such as peroxisome and MAPK signaling pathway (Fishers exact test, q=0.01 and 0.04, Supplementary Fig.9), which are involved in disease and abiotic resistance49,50. These results provide key insights into how the host genetic mechanism drive plant-associated microbiota.

In addition, significant SNP loci located in the generic region were also deeply analyzed (Fig.5, Supplementary Data9). For example, the peak SNP signal si7:13687399 located in the genic region of bHLH35 was associated with 39 common OTUs from different microbial taxonomies such as Acidobacteria (28), Proteobacteria (8) and Bacteroidetes (3). bHLH35 proteins are transcription factors induced by effector-triggered immunity (ETI), and also involved in tolerance to abiotic stresses51. The SNP si1:32157654 located in the generic region of WAK2 (wall-associated receptor kinase 2) was associated with 30 common OTUs, including Acidobacteria (21), Bacteroidetes (4), Proteobacteria (4) and Actinobacteria (1). The WAK2 protein bound to pectin, is required for cell expansion and is induced by a variety of environmental stimuli, including pathogens and wounding52. Similarly, the 50 common OTUs were found to be associated with FLS2 (si7:2994337, Supplementary Data9), a flagellin sensor that perceives conserved microbial-associated molecular patterns (MAMPs) in the extracellular environment53. Clostridia OTU_19207 and Nocardioides OTU_26357 associated si8:20598566 located within the gene of NPF1.2 (Fig.5 and Supplementary Data9), which is involved in ABA importing and nitrate utilization, regulates plant development and influences the root microbiota14,35,54. An NPF1.2 homologue in loci si1:20064466 was significantly associated with Bacillaceae OTU_28839. Collectively, host genes related to plant immunity (RPM1, RGA2, HSL1, CRKs, LRR-RLKs), metabolites (Flavonoids, Diterpenes, amyA, alpha-N-arabinofuranosidase, beta-glucuronosyltransferase), nutrient uptake (Acid phosphatase, Mg2+ transporter, H+-transporting ATPase), plant hormone signal transduction (BRI1, DELLA protein, EFR3, PI-PLC, SDR, ARR1) and others (E3 ubiquitin protein ligase) are perhaps common host genetic factors with function to modulate root microbial composition assembly (Fig.5 and Supplementary Data9).

Manhattan plots show the significant SNPs for microbial abundance. SNPs located in gene coding regions are labeled with numbers. Details of the associations between the host genes and microbial species are given in the table below. All of these associations of SNP loci and microbial OTUs were significantly lesser than 2.01e5.

Plants primarily influence their microbiomes through targeted interactions with key taxonomic groups or diffuse interactions with entire communities55. To further investigate the mode of host-microbe interactions, the hub microbial taxa and non-hub microbial taxa and their associated genes were identified. Firstly, we defined hub taxa as OTU with high values of degree (>400) and closeness centrality (>0.5) in the network as described in a previous study56, resulting in 102 hub OTUs. We identified that 90 hub OTUs and 748 non-hub OTUs had significant associations with the host genetic SNP loci (Supplementary Fig.10A, Supplementary Data9), indicating host plant might interact with these hub microbes and diffusely interact with these non-hub microbes. We aggregated these SNP-associated hub OTUs (90 hub OTUs) and non-hub OTUs (748 OTUs) into 12 and 36 microbial orders, respectively. Comparative analysis showed that one order GP7 was only composed of SNP-associated hub OTUs, and 25 orders such as Sphingobacteriales, Bacillales, Ohtaekwangia, Sphingomonadales and Acidimicrobiales were only composed of SNP-associated non-hub OTUs, and 11 orders were composed of both SNP-associated hub and non-hub OTUs (Supplementary Fig.10B). These data indicated that the foxtail millet employed two modes to structure the rhizoplane microbiota: targeted interaction with several hub microbes and diffused interaction with most of the microbes. To decipher the potential mechanism of the interaction between plant and microbe, the candidate host genes around the SNP loci associated with the hub and non-hub OTUs were extracted separately. The networks showed that the host immune genes FLS2 and transcription factor bHLH35 are widely associated with the hub and non-hub taxa (Supplementary Fig.11A, B). However, the host plant still employed different genes to interact with different taxa (Supplementary Fig.11C), suggesting a taxa-dependent regulation model.

To determine if the genotype-dependent rhizoplane microbiota influence agronomic traits in foxtail millet, we compared the 838 SNP-associated OTUs (mGWAS identified) with the 257 marker OTUs (MWAS identified). We discovered that 219 of the SNP-associated OTUs overlapped with the marker OTUs in our data sets, covering 85.2% of 257 marker OTUs. (Supplementary Fig.12A, 219 out of 257=85.2%). 682 SNP loci were significantly associated with 219 marker OTUs (here called marker OTU-associated SNPs). However, for the 682 marker OTU-associated SNPs, only 4 overlapped with the 45 non-redundant marker SNPs (GWAS identified) that were associated with the aforementioned agronomic traits of foxtail millet (Supplementary Fig.12B). Most of the genetic variations that were associated with marker OTUs were not directly associated with agronomic phenotypes. These genetic variations might affect agronomic phenotypes indirectly, only in the presence of environmental factors such as marker microbes. Moreover, the Mantel test also showed that SNP-associated marker OTUs had higher correlations with the growth trait (MSPD and MSW) than non SNP-associated marker OTUs, while having no difference in correlations with trait TSLW, MSPW, PGW and MSPL (Supplementary Table2). It means that the genotype-dependent marker OTUs might explain more variances in plant growth traits.

To decipher host plant genetic mechanisms for marker microbe selection, KEGG pathway enrichment analysis revealed that the genes within or nearby the significant SNP loci were enriched in pathways related to plant-pathogen interaction (ko04626), MAPK signaling (ko04016), Steroid biosynthesis (ko00100) and so on (Supplementary Data10). Specifically, the genes enriched in plant-pathogen interactions included microbial pattern-recognition receptors (PRRs), disease-resistant genes RPM1 and RPS2, an activator of pathogenesis-related genes PTI1 and PTI6, key regulators of plant immune responses CALM and transcription factor WRKY25. These results suggest that the plant defense genes may also underpin the microbial ecology in the root habitat in addition to protecting from pathogens.

Among the 219 SNP-associated marker OTUs, 77 were highly heritable (Fig.6A). The association between host genetic variation, the abundance of specific marker microbes and phenotypes, especially for 77 genomic heritable marker OTUs were closely examined (Fig.6A, Supplementary Data8). Remarkably, plant defense-related genes and transcription factors, such as the plant immune receptor FLS2 (si7:2994337), transcription factor bHLH35 (si7:13687399) and WAK2 (si:2:5642650) had a dominant impact on the marker OTUs from the phylum of Acidobacteria (Fig.6A). In contrast, genes involved in nutrient uptake, metabolites and abiotic stress response, such as magnesium transporter (si7:19232862), triterpene synthase (si:7:11346839, achilleol B synthase), BGLU12 (si:3:4780643, Beta-glucosidase 12) and RXW8 (si:3:39749463, CSC1-like protein RXW8), mainly associated with marker OTUs from Actinobacteria, Bacteroidetes and Proteobacteria, which mostly contribute positively to the growth and yield traits of foxtail millet (Fig.6A). Other genes involved in plant growth and development processes, such as SUZ12 (Polycomb protein SUZ12) and WAT1 (WAT1-related protein), impacted the marker OTUs from Firmicutes (Bacillaceae OTU_19835) and Proteobacteria (Xanthomonadaceae OTU_10146) respectively, but these marker OTUs have opposite effects on the growth of foxtail millet (Fig.6A). Additionally, we observed strong associations between the positive marker Acidovorax OTU_46 and EREBP-like factor (si7:27291504, dehydration-responsive element-binding protein 1B-like), and between positive marker Kitasatospora OTU_8 and FaQR (si2:36177507, 2-methylene-furan-3-one reductase) (Fig.6A). To explore the host genetic mechanisms that might drive the associations of the plant host gene and rhizoplane microbiota, we examined the specific expression pattern of candidate genes from the RNA-seq datasets obtained from the sterilized soil experiments. Obviously, the genes FaQR, vWA (von Willebrand factor, type A), SUZ12 and EREBP-like factor (ethylene response element binding protein) exhibited significant variation after being inoculated with strain Kita594 (Kitasatospora OTU_8), Baci299 (Bacillaceae OTU_22228), Baci173 (Bacillaceae OTU_19835) and Acid550 (Acidovorax OTU_46) compare to control, respectively (Supplementary Fig.13), implying that the candidate host genes likely interacted with specific bacterial strains.

A Venn diagram displaying the overlaps among 838 SNP associated OTUs, 257 marker OTUs and 281 highly heritable OTUs. B A network of associations between the candidate genes and marker microbial OTUs. Edges between the marker OTUs and host genes were colored according to the correlation coefficients. The pink color represents the positive correlations while the green color represents the negative correlations. The circle represents the OTUs colored according to the phylum taxonomy information, the triangle represents the genes colored according to the function module information, the square represents the growth traits colored in green and the yield traits are shown in yellow. Plant height (C) and root length (D) of seedlings of FaQR reference cultivars (C494 and C1631) and allele cultivars (C571 and C1119) grown axenically (no bacteria, control) or with growth-promoting Kita594. n=22, 26, 36, 37, 50, 46, 45 and 41(from left to right) biological replicates. Plant height (F) and root length (G) of seedlings of SUZ12 reference cultivar (C946 and C306) and allele cultivar (C1296 and C1021) grown axenically (no bacteria, control) or with growth-suppressing Baci173. n=39, 32, 46, 40, 50, 24, 45 and 31 (from left to right) biological replicates. The deviation of promoting and suppressing effect of marker strain Kita594 (E) and Bci173 (H) were calculated separately. n=26, 37, 46, 41, 26, 37, 46 and 41 (from left to right) biological replicates for the treatment with marker strain Kita594 (E). n=32, 40, 24, 31, 32, 40, 24 and 31 (from left to right) biological replicates for the treatment with marker strain Bci173 (H). Different letters in C to H indicate statistical significance (adjusted P<0.05) among the treatments according to one-way ANOVA and LSD test at the 5% level. In C, df=7, F=19.73, adjusted P<2.0e16; in D, df=7, F=13.76, adjusted P=2.09e-15; in E, df=3, F=2.10, adjusted P=0.102; df=3, F=18.29, adjusted P=4.04e10; In F, df=7, F=18.11, adjusted P<2.0e16; in G df=7, F=14.83, adjusted P<2.0e16; in H, df=3, F=19.57, adjusted P=2.0e10; df=3, F=6.751, adjusted P=2.90e4. The box edges depict the 75th and 25th percentiles, respectively and the line within the box represents the median. The whiskers extend 1.5 times the IQR from the top and bottom of the box, respectively.

Finally, based on cultivars with different genotypes, the influence of functional SNPs on marker OTU abundance was thoroughly examined. The abundance of marker OTUs shifted among the different genotypes at the most strongly associated SNPs (Supplementary Fig.14). We hypothesize that host gene-regulated promotion/suppression microbes could establish genotype-dependent microbe-mediated growth phenotypes. To test this hypothesis, we germinated the FaQR and SUZ12 reference and allele foxtail millet cultivars on sterile plates inoculated with a growth-promoting or suppressing strain that corresponds to each cultivar: the growth-promoting strain Kita594 to FaQR reference (C494 and C1631) and allele (C1119 and C571) genotype cultivars, the growth-suppressing strain Baci173 to SUZ12 reference (C946 and C306) and allele (C1021 and C1296) genotype cultivars. Intriguingly, we found that strain Kita594 had a statistically significantly shoot-promoting effect only on the allele cultivars, but not on reference cultivars (Fig.6CE, adjusted P<0.05 by ANOVA-LSD), supporting that plant-growth promoting rhizobacteria support genotype-dependent cooperation with the plant. We observed strong root growth inhibition in seedlings inoculated with the growth-suppressing strain Baci173 (Fig.6FH, adjusted P<0.05 by ANOVA-LSD), and a more significant suppressing effect on root length was observed in the allele cultivars (C1296 and C1021) compared to the reference cultivars (C946 and C306). Significant effects of the interaction between the genotype and strain Kita594 and strain Baci173 on the shoot and root length were also detected by PERMANOVA, respectively (genotypes*Kita594: R2=13.048, P<0.001; genotypes*Baci173: R2=0.07, P<0.001, Supplementary Table3). Together, these results suggest that host genetic variation might impact the interactions between marker strains and host plants, finally affecting the plant phenotypes.

The rest is here:
GWAS, MWAS and mGWAS provide insights into precision agriculture based on genotype-dependent microbial effects in foxtail millet - Nature.com

In this podcast, Motley Fool senior analyst Fool Jim Gillies discusses:

Plus, Motley Fool producer Ricky Mulvey talks with best-selling author Blake Crouch about gene modification, as well as a future that may be closer than most people imagine.

To catch full episodes of all The Motley Fool's free podcasts, check out our podcast center. To get started investing, check out our quick-start guide to investing in stocks. A full transcript follows the video.

This video was recorded on Sept. 28, 2022.

Chris Hill: We've got a closer look at Apple and a future that may be closer than you think. Motley Fool Money starts now. I'm Chris Hill, joining me today, Motley Fool senior analyst Jim Gillies, thanks for being here.

Jim Gillies: Thanks for inviting me.

Chris Hill: Apple has reportedly told suppliers to scrap pre-existing plans to increase production of the iPhone 14. According to a report in Bloomberg, demand for the new iPhones is not as high as previously anticipated. On a day when the overall market is up, Jim, shares of Apple are down more than 3% on this report. I think you and I had the same reaction to this news, it made us both smile.

Jim Gillies: It did. I will fully admit my reaction to Apple being down 3, 4% this morning on a production cut is, oh no, oh terrible. I'm being a little bit facetious of course, but the line from Battlestar Galactica, the reimagined seriesis, "All of this has happened before. All of this will happen again." I look at it a little bit like that. We have seen production shortfalls on prior Apple iPhone model or maybe the iPad wasn't selling as well as iPod. At one point I remember a couple of quarters where they blamed iPad for sales below what some analysts wanted. The stock gets smacked around. Then you take a longer-term, say 15 year. Go look at the 15-year stock chart because the iPhone was introduced in 2007-something. You're going to get one of the prettiest up into the rights you're ever going to see. I have very fond memories of the fourth-quarter of 2018. You may not remember off the top of your head, Chris, but I wrote a column about this in the last week of 2018 and I called it the column, the 2018, the year no one made money.

Because I went through and basically interest rates had gone up, so bond prices had gone down. I know interest rates not to the extent we're currently. Bonds went down, stocks went down, gold went down, silver went down, crypto went down. Of course here in Canada, the big news of 2018 was the legalization of marijuana. In 2018, pot stocks went down for Canadian. So in one of them were the bigger buy the rumor, sell the news style of investing events. Yet in the final quarter of 2018, where Apple suffered a profit warning, a slowdown of production warning much like this, I just smiled like you said, because you were staring at here is the preeminent cash-generating story of our generation. It was trading at 10 11times cash flow. Now, we are not trading, Fools, we are not trading at 11 times cash flow today. We are in fact trading at about 21 times free cash flow, which is decent, yet also probably not a multibagger.

In short order as it was in 2018 at 10 times cash flow, even today's price of Apple, is still well more than a triple if you were a buyer at the end of 2018, early January 2019, which is not bad for the largest publicly traded company in the world to have done in in just over three years. But yes, the 14, sounds like they are going to have less uptake than they perhaps thought they were. I'm still willing to bet, and I'm doing so with my own money. I'm willing to bet that five years from now, number of iPhones they're selling is higher. Five years from now, cash flow generating from it is higher and five years from now, the number of shares outstanding will be lower and the dividend will be higher. So the further it falls, I'm all flat out stated, I hope Apple, 4% is nothing, Chris, I want 24%. Knock Apple to it. Let's go.

Chris Hill: They're still aiming to produce 90 million phones, which is in line with what they produced last year. Not that I've seen a lot of this type of commentary this morning. But these are the situations where you will get some commentary in the financial media about the ripple effect for Apple's suppliers. Whenever I hear that, I just think, who do you think is in charge of this relationship? Do you think it's the suppliers or do you think it's the largest company in the world by market cap? I think it's Apple.

Jim Gillies: Yeah, go back to your, what is it? The Porter's five forces, the competitive analysis from business school. The bargaining power here, Apple has it firmly under lock and key. So there might be some ripple effects, but again, I think this is a case of what is your investing mindset. Boy, right now everything is really negative, almost crushingly so. Historically though, again, the end of 2018, Q4, I write an article in 2018, the year no one made money. Apple is a quadruple from the buyout price you were paying them. Again, it was a better relative valuation thing otherwise. But it is during times when the world sucks investing-wise, that you will make your best investments historically speaking. Now, look, have the rest of your financial life ideally together. If you're running around 50K in credit card debt, stay out of the investing world. If you're looking to buy a house, please keep that money nice and safe. Look, there's some things Putin's going a little squirrelly with his stuff. I don't have, what's a guy -- I don't have a meteorite plan, I don't have a specific plan for if something truly negative happens.

I'll deal with that on that day because I don't care what your emergency fund or how much cash you have set or how you have your financial life set up. If Putin launches a broader war in Europe, we will deal with that when it comes. But in the, assuming that the crazy volatile world of the stock market is, as it ever has been with alternating periods of despair and euphoria, we are in one of the former right now. Certainly, the markets are not happy. I'm just going to say, if you've got cash on the sidelines at a time when the markets are not happy, when the news is almost overwhelmingly pessimistic, that is a great time to start adding to your investments, even if you're just an index fund investor. Especially if you got a free trading account, dribble some money in the index funds, find some companies that you know and you like, you're willing to hold for five years. I am an Apple shareholder. I have added to Apple many times over the years. We'll see where I am in terms of how far this goes down and if I have a window that I'm allowed to trade and maybe I'll add. But these are the times you want to be an investor, even though it doesn't feel like it.

Chris Hill: Jim Gillies, always great talking to you. Thanks for being here.

Jim Gillies: Thank you.

Chris Hill: When we want to talk about the future, we like to check in with industry analysts, but sometimes we like to mix it up and talk with a science fiction writer. That's where the motley part of our show comes in. Ricky Mulvey caught up with Blake Crouch, author of Upgrade, a sci-fi thriller about gene modification that's set in the near future. While he writes about science fiction, Crouch believes this story is about a future that is actually very close.

Ricky Mulvey: Writing a book takes years, you've been involved in dark matter in some capacity, I believe, since 2014, so why take the dive into genetic engineering, CRISPR, or in your book, Scythe?

Blake Crouch: Well, what I've been doing lately with my work realized recently is taking well-worn sci-fi tropes and putting my spin on them. There's been no scarcity of multiverse stories since sci-fi started getting written or time-travel stories, which Recursion basically is. The big next one for me seem to be genetic engineering. What else is more relevant to the times that we're living in what it means to be human? That's what I'm looking for when I start thinking about what my next book might be is what is this: A, something that genre may have done, things that's done well, and B, what is the emerging tech that is relevant to our lives in our world right now. Nothing seems more relevant to me than the gene modification potential that CRISPR affords us.

Ricky Mulvey: In my mind it's straight, it is a phase change for humanity in line with what the atom bomb and the internet. Do you see it in a similar way? Is that why it's more relevant to you than most other topic?

Blake Crouch: Not similar. Unless we end up destroying ourselves with nuclear weapons, which is entirely possible, CRISPR genetic modification maybe not in our lifetime, but maybe in our lifetime is the greatest invention of humanity, period. There's literally nothing. What's bigger? It's wizardry, it's rewriting our own DNA. It's magic.

Ricky Mulvey: You've mentioned in other podcasts that you see two paths for genetic engineering and your book touches on it. What do you think those two paths are and how do you think we avoid the darker one?

Blake Crouch: We avoid the darker one by talking about it, by making the public aware of it. When this book really started, when I was doing some press for Dark Matter and I was on Science Friday and said he knew what my next book should be and he was like have you heard of CRISPR? I'd heard of it, but I really didn't have a full awareness of what it was and this would have been back in 2016. I definitely didn't have enough of an awareness to try to just wing it on Sci Fri.I think that a lot of people still don't really know what it is. I think your average person. "Yeah, it's like gene modification, it's like what they do in the movie sometimes, it's like limitless."

I think it is a real responsibility of scientists, of tastemakers, of entertainers to help educate the public about this stuff because there's such a distrust from the masses I think right now with regards to scientists. I think some of that is the hangover from the way that COVID was rolled out. I understand why it was rolled out that way. I don't think it was a conspiracy, I think it was an evolving situation. People had no idea what was happening and they were reacting in real time. But the public wants science to be exact and accurate and I think there's a little bit of a distrust there. I think that the public needs to be made aware that this technology exists that right now we can edit, it's technically illegal. Embryos can be edited right now. It's highly illegal, but it can happen. This exists.

Ricky Mulvey: It's already happened. Scientists in China, I believe, edited embryos to essentially be less susceptible to getting HIV.

Blake Crouch: Exactly. Successfully and it also weirdly lowers the longevity. People aren't sure why, but that's the thing. You get an added benefit but there is a takeaway and what these are we don't know. It's not one-to-one, it's so unbelievably complicated.

Ricky Mulvey: You researched genetic engineering quite a bit and it is, there is a heaviness with talking about it that makes it intimidating. You worked with a scientist named Michael Wiles. From my understanding, he really pushed you to even go further with what CRISPR could do. How did he do that? What were your conversations with him like?

Blake Crouch: I've had subject matter experts on all my books, but I've never needed one so much and so involved as with this one because the sciences and you punch in and out of it, it's on every page. I would send them a manuscript he would redline it. What I would basically say is, "Hey, this is what I want to happen." Here's the thing. When you're a writer and you want professional scientists to weigh in your stuff, typically what they do is they try to pull you back because they want it to be accurate, they don't want you to break the test tubes. But the stuff with CRISPR is so potential laden and I found the complete opposite was the case here. Dr. Wiles was always like, "Oh, let's go bigger here. Oh no, it could actually do this." The things I didn't even realize we're already doing. It was the complete opposite of almost every other experience I've had.

Ricky Mulvey: There's possibilities where we have tiny pink gorillas, we can change our bone density possibly with CRISPR. You can even edit genes essentially to replace painkillers, to edit the sense of the pain we feel. That's the one where I see the second-order effects being particularly optimistic and dangerous.

Blake Crouch: Yes.

Ricky Mulvey: What are some of the possibilities right now from CRISPR that we're close to that you're excited about or that you're mixed on? That might be a better way of putting it.

Blake Crouch: Well, I'm really excited about the cancer treatments. I think that's hugely exciting. It's obviously a horrific disease and if that could be targeted not through chemo which often kills the subjects as much as what we're trying to eradicate. That could be a massive win and it could also be a win that gives the public a comfort level with this technology. There's still a huge backlash against like GMOs. There's a real hurdle to overcome. We can't even agree to eradicate polio still apparently. You're going to sell the public on rewriting their DNA you can imagine the conspiracy memes that are going to emerge out of this. I think knocking down cancer will be a huge win.

Ricky Mulvey: For me, it would be through epigenetics as my understanding, but you can affect the way that one experiences pain. The clinical application of that would be, hey, let's say you have a surgery. We're going to make a temporary change to your genome so you don't feel pain and then that way we don't have to prescribe you painkillers.

Blake Crouch: That's right.

Ricky Mulvey: The optimistic river of that is that, great, fewer opioids. But there's also the pessimistic part of my mind is that now you have a way of making it so people don't feel pain. I think there might be second-order effects to that that we don't know and what we don't know is what scares me about that. When you hear about a lot of these applications, I was wondering if there was one that was sticking in your mind where you felt extraordinarily mixed on.

Blake Crouch: I'm mixed on all of it because the human genome is such a miracle of complexity. It literally adapted over billions of years to combat external stimuli to survive and to work as a system. It would be us going into the source code of something like the Call of Duty and just changing a few of those ones and zeros, it's not like that, it's not actually ones and zeros. But for the metaphor, I'll go with it. The whole thing just crashes because it's so interconnected. Gene systems are not one-to-one, there's not a pain gene that we can just up or down regulate. It's 40 or 50 or 800 different genes and gene networks all working together to regulate how we experience it. The thing that's really holding us back at this point from truly mastering genome manipulation is really processing power because you need a computer. The same time we have a computer that's powerful enough to really game out our genome and to map genotype to the way it expresses. At that point, you will also have the computing power probably to solve all other things and probably invent super intelligence. It's going to be like a threshold moment.

Ricky Mulvey: Well, I think it's not just processing power, it's also stakes in the case of a lot of CRISPR treatments, you're making a permanent change to one's genome. It's not like you get a do-over I think if you screw up.

Blake Crouch: That's right. Well, there's a couple of layers of editing and the one that's really off-limits is embryonic, it's like editing human zygotes. But that's where the changes are much easier to make and much more long-lasting, to do somatic changes to adults. It's adult specimens. It's really difficult, we're already well on down the path. Yes, some things can be changed but I never read terrible sci-fi, "Oh, we're using gene modification to change the way our face looks." That's actually not the way it works. A lot of times when these experimental gene therapies are attempted out at the somatic level, there are millions of unintended consequences. Again, just complexity. We are far more complex than the most advanced quantum annealing processor that exists out there. We're a biological machine and we definitely don't have the expertise or the understanding to know how each gene system truly expresses in what we see when we we're walking around looking at our fellow human beings.

Ricky Mulvey: You and John Scholes, you have something in common when you write about fake meat in the future and that's that it's never going to taste as good as the real thing. Is that artistic license on your part or do you not imagine a future where let's say a lab-grown steak passes the meat Turing test?

Blake Crouch: The meat Turing test, I love that. I don't know, maybe it will be proved wrong, but I think it's like the uncanny valley of tastes. It's not going to taste exactly the same, I just feel like it won't. I don't feel like it's going to be the matrix when Neo is sitting there, not Neo, but the guy who turns and say, I can't tell. I know it's different but I know it's not real but just tastes through. I just don't think that's going to happen but who knows?

Ricky Mulvey: Blake Crouch, his day job, he writes philosophical thrillers. His latest book is Upgrade. Thank you for coming on Motley Fool Money.

Blake Crouch: Thanks so much, everyone.

Chris Hill: As always, people on the program may have interest in the stocks they talk about and The Motley Fool may have formal recommendations for or against, so don't buy or sell stocks based solely on what you hear. I'm Chris Hill, thanks for listening. We'll see you tomorrow.

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Making Sense of the Latest Apple-iPhone News - The Motley Fool

Gene and cell-based treatment is promising solutions for the control and cure of some chronic and life-threatening diseases such as sickle-cell disease (SCD), haemophilia, blood cancers, and HIV. Most of the current gene therapy clinical trials on SCD and HIV are conducted in North America.The treatment is either by using someone elses cells or those of the patient. Gene therapy, also called genetic engineering, involves getting ones cells (a patient), improving them either by enhancing them to fight disease or as a replacement for the diseased cells and using them to treat the disease.

Unlike in agriculture where a lot of the genetic engineering is on seed, Dr Cissy Kityo, the executive director at Joint Clinical Research Centre (JCRC) says in medicine, the human seed (ova or sperm) or the embryo is not touched.Its not about engineering custom humans as this has no current ethical basis. Therefore, it presents a new treatment paradigm, Dr Kityo says.

Gene therapy is administered once in a lifetime. Therefore, for someone with HIV, that eliminates the burden of taking ARTs. It also has the potential to save the overall healthcare cost and increase the individuals productivity.Research is ongoing to ensure this treatment is effective, safe, and free from off-target effects and any contamination.

The processDr Francis Ssali, the deputy executive director in charge of clinical care and research at JCRC, says genetic modification involves a series of processes, the first of which is to collect specialised white blood cells called T-cells and blood-forming stem cells from the patients blood.These cells are then taken to a clean medical laboratory where they are counted, checked for viability, and purified. Thereafter, the gene to correct the disease is inserted into these cells and this is done by either using special enzymes called CRISPR or by the use of self-inactivating partial viruses called Lentiviral vectors. The lentiviral vector delivers the required gene into the cells without resulting in viral infection in the patients cells, he says.

The process of introducing the corrective gene into the patients cell is called transduction and it can take between four to seven days to perform in the laboratory. Once the cells have received this gene modification, they are checked for quality and safety before they are ready for reinfusion back into the patient.In some instances, the patient is given medical treatment to enable them to receive the gene therapy cells, he adds.However, Dr Ssali says the current approaches to gene-therapy cell manufacturing are labour intensive and take a relatively long time to prepare, and require a large clean laboratory space.

Thankfully, there are newer laboratory instruments that can automate this genetic engineering work in a single closed instrument, with efficiency, he says.Uganda has 1.4 million people living with HIV and 400,000 people living with sickle cells yet adherence to medicine is inconsistent for some.Some HIV-resistant viral variants have emerged which threaten the efficacy of the treatment programme. As such, genetic engineering will be a blessing.Globally, the first-generation cure trials for HIV were done, second-generation trials are coming up and there is hope that soon a short-term cure will be got.

Ugandan perspectiveIn Uganda, Dr Ssali says the hope is that by 2030, Uganda will have controlled HIV/Aids greatly and also contributed to finding a functional cure.Dr Kityo says JCRC hopes to start HIV gene therapy trials in Uganda in 2024.The other focus is technology transfer where these gene therapy products are produced where they are needed, more efficiently, and more cost-effectively. That is why there will be more compact systems rather than the large labs, she adds.

In Africa, Uganda ranks fifth among countries with sickle cell disease and whereas bone-marrow transplants can cure SCD, only 10 percent of the eligible patients can get a matched donor. Nonetheless, with gene therapy, this will not be an issue since the patients own cells are used.Thankfully, the current gene therapy treatment technologies for HIV are the same used in sickle cell cure research. That is why preparing to address HIV also works to tackle the sickle cell disease, Dr Kityo says.

The joint Clinical Research Centre is working towards building the research teams and creating the necessary infrastructure for this novel research and clinical care. Arthur Makara, the coordinator of Uganda Biotechnology and Biosafety Consortium, calls for several partnerships because even when JCRC creates these technologies, they need help to mass produce them for a bigger population. Gene therapy only works on an individual, not on the sperm or ovary. Therefore, Dr Kityo says even after treatment, a sickle cell patient will still have sickle cell gene but normal cells in their marrow and live a normal life.

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Gene therapy brings hope to people with sickle cell, HIV - Monitor

VIRCA Plus Products KALRO Mtwapa Hannington Obiero(right) showing a section of stakeholders a cassava plantation that is in the trial field at KALRO Mtwapa. The Genetically Modified cassavas will be resistant to Cassava Mosaic Disease and Cassava brown stick disease that are a threat to the crop. [Maureen Ongala, Standard]

After 10 long years of battle between proponents and opponents of Genetically Modified (GM) crops, the government finally lifted the ban on GM organisms (GMO). In doing this, it okayed cultivation and importation offood crops and animal feeds produced through biotechnology.

This is a huge success for individuals and organisations who have been lobbying for lifting of the ban. Barely two weeks ago, in an educational workshop on agricultural biotechnology, stakeholders from Association of Kenya Feed Manufacturers (AKEFEMA) called for swift government intervention that would boost feed production and save livestock from starvation.

Kenya has had an overreliance on white maize, which is in short supply, for use in production of both animal feed and human food. As a debilitating drought rages on, putting the lives of millions of Kenyans at risk. Tens of thousands of livestock have also perished.

After feeds manufacturers complained they could not access non-GM yellow maize in the market, the government, in June 2022, allowed 26 companies to import yellow maize that is 99.1 per centnon-GM. This also proved difficult to find in the market. Animal feed continued to be scarce, with GM imports banned.

They remained optimistic that the new government would give a greenlight to import and use GM products, as they saw President William Ruto, a scientist who understands these things and expected him to do what his predecessor(s) did not. And he did just that.

Richard Oduor, a Professor of Molecular and Cell Biology currently serving at Kenyatta University as Director, Research Support and Dissemination said Dr Ruto is a scientist who had pronounced himself very positively to this technology and on that the ban would be lifted a few years ago. And on October 3, 2022. So today, we will breakdown all things GMO.

What is GMO?

Agenetically modified organism (GMO)is an animal, plant ormicrobewhose genetic makeuphas been influenced using genetic engineeringtechniques. Genes, made up of DNA (Deoxyribonucleic acid), a set of instructions that determine cell growth, division and development, can be altered.

In conventional breeding, genes from two organisms mix, creating an organism that carries the characteristics of the two parent organisms. GMOs are manufactured in a more targeted way where, in a lab, genes can be inserted into the nucleus of cells of the organisms that need the modification to pass certain characteristics aimed at making the new organism better than the original one.

The modified cell will grow and divide, withthe resulting new cells adopting the specialised functions as contained in the inserted gene. All of the organisms cells in the regenerated plant contain that new gene.

Why the resistance to GMO?

In September 2012, French molecular biologist Gilles-Eric Seralini published a research in the journalFood and Chemical Toxicology. Christened Long term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize. The research was widely disputed and was, consequently, retracted on November 28, 2013, due tostrongcriticismfrom the scientific community.

The article claimed that rats fed Roundup-resistant GM maize for two years had a higher percentage of tumours and kidney and liver damage than normal controls. The author attributed these results to the endocrine-disrupting effects of Roundup and the metabolic impact of consumption of the transgene in GM maize.

Even as many scientists faulted the research, including in an argument that the research was severely flawed on methodological and ethical grounds, fears of cancerous effects of genetically modified crops persisted. Countries quickly banned GM crops but some later dropped the ban.

How did Kenya react?

In November 2012, President Mwai Kibaki banned GM foods after Public Health minister Beth Mugo raised safety concerns. Kenya Medical Research Institute (KEMRI) had raised a concern on the potential cancerous effects of consumption of GM crops. Some experts say it was a knee-jerk, and emotional, reaction. The ban, however, stuck for nearly 10 years.

What has the authorities been doing about GM crops in Kenya?

Meanwhile, National Biosafety Authority (NBA) has approved a number of projects for contained use trials (research) that include bacterial-wilt-disease-resistant banana, insect-resistant pigeon pea, stress-tolerant cassava, nematode-resistant and virus-resistant yam, among others.

For confined-use trial, most of it being carried out at various Kenya Agriculture and Livestock Research Organisation centres, NBA has approved water-efficient/drought tolerant transgenic maize at Kiboko, virus-resistant transgenic Cassava at Alupe, vitamin-A-enhanced cassava at Alupe, Bio-fortified sorghum at Kiboko and virus- resistant cassava at Mtwapa.

For imports and transits, the authority has approved genetically modified products for importation and transboundary movement through Kenya for humanitarian assistance and relief supplies. These include: insect-resistant/herbicide-tolerant corn soya blend and insect-resistant/herbicide-tolerant maize meal.

What benefit does the country get from lifting GMO?

GMO crops are made to be pest, disease and/or drought resistant. This alleviates food shortages. The crops also grow faster, and are made to be of superior quality. Prof Oduor says GMOs are not a silver bullet but a complementary measure to ensure better food security.

There is no non-GM insulin, yet people use it without complaining. Many solutions to many conditions are out of genetic modification, he says.

How many countries in Africa grow GM crops?

According to Prof Oduor, Nigeria, Ghana, Kenya, Sudan, Ethiopia, Malawi, E-swatini and South Africa do not have a ban on growing of GM crops. Egypt backtracked after having been one of the first countries to favour GMOs, while Burkina Faso abandoned Bt cotton farming due to shorter fibre lint and ginning machines extracting proportionally less lint from harvested cotton bolls.

Why did Kenya government lift ban?

The decision, according to dispatch from the Cabinet, was reached in accordance with the recommendation of the Taskforce to Review Matters Relating to Genetically Modified Foods and Food Safety, and in fidelity with the guidelines of the NBA on all applicable international treaties including the Cartagena Protocol on Biosafety (CPB).

In accordance with the recommendation of the Task Force to Review Matters Relating to Genetically Modified Foods and Food Safety, and in fidelity with the guidelines of the National Biosafety Authority on all applicable international treaties including the Cartagena Protocol on Biosafety (CPB), Cabinet vacated its earlier decision of November 8, 2012 prohibiting the opencultivationof genetically modified crops and theimportationof food crops and animal feeds produced through biotechnology innovations; effectivelyliftingthebanon Genetically Modified Crops. By dint of the executive action opencultivationandimportationof White (GMO) Maize is now authorised, read the statement.

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Century Therapeutics, Inc.

PHILADELPHIA, Oct. 05, 2022 (GLOBE NEWSWIRE) -- Century Therapeutics(NASDAQ: IPSC), an innovative biotechnology company developing induced pluripotent stem cell (iPSC)-derived cell therapies in immuno-oncology, today announced that preclinical data from the Companys iPSC-based cell therapy platform will be presented in two posters at the Society for Immunotherapy of Cancer (SITC) 37th Annual Meeting, on November 8-12, 2022 in Boston, Massachusetts.

Details of the poster presentations are as follows:

Abstract Number:265Title:Empowering iPSC-Derived iNK Cells with Multiple Gene Edits to Improve Persistence and Anti-Tumor EfficacySession Date: Thursday, November 10, 2022Session Time:9:00 AM ET 9:00 PM ETPresenter:Buddha Gurung, PhD, Director, Cell Engineering, Century Therapeutics

Abstract Number:262Title:Multiple Targeting of Solid Tumors with iPSC-derived Gamma Delta CAR T Cells in Combination with Therapeutic Antibodies Session Date: Friday, November 11, 2022Session Time:9:00 AM ET 8:30 PM ETPresenter:Hillary Millar Quinn, Director, In Vivo Pharmacology, Century Therapeutics

About Century TherapeuticsCentury Therapeutics (NASDAQ: IPSC) is harnessing the power of adult stem cells to develop curative cell therapy products for cancer that we believe will allow us to overcome the limitations of first-generation cell therapies. Our genetically engineered, iPSC-derived iNK and iT cell product candidates are designed to specifically target hematologic and solid tumor cancers. We are leveraging our expertise in cellular reprogramming, genetic engineering, and manufacturing to develop therapies with the potential to overcome many of the challenges inherent to cell therapy and provide a significant advantage over existing cell therapy technologies. We believe our commitment to developing off-the-shelf cell therapies will expand patient access and provide an unparalleled opportunity to advance the course of cancer care. For more information on Century Therapeutics please visit http://www.centurytx.com.

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Century Therapeutics Forward-Looking StatementThis press release contains forward-looking statements within the meaning of, and made pursuant to the safe harbor provisions of, The Private Securities Litigation Reform Act of 1995. In some cases, you can identify forward-looking statements by terms such as may, might, will, should, expect, plan, aim, seek, anticipate, could, intend, target, project, contemplate, believe, estimate, predict, forecast, potential or continue or the negative of these terms or other similar expressions. These statements are not guarantees of future performance These risks and uncertainties are described more fully in the Risk Factors section of our most recent filings with the Securities and Exchange Commission and available at http://www.sec.gov. You should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in our forward-looking statements may not be achieved or occur, and actual results could differ materially from those projected in the forward-looking statements. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.

For More Information:Company: Elizabeth Krutoholow investor.relations@centurytx.comInvestors: Melissa Forst/Maghan Meyers century@argotpartners.comMedia: Joshua R. Mansbach century@argotpartners.com

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Century Therapeutics to Present at the SITC 37th Annual Meeting - Yahoo Finance

At around 7 p.m. on Dec. 19, 2020, three young adults and their teacher gathered for dinner at the restaurant of the swank 1880 club in Singapore. They ordered chicken and waffles and, on the side, chicken baos. History Made, proclaimed the menus, because those diners had eaten the worldsfirst portions of chicken meat manufactured from cells, rather than slain birds.

The location was unlikely, but no accident. After a California-based start-up, Eat Just, succeeded in cultivating chicken meat from cells, it chose Esco Aster, a Singapore-based synthetic biology (syn-bio) contract manufacturing company, to manufacture cultivated chicken nuggets andbreasts as well as shredded chicken. Then the Singapore Food Authority (SFA) gave Eat Justpermissiontoproduce small batches of cultured cells in Esco Asters food-safe bioreactors, and to sell the products locally once they had met its stringent food safety criteria. Thus, the SFAbecame theworlds first regulatory authorityto approve the sale of cultured chicken meat.

Unlikeother nations, Singapore is wooing syn-bio start-ups across the world to make the city their home base.In addition to cell-basedmeats, the government is catalyzing the manufacture of proteins from plants, algae, and fungi. Ithas set up aFuture Ready Food Safety Hubto help companies navigate its approvals process, and to speed up the launch of bio-engineered products.

Over two dozen syn-bio food companiessuch as Shiok Meats, which recently launchedthe worlds first lab-grown crab and shrimp meatshave set up shop in Singapore. Thus, the city-state, which has hardly any farmland or livestock, plans to scale new technologies tomeet its goal of producing30% of its food locally by 2030, and boost economic growth by turning intoone of the worlds firstand biggestcultivated meat exporters.

Singapore may be showing the way, but most countries, unaware of the potential of syn-bio, havent put the emergent industry at the top of their policy agendas. As a result, the syn-bio industrys growth may be getting stymied. For instance, several forecasts in 2020 suggested that cultivated meat was likely to grow into a$150 billion segmentby the end of this decade, and account for around 10% of the global meat market. Two years later, that seems unlikely, not because the technologys development has slowed but because governments have been slow to legislate, regulate, and foster the industry.

Its shocking because syn-bio products have several advantages over conventional ones. Theyre sustainable, using little, or no, water, land, or carbon-emitting materialsand much less that most traditional livestock. They promise to make humanhealth better, with new syn-bio therapies likely to vanquish many diseases. And novel products, such as soil-nourishing bacteria, will help boost agriculturalproduction manifold. In fact, the technology offers governments the ability todecouple economiesfrom global supply chains, andreduce their dependence on raw material imports.

Syn-bio is clearly the next growthfrontier, sodeveloping suitable policies will be critical to unlock its benefits. According to aBCG study,syn-bio technologiescould reshape industries that will account for nearly a third of global GDP by 2030 if governments develop the appropriate regulations and rules. Moreover, as Singapore has shown, creating the conditions in which syn-bio start-ups will flourish isnt solely the prerogative of large, industrialized countries.

Although eachnations starting point will differ, every government must tackle challenges on three fronts to benefit from syn-bio.

Governments must, first and foremost, invest in advancing nations and companies knowledge of synthetic biology, much of which is still uncharted territory. As theU.S. recently did, countries can orchestrate syn-bio research by announcing formal policies, creating budgets, and setting up national agencies to spearhead the process.

Policymakers should focus on gathering and synthesizing scientific and technical knowledge by funding basic research programs; creating R&D facilities; and catalyzing the creation of graduate and post-graduate education programs in universities and colleges. One key objective should be to create talent for applied areassuch as bioreactor builders and fermentation specialistsso that they develop efficient microorganisms that use second-generation feedstock, such as organic waste, rather than processed sugars. Another priority should be to create computing resources, in terms of people and processing power, because the amount of biological data available is fast outpacing countries processing capabilities.

Apart from creating national repositories of scientific knowledge that any individual or institution can access, governments must push for the development of open standards and protocols to facilitate knowledge dissemination. They must create trusted data-sharing platforms and partner with institutions such asiGEMandBioBricks, which have developed the Get & Give philosophy and established standards for syn-bio parts to ensure their interoperability. For instance, Googles DeepMind and its A.I.,Alpha Fold, in tandem with a European intergovernmental organization, recently made public the structures of nearly all the proteins known to science.

Nations that are starting out on syn-bio quests must harness international forums and open platforms to move up the learning curve. Syn-bio research is becoming global; in 2022, iGEMs well-known syn-bio competition saw46 countries participating, 50% of which were developing countriestwice as many as a decade ago.

Second, policymakers must support business scaling of syn-bio applications,stipulating design-to-cost milestones to ensure that the efforts develop applications that will make an impact. A recentBCG study, for instance, projected when different industries are likely to be affected by syn-bio technologies. Governments must monitor the maturity of these emerging technologies by tracking cost and scale tipping points, and develop funding roadmaps that will help grow them to commercial scale.

Co-ordination can maintain the design-to-cost focus from the get-go, and help overcome the hurdles in the way of the commercialization of syn-bio technologies. Dont forget, only a few microbes such asE. coliand common yeast have been produced at scale. Others, such as mammalian cells, havent reached that stageyet.

Because syn-bio technologies dont scale linearly, engineering and development will be crucial to make it possible. Governments must use multilateral forums to forge connections between local and global stakeholders, and use technical collaborations to reduce knowledge gaps.

Countries trying to catch up should nurture the capabilities to develop applications that have commercial precedents, such as bio-catalysts and bio-chemicals. They best ways of doing that are to both orchestrate cross-border joint ventures and technology transfers, and intensify research efforts at home. Governments would be wise to attract global investments in late-stage startups, so the latter can scale and wont need to be acquired by multinational giants.

In most countries, incubators and accelerators that have seed funds and innovative financing models will help translate research into commercial ventures, and plant the financial foundations of healthy syn-bio ecosystems. For instance, in 2014,Singapore piloted intellectual property valuations, which raised awareness about IPs use as collateral and helped create an effective syn-bio ecosystem in the city.

Finally, governments must balance the need to create a friendly regulatory environment for syn-bio ventures with the need to win a social license.People have deep suspicions about syn-bio applications, just as they have about organismswhose genetic makeup has been modified in a laboratory using genetic engineering or transgenic technology (GMOs).Policy-makersmust keep educating society about syn-bio technologys potential and risks, and gauge perceptions and acceptance of its applications, so they can make course corrections.

Stakeholders must be involved at every stage of the value chain, from lab to market, to ensure that consumers buy syn-bio products. Its smart to proactively discuss the intent of the new technology. For instance, DARPA quietly launchedInsect Allies, a $45 million project to test the ability of engineered virus-carrying insects to protect crops from pestilence, in 2016. After manyU.S. scientists criticizedthe projects intent, DARPA was forced todefend itselfby highlighting its benefits and describing the safeguards it had deployed.

Syn-bio ventures must ensure the equitable use of shared resources, such as water, if they are to retain the social license from stakeholders such as farmers and indigenous populations. When Amyris set up afermentation facility in Brazilrecently, for example, it sourced feedstock from local sugarcane farms that didnt contribute to deforestation; required minimal irrigation; and didnt suck up drinking water. Local regulators must ensure syn-bio firms adhere to rules and laws even as they engage with local communities to identify all their concerns.

Finally, governments must keep in mind that the same syn-bio products can be created in different ways, and so, the regulatory regimes will need to vary. For instance, startups such as Impossible Foods, Mosa Meat, and Meati all compete in the cultured meats market, but, because they use microbes, cells, and fungi, respectively, to develop products, they must be subject to different legal frameworks. That could create entry barriers if policy-makers dont streamline the regulatory landscape.

Just as the 1990s belonged to the Internet, the 2020s mark syn-bios coming of age. As the worlds knowledge and use of syn-bio technologies grow, governments have no choice but to develop policies that will allow the industry to flourish. Because the technology creates novel and sustainable offerings, policy-makers must come to grips with syn-bio if they wish to boost economic growth even as they safeguard the environment. Only policy-makers that seize this dual opportunity by enacting supportive policies will be able to build their nations competitive advantage for the Bio Age.

ReadotherFortunecolumns by Franois Candelon.

Franois Candelonisa managing director and senior partner at BCG and global director of the BCG Henderson Institute.

Maxime Courtauxis a project leader at BCG and ambassador at the BCG Henderson Institute.

Vinit Patelis a project leader at BCG and ambassador at the BCG Henderson Institute.

Some companies featured in this column are past or current clients of BCG.

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Cultured meat could help solve the climate crisis. Heres what it will take to move it from the lab to the dinner table - Fortune

SAN DIEGO, Oct. 5, 2022 /PRNewswire/ -- Poseida Therapeutics, Inc. (Nasdaq: PSTX), a clinical-stage biopharmaceutical company utilizing proprietary genetic engineering platform technologies to create cell and gene therapeutics with the capacity to cure, today announced that it will present a Trial in Progress poster at the upcoming Society for Immunotherapy of Cancer (SITC) Annual Meeting, being held in Boston and virtually from November 8 12, 2022.

The poster presentation will highlight the trial design, dosing regimen, and study protocol for the Company's ongoing Phase 1 clinical trial of P-MUC1C-ALLO1. The multi-center, open-label, dose escalation study is evaluating patients with locally advanced or metastatic epithelial derived solid tumors that are refractory to standard of care therapy or ineligible or refused another existing treatment. The study is following a 3+3 design and is evaluating the safety, tolerability, and preliminary efficacy of P-MUC1C-ALLO1. The Company expects to report initial clinical data from this trial by the end of 2022 or early 2023.

Details of the presentation are as follows:

Title: Phase 1 study of P-MUC1C-ALLO1 allogeneic CAR-T cells in patients with epithelial-derived cancersPresenter: Jason Henry, MD, Sarah Canon Research InstituteSession Date and Time: Poster Hall opens Friday, November 11, 2022, 9:00 AM - 8:30 PM ETAbstract Number:728Location:Boston Convention & Exhibition Center, Hall C

The poster will also be available to meeting attendees through the virtual poster hall on the SITC virtual meeting platform.

About P-MUC1C-ALLO1P-MUC1C-ALLO1 is an allogeneic CAR-T product candidate in Phase 1 development for multiple solid tumor indications. Poseida believes P-MUC1C-ALLO1 has the potential to treat a wide range of solid tumors derived from epithelial cells, such as breast, colorectal, lung, ovarian, pancreatic and renal carcinomas, as well as other cancers expressing a cancer-specific form of the Mucin 1 protein, or MUC1-C. P-MUC1C-ALLO1 is designed to be fully allogeneic, with genetic edits to eliminate or reduce both host-vs-graft and graft-vs-host alloreactivity. Poseida has demonstrated the elimination of tumor cells to undetectable levels in preclinical models of both triple-negative breast and ovarian cancer.

AboutPoseida Therapeutics, Inc.Poseida Therapeutics is a clinical-stage biopharmaceutical company dedicated to utilizing our proprietary genetic engineering platform technologies to create next generation cell and gene therapeutics with the capacity to cure. We have discovered and are developing a broad portfolio of product candidates in a variety of indications based on our core proprietary platforms, including our non-viral piggyBac DNA Delivery System, Cas-CLOVER Site-specific Gene Editing System and nanoparticle- and AAV-based gene delivery technologies. Our core platform technologies have utility, either alone or in combination, across many cell and gene therapeutic modalities and enable us to engineer our portfolio of product candidates that are designed to overcome the primary limitations of current generation cell and gene therapeutics. To learn more, visitwww.poseida.comand connect with us onTwitterandLinkedIn.

Forward-Looking Statements

Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, expected timing and plans with respect to clinical trials; the potential benefits of Poseida's technology platforms and product candidates; Poseida's plans and strategy with respect to developing its technologies and product candidates; and Poseida's ability to prioritize and utilize its resources efficiently and expected benefits from any such prioritization. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. These forward-looking statements are based upon Poseida's current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, Poseida's reliance on third parties for various aspects of its business; risks and uncertainties associated with development and regulatory approval of novel product candidates in the biopharmaceutical industry; Poseida's ability to retain key scientific or management personnel; and the other risks described in Poseida's filings with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. Poseida undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

SOURCE Poseida Therapeutics, Inc.

Original post:
Poseida Therapeutics to Present Trial in Progress Poster for Phase 1 P-MUC1C-ALLO1 Study at the Society for Immunotherapy of Cancer Annual Meeting -...

The world of science is reaching new heights. Scientists have now developed mosquitoes that will bite you but not cause malaria.

The study was conducted by a team of researchers called Transmission: Zero at the Imperial College of London. The results of the research were published in the Science Advances journal.

Genetically modified mosquitoes have the ability to slow the growth of malaria-causing parasites in their gut, an innovation that can help prevent transmission of the disease to humans.

Owing to the devastating effects of Malaria, which is putting about half of the worlds population at risk, scientists came up with this new method in the hope to deter the growth of the parasite.

Co-author of the study Dr Tibebu Habtewold, from the Department of Life Sciences at Imperial, said: Since 2015, the progress in tackling malaria has stalled. Mosquitoes and the parasites they carry are becoming resistant to available interventions such as insecticides and treatments, and funding has plateaued. We need to develop innovative new tools.

Lets take a closer look at the new research.

How was the research conducted?

Researchers from the Institute for Disease Modelling at the Bill Gates and Melinda Gates Foundation developed a model which can assess the impact of such modifications if used in a variety of African settings.

They found that the modification in question could be effective even where transmission is high.

Team Transmission: Zero engineered the mosquitoes by employing the existing gene drive technology that will spread the modification of the design and drastically cut malaria transmission.

Gene drive is one such powerful weapon that in combination with drugs, vaccines and mosquito control can help stop the spread of malaria and save human lives, study co-lead author Professor George Christophides said.

With partners in Tanzania, the team set up a facility to generate and handle genetically modified mosquitoes and conduct some first tests. These include collecting parasites from locally infected schoolchildren, to ensure the modification works against the parasites circulating in relevant communities.

The team is currently aiming to conduct field trials but will first thoroughly test the safety of the new modification before applying it for real-world tests.

How will it work?

Normally, the disease is transmitted between people after a female mosquito bites someone who is infected with the malaria parasite. It then develops into its next stage in the mosquitos gut and travels to its salivary glands, following which the mosquito becomes capable of infecting the next person it bites.

However, only around 10 per cent of mosquitoes live long enough for the parasite to develop far enough to be infectious. The team aimed to lengthen the odds even further, by extending the time it takes for the parasite to develop in the gut.

These engineered mosquitoes produce compounds that impede the growth of malaria-causing parasites, which are then unlikely to reach the mosquitoes salivary glands and be passed on in a bite before the insects die.

Under laboratory conditions, the technique proved to be an essential tool in reducing the possibility of malaria spread. If proven safe and effective in real-world settings, it could offer a powerful new tool to help eliminate malaria.

Researchers from the Transmission: Zero team, genetically modified the main malaria-carrying species of mosquito in sub-Saharan Africa, Anopheles gambiae, such that the mosquito produces antimicrobial peptides in its guts when it takes a blood meal.

By the time, the next parasite stage could reach the mosquito salivary glands, most mosquitoes in nature are expected to die.

We need to develop innovative new tools because mosquitoes and the parasites they carry are becoming resistant to available interventions such as insecticides and treatments, and funding has plateaued, said co-first author of the study, Tibebu Habtewold.

Delaying the parasites growth in the mosquito has opened many more opportunities to block malaria transmission from mosquitoes to humans, said study co-first author, Astrid Hoermann.

Will the technique be used in real-life settings?

To use genetic modification to prevent malaria spread in the real world, it needs to be spread from lab-bred mosquitoes to wild ones. According to a report by Science Daily, normal interbreeding of the mosquitoes would spread the technique only to a certain extent. Since the innovation has a fitness cost that will reduce the lifespan of mosquitoes, scientists think that it will most likely be quickly eliminated, thanks to natural selection.

The method of gene drive can be added to mosquitoes that would cause the anti-parasite genetic modification to be preferentially inherited, making it spread more widely among any natural population.

Being new, it would, however, require extremely careful planning to minimise risks before any field trials.

The Transmission: Zero team is, therefore, creating two separate but compatible strains of modified mosquitoes one with the anti-parasite modification and one with the gene drive.

They can then test the anti-parasite modification on its own first, only adding in the gene drive once it has been shown to be effective.

They are also fully risk assessing any potential releases of modified mosquitoes, taking into account any potential hazards and making sure they have buy-in from the local community. But they are hopeful that their intervention can ultimately help in eradicating malaria.

How prevalent is malaria?

According to Centres for Disease Control and Prevention (CDC), Malaria remains one of the most severe public health problems worldwide.

Nearly half the worlds population lives in areas that are at risk of malaria transmission, as per the 2021 World Malaria Report. In 2020, the disease caused around 241 million clinical episodes and 627,000 deaths. Almost 95 per cent of these deaths were reported from the African region.

With inputs from agencies

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Explained: How scientists engineered mosquitoes that will cut the transmission of malaria - Firstpost