Characterization of cortical organoids cultured with xanthan gum. Credit score: Nature Biomedical Engineering (2025). DOI: 10.1038/s41551-025-01427-3
An interdisciplinary crew engaged on balls of human neurons referred to as organoids needed to scale up their efforts and tackle essential new questions. The answer was throughout them.
For near a decade now, the Stanford Mind Organogenesis Program has spearheaded a revolutionary strategy to finding out the mind: Fairly than probe intact mind tissues in people and different animals, they develop three-dimensional brain-like tissues within the lab from stem cells, creating fashions referred to as human neural organoids and assembloids.
Starting in 2018 as a Large Concepts in Neuroscience mission of Stanford’s Wu Tsai Neurosciences Institute, this system has introduced collectively neuroscientists, chemists, engineers, and others to deal with the neural circuits concerned in ache, genes that drive neurodevelopmental problems, new methods to check mind circuits, and extra.
Nonetheless, one downside has dogged them: scale. If researchers may produce 1000’s of organoids directly with uniform dimension and form, they may be taught extra about mind improvement and developmental problems, and extra effectively check new medication and gene therapies.
The difficulty is, neural organoids have a behavior of sticking to one another, making it arduous to develop massive batches of them with constant dimension and form.
Now, a crew 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 Drugs, along with Sarah Heilshorn, the Rickey/Nielsen Professor within the College of Engineering, has discovered a easy answer. As they reported of their examine printed June 27 in Nature Biomedical Engineering, all it took to maintain organoids from sticking collectively was xanthan gum, a typical meals additive.
“We can easily make 10,000 of them now,” stated Pasca, the Bonnie Uytengsu and Household Director of the Stanford Mind Organogenesis Program. In line with this system’s dedication to creating their strategies broadly obtainable, they’ve already shared their strategy so others can make the most of it. “This, as with all of our methods, is open and freely accessible. There are already numerous labs that have implemented this technique.”
So few you would identify them
Issues weren’t at all times really easy. A couple of dozen years in the past, Pasca had simply developed a technique for reworking stem cells into the three-dimensional tissues now often known as regionalized neural organoids, and he may solely handle to make just a few of those early cultures.
“In the early days, I had eight or nine of them, and I named each of them after mythological creatures,” Pasca stated.
However Pasca needed to get a very good deal with on mind improvement—particularly, what occurs throughout improvement that results in problems like autism or Timothy syndrome—and deal with different concepts, similar to screening medication for potential unwanted side effects on mind improvement. To do this, he stated, “we needed to produce thousands of organoids, and they should all be the same.”
He additionally realized he would want to contain a variety of researchers. “I thought, “That is an rising area and there are numerous issues we’ll face, and the way in which we’ll face them and remedy them is by implementing progressive applied sciences,'” Pasca stated.
To maneuver ahead, Pasca teamed up with Wu Tsai Neuro affiliate Karl Deisseroth, a bioengineer and neuroscientist, and introduced collectively an interdisciplinary crew to launch the Stanford Mind Organogenesis Program with assist from Wu Tsai Neuro’s Large Concepts in Neuroscience grant.
The nonstick answer
The stickiness downside reared its head quickly after. Organoids have been fusing collectively, leading to smaller numbers of organoids of various sizes and shapes.
“People in the lab would constantly say, ‘I made a hundred organoids, but I ended up with 20,'” Pasca stated.
That was each a blessing and a curse. On the one hand, it instructed that researchers may stick two totally different sorts of organoids collectively—say, a tiny cerebellum and spinal wire—to check the event of extra complicated mind buildings. Certainly, these assembloids are actually a key a part of Pasca’s and his colleagues’ work.
Alternatively, the crew nonetheless wanted to have the ability to create massive numbers of organoids so they may collect exact information on mind improvement, display screen medication 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 totally different supplies with a watch towards making their strategies accessible to others.
“We selected materials that were already considered biocompatible and that would be relatively economical and simple to use, so that our methods could be adopted easily by other scientists,” Heilshorn stated.
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 unwanted side effects on organoid improvement. That meant that researchers may preserve the organoids separated with out biasing their experimental outcomes.
Scaling up ultimately
To show the potential of the approach, the crew used it to handle a real-world difficulty: Docs usually hesitate to prescribe probably helpful medication to pregnant individuals and infants as a result of they do not know whether or not these medication would possibly hurt growing brains. (Though FDA-approved medication undergo in depth testing, moral considerations imply they’re typically not examined on pregnant individuals or infants.)
To indicate how organoids handle that downside, co-lead writer Genta Narazaki, a visiting researcher in Pasca’s lab on the time the analysis was performed, first grew 2,400 organoids in batches. Then, Narazaki added one in every of 298 FDA–accredited medication to every batch to see if any of them would possibly trigger progress defects. Working carefully with co-lead writer Yuki Miura within the Pasca lab, Narazaki confirmed that a number of medication, together with one used to deal with breast most cancers, stunted the expansion of the organoids, suggesting they might be dangerous to mind improvement.
That experiment exhibits that researchers may uncover potential unwanted side effects—and accomplish that very effectively, Pasca stated, “One single experimenter produced thousands of cortical organoids on their own and tested almost 300 drugs.”
Pasca and his Stanford Mind Organogenesis Program colleagues are actually hoping to make use of their approach to make progress on a lot of neuropsychiatric problems, similar to autism, epilepsy, and schizophrenia. “Addressing those diseases is really important, but unless you scale up, there’s no way to make a dent,” Pasca stated. “That’s the goal right now.”
Extra data:
Genta Narazaki et al, Scalable manufacturing of human cortical organoids utilizing a biocompatible polymer, Nature Biomedical Engineering (2025). DOI: 10.1038/s41551-025-01427-3
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