Wikipedia

Sergiu P. Pașca

Sergiu P. Pașca (born January 30, 1982) is a Romanian-American scientist and physician at Stanford University in California. He is renowned for his groundbreaking work creating and developing stem cell-based models of the human brain to gain insights into neuropsychiatric disease. His lab was the first to develop and name assembloids: multi-unit self-organizing structures created in 3D cultures that allow for the study of human neural circuit and systems functions in vitro.[1] Pașca’s lab generated and published human cortico-striatal[2] and cortico-motor[3] assembloids in 2020. Combining regionalized neural organoids pioneered in the lab and studies with human forebrain assembloids[4] and transplantation, in 2024, Pașca developed a therapeutic for a severe genetic disorder called Timothy Syndrome,[5] which was published on the cover of Nature.

Sergiu P. Pașca
Pașca in 2018
Born(1982-01-30)January 30, 1982
Cluj-Napoca, Romania
NationalityAmerican & Romanian
Alma materIuliu Hațieganu University of Medicine and Pharmacy
Scientific career
FieldsNeuroscience, Biology, Stem Cell
InstitutionsStanford University
Academic advisorsRicardo Dolmetsch
Websitewww.pascalab.org

Pașca is a pioneering neuroscientist and stem cell biologist and holds the Kenneth T. Norris Endowed Professorship in Psychiatry and Behavioral Sciences at Stanford University.[6] He founded and leads the Stanford Brain Organogenesis Program[7] as the Bonnie Uytengsu and Family Founding Director. He is part of the Stanford Neurosciences Institute, Stanford Bio-X and he is a fellow of the ChEM-H Institute at Stanford.[6] Pașca was listed among New York Times Visionaries in Medicine and Sciences, he is the recipient of the 2018 Vilcek Award for Creative Biomedical Promise from the Vlicek Foundation,[8] and the 2022 IBRO-Kemali Neuroscience Prize,[9] and he holds a Doctor Honoris Causa.[10] In 2022, he gave a TED talk on reverse engineering the human brain in the laboratory[11] and in 2023 he became a Knight of the Order of Merit of Romania.[12]

Early life and education

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Pașca was born in Cluj-Napoca, in the region of Transylvania. He was raised in nearby Aiud during the last years of communism.[13] Pașca showed early on an interest in chemistry. He set up his first science lab at the age of 11, in the basement of his parents’ house.[14] In the final year of high school, he won a prize in the national chemistry Olympiad, earning a scholarship to attend the university of his choice in Romania. In 2001, Pașca enrolled in the Iuliu Hațieganu University of Medicine and Pharmacy at Cluj-Napoca.[6] As a medical student, he worked with Professor Maria Dronca to explore biochemical defects in autism spectrum disorders. At the same time, he studied electrophysiology at the Max Planck Institute for Brain Research in Frankfurt in Germany under Dr Danko Nikolic. After obtaining his M.D. in 2007, Pașca went to Stanford University in early 2009 as a postdoctoral fellow with Professor Ricardo Dolmetsch. At Stanford, he developed methods to derive neurons from induced pluripotent stem cells (iPSC) and used these neural cultures to identify cellular phenotypes associated with brain disorders, including Timothy syndrome and Dravet syndrome.[15][16][17][18]

In 2014, he was recruited as a tenure-track Assistant Professor at Stanford University and opened his own laboratory.[19] He became a tenured Associate Professor in 2020 and full Professor in 2022. He was soon after named an Endowed Professor at Stanford University.[6]

In 2023, he received a Doctor Honoris Causa (D.H.C.) from Iuliu Hatieganu Medical School in Cluj-Napoca, Romania.

His personal trajectory was described in a Quanta profile[20] by the American journalist Claudia Dreyfus.

Pașca has two children.

Research

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Pașca’s laboratory at Stanford University explores the biological mechanisms of neurodevelopmental disorders, such as autism spectrum disorders, epilepsy and schizophrenia, using cellular models of the human brain.[19] Pașca developed some of the early in-a-dish models of disease by deriving neurons from skin cells taken from patients with genetic forms of autism and other neurodevelopmental disorders.[21][22] These patient neurons helped uncover the cellular defects of genetic mutations and demonstrated the promise of this novel technology. In 2024, his lab reported a therapeutic developed exclusively with human stem cell-based models.[5]

Neural organoids

In his laboratory, Pașca introduced the use of instructive signals to develop lab-grown self-assembling three-dimensional (3D) structures called regionalized neural spheroids or organoids.[1] Through application of various guidance molecules, Pașca ’s lab has developed about a dozen distinct neural organoids representing different brain areas, including the cerebral cortex, ventral forebrain, striatum, spinal cord, thalamus and others. This method was listed among the Key Advances in hiPSC Disease Modeling of the Last Decade by the journal Cell Stem Cell,[23] and Organoids were named Methods of the Year in 2017 by Nature Methods.[24] These 3D brain tissue resemble specific regions of the nervous system[25][26] and his laboratory has maintained these cultures for over 1000 days in vitro and demonstrated advanced cell maturation, including astrocytes, into postnatal stages according to an intrinsic clock. His work on astrocytes was inspired by the late Stanford neurobiologist Ben Barres.

Assembloids

Pașca has demonstrated that brain-region specific organoids can be fused to form brain assembloids, which spontaneously integrate and demonstrate emergent properties. He has employed this preparation to study the cross-talk between cells in the developing human brain and to mimic human brain circuits in a dish. Pașca coined the term assembloids in 2018[1] referring to the first forebrain assembloids developed in early 2017.[4] This work was listed among the Top Research Advances of 2017 by the National Institutes of Health.[27] His lab has subsequently developed cortico-striatal[2] and three-part cortico-spinal-muscle assembloids.[3] By combining assembloids with CRISPR screening, Pașca lab mapped hundreds of autism-related genes to interneuron development stages, which also revealed an unknown role of the endoplasmic reticulum in migration.[28]

In 2024, his lab reported the first four-part assembloids that model the somatosensory pathway,[29] enabling activity monitoring of the entire circuit and response to noxious stimuli. Assembloids are now widely used to model complex cell-cell interactions in other systems and organs, including the gut, immune system, cancer, etc.

Assembloids have been useful for studying neural migration, circuit formation, and unveiling a surprising ability of neural circuits to self-assemble, ex vivo, from parts.

Transplantation of organoids

In 2022, his group demonstrated the successful integration of human cortical organoids into the developing rat cerebral cortex. Human neurons displayed advanced maturation in vivo, responded to whisker stimulation and were capable of influencing the behavior of the rat in a reward task.[30]

This work was extensively covered by the press.[31][32][33][34][35] Pașca discussed the ethical implications of his work with the ethicist Insoo Hyun in a video material[36] filmed at the Boston Science Museum. Pașca acknowledged that organoid transplantation offers great promise for characterizing human cellular processes in vivo but encourages caution and ethical consideration in pursuing these experiments.

Stanford Brain Organogenesis

In 2019, Pașca founded the Stanford Brain Organogenesis Program, which is a university wide effort to leverage technologies developed at Stanford to advance our understanding of human brain development and circuit assembly. The program includes Karl Deisseroth, Zhenan Bao, Bianxiao Cui, Michael Lin, Sarah Heilshorn and Hank Greely . Pașca serves as the Bonnie Uytengsu and Family Director. The program is also broadly sharing organoid and assembloids technologies through a free, hands-on course course that brings student from all over the world.[37]

Teaching and public engagement

At Stanford, Pașca teaches neural development and principles of drug discovery in neuroscience. Pașca is also the co-director of the CSHL Workshop on autism spectrum disorders.[38]

In 2022, he gave a TED talk[39] at the Vancouver event describing the potential of human cellular models to understand disease. 

Honors

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Pașca is a Chan Zuckerberg Initiative Ben Barres Investigator and a CZ BioHub Investigator. He was a New York Stem Cell Foundation Roberston Stem Cell Investigator. His researched activity gained him several awards:

  • Schaller Prize for Translational Neuroscience (2024)[40]
  • ISSCR Momentum Award, International Society for Stem Cell Research (2024)[41]
  • Knight of the Order of Merit, The Chancery of Orders (2023)[12]
  • Sumitomo/Sunovion Prize, International College of Neuropsychopharmacology (2023)[42]
  • Doctor Honoris Causa (D.H.C.), Hatieganu Medical School (2023)[10]
  • IBRO Dargut and Milena Kemali International Prize for Basic and Clinical Neurosciences (2022)[43]
  • Judson Daland Prize for Outstanding Achievement in Clinical Investigation, American Society of Philosophy (2021)[44]
  • Joseph Altman Award in Developmental Neuroscience (2021)[45]
  • Schizophrenia Basic Research Award (2021)[46]
  • C.J. Herrick Award in Neuroanatomy (2020)
  • A.E.Bennett Award, Society of Biological Psychiatry (2018)[47]
  • Daniel H. Efron Award, American College of Neuropsychopharmacology (2018)[48]
  • Günter Blobel Award, American Society of Cell Biology (2018)[49]
  • New York Times Visionaries in Science and Medicine (2018)[50]
  • Vilcek Award for Creative Biomedical Promise (2018)[51]
  • Jordi Folch-Pi Award, American Society for Neurochemistry (2017)[52]
  • NARSAD Independent Investigator Award (2017)[53]
  • NIMH Director's BRAINS Award (2015)
  • MQ Fellow Award for Transforming Mental Health (2014)[54]
  • Sammy Kuo Award (2012)[55]
  • IBRO Outstanding Research Fellow (2009)

In Romania, he was recognized as the Best Romanian student studying abroad in 2012.[56]

References

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  1. ^ a b c Pașca, Sergiu P. (2018). "The rise of three-dimensional human brain cultures". Nature. 553 (7689): 437–445. Bibcode:2018Natur.553..437P. doi:10.1038/nature25032. ISSN 1476-4687. PMID 29364288. S2CID 205262820.
  2. ^ a b Miura, Yuki; Li, Min-Yin; Birey, Fikri; Ikeda, Kazuya; Revah, Omer; Thete, Mayuri Vijay; Park, Jin-Young; Puno, Alyssa; Lee, Samuel H.; Porteus, Matthew H.; Pașca, Sergiu P. (December 2020). "Generation of human striatal organoids and cortico-striatal assembloids from human pluripotent stem cells". Nature Biotechnology. 38 (12): 1421–1430. doi:10.1038/s41587-020-00763-w. ISSN 1546-1696. PMC 9042317.
  3. ^ a b Andersen, Jimena; Revah, Omer; Miura, Yuki; Thom, Nicholas; Amin, Neal D.; Kelley, Kevin W.; Singh, Mandeep; Chen, Xiaoyu; Thete, Mayuri Vijay; Walczak, Elisabeth M.; Vogel, Hannes; Fan, H. Christina; Paşca, Sergiu P. (2020-12-23). "Generation of Functional Human 3D Cortico-Motor Assembloids". Cell. 183 (7): 1913–1929.e26. doi:10.1016/j.cell.2020.11.017. ISSN 0092-8674. PMC 8711252.
  4. ^ a b Birey, Fikri; Andersen, Jimena; Makinson, Christopher D.; et al. (2017). "Assembly of functionally integrated human forebrain spheroids". Nature. 545 (7652): 54–59. Bibcode:2017Natur.545...54B. doi:10.1038/nature22330. ISSN 1476-4687. PMC 5805137. PMID 28445465.
  5. ^ a b Chen, Xiaoyu; Birey, Fikri; Li, Min-Yin; Revah, Omer; Levy, Rebecca; Thete, Mayuri Vijay; Reis, Noah; Kaganovsky, Konstantin; Onesto, Massimo; Sakai, Noriaki; Hudacova, Zuzana; Hao, Jin; Meng, Xiangling; Nishino, Seiji; Huguenard, John (2024-04-25). "Antisense oligonucleotide therapeutic approach for Timothy syndrome". Nature. 628 (8009): 818–825. doi:10.1038/s41586-024-07310-6. ISSN 0028-0836. PMC 11043036. PMID 38658687.
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  8. ^ Lisa M. Krieger (February 1, 2018). "Stanford scientist wins award for immigrant scientists". The Mercury News. Retrieved January 13, 2018.
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  15. ^ Krey, Jocelyn F.; Pașca, Sergiu P.; Shcheglovitov, Aleksandr; et al. (2013). "Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons". Nature Neuroscience. 16 (2): 201–209. doi:10.1038/nn.3307. ISSN 1546-1726. PMC 3568452. PMID 23313911.
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  17. ^ Sun, Yishan; Paşca, Sergiu P; Portmann, Thomas; et al. (26 July 2016). "A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients". eLife. 5. doi:10.7554/eLife.13073. ISSN 2050-084X. PMC 4961470. PMID 27458797.
  18. ^ Tian, Yuan; Voineagu, Irina; Paşca, Sergiu P.; et al. (2014). "Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome". Genome Medicine. 6 (10): 75. doi:10.1186/s13073-014-0075-5. ISSN 1756-994X. PMC 4213483. PMID 25360157.
  19. ^ a b "Pașca Lab @ Stanford University - Home". Pascalab.org. 2018-05-24. Retrieved 2018-06-07.
  20. ^ Dreifus, Claudia (October 12, 2022). "Human Brains Are Hard to Study. He Grows Useful Substitutes". Quanta Magazine.
  21. ^ Paşca, Sergiu P.; Panagiotakos, Georgia; Dolmetsch, Ricardo E. (2014). "Generating human neurons in vitro and using them to understand neuropsychiatric disease". Annual Review of Neuroscience. 37: 479–501. doi:10.1146/annurev-neuro-062012-170328. ISSN 1545-4126. PMID 25002278.
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  23. ^ Passier, Robert; Orlova, Valeria; Mummery, Christine (March 2016). "Complex Tissue and Disease Modeling using hiPSCs". Cell Stem Cell. 18 (3): 309–321. doi:10.1016/j.stem.2016.02.011. PMID 26942851.
  24. ^ "Method of the Year 2017: Organoids". Nature Methods. 15: 1. 3 January 2018. doi:10.1038/nmeth.4575.
  25. ^ Paşca, Anca M.; Sloan, Steven A.; Clarke, Laura E.; et al. (2015). "Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture". Nature Methods. 12 (7): 671–678. doi:10.1038/nmeth.3415. ISSN 1548-7105. PMC 4489980. PMID 26005811.
  26. ^ Sloan, Steven A.; Darmanis, Spyros; Huber, Nina; et al. (16 August 2017). "Human Astrocyte Maturation Captured in 3D Cerebral Cortical Spheroids Derived from Pluripotent Stem Cells". Neuron. 95 (4): 779–790.e6. doi:10.1016/j.neuron.2017.07.035. ISSN 1097-4199. PMC 5890820. PMID 28817799.
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  28. ^ Meng, Xiangling; Yao, David; Imaizumi, Kent; Chen, Xiaoyu; Kelley, Kevin W.; Reis, Noah; Thete, Mayuri Vijay; Arjun McKinney, Arpana; Kulkarni, Shravanti; Panagiotakos, Georgia; Bassik, Michael C.; Pașca, Sergiu P. (October 2023). "Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment". Nature. 622 (7982): 359–366. doi:10.1038/s41586-023-06564-w. ISSN 1476-4687. PMC 10567561. PMID 37758944.
  29. ^ Kim, Ji-il; Imaizumi, Kent; Thete, Mayuri Vijay; Hudacova, Zuzana; Jurjuţ, Ovidiu; Amin, Neal D.; Scherrer, Grégory; Paşca, Sergiu P. (2024-03-12), Human assembloid model of the ascending neural sensory pathway, doi:10.1101/2024.03.11.584539, PMC 10979925, PMID 38559133, retrieved 2024-06-19
  30. ^ Revah, Omer; Gore, Felicity; Kelley, Kevin W.; Andersen, Jimena; Sakai, Noriaki; Chen, Xiaoyu; Li, Min-Yin; Birey, Fikri; Yang, Xiao; Saw, Nay L.; Baker, Samuel W.; Amin, Neal D.; Kulkarni, Shravanti; Mudipalli, Rachana; Cui, Bianxiao (2022-10-13). "Maturation and circuit integration of transplanted human cortical organoids". Nature. 610 (7931): 319–326. Bibcode:2022Natur.610..319R. doi:10.1038/s41586-022-05277-w. ISSN 0028-0836. PMC 9556304. PMID 36224417.
  31. ^ Zimmer, Carl (2022-10-12). "Human Brain Cells Grow in Rats, and Feel What the Rats Feel". The New York Times. ISSN 0362-4331. Retrieved 2023-11-01.
  32. ^ Cookson, Clive (2022-10-12). "Human-to-rat brain tissue implant boosts psychiatric disease research". Financial Times. Retrieved 2023-11-01.
  33. ^ Sample, Ian; editor, Ian Sample Science (2022-10-12). "Human neurons transplanted into rats to help study brain disorders". The Guardian. ISSN 0261-3077. Retrieved 2023-11-01. {{cite news}}: |last2= has generic name (help)
  34. ^ "What happens when human brain tissue is implanted into rats". The Economist. ISSN 0013-0613. Retrieved 2023-11-01.
  35. ^ "Un organoïde cérébral humain implanté dans un cerveau de rat". Le Monde.fr (in French). 2022-10-31. Retrieved 2023-11-01.
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  37. ^ "Stanford Brain Organogenesis Workshop". Stanford Brain Organogenesis. Retrieved 2023-11-17.
  38. ^ "Workshop on Autism Spectrum Disorders | CSHL". meetings.cshl.edu. Retrieved 2022-04-14.
  39. ^ Pasca, Sergiu P. (2022-08-24), Sergiu P. Pasca: How we're reverse engineering the human brain in the lab, retrieved 2023-11-17
  40. ^ University, © Stanford; Stanford; California 94305 (2024-06-05). "Sergiu Pasca Wins the 2024 Schaller Prize for Translational Neuroscience". Welcome to Bio-X. Retrieved 2024-06-19.{{cite web}}: CS1 maint: numeric names: authors list (link)
  41. ^ "Sergiu P. Paşca Receives the 2024 ISSCR Momentum Award for his Pioneering Work in Neurodevelopment and Disease". International Society for Stem Cell Research. Retrieved 2024-06-19.
  42. ^ "Brain Health Research Awards". cinp.org. Retrieved 2023-11-17.
  43. ^ "IBRO-Kemali Prize Awarded to Dr. Sergiu P. Pasca". IBRO. 2021-09-20. Retrieved 2022-05-15.
  44. ^ "2021 Judson Daland Prize". American Philosophical Society. Retrieved 2022-05-15.
  45. ^ "Announcement of the Awardee of the 2021 Joseph Altman Award in Developmental Neuroscience". The Japan Neuroscience Society. Retrieved 2022-05-15.
  46. ^ "2021 Basic Research Award | Schizophrenia International Research Society". Retrieved 2022-05-15.
  47. ^ "A.E. Bennett Basic Research Award | Society of Biological Psychiatry". Retrieved 2022-05-15.
  48. ^ "Daniel H. Efron Research Previous Award Winners". ACNP. Retrieved 2022-05-15.
  49. ^ "Neuroscientist and Stem Cell Biologist Sergiu Pasca to Receive ASCB Early Career Life Scientist Award". ASCB. 2018-10-17. Retrieved 2022-05-15.
  50. ^ Weintraub, Karen (2018-05-24). "Using Medicine and Science to Improve the Quality of Life". The New York Times. ISSN 0362-4331. Retrieved 2022-05-15.
  51. ^ "Sergiu P. Pasca". Vilcek Foundation. Retrieved 2022-05-15.
  52. ^ "American Society for Neurochemistry - Recipients of the Jordi Folch-Pi Award". www.asneurochem.org. Retrieved 2022-05-15.
  53. ^ "Sergiu P. Pasca, M.D." Brain & Behavior Research Foundation. 2017-07-18. Retrieved 2022-05-15.
  54. ^ "Identifying cellular mechanisms of disease and novel therapeutic targets in neurons derived from patients with schizophrenia | MQ Mental Health Research". www.mqmentalhealth.org. 2020-10-28. Retrieved 2022-05-15.
  55. ^ University, © Stanford; Stanford; California 94305 (2017-07-03). "Sammy Kuo Award Winners". Wu Tsai Neurosciences Institute. Retrieved 2022-05-15.{{cite web}}: CS1 maint: numeric names: authors list (link)
  56. ^ Craciun, Oana (14 January 2013). "EXCLUSIV Sergiu Pașca, studentul român al anului 2012 din străinătate: "Ar fi trebuit să plec la studii mai devreme"". Adevărul (in Romanian). Retrieved 13 March 2016.
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