Novel Therapeutics and Advanced Diagnostics > Mini Brains, Major Breakthroughs

Mini Brains, Major Breakthroughs

Transforming addiction treatment with organoid research

By Alison Caldwell, Ph.D. Photography by Paul Flessland Illustrations by Jason Schneider

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In a laboratory at Mayo Clinic, tiny clusters of human brain cells pulse with electrical activity. No larger than a pea, these three-dimensional structures are organoids — miniature living models of the human brain, grown in a dish from a patient’s own cells.

These “mini brains” allow researchers to witness in real time how different types of brain cells respond to different drugs, offering insights into psychiatric illnesses that were impossible to observe just a few years ago.

For millions of people worldwide struggling with poorly understood and difficult-to-treat alcohol and substance use disorders, these remarkable mini brains may revolutionize medicine’s understanding and treatment of addiction. Thanks to organoids, Ming-Fen Ho, Ph.D., and other researchers at Mayo Clinic are putting together the addiction puzzle, one piece at a time.

The Addiction Challenge

Substance use disorders and addiction have a wide range of impacts, spanning from the social and psychological to the physical. In 2020, over 14% of people in the U.S. aged 12 or older had experienced a substance use disorder in the prior year.

Addiction is extremely difficult to treat, not only because of the social stigma connected with the condition, but also because to scientists and clinicians the brain remains mostly a “black box.”

As neuroscientists make strides in understanding the molecular underpinnings of the brain via preclinical models, mental illnesses remain difficult to address.

"In psychiatry we don't have access to living human brain tissue,” says Dr. Ho, a stem cell biologist in the Department of Psychiatry and Psychology. “This is a major challenge for our research. It's not like cancer.

“When a patient has breast cancer, you can do a biopsy, you can study the tumor itself, but this is not what's happening in psychiatry. When patients come in with depression, we can’t ask them to give us a chunk of brain tissue to study."

As a result, clinicians remain in the dark about why some medications can work extremely well for certain patients with addiction while proving to be totally ineffective for others. But technologies like organoids are opening new avenues for understanding conditions like addiction, providing hope for these patients.

Understanding Organoids

Organoids represent a step beyond most preclinical models, allowing researchers to use a patient’s own cells to generate tiny organ-like models for research and testing. The process begins with a blood sample from a patient, which is used to generate induced pluripotent stem cells (iPSCs) — cells that are reprogrammed to an embryonic-like state, with the potential to develop into almost any cell type.

The iPSCs are guided into becoming early precursors of brain cells through specific chemical signals, then transferred into a special three-dimensional culture environment to allow them to organize into shapes similar to developing brain tissue.

Over the span of a few weeks or months, the organoids continue to develop and become more complex, containing a variety of brain cell types including neurons, astrocytes, oligodendrocytes, microglia and more. Collectively, these cells interact in ways similar to real brain tissue, providing a more relevant model than traditional two-dimensional cell cultures. In turn, this provides deeper insights when studying complex neurological conditions such as addiction, depression and schizophrenia.

The technology behind these models is complex, and Dr. Ho says it wouldn’t be possible without the collaborative Mayo Clinic environment.

"Mayo has a very unique culture and environment to make this possible,” she says. “This research is truly a team effort — it doesn’t come from just one person overnight. We start small, but we move really fast because the technology changes so quickly.”

Building the Foundation for Discovery

Mayo Clinic’s comprehensive infrastructure for organoid development enables the groundbreaking addictions work. This includes a massive biobank of blood samples from patients with a variety of mental health disorders, which has generated an iPSC biobank with hundreds of cell lines, each linked to comprehensive clinical data. In addition, Mayo Clinic’s cross-disciplinary approach to care and research has psychiatrists, bioinformaticians and biologists working together to care for patients, collect clinical data, and translate that data into new discoveries that lead to therapies and cures.

Combined with advanced technology platforms, this ecosystem allows scientists like Dr. Ho unprecedented access to a breadth and depth of data on conditions like addiction. And Dr. Ho is dedicated to turning those insights into meaningful changes for patients.

A Winding Road

Dr. Ho brings an unusual perspective to her work, as she originally pursued training as a registered nurse, where she worked directly with patients. In her interactions with patients, she says, “I saw that modern medicine is not perfect, and there was so much we could improve.” Concurrently, she noticed the engaging work of her physician partners who conducted research alongside their clinical responsibilities.

Though she had no formal scientific background, after practicing as a nurse for two years, she made a leap into research, moving to Australia to pursue a Ph.D. in molecular genetics. Following her dissertation, she came to Mayo Clinic as a research fellow in rheumatology but eventually found her way to neuropsychiatric disorders like depression and addiction.

“I was interested in the complexity of these conditions,” she says. “In addition to the overall complexity of the brain and the challenges we face with understanding it, patients rarely experience a single mental health disorder. Half of patients with alcohol addiction are depressed, and often people with depression struggle with substance abuse. The underlying biology is intertwined. There is a lot to discover here.”

It took Dr. Ho over a year of daily practice and experimentation to master the process of turning stem cells into brain organoids. Now, she and her team manage over 500 cell lines derived from patients.

Decoding Drug Responses

One major area of focus in Dr. Ho’s work is understanding the neurobiology of alcohol disorder and identifying biomarkers that may help predict treatment response.

In a 2024 study, under senior author and pharmacologist Richard Weinshilboum, M.D., Dr. Ho and a team of researchers discovered that certain genetic variants can influence how well patients respond to acamprosate, a medication used to treat alcohol disorder. This discovery could help clinicians predict which patients are most likely to benefit from this treatment.

The power of this research lies in its "multi-omics" approach. "Our work moves beyond traditional pharmacogenomics, which looks at how genes affect drug response, to a broader approach," says Dr. Weinshilboum, from the Center for Individualized Medicine and Department of Molecular Pharmacology and Experimental Therapeutics and Mary Lou and John H. Dasburg Professor of Cancer Genomics Research. "We examine proteins, genes and RNA all together, a multipronged strategy that enhances our understanding of this disorder."

Combining these types of insights with patient-derived organoids, researchers can better understand how each patient’s unique biology influences their neural responses to substances like alcohol or opioids, and how they respond to different treatments.

In one of her earlier studies, Dr. Ho discovered surprising differences between drugs that were expected to work similarly. She examined how mini brains responded to oxycodone (a common opioid pain killer) and buprenorphine (a drug used to treat opioid addiction). Both drugs target the same receptors in the brain but behaved completely differently at the cellular level. While oxycodone primarily affected neurons and activated immune-related signaling pathways, buprenorphine affected other types of brain cells without increasing immune signaling. 

“This approach allows us to examine both the activity of living cells and gene expression after treatment," says Dr. Ho. "We can observe changes that would be impossible to study safely in living humans.”

Ultimately, this research could lead to personalized treatment approaches.

“Every drug has a unique signature in the brain,” says Dr. Ho. “Patient-specific organoids will allow us to predict how a given drug might affect that person’s brain and determine the best therapeutic approach for each person.”

Precision Medicine in Action

This approach to research and treatment exemplifies Mayo Clinic's Bold. Forward. strategy to transform healthcare, moving away from population-based, one-size-fits-all approaches and toward proactive, personalized medicine.

The implications extend far beyond addiction treatment. Dr. Ho envisions a future where organoids become standard tools for drug discovery across psychiatry. “In cancer, they have clinical trials every day and new drugs almost every year,” she says. “But to develop one medication from the day you identify a compound to the day you get Food and Drug Administration approval requires at least 10 to 15 years on average. In psychiatry, we don't have as many targets for clinical trials, and for most addictions, we don't even have medications for treatment.”

Our research has the potential to predict whether a treatment will help or potentially cause harm before we even give the medication to a patient. That's the kind of precision medicine that can truly change lives.

— Ming-Fen Ho, Ph.D.

Patient-derived brain organoids could accelerate this timeline by serving as screening platforms for potential therapies. Rather than spending years testing compounds that may ultimately fail in clinical trials, researchers could identify promising candidates much earlier in the process.

The technology also holds promise beyond substance abuse, with potential applications for depression, schizophrenia and neurodegenerative diseases like dementia. As artificial intelligence and machine learning capabilities continue to advance, researchers will be better equipped to analyze the vast amounts of data these models generate, potentially uncovering patterns invisible to the human eye.

A Vision of Hope

Back in the laboratory, the tiny clusters of brain cells continue their rhythmic pulsing. Each recorded signal represents a step closer to understanding the human brain, one of medicine's most challenging frontiers. What once seemed like an insurmountable black box is slowly yielding its secrets.

This critical work has been made possible with support from the Terrance and Bette Noble Foundation, Donna M. Giordano, and other generous benefactors whose philanthropy has helped advance Dr. Ho’s organoid research and its applications in addiction treatment.

For the millions of people and families affected by addiction and other mental health conditions, these mini brains represent more than scientific curiosity. They embody hope for a future where psychiatric care moves beyond trial and error, where treatments can be tailored to individual biology, and where the stigma surrounding mental illness gives way to the recognition that these are medical conditions deserving of precision treatment.

For Dr. Ho, whose journey from nursing to neuroscience research was driven by a desire to improve patient care, this work represents the culmination of years spent seeking better answers.

“As a nurse, I followed protocols created by others,” she says. “But as a scientist, I can create new knowledge that can truly help patients. Our research has the potential to predict whether a treatment will help or potentially cause harm before we even give the medication to a patient. That's the kind of precision medicine that can truly change lives.”