Space-Grown Organoids and Proteomics Advance Human Disease Research
Space-grown organoids and proteomics are helping researchers study disease in new ways.
Miniature human brains floating aboard the International Space Station (ISS) may sound like science fiction, but for some researchers, space is becoming an invaluable laboratory for studying human disease.
As new approach methods (NAMs) continue to gain traction across biomedical research, scientists are turning to organoids—3D tissue models—to answer questions that are difficult to address using traditional animal models. At the same time, advances in proteomics are providing insights into how these systems function at a molecular level. Together, these technologies are creating new opportunities for disease modeling.
In an unexpected twist, spaceflight is emerging as a valuable platform for both, offering a new environment in which biological processes can be studied in ways that are difficult to replicate on Earth.
Researchers such as Dr. Alysson Muotri, a professor at the University of California, San Diego and the director of the Integrated Space Stem Cell Orbital Research (ISSCOR) Center, and Dr. Meenal Datta, an associate professor at the University of Notre Dame, are among those exploring how organoids, proteomics, and space biology can be combined to advance our understanding of human disease.
Why NAMs are opening new opportunities for proteomics
The use of organoids has expanded rapidly over the past decade as researchers seek more human-relevant systems for studying disease. Often generated from induced pluripotent stem cells (iPSCs), organoids can recreate key structural and functional features of human tissues, including the brain, intestine, liver, and lungs.
“Organoid-based systems offer the possibility to study human conditions in relevant tissues using a human genetic background,” said Muotri.
Unlike traditional animal models, organoids can also retain the genetic makeup of individual patients, enabling scientists to investigate disease in a biologically relevant context.
This ability is particularly valuable since findings from animal models do not always translate successfully to humans. While animal research has been vital in advancing biomedical science, differences between species can create important discrepancies in physiology. These differences can become even more pronounced at the proteomic level, where protein abundance and activity do not always mirror gene expression patterns. Animals also do not always have the human protein (ortholog) present and may have a different isoform profile to humans.
Organoids also have practical advantages as researchers can generate large numbers of organoids, allowing experiments to be repeated across diverse genetic backgrounds without many of the logistical limitations associated with animal studies.
“Different from animals, we can have unlimited stem cell-derived organoids to perform several experiments using a diverse human genetic background. This helps to accelerate discoveries, shortening the time to clinical trials and increasing the translational capacity,” Muotri explained.
Patient-derived organoids have become particularly valuable for modeling complex diseases. Brain organoids carrying mutations associated with Rett syndrome can reproduce aspects of human neurodevelopment that are difficult to capture in animal systems. Similarly, cancer organoids can recreate tumor architecture and cellular interactions in ways that more closely resemble human disease.
“I think it's very useful to have multiple models of a disease,” said Datta.
Rather than acting solely as ethical alternatives to animal models, organoids are increasingly being viewed as scientifically advantageous systems that can reveal aspects of human biology unavailable elsewhere. When combined with proteomics, these models allow researchers to better understand how diseases develop and respond to environmental change.
Why are researchers taking organoids into space?
While organoids are already powerful experimental systems on Earth, space provides something else entirely: a unique biological environment that can accelerate and amplify cellular processes.
Historically, space biology has focused on understanding how microgravity affects astronauts and living organisms. However, researchers are now viewing space as a tool that can help answer fundamental questions about human disease.
“The space environment is harsh on the human body. After a period in space, human cells show signs of accelerated senescence. While this is bad news for astronauts, over the past decade, we have learned how to leverage spaceflights to compress the developmental time of human neurodevelopment,” said Muotri.
His group has used brain organoids aboard the ISS to investigate neurodevelopmental disorders. By accelerating biological processes that normally unfold over months or years, microgravity may enable researchers to observe disease-related changes in a fraction of the time.
“The research has led to the first clinical trial for a neurological condition with space-enabled discoveries done with human brain organoids,” Muotri said.
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Datta's research explores a different disease area but reaches similar conclusions about the value of space-based models. Her team has developed glioblastoma organoids to investigate one of the most aggressive and treatment-resistant forms of brain cancer.
“We have been inspired by the work of Muotri and others, so we have flown cancer organoids specifically for glioblastoma,” said Datta. “We have fundamental questions in our lab that we're interested in, some centered around mechanobiology, and being able to alter gravity is very useful for studying those mechanobiological processes.”
“We're also interested in developing better models, or NAMs, for cancer, the immune system, and for other diseases,” explained Datta. “It is a struggle to produce reproducible and robust organoids on the ground, unlike genetically engineered mouse models that are clones.”
Results from the team's recent glioblastoma experiment suggest that microgravity may help overcome some of those limitations.
“In our first space flight with these glioblastoma organoids, we combined cancer cells and immune cells and we found that we have more matured and developed tumors when we grow them in space vs the same time on ground, which recapitulates a highly aggressive and immunosuppressive disease state that we see in patients, which is exactly what we were hoping to model,” said Datta.
One possible explanation for this accelerated biology is that microgravity removes many of the physical forces that influence biological systems on Earth.
“The fact that you're able to escape Earth's gravity and its gravitational effects, such as sedimentation and buoyancy, free convection, hydrostatic pressure, etc.,—those are all physical artifacts that compromise our ability to engineer 3D models on the ground,” said Datta.
As a result, organoids can develop in ways that more closely resemble human tissues.
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“Microgravity allows us to do this more robustly and reproducibly, and then an added benefit is that we have this accelerated development in space,” added Datta. “Depending on your biological system of interest, that could look like maturation, aging, dysfunction, or disease; space is basically an accelerator for biological research.”
However, although useful, neither of these researchers views these systems as perfect reproductions of disease.
“A model is a model, it's never going to perfectly recapitulate the human disease, but I think that you can learn something from each one. These space-grown organoids fit into that compendium of models that we need to fully understand the disease.” — Dr. Meenal Datta.
Proteomics as the bridge between NAMs and space biology
Organoids may provide the model, and space may provide the environment, but interpreting what happens inside these systems requires another layer of analysis, which is where proteomics comes in.
While genomic and transcriptomic methods reveal what cells could do, proteins provide a direct readout of what the cells are doing. As the functional molecules responsible for most biological processes, proteins offer a closer connection to cellular phenotype and disease progression.
“Recent research comparing gene expression at RNA and protein levels has suggested that the RNA does not always predict the amount of protein in the tissue. Plus, this inconsistency is even more pronounced in the brain,” explained Muotri. “Different from gene transcription, proteins are the effectors, the phenotypes of a cell.”
His group recently generated one of the most comprehensive proteomic datasets from space-grown organoids, mapping ~6,000 protein groups from human brain organoids that spent 30 days aboard the ISS. The dataset revealed both a stable core proteome and protein signatures that responded specifically to the space environment.
Continued advances in proteomic technologies are expanding what researchers can learn from these systems.
“The ISSCOR has created novel tools to perform single-cell proteomics, allowing us to investigate the protein abundance in several cell types from the same tissue,” Muotri said. “This new technology is revealing novel biology, including the identification of novel cell types and transient states, and perturbation at the protein level that was not possible to detect at RNA levels.”
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Datta's group similarly relies on protein-level analyses, although as part of a broader multiomics strategy.
“We are very interested in multiomics, because when it comes to these cancer–immune interactions or mechanobiological processes, these occur at multiple levels,” said Datta.
Proteomics provides an important layer of validation for findings generated through transcriptomics and other approaches.
“Protein is the confirmation of those potential pathways; you really have to see results at the protein level for it to be real.” — Dr. Meenal Datta.
This is especially valuable in spaceflight research, where samples are often limited, expensive, and difficult to obtain. By extracting as much information as possible from a small number of precious organoids, proteomics enables researchers to identify pathways associated with disease progression, cellular stress, maturation, and adaptation. Combined with transcriptomics, spatial biology, and imaging approaches, it is helping take space-grown organoids from interesting experimental systems into powerful platforms for biomedical discovery.
A new era for NAMs and proteomics
Bringing together NAMs, space biology, and proteomics is creating new opportunities to study human disease in ways that were previously impossible.
For many, these systems represent something entirely new.
“Brain organoids are a very complementary system to animal models, but these space-grown organoids are a completely new type of experimental system, opening new ways to study aging, regeneration, and degeneration,” said Muotri.
“My hope is that space organoids will accelerate and potentially replace part of the preclinical discovery pipeline, because the models that we use here on the ground, whether in vitro or in vivo, are just taking too long to go from discovery to patient,” added Datta.
While the field remains in its early stages, it seems that the fastest way to understand human biology is to place it somewhere it was never meant to be.
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