Sergiu P. Pașca Explained

Sergiu P. Pașca
Birth Date:30 January 1982
Birth Place:Cluj-Napoca, Romania
Nationality:American & Romanian
Fields:Neuroscience, Biology, Stem Cell
Workplaces:Stanford University
Alma Mater:Iuliu Hațieganu University of Medicine and Pharmacy
Academic Advisors:Ricardo Dolmetsch

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. Pașca’s lab generated and published human cortico-striatal and cortico-motor assembloids in 2020. Combining regionalized neural organoids pioneered in the lab and studies with human forebrain assembloids[1] and transplantation, in 2024, Pașca developed a therapeutic for a severe genetic disorder called Timothy Syndrome,[2] which was published on the cover of Nature.

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. He founded and leads the Stanford Brain Organogenesis Program[3] 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.[4] 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,[5] and the 2022 IBRO-Kemali Neuroscience Prize,[6] and he holds a Doctor Honoris Causa.[7] In 2022, he gave a TED talk on reverse engineering the human brain in the laboratory[8] and in 2023 he became a Knight of the Order of Merit.[9]

Early life and education

Pașca was born in Cluj-Napoca, in the region of Transylvania. He was raised in nearby Aiud during the last years of communism.[10] 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.[11] 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.[4] 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.[12] [13] [14] [15]

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

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[16] by the American journalist Claudia Dreyfus.

Pașca has two children.

Research

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.[17] 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.[18] [19] 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.

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.[20] 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,[21] and Organoids were named Methods of the Year in 2017 by Nature Methods.[22] These 3D brain tissue resemble specific regions of the nervous system[23] [24] 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 referring to the first forebrain assembloids developed in early 2017. This work was listed among the Top Research Advances of 2017 by the National Institutes of Health.[25] His lab has subsequently developed cortico-striatal[26] and three-part cortico-spinal-muscle assembloids.[27] 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, 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.[29]

This work was extensively covered by the press.[30] [31] [32] [33] [34] Pașca discussed the ethical implications of his work with the ethicist Insoo Hyun in a video material 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.[35]

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.[36]

His lab has been organizing a highly popular, tuition free, course for students from all over the world who come and learn hands-on the technique developed in his lab.

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

Honors

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:

In Romania, he was recognized as the Best Romanian student studying abroad in 2012.[53]

Notes and References

  1. Birey . Fikri . Andersen . Jimena . Makinson . Christopher D. . Islam . Saiful . Wei . Wu . Huber . Nina . Fan . H. Christina . Metzler . Kimberly R. Cordes . Panagiotakos . Georgia . Thom . Nicholas . O'Rourke . Nancy A. . Steinmetz . Lars M. . Bernstein . Jonathan A. . Hallmayer . Joachim . Huguenard . John R. . 3 . 2017 . Assembly of functionally integrated human forebrain spheroids . Nature . 545 . 7652 . 54–59 . 2017Natur.545...54B . 10.1038/nature22330 . 1476-4687 . 5805137 . 28445465 . Paşca . Sergiu P..
  2. 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 . en . 628 . 8009 . 818–825 . 10.1038/s41586-024-07310-6 . 0028-0836 . 11043036 . 38658687.
  3. Web site: 8 October 2018 . Stanford Brain Organogenesis Program .
  4. Web site: Sergiu P. Pașca's Profile | Stanford Profiles . Profiles.stanford.edu . 2018-06-07.
  5. News: Stanford scientist wins award for immigrant scientists. Lisa M. Krieger. January 13, 2018. The Mercury News. February 1, 2018.
  6. Web site: admin . 2021-09-20 . IBRO-Kemali Prize Awarded to Dr. Sergiu P. Pasca . 2023-10-23 . IBRO . en-US.
  7. Web site: 2023-04-29 . Sergiu Pașca a primit titlul de Doctor Honoris Causa al UMF Cluj. Fostul student al universității, un lider internațional în neuroștiințe: "E important ca tinerii să se pregătească în străinătate și să se întoarcă în țară" . 2023-10-23 . monitorulcj.ro . ro.
  8. Web site: Sergiu P. Pasca: How we're reverse engineering the human brain in the lab . 24 August 2022 .
  9. Web site: 2023-03-28 . Stanford University researcher Sergiu Pasca decorated by President Klaus Iohannis . 2023-10-23 . Stiri pe surse . en.
  10. Web site: The Vilcek Foundation - Sergiu P. Pașca . www.vilcek.org . 7 June 2018.
  11. Web site: Rising Star: Sergiu Pașca, scientist at play Spectrum Autism Research News . Spectrum Autism Research News . 7 June 2018 . 19 February 2015.
  12. Krey . Jocelyn F. . Pașca . Sergiu P. . Shcheglovitov . Aleksandr . Yazawa . Masayuki . Schwemberger . Rachel . Rasmusson . Randall . Dolmetsch . Ricardo E. . 3 . Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons . Nature Neuroscience . 2013 . 16 . 2 . 201–209 . 10.1038/nn.3307 . 23313911 . 1546-1726. 3568452 .
  13. Paşca . Sergiu P. . Portmann . Thomas . Voineagu . Irina . Yazawa . Masayuki . Shcheglovitov . Aleksandr . Paşca . Anca M. . Cord . Branden . Palmer . Theo D. . Chikahisa . Sachiko . Nishino . Seiji . Bernstein . Jonathan A. . Hallmayer . Joachim . Geschwind . Daniel H. . Dolmetsch . Ricardo E. . 3 . Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome . Nature Medicine . 27 November 2011 . 17 . 12 . 1657–1662 . 10.1038/nm.2576 . 22120178 . 1546-170X. 3517299 .
  14. Sun . Yishan . Paşca . Sergiu P . Portmann . Thomas . Goold . Carleton . Worringer . Kathleen A . Guan . Wendy . Chan . Karen C . Gai . Hui . Vogt . Daniel . Chen . Ying-Jiun J . Mao . Rong . Chan . Karrie . Rubenstein . John LR . Madison . Daniel V . Hallmayer . Joachim . Froehlich-Santino . Wendy M . Bernstein . Jonathan A . Dolmetsch . Ricardo E . 3 . A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients . eLife . 26 July 2016 . 5 . 10.7554/eLife.13073 . en . 2050-084X. 4961470 . 27458797 . free .
  15. Tian . Yuan . Voineagu . Irina . Paşca . Sergiu P. . Won . Hyejung . Chandran . Vijayendran . Horvath . Steve . Dolmetsch . Ricardo E. . Geschwind . Daniel H. . 3 . Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome . Genome Medicine . 2014 . 6 . 10 . 75 . 10.1186/s13073-014-0075-5 . 25360157 . 1756-994X. 4213483 . free .
  16. Web site: Dreifus . Claudia . October 12, 2022 . Human Brains Are Hard to Study. He Grows Useful Substitutes. . Quanta Magazine.
  17. Web site: Pașca Lab @ Stanford University - Home . Pascalab.org . 2018-05-24 . 2018-06-07.
  18. Paşca . Sergiu P. . Panagiotakos . Georgia . Dolmetsch . Ricardo E. . Generating human neurons in vitro and using them to understand neuropsychiatric disease . Annual Review of Neuroscience . 2014 . 37 . 479–501 . 10.1146/annurev-neuro-062012-170328 . 25002278 . 1545-4126.
  19. Web site: The Vilcek Foundation - Sergiu P. Pașca . Vilcek.org . 2018-06-07.
  20. Pașca . Sergiu P. . The rise of three-dimensional human brain cultures . Nature . 2018 . 553 . 7689 . 437–445 . 10.1038/nature25032 . 29364288 . 2018Natur.553..437P . 205262820 . 1476-4687.
  21. Passier . Robert . Orlova . Valeria . Mummery . Christine . Complex Tissue and Disease Modeling using hiPSCs . Cell Stem Cell . March 2016 . 18 . 3 . 309–321 . 10.1016/j.stem.2016.02.011. 26942851 . free .
  22. Method of the Year 2017: Organoids . Nature Methods . 1 . 10.1038/nmeth.4575 . 3 January 2018 . 15. free .
  23. Paşca . Anca M. . Sloan . Steven A. . Clarke . Laura E. . Tian . Yuan . Makinson . Christopher D. . Huber . Nina . Kim . Chul Hoon . Park . Jin-Young . O'Rourke . Nancy A. . Nguyen . Khoa D. . Smith . Stephen J. . Huguenard . John R. . Geschwind . Daniel H. . Barres . Ben A. . Paşca . Sergiu P. . 3 . Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture . Nature Methods . 2015 . 12 . 7 . 671–678 . 10.1038/nmeth.3415 . 26005811 . 1548-7105. 4489980 .
  24. Sloan . Steven A. . Darmanis . Spyros . Huber . Nina . Khan . Themasap A. . Birey . Fikri . Caneda . Christine . Reimer . Richard . Quake . Stephen R. . Barres . Ben A. . Paşca . Sergiu P. . 3 . Human Astrocyte Maturation Captured in 3D Cerebral Cortical Spheroids Derived from Pluripotent Stem Cells . Neuron . 16 August 2017 . 95 . 4 . 779–790.e6 . 10.1016/j.neuron.2017.07.035 . 28817799 . 1097-4199 . 5890820.
  25. Web site: 2017 Research Highlights — Insights from the Lab . National Institutes of Health (NIH) . 7 June 2018 . en . 15 December 2017.
  26. 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 . en . 38 . 12 . 1421–1430 . 10.1038/s41587-020-00763-w . 1546-1696. 9042317 .
  27. 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 . 10.1016/j.cell.2020.11.017 . 0092-8674. free . 8711252 .
  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 . en . 622 . 7982 . 359–366 . 10.1038/s41586-023-06564-w . 1476-4687 . 10567561 . 37758944.
  29. 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 . en . 610 . 7931 . 319–326 . 10.1038/s41586-022-05277-w . 0028-0836 . 9556304 . 36224417. 2022Natur.610..319R .
  30. News: Zimmer . Carl . 2022-10-12 . Human Brain Cells Grow in Rats, and Feel What the Rats Feel . en-US . The New York Times . 2023-11-01 . 0362-4331.
  31. News: Cookson . Clive . 2022-10-12 . Human-to-rat brain tissue implant boosts psychiatric disease research . Financial Times . 2023-11-01.
  32. News: Sample . Ian . editor . Ian Sample Science . 2022-10-12 . Human neurons transplanted into rats to help study brain disorders . en-GB . The Guardian . 2023-11-01 . 0261-3077.
  33. News: What happens when human brain tissue is implanted into rats . The Economist . 2023-11-01 . 0013-0613.
  34. News: 2022-10-31 . Un organoïde cérébral humain implanté dans un cerveau de rat . fr . Le Monde.fr . 2023-11-01.
  35. Web site: Stanford Brain Organogenesis Workshop . 2023-11-17 . Stanford Brain Organogenesis . en.
  36. Web site: Workshop on Autism Spectrum Disorders CSHL . 2022-04-14 . meetings.cshl.edu.
  37. Web site: University . © Stanford . Stanford . California 94305 . 2024-06-05 . Sergiu Pasca Wins the 2024 Schaller Prize for Translational Neuroscience . 2024-06-19 . Welcome to Bio-X . en.
  38. Web site: Sergiu P. Paşca Receives the 2024 ISSCR Momentum Award for his Pioneering Work in Neurodevelopment and Disease . 2024-06-19 . International Society for Stem Cell Research . en-US.
  39. Web site: Brain Health Research Awards . 2023-11-17 . cinp.org.
  40. Web site: 2021-09-20 . IBRO-Kemali Prize Awarded to Dr. Sergiu P. Pasca . 2022-05-15 . IBRO . en-US.
  41. Web site: 2021 Judson Daland Prize . 2022-05-15 . American Philosophical Society . en.
  42. Web site: Announcement of the Awardee of the 2021 Joseph Altman Award in Developmental Neuroscience . 2022-05-15 . The Japan Neuroscience Society.
  43. Web site: 2021 Basic Research Award Schizophrenia International Research Society . 2022-05-15 . en-US.
  44. Web site: A.E. Bennett Basic Research Award Society of Biological Psychiatry . 2022-05-15 . en-US.
  45. Web site: Daniel H. Efron Research Previous Award Winners . 2022-05-15 . ACNP . en-US.
  46. Web site: 2018-10-17 . Neuroscientist and Stem Cell Biologist Sergiu Pasca to Receive ASCB Early Career Life Scientist Award . 2022-05-15 . ASCB . en-US.
  47. News: Weintraub . Karen . 2018-05-24 . Using Medicine and Science to Improve the Quality of Life . en-US . The New York Times . 2022-05-15 . 0362-4331.
  48. Web site: Sergiu P. Pasca . 2022-05-15 . Vilcek Foundation . en-US.
  49. Web site: American Society for Neurochemistry - Recipients of the Jordi Folch-Pi Award . 2022-05-15 . www.asneurochem.org.
  50. Web site: 2017-07-18 . Sergiu P. Pasca, M.D. . 2022-05-15 . Brain & Behavior Research Foundation . en.
  51. Web site: 2020-10-28 . Identifying cellular mechanisms of disease and novel therapeutic targets in neurons derived from patients with schizophrenia MQ Mental Health Research . 2022-05-15 . www.mqmentalhealth.org . en-us.
  52. Web site: University . © Stanford . Stanford . California 94305 . 2017-07-03 . Sammy Kuo Award Winners . 2022-05-15 . Wu Tsai Neurosciences Institute . en.
  53. Web site: EXCLUSIV Sergiu Pașca, studentul român al anului 2012 din străinătate: "Ar fi trebuit să plec la studii mai devreme" . Craciun, Oana. Adevărul. 14 January 2013 . 13 March 2016 . ro.

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