ABOVE: As researchers advance the complexity of mini brains, they grapple with major ethical questions about consciousness in a culture dish. Muotri Lab, UC San Diego

At the University of California, San Diego, Alysson Muotri’s research interests break though barriers of space and time. Conjuring scenes from a science fiction film, Muotri studies brain organoids—miniature brains derived from human pluripotent stem cells that exhibit spontaneous neural oscillations, or rudimentary brainwaves. While these organoids mimic human brain development remarkably well, their use as models for studying Alzheimer’s disease and dementia is limited by the late onset of these disorders. To overcome the impracticality of waiting decades for brain organoids to sufficiently mature, Muotri sends them on NASA space missions to experience microgravity. When they return to earth, the cells undergo accelerated aging, making them ideal models for brain disorders that manifest later in life. Muotri’s space and time traveling mini brains advance scientists’ understanding of how aging affects the brain and transform futuristic concepts into reality.

          Alysson Muotri, PhD
Alysson Muotri, PhD 
Director, Stem Cell Program 
Professor of Pediatrics and Cellular & Molecular Medicine
University of California, San Diego
Muotri Lab, UC San Diego

What inspired you to collaborate with NASA?

I began looking for ways to speed up brain organoid maturation and came across literature suggesting that the activity of human telomeres is altered after exposure to microgravity. I thought that space travel may be an intriguing way to age brain organoid cells without having to manipulate them genetically or pharmacologically. I discussed these ideas with a group of science fiction enthusiasts from the University of California, San Diego. We asked questions like if we colonize Mars in the future, would the brains of human embryos function normally? How would the human brain develop in space? Sending human brain organoids to the space station seemed like an exciting project. It took almost ten years to bring these ideas to fruition because funding agencies were not interested at first. I did not have experience in space research, so the first mission was self-funded. Once we produced results, I received grants for the follow-up missions.

          Brain organoids in a culture dish
Muotri’s team grows brain organoids in a culture dish, then prepares them for lift off in collaboration with NASA.
Muotri Lab, UC San Diego

What have you learned from previous space missions?

Our missions usually last one month. When the organoids return, we perform gene expression studies and some histology analyses. In the first mission, we learned that the organoids survive in microgravity. Their shape is different because microgravity affects the migration pattern of the organoid cells during cortical formation. Gene expression after the mission showed signs of cellular senescence, such as increased inflammation, and we found alterations in telomeres as expected. The second mission was designed to validate some of the findings from the first mission. Unfortunately, due to a technical malfunction, we lost contact with the organoids and were unable to feed them, so they eventually died. We fixed the system hardware problems to improve reliability for future missions.

          High-resolution imaging of immunostained organoids
Muotri’s team performs high-resolution imaging of immunostained organoids to help them understand how the resident cells age after space missions.
Muotri Lab, UC San Diego

What are the challenges of studying organoids in space?

We grow the organoids and optimize their survival within a bioengineered, shoebox-sized system that will sustain them during the space mission. This autonomous system includes a battery, incubator, media replacement mechanism, camera, and microscope. The astronauts do not maintain the organoids. They just plug the system into a power cabinet and at the end of the mission they remove it, place it back in the capsule, and we pick it up. We create synchronous controls on earth to replicate the conditions of space flight, for example, shaking the boxes to mimic turbulence on the rocket. We use simulated microgravity as a control, but we cannot continually recreate microgravity for 30 days. It is impossible to replicate space conditions on earth, even with technologies like bioreactors, centrifuges, or other simulators. You can get close to it, but it’s not the same. We also grow several batches of organoids in parallel to accommodate potential last-minute changes in the rocket launch schedule.

     immunostained organoid
Slicing through a brain organoid and performing immunostaining reveals the inner space of mini brains.
Muotri Lab, UC San Diego

What are the broader implications of this work?

This work is a potential game changer for modeling late onset neurodegenerative diseases such as Alzheimer’s disease. In terms of cellular aging, we estimate that one month on the space station is equivalent to between 10–30 years on earth. If we can grow organoids in space for six months and then study them for their susceptibility to Alzheimer’s disease, we may be able to observe the presence of disease markers such as plaques and tangles and use the organoids to screen drugs. The idea of using the space station as an incubator for aging may be transformative.

     Image light microscopy to gain a bird’s-eye view of brain organoids
Muotri’s team uses light microscopy to gain a bird’s-eye view of brain organoids and understand their overall size, shape, and density while growing in culture.
Muotri Lab, UC San Diego

What are the ethical considerations for working with brain organoids?

This is all brand new. The ethical considerations are a gray zone now and will likely evolve to include a formal code of ethical conduct as we rapidly increase the complexity of brain organoids. Researchers are now vascularizing the organoids so that they grow larger and exhibit more neural oscillations. They are also attaching retinas to them so they can start receiving visual inputs. As we do these things, we get closer and closer to mimicking the human brain, in which case, the central question becomes, “Have brain organoids reached a level of consciousness where they are self aware and if so, what is their moral status?” 

     Brain organoid
Brain organoids are a world all their own. Using them as models for neurodegenerative diseases holds great promise for developing future therapies.
Muotri Lab, UC San Diego

This interview has been condensed and edited for clarity.