Defining and benchmarking open problems in single-cell analysis

Malte D Luecken^#^{1

2}, Scott Gigante^#³, Daniel B Burkhardt^#⁴, Robrecht Cannoodt^#^{5

6

7}, Daniel C Strobl^{1

8

9}, Nikolay S Markov¹⁰, Luke Zappia^{1

5

11}, Giovanni Palla^{1

9}, Wesley Lewis¹², Daniel Dimitrov¹³, Michael E Vinyard^{14

15

16}, D S Magruder¹⁷, Michaela F Mueller^{1

2

9}, Alma Andersson^{18

19

20}, Emma Dann²¹, Qian Qin¹⁵, Dominik J Otto^{22

23

24}, Michal Klein²⁵, Olga Borisovna Botvinnik^{26

27}, Louise Deconinck^{6

7}, Kai Waldrant⁵, Sai Nirmayi Yasa⁵, Artur Szałata^{1

11}, Andrew Benz²⁸, Zhijian Li^{15

16}; Open Problems Jamboree Members; Jonathan M Bloom²⁹, Angela Oliveira Pisco^{26

30}, Julio Saez-Rodriguez¹³, Drausin Wulsin³, Luca Pinello¹⁶, Yvan Saeys^{6

7

31}, Fabian J Theis^{32

33

34}, Smita Krishnaswamy^{35

36

37}

Collaborators, Affiliations

Collaborators

Affiliations

¹ Institute of Computational Biology, Helmholtz Munich, Neuherberg, Germany.
² Institute of Lung Health & Immunity, Helmholtz Munich; Member of the German Center for Lung Research (DZL), Munich, Germany.
³ Immunai, New York, USA.
⁴ NVIDIA, Santa Clara, CA, USA.
⁵ Data Intuitive, Lebbeke, Belgium.
⁶ Data Mining and Modelling for Biomedicine group, VIB Center for Inflammation Research, Ghent, Belgium.
⁷ Department of Applied Mathematics, Computer Science, and Statistics, Ghent University, Ghent, Belgium.
⁸ Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany.
⁹ TUM School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany.
¹⁰ Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹¹ Department of Mathematics, School of Computing, Information and Technology, Technical University of Munich, Munich, Germany.
¹² Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
¹³ Faculty of Medicine and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg University, Heidelberg, Germany.
¹⁴ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
¹⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁶ Molecular Pathology Unit, Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
¹⁷ Department of Computer Science, Yale University, New Haven, CT, USA.
¹⁸ Genentech Inc, South San Francisco, CA, USA.
¹⁹ Gene Technology, Royal Institute of Technology (KTH), Stockholm, Sweden.
²⁰ Science for Life Laboratory (SciLifeLab), Solna, Sweden.
²¹ Wellcome Sanger Institute, Cambridge, UK.
²² Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
²³ Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
²⁴ Translational Data Science IRC, Fred Hutchinson Cancer Center, Seattle, WA, USA.
²⁵ Apple, Paris, France.
²⁶ Data Sciences Platform, Chan Zuckerberg Biohub, San Francisco, CA, USA.
²⁷ Bridge Bio Pharma, Palo Alto, CA, USA.
²⁸ Cellarity, Inc, Somerville, MA, USA.
²⁹ Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, USA.
³⁰ Insitro, South San Francisco, USA.
³¹ VIB Center for AI & Computational Biology (VIB.AI), Ghent, Belgium.
³² Institute of Computational Biology, Helmholtz Munich, Neuherberg, Germany. fabian.theis@helmholtz-munich.de.
³³ Department of Mathematics, School of Computing, Information and Technology, Technical University of Munich, Munich, Germany. fabian.theis@helmholtz-munich.de.
³⁴ Cellular Genetics Programme, Wellcome Sanger Institute, Hinxton, UK. fabian.theis@helmholtz-munich.de.
³⁵ Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA. smita.krishnaswamy@yale.edu.
³⁶ Department of Computer Science, Yale University, New Haven, CT, USA. smita.krishnaswamy@yale.edu.
³⁷ Department of Genetics, Yale University, New Haven, CT, USA. smita.krishnaswamy@yale.edu.

^# Contributed equally.

PMID: 40595413
DOI: 10.1038/s41587-025-02694-w

Defining and benchmarking open problems in single-cell analysis

Malte D Luecken et al. Nat Biotechnol. 2025 Jul.

. 2025 Jul;43(7):1035-1040.

doi: 10.1038/s41587-025-02694-w.

Authors

Collaborators

Affiliations

¹ Institute of Computational Biology, Helmholtz Munich, Neuherberg, Germany.
² Institute of Lung Health & Immunity, Helmholtz Munich; Member of the German Center for Lung Research (DZL), Munich, Germany.
³ Immunai, New York, USA.
⁴ NVIDIA, Santa Clara, CA, USA.
⁵ Data Intuitive, Lebbeke, Belgium.
⁶ Data Mining and Modelling for Biomedicine group, VIB Center for Inflammation Research, Ghent, Belgium.
⁷ Department of Applied Mathematics, Computer Science, and Statistics, Ghent University, Ghent, Belgium.
⁸ Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany.
⁹ TUM School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany.
¹⁰ Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹¹ Department of Mathematics, School of Computing, Information and Technology, Technical University of Munich, Munich, Germany.
¹² Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
¹³ Faculty of Medicine and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg University, Heidelberg, Germany.
¹⁴ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
¹⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁶ Molecular Pathology Unit, Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
¹⁷ Department of Computer Science, Yale University, New Haven, CT, USA.
¹⁸ Genentech Inc, South San Francisco, CA, USA.
¹⁹ Gene Technology, Royal Institute of Technology (KTH), Stockholm, Sweden.
²⁰ Science for Life Laboratory (SciLifeLab), Solna, Sweden.
²¹ Wellcome Sanger Institute, Cambridge, UK.
²² Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
²³ Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
²⁴ Translational Data Science IRC, Fred Hutchinson Cancer Center, Seattle, WA, USA.
²⁵ Apple, Paris, France.
²⁶ Data Sciences Platform, Chan Zuckerberg Biohub, San Francisco, CA, USA.
²⁷ Bridge Bio Pharma, Palo Alto, CA, USA.
²⁸ Cellarity, Inc, Somerville, MA, USA.
²⁹ Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, USA.
³⁰ Insitro, South San Francisco, USA.
³¹ VIB Center for AI & Computational Biology (VIB.AI), Ghent, Belgium.
³² Institute of Computational Biology, Helmholtz Munich, Neuherberg, Germany. fabian.theis@helmholtz-munich.de.
³³ Department of Mathematics, School of Computing, Information and Technology, Technical University of Munich, Munich, Germany. fabian.theis@helmholtz-munich.de.
³⁴ Cellular Genetics Programme, Wellcome Sanger Institute, Hinxton, UK. fabian.theis@helmholtz-munich.de.
³⁵ Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA. smita.krishnaswamy@yale.edu.
³⁶ Department of Computer Science, Yale University, New Haven, CT, USA. smita.krishnaswamy@yale.edu.
³⁷ Department of Genetics, Yale University, New Haven, CT, USA. smita.krishnaswamy@yale.edu.

^# Contributed equally.

PMID: 40595413
DOI: 10.1038/s41587-025-02694-w

No abstract available

PubMed Disclaimer

Conflict of interest statement

Competing interests: M.D.L. consults for CatalYm GmbH, contracted for the Chan Zuckerberg Initiative and received speaker fees from Pfizer and Janssen Pharmaceuticals. S.G. has equity interest in Immunai Inc. D.B.B. is a paid employee of and has equity interest in NVIDIA. R.C. has equity interest in Data Intuitive BV. L.Z. has consulted for Lamin Labs GmbH. W.L. contracted for Protein Evolution Incorporated. From 2019 to 2022, A.A. was a consultant for 10x Genomics. From October 2023, E.D. has been a consultant for EnsoCell Therapeutics. O.B.B is currently an employee of Bridge Bio Pharma. A.S. consults for Cellarity Inc. and Exvivo Labs Inc. A.B. is a paid employee of and has equity interest in Cellarity, Inc. J.B. has equity interest in Cellarity, Inc. J.S.-R. reports funding from GSK, Pfizer and Sanofi and fees or honoraria from Travere Therapeutics, Stadapharm, Astex, Owkin, Pfizer and Grunenthal. D.W. has equity interest in Immunai Inc. F.J.T. consults for Immunai Inc., Singularity Bio B.V., CytoReason Ltd and Cellarity, and has ownership interest in Dermagnostix GmbH and Cellarity. S.K. is a visiting professor at Meta and scientific advisor at Ascent Bio, Inc. E.d.V.B has ownership interest in Retro Biosciences and ImYoo Inc and is employed by ImYoo Inc. A.T.C. is an employee of Orion Medicines. B.D. is a paid employee of and has equity interest in Cellarity Inc. A.G. is currently an employee of Google DeepMind. Google DeepMind has not directed any aspect of this study nor exerts any commercial rights over the results. R.L. is an employee of Genentech. V.S. has ownership interest in Altos Labs and Vesalius Therapeutics. A.T. has an ownership interest in Dreamfold.

Update of

Defining and benchmarking open problems in single-cell analysis.
Luecken MD, Gigante S, Burkhardt DB, Cannoodt R, Strobl DC, Markov NS, Zappia L, Palla G, Lewis W, Dimitrov D, Vinyard ME, Magruder DS, Andersson A, Dann E, Qin Q, Otto DJ, Klein M, Botvinnik OB, Deconinck L, Waldrant K; Open Problems Jamboree Members; Bloom JM, Pisco AO, Saez-Rodriguez J, Wulsin D, Pinello L, Saeys Y, Theis FJ, Krishnaswamy S. Luecken MD, et al. Res Sq [Preprint]. 2024 Apr 4:rs.3.rs-4181617. doi: 10.21203/rs.3.rs-4181617/v1. Res Sq. 2024. Update in: Nat Biotechnol. 2025 Jul;43(7):1035-1040. doi: 10.1038/s41587-025-02694-w. PMID: 38645152 Free PMC article. Updated. Preprint.

References

1. Zappia, L., Phipson, B. & Oshlack, A. PLOS Comput. Biol. 14, e1006245 (2018). - PubMed - PMC
1. Heumos, L. et al. Nat. Rev. Genet. 24, 550–572 (2023). - PubMed
1. Luecken, M. D. & Theis, F. J. Mol. Syst. Biol. 15, e8746 (2019). - PubMed - PMC
1. Donoho, D. J. Comput. Graph. Stat. 26, 745–766 (2017).
1. Sonrel, A. et al. Genome Biol. 24, 119 (2023). - PubMed - PMC

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Defining and benchmarking open problems in single-cell analysis

Collaborators

Affiliations

Defining and benchmarking open problems in single-cell analysis

Authors

Collaborators

Affiliations

Conflict of interest statement

Update of

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