A meals additive made mass manufacturing of mind organoids doable. Researchers can now examine improvement and illness at scale.
A cross-disciplinary group of Wu Tsai Neuro researchers working with clusters of human neurons often known as organoids aimed to increase their work and pursue bigger scientific questions. The answer was throughout them.
For almost ten years, the Stanford Mind Organogenesis Program has superior a transformative solution to examine the mind. As a substitute of counting on intact mind tissue from people or animals, the crew grows three-dimensional brain-like constructions within the lab utilizing stem cells, producing fashions known as human neural organoids and assembloids.
Launched in 2018 as a part of the Wu Tsai Neurosciences Institute’s Large Concepts in Neuroscience initiative, this system united neuroscientists, chemists, engineers, and different consultants to research areas resembling ache pathways, genetic drivers of neurodevelopmental problems, and revolutionary strategies for exploring mind circuits.
But one persistent problem has restricted progress: scale. To achieve deeper insights into mind improvement, uncover the roots of developmental problems, and successfully check new therapies, researchers want the flexibility to generate hundreds of organoids concurrently, every with constant dimension and form.
Tackling the stickiness drawback
The problem lies within the tendency of neural organoids to clump collectively, which prevents researchers from producing massive numbers of them with uniform dimension and form.
To deal with this, a gaggle of neuroscientists and engineers led by Wu Tsai Neuro associates Sergiu Pasca, the Kenneth T. Norris, Jr. Professor of Psychiatry and Behavioral Sciences within the College of Medication, and Sarah Heilshorn, the Rickey/Nielsen Professor within the College of Engineering, recognized a surprisingly easy repair. As described of their June 27 report in Nature Biomedical Engineering, the important thing was xanthan gum, a extensively used meals additive that saved the organoids separate.
“We will simply make 10,000 of them now,” mentioned Pasca, the Bonnie Uytengsu and Household Director of the Stanford Mind Organogenesis Program. In line with this system’s dedication to creating their strategies extensively out there, they’ve already shared their strategy so others can benefit from it. “This, as with all of our strategies, is open and freely accessible. There are already quite a few labs which have carried out this method.”
Early days of mind organoid research
The trail to scaling up was not all the time easy. A few dozen years in the past, Pasca had simply established a way for turning stem cells into three-dimensional brain-like tissues, now referred to as regionalized neural organoids. At the moment, he might solely produce a small handful of those early fashions.
“Within the early days, I had eight or 9 of them, and I named every of them after mythological creatures,” Pasca recalled.
Pasca’s final objective, nevertheless, was to achieve deeper perception into how the mind develops—significantly the processes that may result in situations resembling autism or Timothy syndrome. He was additionally all for utilizing organoids to check potential unintended effects of medicine on mind improvement. To pursue these questions, he defined, “we wanted to supply hundreds of organoids, and they need to all be the identical.”
He understood that progress would require collaboration throughout a number of disciplines. “I assumed, ‘That is an rising discipline and there are a variety of issues we’re going to face, and the way in which we’re going to face them and resolve them is by implementing revolutionary applied sciences,’” Pasca mentioned.
With this imaginative and prescient in thoughts, he partnered with Wu Tsai Neuro affiliate Karl Deisseroth, a neuroscientist and bioengineer, and assembled a broad crew of consultants. Collectively, with assist from Wu Tsai Neuro’s Large Concepts in Neuroscience initiative, they launched the Stanford Mind Organogenesis Program.
The nonstick answer emerges
The stickiness drawback reared its head quickly after. Organoids have been fusing collectively, leading to smaller numbers of organoids of various sizes and styles.
“Individuals within the lab would always say, ‘I made 100 organoids, however I ended up with twenty,’” Pasca mentioned.
That was each a blessing and a curse. On the one hand, it recommended that researchers might stick two completely different sorts of organoids collectively—say, a tiny cerebellum and spinal twine—to review the event of extra complicated mind constructions. Certainly, these assembloids are actually a key a part of Pasca and his colleagues’ work.
Then again, the crew nonetheless wanted to have the ability to create massive numbers of organoids so they might collect exact knowledge on mind improvement, display screen medicine for progress defects, or perform any variety of different initiatives at scale.
One risk can be to develop every organoid in a separate dish, however doing so is usually inefficient. As a substitute, the lab wanted one thing to maintain organoids aside whereas rising them in batches, so Pasca labored with Heilshorn, a Stanford Mind Organogenesis Program collaborator and supplies engineer, to check out some choices.
The crew finally checked out 23 completely different supplies with an eye fixed towards making their strategies accessible to others.
“We chosen supplies that have been already thought of biocompatible and that might be comparatively economical and easy to make use of, in order that our strategies could possibly be adopted simply by different scientists,” Heilshorn mentioned.
To check every one, they first grew organoids in a nutrient-rich liquid for six days, then added one of many check supplies. After one other 25 days, the crew merely counted what number of organoids remained.
Even in small quantities, xanthan gum prevented organoids from fusing collectively, and it did so with none unintended effects on organoid improvement. That meant that researchers might hold the organoids separated with out biasing their experimental outcomes.
Scaling as much as drug testing
To reveal the potential of the method, the crew used it to handle a real-world challenge: Medical doctors usually hesitate to prescribe doubtlessly useful medicine to pregnant folks and infants as a result of they don’t know whether or not these medicine would possibly hurt growing brains. (Though FDA-approved medicine undergo intensive testing, moral considerations imply they’re usually not examined on pregnant folks or infants.)
To point out how organoids handle that drawback, co-lead creator Genta Narazaki, a visiting researcher in Pasca’s lab on the time the analysis was accomplished, first grew 2,400 organoids in batches. Then, Narazaki added one in every of 298 FDA–authorised medicine to every batch to see if any of them would possibly trigger progress defects. Working intently with co-lead creator Yuki Miura within the Pasca lab, Narazaki confirmed that a number of medicine, together with one used to deal with breast most cancers, stunted the expansion of the organoids, suggesting they could possibly be dangerous to mind improvement.
That experiment exhibits that researchers might uncover potential unintended effects—and achieve this very effectively, Pasca mentioned: “One single experimenter produced hundreds of cortical organoids on their very own and examined virtually 300 medicine.”
Pasca and his Stanford Mind Organogenesis Program colleagues are actually hoping to make use of their method to make progress on a variety of neuropsychiatric problems, resembling autism, epilepsy, and schizophrenia. “Addressing these illnesses is de facto vital, however except you scale up, there’s no solution to make a dent,” Pasca mentioned. “That’s the objective proper now.”
Reference: “Scalable manufacturing of human cortical organoids utilizing a biocompatible polymer” by Genta Narazaki, Yuki Miura, Sergey D. Pavlov, Mayuri Vijay Thete, Julien G. Roth, Merve Avar, Sungchul Shin, Ji-il Kim, Zuzana Hudacova, Sarah C. Heilshorn and Sergiu P. Pașca, 27 June 2025, Nature Biomedical Engineering.
DOI: 10.1038/s41551-025-01427-3
This work was supported by the Stanford Mind Organogenesis Large Thought Grant from the Wu Tsai Neurosciences Institute, the U.S. National Institutes of Health (MH107800, R01 EB027171, and R01 MH137333), the NYSCF Robertson Stem Cell Investigator Award, the Kwan Research Fund, the Coates Foundation, the Senkut Research Funds, The Ludwig Foundation, the Chan Zuckerberg Initiative Ben Barres Investigator Award, Stanford Medicine Dean’s Fellowship, the U.S. National Science Foundation (CBET 2033302, DMR 2103812, and DMR 2427971), a TAA Young Investigator Award, a Stanford Maternal and Child Health Research Institute Postdoctoral Fellowship, the Stanford Bio-X Undergraduate Summer Research Program, and SNSF Postdoc.Mobility Grant (222016).
Narasaki was an employee of Daiichi-Sankyo Co., Ltd, during the duration of this study, but the company did not have any input on the design of experiments and interpretation of the data. Stanford University holds a patent that covers the generation of cortical organoids (US patent 62/477,858), which has been commercially licensed to STEMCELL Technologies. Pasca is listed as an inventor on this patent. The other authors declare no competing interests.
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