Equity and modeling in sustainability science: Examples and opportunities throughout the process.

Equity is core to sustainability, but current interventions to enhance sustainability often fall short in adequately addressing this linkage. Models are important tools for informing action, and their development and use present opportunities to center equity in process and outcomes. This Perspective highlights progress in integrating equity into systems modeling in sustainability science, as well as key challenges, tensions, and future directions. We present a conceptual framework for equity in systems modeling, focused on its distributional, procedural, and recognitional dimensions. We discuss examples of how modelers engage with these different dimensions throughout the modeling process and from across a range of modeling approaches and topics, including water resources, energy systems, air quality, and conservation. Synthesizing across these examples, we identify significant advances in enhancing procedural and recognitional equity by reframing models as tools to explore pluralism in worldviews and knowledge systems; enabling models to better represent distributional inequity through new computational techniques and data sources; investigating the dynamics that can drive inequities by linking different modeling approaches; and developing more nuanced metrics for assessing equity outcomes. We also identify important future directions, such as an increased focus on using models to identify pathways to transform underlying conditions that lead to inequities and move toward desired futures. By looking at examples across the diverse fields within sustainability science, we argue that there are valuable opportunities for mutual learning on how to use models more effectively as tools to support sustainable and equitable futures.

Refining greenhouse gas emission factors for Indonesian peatlands and mangroves to meet ambitious climate targets.

For countries' emission-reduction efforts under the Paris Agreement to be effective, baseline emission/removals levels and reporting must be as transparent and accurate as possible. For Indonesia, which holds among the largest area of tropical peatlands and mangrove forest in the world, it is particularly important for these high-carbon ecosystems to produce high-accuracy greenhouse gas inventory and to improve national forest reference emissions level/forest reference level. Here, we highlight the opportunity for refining greenhouse gas emission factors (EF) of peatlands and mangroves and describe scientific challenges to support climate policy processes in Indonesia, where 55 to 59% of national emission reduction targets by 2030 depend on mitigation in Forestry and Other Land Use. Based on the stock-difference and flux change approaches, we examine higher-tier EF for drained and rewetted peatland, peatland fires, mangrove conversions, and mangrove on peatland to improve future greenhouse gas flux reporting in Indonesia. We suggest that these refinements will be essential to support Indonesia in achieving Forest and Other Land Use net sink by 2030 and net zero emissions targets by 2060 or earlier.

The first peoples of the Atacama Desert lived among the trees: A 11,600- to 11,200-year-old grove and congregation site.

In deserts, water has been singled out as the most important factor for choosing where to settle, but trees were likely an important part of the landscape for hunter-gatherers beyond merely constituting an economic resource. Yet, this critical aspect has not been considered archaeologically. Here, we present the results of mapping and radiocarbon dating of a truly unique archaeological record. Over 150 preserved stumps around five Late Pleistocene/Early Holocene archaeological campsites (12,800 to 11,200 cal BP) show that trees were key features in the creation of everyday habitats for the first inhabitants of the Atacama Desert. At two of these sites, QM12 and QM35, the spatial and chronological correlation between trees and hearths reveals that people located their homes under the tree canopy. At residential site QM35, artifact distribution coincides with a grove dated to ~11,600 to 11,200 cal BP. A third residential area (QM32) occurred along the grove margins ~12,000 to 11,200 cal BP. Based on the distinct cultural material of these two camps, we propose that two different groups intermittently shared this rich wetland-grove environment. The tree taxa suggest a preference for the native Schinus molle, a tree scarcely present on the landscape today, over the endemic, nitrogen-fixing Strombocarpa tamarugo, both for toolmaking and firewood and even though the S. tamarugo was locally more abundant. Together with the spatial and chronological coincidence of campsites, hearths, and trees, we propose that people spared the most abundant and resilient species to create their homes, in turn promoting fertility oases amid the Atacama's hyperaridity.

The benefits of nature exposure: The need for research that better informs implementation.

Concern about humanity's detachment from nature has spawned a global push to increase the availability of green spaces within cities. One impetus for this movement is a growing collection of studies documenting an association between improved human well-being and exposure to nature. The challenge lies in translating this research into pragmatic recommendations for cities. The usefulness of the existing research portfolio is diminished by the limitations of prevailing research designs. For example, most nature exposure studies (>80%) are observational. The rare randomized manipulative experiments tend to be indoors or virtual and rely on nature exposures on the order of ten to fifteen minutes. "Nature" and "biodiversity" are commonly invoked together as benefiting human well-being despite little evidence that biodiversity has particular importance for human psychological and emotional health. The most glaring gap in nature exposure research is the neglect of differences among cultures and ethnic groups with respect to the nature they prefer. In the few cases where researchers looked for differences among groups, they often found heterogeneous responses. Finally, few studies have compared greening interventions to other possible efforts to improve urban life. Thus, the utopian city of the future might be resplendent with urban parks on every block, but it is not clear whether those parks should offer basketball and pickleball courts, or small woodlands with a cornucopia of birds. We advocate for the next generation of nature exposure research that better informs the envisioning of our future sustainable cities with enhanced and equitable access to nature.

Reimagining infrastructure for a biodiverse future.

Civil infrastructure will be essential to face the interlinked existential threats of climate change and rising resource demands while ensuring a livable Anthropocene for all. However, conventional infrastructure planning largely neglects the contributions and maintenance of Earth's ecological life support systems, which provide irreplaceable services supporting human well-being. The stability and performance of these services depend on biodiversity, but conventional infrastructure practices, narrowly focused on controlling natural capital, have inadvertently degraded biodiversity while perpetuating social inequities. Here, we envision a new infrastructure paradigm wherein biodiversity and ecosystem services are a central objective of civil engineering. In particular, we reimagine infrastructure practice such that 1) ecosystem integrity and species conservation are explicit objectives from the outset of project planning; 2) infrastructure practices integrate biodiversity into diverse project portfolios along a spectrum from conventional to nature-based solutions and natural habitats; 3) ecosystem functions reinforce and enhance the performance and lifespan of infrastructure assets; and 4) civil engineering promotes environmental justice by counteracting legacies of social inequity in infrastructure development and nature conservation. This vision calls for a fundamental rethinking of the standards, practices, and mission of infrastructure development agencies and a broadening of scope for conservation science. We critically examine the legal and professional precedents for this paradigm shift, as well as the moral and economic imperatives for manifesting equitable infrastructure planning that mainstreams biodiversity and nature's benefits to people. Finally, we set an applied research agenda for supporting this vision and highlight financial, professional, and policy pathways for achieving it.

Megaherbivores modify forest structure and increase carbon stocks through multiple pathways.

Megaherbivores have pervasive ecological effects. In African rainforests, elephants can increase aboveground carbon, though the mechanisms are unclear. Here, we combine a large unpublished dataset of forest elephant feeding with published browsing preferences totaling nearly 200,000 records covering >800 plant species and with nutritional data for 145 species. Elephants increase carbon stocks by: 1) promoting high wood density trees via preferential browsing on leaves from low wood density species, which are more palatable and digestible; and 2) dispersing seeds of trees that are relatively large and have the highest average wood density among tree guilds based on dispersal mode. Loss of forest elephants could cause an increase in abundance of fast-growing low wood density trees and a 6% to 9% decline in aboveground carbon stocks due to regeneration failure of elephant-dispersed trees. These results demonstrate the importance of megaherbivores for maintaining diverse, high-carbon tropical forests. Successful elephant conservation will contribute to climate mitigation at a globally-relevant scale.

Unraveling complex causal processes that affect sustainability requires more integration between empirical and modeling approaches.

Scientists seek to understand the causal processes that generate sustainability problems and determine effective solutions. Yet, causal inquiry in nature-society systems is hampered by conceptual and methodological challenges that arise from nature-society interdependencies and the complex dynamics they create. Here, we demonstrate how sustainability scientists can address these challenges and make more robust causal claims through better integration between empirical analyses and process- or agent-based modeling. To illustrate how these different epistemological traditions can be integrated, we present four studies of air pollution regulation, natural resource management, and the spread of COVID-19. The studies show how integration can improve empirical estimates of causal effects, inform future research designs and data collection, enhance understanding of the complex dynamics that underlie observed temporal patterns, and elucidate causal mechanisms and the contexts in which they operate. These advances in causal understanding can help sustainability scientists develop better theories of phenomena where social and ecological processes are dynamically intertwined and prior causal knowledge and data are limited. The improved causal understanding also enhances governance by helping scientists and practitioners choose among potential interventions, decide when and how the timing of an intervention matters, and anticipate unexpected outcomes. Methodological integration, however, requires skills and efforts of all involved to learn how members of the respective other tradition think and analyze nature-society systems.

Detection of Gastrointestinal Bleeding with Large Language Models to Aid Quality Improvement and Appropriate Reimbursement.

BACKGROUND & AIMS: Early identification and accurate characterization of overt gastrointestinal bleeding (GIB) enables opportunities to optimize patient management and ensures appropriately risk-adjusted coding for claims-based quality measures and reimbursement. Recent advancements in generative artificial intelligence, particularly large language models (LLMs), create opportunities to support accurate identification of clinical conditions. In this study, we present the first LLM-based pipeline for identification of overt GIB in the electronic health record (EHR). We demonstrate two clinically relevant applications: the automated detection of recurrent bleeding and appropriate reimbursement coding for patients with GIB. METHODS: Development of the LLM-based pipeline was performed on 17,712 nursing notes from 1,108 patients who were hospitalized with acute GIB and underwent endoscopy in hospital from 2014 to 2023. The pipeline was used to train an EHR-based machine learning model for detection of recurrent bleeding on 546 patients presenting to two hospitals and externally validated on 562 patients presenting to four separate hospitals. The pipeline was used to develop an algorithm for appropriate reimbursement coding on 7,956 patients who underwent endoscopy in hospital from 2019 to 2023. RESULTS: The LLM-based pipeline accurately detected melena (positive predictive value=0.972; sensitivity=0.900), hematochezia (0.900; 0.908), and hematemesis (0.859; 0.932). The EHR-based machine learning model identified recurrent bleeding with AUC=0.986, sensitivity=98.4%, and specificity=97.5%. The reimbursement coding algorithm resulted in an average per-patient reimbursement increase of $1,299 to 3,247 with a total difference of $697,460 to $1,743,649. CONCLUSION: An LLM-based pipeline can robustly detect overt GIB in the EHR with clinically relevant applications in detection of recurrent bleeding and appropriate reimbursement coding.

Topological defect-mediated morphodynamics of active-active interfaces.

Physical interfaces widely exist in nature and engineering. Although the formation of passive interfaces is well elucidated, the physical principles governing active interfaces remain largely unknown. Here, we combine simulation, theory, and cell-based experiment to investigate the evolution of an active-active interface. We adopt a biphasic framework of active nematic liquid crystals. We find that long-lived topological defects mechanically energized by activity display unanticipated dynamics nearby the interface, where defects perform "U-turns" to keep away from the interface, push the interface to develop local fingers, or penetrate the interface to enter the opposite phase, driving interfacial morphogenesis and cross-interface defect transport. We identify that the emergent interfacial morphodynamics stems from the instability of the interface and is further driven by the activity-dependent defect-interface interactions. Experiments of interacting multicellular monolayers with extensile and contractile differences in cell activity have confirmed our predictions. These findings reveal a crucial role of topological defects in active-active interfaces during, for example, boundary formation and tissue competition that underlie organogenesis and clinically relevant disorders.

Synergistic dual conversion reactions assisting Pb-S electrochemistry for energy storage.

SignificanceBased on the analysis of three thermodynamic parameters of various M-S systems (solubility of metal sulfides [MxSy] in aqueous solution, volume change of the metal-sulfur [M-S] battery system, and the potential of S/MxSy cathode redox couple), an aqueous Pb-S battery operated by synergistic dual conversion reactions (cathode: S⇄PbS, anode: Pb2+⇄PbO2) has been officially reported. Benefitting from the inherent insolubility of PbS and a conversion-type counter electrode, the aqueous Pb-S battery exhibited two advantages: it is shuttle effect free and has a dendrite-free nature. Moreover, the practical value of the Pb-S battery was further certified by the prototype S|Pb(NO3)2ǁZn(NO3)2|Zn hybrid cell, which afforded an energy density of 930.9 Wh kg-1sulfur.

Financing conservation by valuing carbon services produced by wild animals.

Filling the global biodiversity financing gap will require significant investments from financial markets, which demand credible valuations of ecosystem services and natural capital. However, current valuation approaches discourage investment in conservation because their results cannot be verified using market-determined prices. Here, we bridge the gap between finance and conservation by valuing only wild animals' carbon services for which market prices exist. By projecting the future path of carbon service production using a spatially explicit demographic model, we place a credible value on the carbon capture services produced by African forest elephants. If elephants were protected, their services would be worth $20.8 billion ($10.3 to $29.7 billion) and $25.9 billion ($12.8 to $37.6 billion) for the next 10 and 30 y, respectively, and could finance antipoaching and conservation programs. Elephant population growth would generate a carbon sink of 109 MtC (64 to 153) across tropical Africa in the next 30 y. Avoided elephant extinction would also prevent the loss of 93 MtC (46 to 130), which is the contribution of the remaining populations. Uncertainties in our projections are controlled mainly by forest regeneration rates and poaching intensity, which indicate that conservation can actively reduce uncertainty for increased financial and biodiversity benefits. Our methodology can also place lower bounds on the social cost of nature degradation. Poaching would result in $2 to $7 billion of lost carbon services within the next 10 to 30 y, suggesting that the benefits of protecting elephants far outweigh the costs. Our methodology enables the integration of animal services into global financial markets with major implications for conservation, local socioeconomies, and conservation.

Changes in frailty and incident cardiovascular disease in three prospective cohorts.

BACKGROUND AND AIMS: Previous studies found that frailty was an important risk factor for cardiovascular disease (CVD). However, previous studies only focused on baseline frailty status, not taking into consideration the changes in frailty status during follow-up. The aim of this study was to investigate the associations of changes in frailty status with incident CVD. METHODS: This study used data of three prospective cohorts: China Health and Retirement Longitudinal Study (CHARLS), English Longitudinal Study of Ageing (ELSA), and Health and Retirement Study (HRS). Frailty status was evaluated by the Rockwood frailty index and classified as robust, pre-frail, or frail. Changes in frailty status were assessed by frailty status at baseline and the second survey which was two years after the baseline. Cardiovascular disease was ascertained by self-reported physician-diagnosed heart disease (including angina, heart attack, congestive heart failure, and other heart problems) or stroke. Cox proportional hazard models were used to calculate the hazard ratio (HR) and 95% confidence interval (95% CI) after adjusting for potential confounders. RESULTS: A total of 7116 participants from CHARLS (female: 48.6%, mean age: 57.4 years), 5303 from ELSA (female: 57.7%, mean age: 63.7 years), and 7266 from HRS (female: 64.9%, mean age: 65.1 years) were included according to inclusion and exclusion criteria. The median follow-up periods were 5.0 years in the CHARLS, 10.7 years in the ELSA, and 9.5 years in the HRS. Compared with stable robust participants, robust participants who progressed to pre-frail or frail status had increased risks of incident CVD (CHARLS, HR = 1.84, 95% CI: 1.54-2.21; ELSA, HR = 1.53, 95% CI: 1.25-1.86; HRS, HR = 1.59, 95% CI: 1.31-1.92). In contrast, frail participants who recovered to robust or pre-frail status presented decreased risks of incident CVD (CHARLS, HR = 0.62, 95% CI: 0.47-0.81; ELSA, HR = 0.49, 95% CI: 0.34-0.69; HRS, HR = 0.70, 95% CI: 0.55-0.89) when compared with stable frail participants. These decreased risks of incident CVD were also observed in pre-frail participants who recovered to robust status (CHARLS, HR = 0.66, 95% CI: 0.52-0.83; ELSA, HR = 0.65, 95% CI: 0.49-0.85; HRS, HR = 0.71, 95% CI: 0.56-0.91) when compared with stable pre-frail participants. CONCLUSIONS: Different changes in frailty status are associated with different risks of incident CVD. Progression of frailty status increases incident CVD risks, while recovery of frailty status decreases incident CVD risks.

The global value of freshwater lakes.

Lakes face threats from human activities like unsustainable development, population growth and industrial technologies. These challenges impact the ecosystem services of lakes. Research has assessed the monetary value of services from freshwater biomes annually. This article reviews these values, estimating lakes' global ecosystem services to be within the region of USD 1.3-5.1 trillion annually. Their natural asset value is estimated at USD 87-340 trillion, comparable to the monetary value of global real estate, assuming a relatively high social discount rate to account for future increased standards of living. Considering environmental degradation, future generations may experience a lower living standard. Using a 0.1% discount rate, recognizing potential harm and aligning with indigenous values raises the lakes' value to USD 1300-5100 trillion, which is at least equal to the global monetary value of wealth created. This valuation is shared by all as a collective asset, unlike the skewed distribution of created wealth.

Principles for area-based biodiversity conservation.

Recent international agreements have strengthened and expanded commitments to protect and restore native habitats for biodiversity protection ("area-based biodiversity conservation"). Nevertheless, biodiversity conservation is hindered because how such commitments should be implemented has been strongly debated, which can lead to suboptimal habitat protection decisions. We argue that, despite the debates, there are three essential principles for area-based biodiversity conservation. These principles are related to habitat geographic coverage, amount, and connectivity. They emerge from evidence that, while large areas of nature are important and must be protected, conservation or restoration of multiple small habitat patches is also critical for global conservation, particularly in regions with high land use. We contend that the many area-based conservation initiatives expected in the coming decades should follow the principles we identify, regardless of ongoing debates. Considering the importance of biodiversity for maintenance of ecosystem services, we suggest that this would bring widespread societal benefits.

A perspective on epigenomic aging processes in the human brain and their plasticity in patients with mental disorders - a systematic review.

The debate surrounding nature versus nurture remains a central question in neuroscience, psychology, and in psychiatry, holding implications for both aging processes and the etiology of mental illness. Epigenetics can serve as a bridge between genetic predisposition and environmental influences, thus offering a potential avenue for addressing these questions. Epigenetic clocks, in particular, offer a theoretical framework for measuring biological age based on DNA methylation signatures, enabling the identification of disparities between biological and chronological age. This structured review seeks to consolidate current knowledge regarding the relationship between mental disorders and epigenetic age within the brain. Through a comprehensive literature search encompassing databases such as EBSCO, PubMed, and ClinicalTrials.gov, relevant studies were identified and analyzed. Studies that met inclusion criteria were scrutinized, focusing on those with large sample sizes, analyses of both brain tissue and blood samples, investigation of frontal cortex markers, and a specific emphasis on schizophrenia and depressive disorders. Our review revealed a paucity of significant findings, yet notable insights emerged from studies meeting specific criteria. Studies characterized by extensive sample sizes, analysis of brain tissue and blood samples, assessment of frontal cortex markers, and a focus on schizophrenia and depressive disorders yielded particularly noteworthy results. Despite the limited number of significant findings, these studies shed light on the complex interplay between epigenetic aging and mental illness. While the current body of literature on epigenetic aging in mental disorders presents limited significant findings, it underscores the importance of further research in this area. Future studies should prioritize large sample sizes, comprehensive analyses of brain tissue and blood samples, exploration of specific brain regions such as the frontal cortex, and a focus on key mental disorders. Such endeavors will contribute to a deeper understanding of the relationship between epigenetic aging and mental illness, potentially informing novel diagnostic and therapeutic approaches.

Norcantharidin Enhances the Antitumor Effect of 5-Fluorouracil by Inducing Apoptosis of Cervical Cancer Cells: Network Pharmacology, Molecular Docking, and Experimental Validation.

The high recurrence rate of cervical cancer is a leading cause of cancer deaths in women. 5-Fluorouracil (5-FU) is an antitumor drug used to treat many types of cancer, but its diminishing effectiveness and side effects limit its use. Norcantharidin (NCTD), a demethylated derivative of cantharidin, exhibits various biological activities. Here, we investigated whether NCTD could potentiate 5-FU to induce cervical cancer cell death. To assess the cell viability and synergistic effects of the drugs, cell counting kit-8 and colony formation assays were performed using HR-HPV-positive cervical cancer cell lines. Annexin V-FITC/PI staining and TUNEL assays were performed to confirm the induction of apoptosis. The synergistic effect of NCTD on the antitumor activity of 5-FU was analyzed using network pharmacology, molecular docking, and molecular dynamics simulations. Apoptosis-related proteins were examined using immunoblotting. The combination of NCTD and 5-FU was synergistic in cervical cancer cell lines. Network pharmacological analysis identified 10 common targets of NCTD and 5-FU for cervical cancer treatment. Molecular docking showed the strong binding affinity of both compounds with CA12, CASP9, and PTGS1. Molecular dynamics simulations showed that the complex system of both drugs with caspase-9 could be in a stable state. NCTD enhanced 5-FU-mediated cytotoxicity by activating apoptosis-related proteins. NCTD acts synergistically with 5-FU to inhibit cervical cancer cell proliferation. NCTD enhances 5-FU-induced apoptosis in cervical cancer cell lines via the caspase-dependent pathway.

Sepsis induced dysfunction of liver type 1 innate lymphoid cells.

BACKGROUND: Sepsis is a life-threatening condition triggered by uncontrolled immune responses to infection, leading to widespread inflammation, tissue damage, organ dysfunction, and potentially death. The liver plays a crucial role in the immune response during sepsis, serving as a major site for immune cell activation and cytokine production. Liver type 1 innate lymphoid cells (ILCs) consist of NK cells and ILC1s. They maintain the local immune microenvironment by directly eliminating target cells and secreting cytokines. However, the specific roles and pathological changes of liver-resident NK cells and ILC1s during sepsis remain poorly understood. RESULTS: This study aims to investigate the pathological changes of NK cells and ILC1s, which might contribute the dysfunction of liver. Sepsis mouse model was established by cecal ligation and puncture (CLP). Mouse immune cells from liver were isolated, and the surface makers, gene expression profiles, cytokine response and secretion, and mitochondrial function of NK (Natural Killer) cells and ILC1s (Innate Lymphoid Cell 1) were analyzed. A significant decrease in the number of mature NK cells was observed in the liver after CLP. Furthermore, the secretion of interferon-gamma (IFN-γ) was found to be reduced in spleen and liver NK cells when stimulated by IL-18. Mitochondrial activities in both liver NK cells and ILC1 were found to be increased during sepsis, suggesting an enhanced metabolic response in these cells to combat the infection. However, despite this heightened activity, liver NK cells exhibited a decreased level of cytotoxicity, which might impact their ability to target infected cells effectively. RNA sequencing supported and provided the potential mechanisms for the proinflammatory effects and exhaustion like phenotypes of liver NK cells. CONCLUSIONS: Sepsis induces dysfunction and exhaustion-like phenotypes in liver NK cells and ILC1, which might further impair other immune cells and represent a potential therapeutic target for sepsis.

A century of wild bee sampling: historical data and neural network analysis reveal ecological traits associated with species loss.

We analysed the wild bee community sampled from 1921 to 2018 at a nature preserve in southern Michigan, USA, to study long-term community shifts in a protected area. During an intensive survey in 1972 and 1973, Francis C. Evans detected 135 bee species. In the most recent intensive surveys conducted in 2017 and 2018, we recorded 90 species. Only 58 species were recorded in both sampling periods, indicating a significant shift in the bee community. We found that the bee community diversity, species richness and evenness were all lower in recent samples. Additionally, 64% of the more common species exhibited a more than 30% decline in relative abundance. Neural network analysis of species traits revealed that extirpation from the reserve was most likely for oligolectic ground-nesting bees and kleptoparasitic bees, whereas polylectic cavity-nesting bees were more likely to persist. Having longer phenological ranges also increased the chance of persistence in polylectic species. Further analysis suggests a climate response as bees in the contemporary sampling period had a more southerly overall distribution compared to the historic community. Results exhibit the utility of both long-term data and machine learning in disentangling complex indicators of bee population trajectories.

Rational design of a bacterial import system for new-to-nature molecules.

Integration of novel compounds into biological processes holds significant potential for modifying or expanding existing cellular functions. However, the cellular uptake of these compounds is often hindered by selectively permeable membranes. We present a novel bacterial transport system that has been rationally designed to address this challenge. Our approach utilizes a highly promiscuous sulfonate membrane transporter, which allows the passage of cargo molecules attached as amides to a sulfobutanoate transport vector molecule into the cytoplasm of the cell. These cargoes can then be unloaded from the sulfobutanoyl amides using an engineered variant of the enzyme γ-glutamyl transferase, which hydrolyzes the amide bond and releases the cargo molecule within the cell. Here, we provide evidence for the broad substrate specificity of both components of the system by evaluating a panel of structurally diverse sulfobutanoyl amides. Furthermore, we successfully implement the synthetic uptake system in vivo and showcase its functionality by importing an impermeant non-canonical amino acid.

Combinatorial biosynthesis in yeast leads to over 200 diterpenoids.

Diterpenoids form a diverse group of natural products, many of which are or could become pharmaceuticals or industrial chemicals. The modular character of diterpene biosynthesis and the promiscuity of the enzymes involved make combinatorial biosynthesis a promising approach to generate libraries of diverse diterpenoids. Here, we report on the combinatorial assembly in yeast of ten diterpene synthases producing (+)-copalyl diphosphate-derived backbones and four cytochrome P450 oxygenases (CYPs) in diverse combinations. This resulted in the production of over 200 diterpenoids. Based on literature and chemical database searches, 162 of these compounds can be considered new-to-Nature. The CYPs accepted most substrates they were given but remained regioselective with few exceptions. Our results provide the basis for the systematic exploration of the diterpenoid chemical space in yeast using sequence databases.