The evolution of pathway enzymes enhances the biosynthesis of high-value chemicals, crucial for pharmaceutical, and agrochemical applications. However, unpredictable evolutionary landscapes of pathway genes often hinder successful evolution. Here, the presence of complex epistasis is identifued within the representative naringenin biosynthetic pathway enzymes, hampering straightforward directed evolution. Subsequently, a biofoundry-assisted strategy is developed for pathway bottlenecking and debottlenecking, enabling the parallel evolution of all pathway enzymes along a predictable evolutionary trajectory in six weeks. This study then utilizes a machine learning model, ProEnsemble, to further balance the pathway by optimizing the transcription of individual genes. The broad applicability of this strategy is demonstrated by constructing an Escherichia coli chassis with evolved and balanced pathway genes, resulting in 3.65 g L-1 naringenin. The optimized naringenin chassis also demonstrates enhanced production of other flavonoids. This approach can be readily adapted for any given number of enzymes in the specific metabolic pathway, paving the way for automated chassis construction in contemporary biofoundries.

Multi-year El Niño events induce severe and persistent floods and droughts worldwide, with significant socioeconomic impacts, but the causes of their long-lasting behaviors are still not fully understood. Here we present a two-way feedback mechanism between the tropics and extratropics to argue that extratropical atmospheric variability associated with the North Pacific Oscillation (NPO) is a key source of multi-year El Niño events. The NPO during boreal winter can trigger a Central Pacific El Niño during the subsequent winter, which excites atmospheric teleconnections to the extratropics that re-energize the NPO variability, then re-triggers another El Niño event in the following winter, finally resulting in persistent El Niño-like states. Model experiments, with the NPO forcing assimilated to constrain atmospheric circulation, reproduce the observed connection between NPO forcing and the occurrence of multi-year El Niño events. Future projections of Coupled Model Intercomparison Project phases 5 and 6 models demonstrate that with enhanced NPO variability under future anthropogenic forcing, more frequent multi-year El Niño events should be expected. We conclude that properly accounting for the effects of the NPO on the evolution of El Niño events may improve multi-year El Niño prediction and projection.