Common Food Additive Solves Decades-Long Neuroscience Problem

A food additive made mass production of brain organoids possible. Researchers can now study development and disease at scale.

A cross-disciplinary group of Wu Tsai Neuro researchers working with clusters of human neurons known as organoids aimed to expand their work and pursue larger scientific questions. The solution was all around them.

For nearly ten years, the Stanford Brain Organogenesis Program has advanced a transformative way to study the brain. Instead of relying on intact brain tissue from humans or animals, the team grows three-dimensional brain-like structures in the lab using stem cells, producing models referred to as human neural organoids and assembloids.

Launched in 2018 as part of the Wu Tsai Neurosciences Institute’s Big Ideas in Neuroscience initiative, the program united neuroscientists, chemists, engineers, and other experts to investigate areas such as pain pathways, genetic drivers of neurodevelopmental disorders, and innovative methods for exploring brain circuits.

Yet one persistent challenge has limited progress: scale. To gain deeper insights into brain development, uncover the roots of developmental disorders, and effectively test new therapies, researchers need the ability to generate thousands of organoids simultaneously, each with consistent size and shape.

Tackling the stickiness problem

The difficulty lies in the tendency of neural organoids to clump together, which prevents researchers from producing large numbers of them with uniform size and shape.

To address this, a group of neuroscientists and engineers led by Wu Tsai Neuro affiliates Sergiu Pasca, the Kenneth T. Norris, Jr. Professor of Psychiatry and Behavioral Sciences in the School of Medicine, and Sarah Heilshorn, the Rickey/Nielsen Professor in the School of Engineering, identified a surprisingly straightforward fix. As described in their June 27 report in Nature Biomedical Engineering, the key was xanthan gum, a widely used food additive that kept the organoids separate.

“We can easily make 10,000 of them now,” said Pasca, the Bonnie Uytengsu and Family Director of the Stanford Brain Organogenesis Program. In keeping with the program’s commitment to making their techniques widely available, they’ve already shared their approach so others can take advantage of it. “This, as with all of our methods, is open and freely accessible. There are already numerous labs that have implemented this technique.”

Early days of brain organoid studies

The path to scaling up was not always straightforward. About a dozen years ago, Pasca had just established a method for turning stem cells into three-dimensional brain-like tissues, now called regionalized neural organoids. At that time, he could only produce a small handful of these early models.

“In the early days, I had eight or nine of them, and I named each of them after mythological creatures,” Pasca recalled.

Pasca’s ultimate goal, however, was to gain deeper insight into how the brain develops—particularly the processes that can lead to conditions such as autism or Timothy syndrome. He was also interested in using organoids to test potential side effects of drugs on brain development. To pursue these questions, he explained, “we needed to produce thousands of organoids, and they should all be the same.”

He understood that progress would require collaboration across multiple disciplines. “I thought, ‘This is an emerging field and there are a lot of problems we’re going to face, and the way we’re going to face them and solve them is by implementing innovative technologies,’” Pasca said.

With this vision in mind, he partnered with Wu Tsai Neuro affiliate Karl Deisseroth, a neuroscientist and bioengineer, and assembled a broad team of experts. Together, with support from Wu Tsai Neuro’s Big Ideas in Neuroscience initiative, they launched the Stanford Brain Organogenesis Program.

The nonstick solution emerges

The stickiness problem reared its head soon after. Organoids were fusing together, resulting in smaller numbers of organoids of different shapes and sizes.

“People in the lab would constantly say, ‘I made a hundred organoids, but I ended up with twenty,’” Pasca said.

That was both a blessing and a curse. On the one hand, it suggested that researchers could stick two different kinds of organoids together—say, a tiny cerebellum and spinal cord—to study the development of more complex brain structures. Indeed, these assembloids are now a key part of Pasca and his colleagues’ work.

On the other hand, the team still needed to be able to create large numbers of organoids so they could gather precise data on brain development, screen drugs for growth defects, or carry out any number of other projects at scale.

One possibility would be to grow each organoid in a separate dish, but doing so is often inefficient. Instead, the lab needed something to keep organoids apart while growing them in batches, so Pasca worked with Heilshorn, a Stanford Brain Organogenesis Program collaborator and materials engineer, to try out some options.

The team ultimately looked at 23 different materials with an eye toward making their methods 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 said.

To test each one, they first grew organoids in a nutrient-rich liquid for six days, then added one of the test materials. After another 25 days, the team simply counted how many organoids remained.

Even in small amounts, xanthan gum prevented organoids from fusing together, and it did so without any side effects on organoid development. That meant that researchers could keep the organoids separated without biasing their experimental results.

Scaling up to drug testing

To demonstrate the potential of the technique, the team used it to address a real-world issue: Doctors often hesitate to prescribe potentially beneficial drugs to pregnant people and babies because they don’t know whether those drugs might harm developing brains. (Although FDA-approved drugs go through extensive testing, ethical concerns mean they are generally not tested on pregnant people or babies.)

To show how organoids address that problem, co-lead author Genta Narazaki, a visiting researcher in Pasca’s lab at the time the research was done, first grew 2,400 organoids in batches. Then, Narazaki added one of 298 FDA–approved drugs to each batch to see if any of them might cause growth defects. Working closely with co-lead author Yuki Miura in the Pasca lab, Narazaki showed that several drugs, including one used to treat breast cancer, stunted the growth of the organoids, suggesting they could be harmful to brain development.

That experiment shows that researchers could uncover potential side effects—and do so very efficiently, Pasca said: “One single experimenter produced thousands of cortical organoids on their own and tested almost 300 drugs.”

Pasca and his Stanford Brain Organogenesis Program colleagues are now hoping to use their technique to make progress on a number of neuropsychiatric disorders, such as autism, epilepsy, and schizophrenia. “Addressing those diseases is really important, but unless you scale up, there’s no way to make a dent,” Pasca said. “That’s the goal right now.”

Reference: “Scalable production of human cortical organoids using 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 Brain Organogenesis Big Idea 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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