AbstractTo 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.This is a preview of subscription content, access via your institutionAccess optionsAccess Nature and 54 other Nature Portfolio journalsGet Nature+, our best-value online-access subscription27,99 € / 30 dayscancel any timeLearn moreSubscribe to this journalReceive 52 print issues and online access199,00 € per yearonly 3,83 € per issueLearn moreBuy this articlePurchase on SpringerLinkInstant access to the full article PDF.39,95 €Prices may be subject to local taxes which are calculated during checkoutFig. 1: Conceptual roadmap of the virtual yeast AI agent.Fig. 2: Architectural framework for each functional module of the virtual yeast agent.Fig. 3: Closed-loop active learning drives iterative refinement of virtual yeast models.ReferencesAbramson, J. et al. 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U24A20476 and 92259201); the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0533300); the National Key R&D Program of China (grant nos. 2022YFF0608403 and 2020YFE0202200); the National Natural Science Foundation of China (32088101); the ‘Pioneer’ and ‘Leading Goose’ R&D Program of Zhejiang (grant no. 2023C03056); the State Key Laboratory of Medical Proteomics (SKLP-K202406); the Shanghai Municipal Science and Technology Major Project (2025SHZDZX026D07); the Zhejiang Provincial Natural Science Foundation of China (LMS26C050002 and LQ24C050002); and the National Natural Science Foundation of China (grant no. 32401239). Funding was provided by the State Key Laboratory of Medical Proteomics (SKLP-Y202403); the National Natural Science Foundation of China (12288101, 8206100646 and T2321001); the Clinical Medicine Plus X-Young Scholars Project, Peking University; the Fundamental Research Funds for the Central Universities (PKU2025PKULCXQ031); SNF Sinergia (CRSII5_189952); Novartis Forschungsstiftung (FN24-0000000612); the Desirée and Niels Yde Foundation (543-23); the National Natural Science Foundation of China (32470878, 32122032 and 31970750); the Zhejiang Provincial Natural Science Foundation (QKWL25H0901); the National Natural Science Foundation of China (grant no. 32470663); the Guangdong Pearl River Talents Program (grant no. 2019QN01Y183); the National Institutes of Health grant (R01HG012446); the Young Talents Program of Sun Yat-sen University Cancer Center (grant no. YTP-SYSUCC-0042); the Ministry of Science and Technology of the People’s Republic of China (2024YFA0916903); the National Natural Science Foundation of China (32122042 and 32071208); the Zhejiang Provincial Natural Science Foundation (DQ24C050001); the National Natural Science Foundation of China (nos. 12371485, T2341007, T2350003 and 12131020); the Science and Technology Commission of Shanghai Municipality (no. 23JS1401300); the Zhejiang Province Vanguard Goose-Leading Initiative (no. 2025C01114); the National Science and Technology Major Project (grant no. 2022ZD0115004); The Luxembourg National Research Fund with the German Research Foundation (INTER/DFG/23/18289476/TRIUMPH); and the National Natural Science Foundation of China (grant no. 32270796). We thank the Proteomic Navigator of the Human Body (π-HuB) Project for support, and R. Aebersold and M. Mann for helpful discussions.Author informationAuthors and AffiliationsAffiliated Hangzhou First People’s Hospital, State Key Laboratory of Medical Proteomics, School of Medicine, School of Future Biomedicine, Westlake University, Hangzhou, ChinaLiujia Qian, Zizhuo Zhou, Zhen Dong, Zhenwu Dai, Shuaiyao Wang, Heng Jiang, Rui Sun, Zhaoxing Li, Yaming Deng, Yi Chen, Xue Cai, Yingrui Wang, Qi Xiao, Yi Zhu, Xiaofan Zhang & Tiannan GuoWestlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, ChinaLiujia Qian, Zizhuo Zhou, Zhen Dong, Zhenwu Dai, Shuaiyao Wang, Heng Jiang, Rui Sun, Zhaoxing Li, Yaming Deng, Yi Chen, Xue Cai, Yingrui Wang, Qi Xiao, Yi Zhu, Xiaofan Zhang & Tiannan GuoResearch Center for Industries of the Future, School of Life Sciences, Westlake University, Hangzhou, ChinaLiujia Qian, Zizhuo Zhou, Zhen Dong, Zhenwu Dai, Shuaiyao Wang, Heng Jiang, Rui Sun, Zhaoxing Li, Yaming Deng, Yi Chen, Xue Cai, Yingrui Wang, Qi Xiao, Yi Zhu, Xiaofan Zhang & Tiannan GuoCenter for Machine Learning Research, Peking University, Beijing, ChinaPeijie Zhou, Xudong Zhang, Jianzhe Li & Weinan EAI for Science Institute, Beijing, ChinaPeijie Zhou, Han Wen & Weinan ENational Engineering Laboratory for Big Data Analysis and Applications, Beijing, ChinaPeijie ZhouCenter for Data Science, Peking University, Beijing, ChinaPeijie Zhou, Xudong Zhang, Jianzhe Li & Weinan EShanghai Artificial Intelligence Laboratory, Shanghai, ChinaZhangyang Gao, Lei Bai & Bowen ZhouResearch Institute of Intelligent Complex Systems, Fudan University, Shanghai, ChinaSiqi SunStanford Genome Technology Center, Stanford University, Palo Alto, CA, USAKevin R. RoyDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USAKevin R. Roy & Lars M. SteinmetzDepartment of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, SwitzerlandNicola ZamboniThe Donnelly Centre, University of Toronto, Toronto, Ontario, CanadaCharles Boone, Michael Costanzo & Brenda AndrewsDepartment of Molecular Genetics, University of Toronto, Toronto, Ontario, CanadaCharles Boone, Michael Costanzo & Brenda AndrewsInstitute of Research on Cancer and Ageing of Nice (IRCAN), Faculté de Médecine, Nice, FranceGianni LitiState Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, ChinaJia-Xing YueDepartment of Biochemistry, Charité-Universitätsmedizin Berlin, Berlin, GermanyMarkus RalserExploratory Diagnostic Sciences, Berlin Institute of Health at Charité, Berlin, GermanyMarkus RalserCenter for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UKMarkus RalserMax Planck Institute for Molecular Genetics, Berlin, GermanyMarkus RalserLuxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, LuxembourgEvan WilliamsDepartment of Biomedicine, University of Basel, Basel, SwitzerlandMattia ZampieriDepartment of Artificial Intelligence, School of Engineering, Westlake University, Hangzhou, ChinaTailin WuBiomedical Research Core Facilities, Westlake University, Hangzhou, ChinaYalin WangInstitute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, ChinaFeiran LiUniversité de Strasbourg, CNRS, Inserm, IGBMC UMR 7104-UMR-S 1258, Illkirch, FranceJoseph SchachererState Key Laboratory of Microbial Metabolism and Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, ChinaZhiping XieSouth China Hospital, Health Science Center, Guangdong Key Laboratory of Genome Instability and Disease Prevention, Shenzhen University School of Medicine, Shenzhen, ChinaHuiqiang LouState Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Research Unit of Proteomics Driven Cancer Precision Medicine (Chinese Academy of Medical Sciences), Beijing, ChinaXiaowen Wang, Linhai Xie & Fuchu HeInternational Academy of Phronesis Medicine (Guangdong), Guangzhou, ChinaLinhai Xie, Fuchu He & Jing YangDP Technology Co. Ltd., Beijing, ChinaHan WenBeijing Advanced Center of RNA Biology (BEACON), Peking University, Beijing, ChinaHan WenState Key Laboratory of Medical Proteomics, Beijing, ChinaHan WenState Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Center for Life Sciences, College of Future Technology, Peking University, Beijing, ChinaLiangyi ChenWestlake Laboratory of Life Sciences and Biomedicine, Hangzhou, ChinaKai Lei, Huaizong Shen & Kiryl PiatkevichKey Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, ChinaKai LeiInstitute of Biology, Westlake Institute for Advanced Study, Hangzhou, ChinaKai Lei & Huaizong ShenBruker Switzerland AG, Faellanden, SwitzerlandGeorge RosenbergerZhejiang Key Laboratory of Structural Biology, School of Life Sciences, Westlake University, Hangzhou, ChinaHuaizong ShenShenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaGaowen LiuNational Biomedical Imaging Center, College of Future Technology, Peking University, Beijing, ChinaLei MaState Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, ChinaHui LuSJTU-Yale Joint Center of Biostatistics and Data Science, National Center for Translational Medicine, MoE Key Lab of Artificial Intelligence, AI Institute Shanghai Jiao Tong University, Shanghai, ChinaHui LuShanghai Engineering Research Center for Big Data in Pediatric Precision Medicine, NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, ChinaHui LuSchool of Life Sciences, Westlake University, Hangzhou, ChinaKiryl PiatkevichInstitute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, ChinaKiryl PiatkevichManchester Institute of Biotechnology, University of Manchester, Manchester, UKYizhi CaiGenerative and Synthetic Genomics, Wellcome Sanger Institute, Cambridge, UKYizhi CaiShenzhen Institute of Synthetic Biology, Chinese Academy of Sciences, Shenzhen, ChinaYuping ChenShenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaYuping ChenSchool of Mathematical Sciences, Peking University, Beijing, ChinaWeinan EState Key Laboratory of Gene Function and Modulation Research, Biomedical Pioneering Innovative Center (BIOPIC) and Beijing Advanced Innovation Center for Genomics (ICG), School of Life Sciences, Center for Bioinformatics (CBI), Peking University, Beijing, ChinaGe GaoSchool of Mathematical Sciences and School of AI, Shanghai Jiao Tong University, Shanghai, ChinaLuonan ChenAI Laboratory, Research Center for Industries of the Future, Westlake University, Hangzhou, ChinaStan Z. LiBiodesign Center, State Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, ChinaHongwu MaNational Center of Technology Innovation for Synthetic Biology, Tianjin, ChinaHongwu MaDepartment of Chemistry, Fudan University, Shanghai, ChinaLiang QiaoGenome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, GermanyLars M. SteinmetzDZHK (German Centre for Cardiovascular Research), Heidelberg, GermanyLars M. SteinmetzStanford Genome Technology Center, Palo Alto, CA, USALars M. SteinmetzCenter for Interdisciplinary Studies, Westlake University, Hangzhou, ChinaLeihan Tang & Yifan YangWuhan Metware Biotechnology Co. Ltd., Wuhan, ChinaTang TangGuangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, ChinaJing YangState Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences Beijing, Beijing Institute of Lifeomics, Beijing, ChinaJing YangSchool of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, ChinaJing YangAutolab, Westlake University, Hangzhou, ChinaKaicheng YuSchool of Engineering, Research Center for Industries of the Future, Westlake University, Hangzhou, ChinaJianyang ZengMedical Artificial Intelligence Laboratory, Westlake University, Hangzhou, ChinaYefeng ZhengDepartment of Electronic Engineering, Tsinghua University, Beijing, ChinaBowen ZhouAuthorsLiujia QianView author publicationsSearch author on:PubMed Google ScholarZizhuo ZhouView author publicationsSearch author on:PubMed Google ScholarPeijie ZhouView author publicationsSearch author on:PubMed Google ScholarZhen DongView author publicationsSearch author on:PubMed Google ScholarXudong ZhangView author publicationsSearch author on:PubMed Google ScholarZhenwu DaiView author publicationsSearch author on:PubMed Google ScholarZhangyang GaoView author publicationsSearch author on:PubMed Google ScholarSiqi SunView author publicationsSearch author on:PubMed Google ScholarKevin R. RoyView author publicationsSearch author on:PubMed Google ScholarShuaiyao WangView author publicationsSearch author on:PubMed Google ScholarNicola ZamboniView author publicationsSearch author on:PubMed Google ScholarCharles BooneView author publicationsSearch author on:PubMed Google ScholarMichael CostanzoView author publicationsSearch author on:PubMed Google ScholarJianzhe LiView author publicationsSearch author on:PubMed Google ScholarGianni LitiView author publicationsSearch author on:PubMed Google ScholarJia-Xing YueView author publicationsSearch author on:PubMed Google ScholarMarkus RalserView author publicationsSearch author on:PubMed Google ScholarEvan WilliamsView author publicationsSearch author on:PubMed Google ScholarMattia ZampieriView author publicationsSearch author on:PubMed Google ScholarHeng JiangView author publicationsSearch author on:PubMed Google ScholarTailin WuView author publicationsSearch author on:PubMed Google ScholarYalin WangView author publicationsSearch author on:PubMed Google ScholarFeiran LiView author publicationsSearch author on:PubMed Google ScholarJoseph SchachererView author publicationsSearch author on:PubMed Google ScholarRui SunView author publicationsSearch author on:PubMed Google ScholarZhaoxing LiView author publicationsSearch author on:PubMed Google ScholarYaming DengView author publicationsSearch author on:PubMed Google ScholarYi ChenView author publicationsSearch author on:PubMed Google ScholarZhiping XieView author publicationsSearch author on:PubMed Google ScholarHuiqiang LouView author publicationsSearch author on:PubMed Google ScholarXiaowen WangView author publicationsSearch author on:PubMed Google ScholarLinhai XieView author publicationsSearch author on:PubMed Google ScholarHan WenView author publicationsSearch author on:PubMed Google ScholarLiangyi ChenView author publicationsSearch author on:PubMed Google ScholarKai LeiView author publicationsSearch author on:PubMed Google ScholarGeorge RosenbergerView author publicationsSearch author on:PubMed Google ScholarXue CaiView author publicationsSearch author on:PubMed Google ScholarYingrui WangView author publicationsSearch author on:PubMed Google ScholarQi XiaoView author publicationsSearch author on:PubMed Google ScholarHuaizong ShenView author publicationsSearch author on:PubMed Google ScholarGaowen LiuView author publicationsSearch author on:PubMed Google ScholarLei MaView author publicationsSearch author on:PubMed Google ScholarBrenda AndrewsView author publicationsSearch author on:PubMed Google ScholarHui LuView author publicationsSearch author on:PubMed Google ScholarKiryl PiatkevichView author publicationsSearch author on:PubMed Google ScholarYi ZhuView author publicationsSearch author on:PubMed Google ScholarLei BaiView author publicationsSearch author on:PubMed Google ScholarYizhi CaiView author publicationsSearch author on:PubMed Google ScholarYuping ChenView author publicationsSearch author on:PubMed Google ScholarWeinan EView author publicationsSearch author on:PubMed Google ScholarGe GaoView author publicationsSearch author on:PubMed Google ScholarFuchu HeView author publicationsSearch author on:PubMed Google ScholarLuonan ChenView author publicationsSearch author on:PubMed Google ScholarStan Z. LiView author publicationsSearch author on:PubMed Google ScholarHongwu MaView author publicationsSearch author on:PubMed Google ScholarLiang QiaoView author publicationsSearch author on:PubMed Google ScholarLars M. SteinmetzView author publicationsSearch author on:PubMed Google ScholarLeihan TangView author publicationsSearch author on:PubMed Google ScholarTang TangView author publicationsSearch author on:PubMed Google ScholarXiaofan ZhangView author publicationsSearch author on:PubMed Google ScholarJing YangView author publicationsSearch author on:PubMed Google ScholarYifan YangView author publicationsSearch author on:PubMed Google ScholarKaicheng YuView author publicationsSearch author on:PubMed Google ScholarJianyang ZengView author publicationsSearch author on:PubMed Google ScholarYefeng ZhengView author publicationsSearch author on:PubMed Google ScholarBowen ZhouView author publicationsSearch author on:PubMed Google ScholarTiannan GuoView author publicationsSearch author on:PubMed Google ScholarContributionsT.G. conceived and supervised the study, provided overall conceptual guidance and critically revised the manuscript. L. Qian drafted the manuscript and performed comprehensive revisions of the text and figures. Z. Z., P.Z. and Z.G. contributed to the AI sections, including content development and revision. Z. Dong contributed to the spatial omics-related content. Xudong Zhang contributed to the active learning-related content. Z. Dai curated and organized the datasets. K.R.R., C.B., M.C., G. Liti, J.-X.Y., M.R., E.W., F.L., J.S., R.S., Z.X., H. Lou, K.L., G. Liu, B.A., Y. Cai, Yuping Chen, H.M., L.M.S., L.T. and Y.Y. contributed to the yeast biology-related content, including domain expertise, discussion and revision. S.S., J.L., H.J., T.W., Z.L., Y.D., Yi Chen, H.W., L.M., H. Lu, L.B., W.E., G.G., Luonan Chen, S.Z.L., Xiaofan Zhang, K.Y., J.Z., Y. Zheng and B.Z. contributed to AI algorithms and computational methodology, including technical input and revision. S.W., N.Z., M.Z., Yingrui Wang, X.W., L.X., Liangyi Chen, G.R., X.C., Yalin Wang, Q.X., H.S., K.P., Y. Zhu, F.H., L. Qiao, T.T. and J.Y. contributed to omics and imaging technologies, including data interpretation, technical development and manuscript revision. All authors reviewed and approved the final manuscript.Corresponding authorCorrespondence to Tiannan Guo.Ethics declarationsCompeting interestsT.G. and Y. Zhu are shareholders of Westlake Omics. T.T. is a shareholder of Wuhan Metware Biotechnology. 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