Lila Sciences

Tryptophan-drived neuroactive compounds, including serotonin, melatonin, 5-hydroxytryptophan (5-HTP), psilocybin, and related indole derivatives, represent an important class of therapeutics for depression and other neuropsychiatric disorders. However, conventional production through chemical synthesis or natural extraction remains limited by low sustainability, poor selectivity, and high manufacturing costs. Advances in synthetic biology, metabolic engineering, and enzyme engineering have enabled the development of microbial cell factories for the efficient biosynthesis of these high-value compounds. This Review highlights recent progress in engineering microbial platforms for antidepressant tryptophan derivatives, focusing on tryptophan overproduction, hydroxylation biocatalysts, downstream biosynthetic pathways, and cofactor engineering. We further discuss the emerging roles of bacterial heme-dependent tryptophan hydroxylases and AI-assisted enzyme and pathway engineering in expanding the biosynthetic toolbox. Finally, we outline current challenges and future opportunities for integrating intelligent strain design with advanced bioprocess engineering to advance the biomanufacturing of tryptophan-derived neuroactives.

Heart failure (HF) is a common condition with substantial geographical variation in its prevalence and underlying etiologies. Consistent and comparable data on the burden of HF within populations are needed to inform health system priorities. To estimate the global burden of HF. This cross-sectional study estimates disease burden using Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) methodologies to integrate multiple information sources. Data come from 204 countries and territories from 1990 to 2023 representing the global population with prevalent HF. HF and underlying etiologies. Estimates with 95% uncertainty intervals (UIs) for the prevalence and years lived with disability (YLDs) for HF by age, sex, location, year, and underlying etiology. Globally, there were 56.0 million (95% UI, 49.9-62.2 million) estimated cases of HF in 2023. The estimated prevalence of HF generally increased with age for all locations. While ischemic heart disease and hypertensive heart disease were the 2 most common etiologies globally among older adults, there was substantial variation in etiological pattern by location and age. Congenital heart anomalies and rheumatic heart disease (RHD) were common etiologies in children and young adults, while the proportion of HF due to alcohol use peaked in middle adulthood. Location-specific estimates highlighted regions with higher burden of HF due to specific etiologies, including RHD (south Asia, east Asia, Oceania, southeast Asia, central sub-Saharan Africa, eastern sub-Saharan Africa, southern sub-Saharan Africa, and western sub-Saharan Africa), alcohol use (eastern Europe, Australasia, the Caribbean, and central Europe), and Chagas disease (southern, Andean, tropical, and central Latin America). Heart failure is a significant global public health burden, and the impact is likely to increase as populations age. However, most HF etiologies can be prevented by interventions that reduce exposure to modifiable risk factors, such as elevated blood pressure, excessive alcohol consumption, and tobacco use. Etiology- and location-specific estimates can provide necessary information for public health officials to determine how best to prioritize interventions to reduce HF disease burden.

Despite a general improvement in the HIV burden over the past two decades, gendered social determinants including intimate partner violence (IPV) continue to affect women's vulnerability to HIV, which could be further exacerbated as resources dwindle over the coming years. Our study aimed to quantify recent trends in the HIV burden, the magnitude of the HIV burden associated with IPV, and the potential impact of declining financial support globally. Using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 framework, we estimated annual HIV incidence, prevalence, and mortality for 204 countries and territories from 1990 to 2023, disaggregated by age and sex. Input data included national HIV programme reports, population-based serosurveys, clinical and vital registration data, and systematically reviewed literature. Countries and territories were grouped according to the availability and completeness of HIV prevalence and mortality data, with tailored modelling approaches applied for each group. To characterise the potential contributions of IPV to the HIV burden, time series estimates of IPV prevalence by location and effect size estimates were combined to generate population attributable fractions of the HIV burden. To forecast future trends and assess the potential impact of reductions in development assistance for health, we used a non-parametric stochastic frontier approach to estimate how funding levels could affect antiretroviral therapy (ART) coverage. Adjustments in future ART coverage were integrated into our forecasts, altering projected rates of HIV-related incidence and mortality. We compared scenarios with and without funding cuts, quantifying the potential epidemiological effects of reduced ART availability by sex. Between 2003 and 2023, the annual number of new HIV infections declined globally, from 2·85 million (95% uncertainty interval [UI] 2·76-2·96) to 2·06 million (1·88-2·29). Meanwhile, HIV-related deaths decreased from a peak of 1·71 million (1·61-1·83) in 2004 to 0·83 million (0·73-0·96) in 2023. The number of people living with HIV rose from 26·3 million (25·5-27·3) in 2003 to 42·4 million (40·3-44·4) in 2023, reflecting improved survival associated with ART expansion. Although females continued to have higher prevalence of HIV than males in 2023 (23·4 million [22·2-24·6] vs 19·1 million [17·6-20·5]), the gap in incidence between females and males has substantially declined. Regionally, sub-Saharan Africa had the greatest declines in both incidence (64·3%; 58·0-68·6) and mortality (74·6%; 70·4-78·5) between 2003 and 2023, while central Europe, eastern Europe, and central Asia recorded the highest increases in incidence rates (232·1%; 146·5-299·1) and mortality rates (37·8%; 31·2-45·5) during this period. IPV was associated with an estimated 10·7% (1·6-20·4) of HIV-related deaths among females aged 15 years and older globally in 2023, corresponding to 40 700 (6400-80 600) deaths, with the highest population attributable fractions observed in Oceania (17·4%; 2·8-33·1), central sub-Saharan Africa (14·2%; 2·1-29·4), and eastern sub-Saharan Africa (13·2%; 2·0-25·3). Forecasts indicate that funding reductions could decrease ART coverage by 8·1% globally between 2025 and 2030, resulting in approximately 1·6 million new HIV infections among females and 1·3 million new HIV infections among males, alongside 790 600 and 670 600 HIV-related deaths, respectively. These impacts are primarily concentrated in sub-Saharan Africa. Despite two decades of substantial progress, the global HIV response remains highly sensitive to gendered social determinants and funding stability. The potential contribution of IPV to HIV-related mortality among women underscores the need for integrated interventions that address violence prevention and post-violence care alongside HIV treatment. The projected effects of funding cuts-millions of additional infections and deaths-highlight the fragility of the gains achieved and the urgent need to protect HIV financing. Achieving and sustaining the UNAIDS 2030 targets will require renewed investment, gender-responsive programming, and resilient health systems capable of providing equitable access to care. Gates Foundation and the US National Institute of Allergy and Infectious Diseases.

Endoscopic full-thickness resection (EFTR) has emerged as a minimally invasive treatment for small gastrointestinal subepithelial neoplasms (SETs). In particular, the development of novel closure methods such as clip-line and various endoscopic suturing techniques has enabled the secure closure of any resultant defects. During the Advanced Therapeutic Endoscopy session at the Endoscopic Forum Japan 2025, we summarized the current status of EFTR for SETs and discussed future clinical applications for epithelial neoplasms from oncological and technical perspectives. Although predominantly documented in gastric subepithelial neoplasms, EFTR is also used to treat select esophageal, duodenal, and colorectal SETs. While extensively evaluated for gastric gastrointestinal stromal tumors (GISTs), relatively low R0 resection rates have limited its broader clinical adoption; however, the novel no-touch EFTR technique could overcome this challenge and facilitate the adoption of this procedure for small gastric GISTs. Applying EFTR to epithelial tumors requires strict assessment of oncological clearance, given the risks of lymph node metastasis and peritoneal seeding following full-thickness breaches. At the end of the session, we voted on the appropriateness of EFTR for epithelial neoplasms across different organs, balancing oncological risks against technical feasibility. All nine participants (100%) supported EFTR for rectal lesions, and eight (89%) supported its use for gastric lesions. Future investigations and technical innovations are required to expand the clinical indications for EFTR in epithelial neoplasms.

To advance the computational simulation of cellular life, we propose a virtual yeast, an artificial intelligence (AI)-driven agent that models eukaryotic cellular behaviours by integrating multimodal biological data, mechanistic reasoning and active experimentation using Saccharomyces cerevisiae as a genetically tractable and data-rich model system. Cellular complexity is decomposed into eight function-centred modules, spanning genetic, metabolic and structural systems, each realized as a domain-specific AI tool coordinated through a large language model-based orchestration layer. Built on three data pillars, namely, mechanistic knowledge, subcellular architecture and dynamic states, the system integrates representation learning and generative modelling within a closed-loop learning pipeline that autonomously designs and executes experiments. The virtual yeast serves as both a conceptual and an operational platform to optimize biosynthetic pathways, support the generation and prioritization of hypotheses across diverse cellular processes, and accelerate target discovery. By coupling biological realism with autonomous AI reasoning, the virtual yeast establishes a generalizable blueprint for constructing virtual eukaryotic cells and advancing synthetic biology.

Enhancers are key regulators of mammalian gene expression, yet how they interact with promoters in space (contact vs. action-at-a-distance) and in time (transient vs. stable) remains poorly understood. Recent studies suggest that enhancers can activate promoters across distances exceeding 200 nanometers, challenging classical contact models, but limited spatiotemporal resolution has obscured the mechanistic details of enhancer-promoter (E-P) interactions and their link to transcription. Here, we engineered a synthetic biology platform optimized for the simultaneous visualization of E-P 3D distance and nascent transcription using super-resolution live-cell imaging. By applying five complementary approaches integrating imaging, 3D genomics, and gene expression data across cell lines, we estimate that transcriptional activation is mediated by ~25-42 nanometer contacts on the seconds timescale. Our results support a transient contact mechanism for E-P-mediated gene activation.

Microbial cell factories represent sustainable platforms for the production of fuels, chemicals, and therapeutics, but their development is limited by challenges in pathway discovery, enzyme optimization, and metabolic regulation. Recent advances in artificial intelligence and machine learning are reshaping this field by enabling predictive pathway design, enhanced protein engineering, and dynamic network regulation. Emerging strategies such as graph neural networks, generative models, and reinforcement learning (RL) now allow systematic exploration of vast design spaces with enhanced accuracy and scalability. This review highlights recent advancements in microbial engineering. It discusses how AI-driven frameworks are advancing the field from experience-guided and rule-based engineering toward data-driven, model-assisted, and increasingly autonomous workflows. These changes lay the foundation for next-generation biomanufacturing.