The project, which includes investigators from UCLA, the University of Southern California (USC), and the University of Münster in Germany, is funded by a three-year, $9 million grant from Aligning Science Across Parkinson’s, in partnership with The Michael J. Fox Foundation for Parkinson’s Research.

In the debilitating neurodegenerative condition, one of the major problems is that brain cells producing dopamine—the chemical in the brain that helps nerves coordinate muscle movement—die more rapidly than normal. As these cells die off, patients experience tremor, stiffness, and movement and balance issues.

“We think that Parkinson’s disease is caused by a combination of genetic traits in the patient and environmental exposures—especially to certain pesticides and air pollution,” said Clive Svendsen, PhD, executive director of the Cedars- Sinai Board of Governors Regenerative Medicine Institute and one of the principal investigators of the study. “It seems the genes load the gun while the environment pulls the trigger. With this grant, we will generate lines of stem cells from people living in a pesticide-treated area in the San Fernando Valley and attempt to figure out why some developed Parkinson’s and some did not.”

Svendsen said that only about 5%-10% of Parkinson’s disease cases are caused by a single genetic mutation, and evidence is building that mutations in many other areas of the genome may also contribute to disease.  

“If you have mutations in an array of different genes, we know that increases your risk for developing Parkinson’s,” Svendsen said. “We are trying to determine which of those genetic vulnerabilities interact with pesticides—and how. If we can figure that out, we can begin to think about new approaches to treatment.”

The team will recruit groups of relatives—some who developed Parkinson’s disease and some who did not. Investigators will reprogram participants’ cells to create induced pluripotent stem cells, which they can then turn into dopamine-producing neurons that replicate the brain cells at risk in Parkinson’s patients. They will then expose those cells to the pesticides or air pollution present where the participants live.

“By investigating how the environment and a person’s unique genetics interact to drive Parkinson’s, this team is uncovering the diverse biological drivers of the disease,” said Sonya Dumanis, PhD, managing director of ASAP. “This is exactly the kind of bold, integrative science the Collaborative Research Network is designed to accelerate. With a better understanding of these disease mechanisms, we can lay the groundwork for new, personalized therapeutics and better outcomes for Parkinson's patients."

 The investigators’ theory is that the dopamine neurons generated from people with Parkinson’s disease will die more quickly after pesticide exposure than the neurons from family members exposed to the same pesticides or air pollution who did not develop the disease.

“If that turns out to be the case, we can compare the genetic makeup of those individuals, and the proteins their genes express, and try to figure out what triggered the development of Parkinson’s disease in some of them but not others,” Svendsen said.

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More than 30% of clinical trials fail due to adverse drug reactions, and the up to $5,054,235.00 contract award by the Advanced Research Projects Agency for Health (ARPA-H) Computational ADME-Tox and Physiology Analysis for Safer Therapeutics (CATALYST) program, will address this longstanding challenge in drug development.

“Each year, many promising drugs fail in trials because animal tests and short-term lab studies cannot predict how medicines behave in real people over time,” said Nicholas Tatonetti, PhD, vice chair of Computational Biomedicine at Cedars-Sinai and the project's lead investigator. “These failures delay lifesaving treatments and drive up drug development costs.”

The new platform, called KronosRx, aims to reduce these failures by applying AI tools to “patient avatars”—sophisticated organoids and organ-on-chip systems derived from human stem cells—to help investigators predict drug toxicity that might otherwise harm clinical trial participants.

The avatars use tiny numbers of cells to mimic the function of whole organs and their immediate response to experimental medications. The AI models in the platform are trained using millions of anonymous patient data points from Cedars-Sinai’s extensive electronic health record network. The resulting platform can forecast an organ’s response to a medication over time—and across the diverse population of patients reflected in the Cedars-Sinai data.

“These AI systems don’t just predict whether a drug is safe or toxic; they model how risk evolves dynamically, accounting for age, a patient’s health, and other medications they might be taking,” Tatonetti said.

Investigators hope this approach will allow better predictive modeling that can evolve over time, reducing reliance on animal studies and improving safety for all patients.

“By creating a more reliable and human-relevant method for safety assessment, the KronosRx project aims to improve clinical trials and to shorten development timelines,” said Clive Svendsen, PhD, executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and an investigator on the KronosRx project.

The Cedars-Sinai KronosRx team includes leaders in computational biomedical innovation, stem cell biology and health informatics.

Tatonetti is leading project integration using biomedical data science and AI-driven drug discovery methods. Svendsen is applying induced pluripotent stem cells and organ chip technologies to better understand how common drugs may cause rare neurological side effects.

Arun Sharma, PhD, director of the Cedars-Sinai Center for Space Medicine Research in the Board of Governors Regenerative Medicine Institute, is using patient-specific cardiac organoid and organ chip systems to assess drug-induced cardiotoxicity. Graciela Gonzalez-Hernandez, PhD, professor and vice chair for Research and Education in the Department of Computational Biomedicine, is advancing the project’s AI and unstructured text data integration to connect molecular and clinical phenotypes.

The ultimate goal, Svendsen said, is to make critical treatments available to patients sooner.

“This approach allows AI to continually refine its forecasts as new evidence emerges, bridging the gap between computational prediction and real-world patient outcomes,” Svendsen said.

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There are currently three types of NAMS: organoids, organ-on-chip technology, and computational, or “in silico,” models.

In an editorial published this fall in the journal Cell Stem Cell, Svendsen discussed the promise and challenges surrounding these methods. He shared some of his thoughts with the Cedars-Sinai Newsroom.

How do the various new approaches work?

Organoids are small bundles of human cells that can mimic some of the function of complete organs.  While they can be generated from some adult human organs such as the gut, these adult organoids often have limited potential for cultivation and replication.  Instead we grow organoids from induced pluripotent stem cells, or iPSCs, which are mature adult human cells that have been reprogrammed into a state where they are immortal, can be replicated indefinitely and can become almost any cell type.

In organ-on-chip models, iPSC-derived organ-specific cells are grown in specially designed chips that mimic fluid flow in the body and replicate conditions cells would experience in an actual organ. In some cases, investigators are linking different types of organ chips—brain, heart, liver—as a way to replicate a complete human system.

With in silico models, AI tools are applied to large databases of human and animal data. These tools allow us to forecast how a drug works or whether it's toxic, based on data from similar drugs that have already undergone animal or human testing.

Why do we use animals, particularly mice, for medical research?

Mice and other animals provide us with a living physiological system with organs and circulation, which is something we haven’t been able to fully replicate in a laboratory dish. They also breed and age quickly, and we have learned to genetically engineer them to mimic many human diseases and conditions.

What is the downside to mice as a stand-in for humans?

Mouse biology and human biology are different in some important ways, including at the molecular level. In one recent case, we were studying a rare disease in children that hinges on a missing gene. When we attempted to create mice with this same disease by “knocking out” that gene—nothing happened. The mice did not develop the disease. It turns out that mice have another gene with very similar functions that is missing in humans. There are millions of genetic differences between mice and humans, and the smallest one can make a huge difference.

Which of the alternative approaches is most developed?

In silico is probably farthest ahead because AI is moving so quickly and we have so much data. Investigators who want to test a new drug can apply AI tools and plug the drug into large publicly available databases to learn how cells might react to that drug. And investigators who have discovered a genetic pathway that is potentially involved in a disease can plug the changes they observed into these databases to determine which drugs might reverse those changes.

Are we ready to make the leap from animal studies to these new scientific methods?

We are entering a transition period where these new technologies are starting to be used to enable new drug development.  These technologies are very, very new and there are only a few examples of where they have been successfully used as an alternative to laboratory animal research.  However,  with many exciting studies on the way, this is set to change in the near future. Stay tuned!

What should we do in the meantime?

Right now, combining some of these new methods with animal models is the best option. A laboratory animal is a complete living specimen. An organoid or organ chip offers actual human biology. And combining AI technology, animal models and organoids to test the same theory about how an organ works, how it goes wrong or how it may react to a new drug will ultimately be incredibly powerful. If all three approaches agree, you have a much greater chance of discovering something important for human health.  

Simultaneously, we will continue to study and test whether the new methods can provide more accurate information about human biology than laboratory animals can. I believe they eventually will, because we're constantly refining and improving NAMS technology. Ultimately, this will also provide a way to tailor our treatments to individuals as we can generate their organoids or organ chips, discover successful drug interactions, and then administer that drug to the same patient.  

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“Previous studies have shown that transfusions of blood or plasma from young mice improved cognitive decline in older mice, but that is difficult to translate into a therapy,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute and senior author of the study. “Our approach was to use young immune cells that we can manufacture in the lab—and we found that they have beneficial effects in both aging mice and mouse models of Alzheimer’s disease.”

The immune cells, called mononuclear phagocytes, circulate throughout the body disposing of harmful substances, but become less effective as we age.

The investigators used human induced pluripotent stem cells, which are adult cells that have been taken “back in time” to an early embryonic state, to generate young mononuclear phagocytes. When the young cells were infused into aging mice or a mouse model of Alzheimer’s disease, investigators noted several important changes.

First, the mice receiving the young cells performed better on memory tests than mice without cell treatment. These mice were also found to have more “mossy cells” in the hippocampus, a brain region critical for learning and memory.

“The numbers of mossy cells decline with aging and Alzheimer’s disease,” said Alexendra Moser, PhD, a project scientist in the Svendsen Lab and lead author of the study. “We did not see that decline in mice receiving young mononuclear phagocytes, and we believe this may be responsible for some of the memory improvements that we observed.”

Mice receiving the young mononuclear phagocytes also had healthier immune cells, called microglia, in their brains. These microglia use long thin branches to detect and clear debris and damaged cells. The branches shrink and retract due to aging and Alzheimer’s disease, but they remained long and healthy in mice receiving the therapy.

The mechanism behind the effects in the brain remain to be established. As the young mononuclear phagocytes did not appear to enter the brain, investigators believe the cells may have worked indirectly.

The cells could have released antiaging proteins or even tiny particles called extracellular vesicles, which are small enough to enter the brain. Or they could have absorbed pro-aging factors from the blood to keep them out of the brain. The mechanism of protection is the focus of ongoing studies to determine the most effective way to turn these findings into a therapy that could be used in a clinical trial in patients. 

“Because these young immune cells are created from stem cells, they could be used as personalized therapy with unlimited availability,” said Jeffrey A. Golden, MD, executive vice dean for Education and Research. “These findings show that short-term treatment improved cognition and brain health, making them a promising candidate to address age- and Alzheimer’s disease-related cognitive decline.”

Additional authors include Luz Jovita Dimas-Harms, Rachel M. Lipman, Jake Inzalaco, Shaughn Bell, Michelle Alcantara, Erikha Valenzuela, George Lawless, Simion Kreimer, Sarah J. Parker, and Helen S. Goodridge.

Funding: This work was supported by the Universal Sunlight Foundation, the Cedars-Sinai Center for Translational Geroscience, and the Cedars-Sinai Board of Governors Regenerative Medicine Institute.

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, hosted by Cedars-Sinai on Oct. 25.

“This meeting isn’t just for scientists,” said Michael I. Lewis, MD, program director of The Alpha Clinic at Cedars-Sinai and professor of Medicine. “It is for clinicians, patients and members of the public who are interested in learning more about cell and gene therapies, emerging technologies, innovative clinical trial designs and issues surrounding accessibility to these therapies for patients, such as financial barriers.”  

The symposium, sponsored by the California Institute for Regenerative Medicine (CIRM), will take place from 9 a.m.-5 p.m. at the Cedars-Sinai Silver Screen Theater in the Pacific Design Center. Virtual registration is also available.

Scientists from all nine California Alpha Clinics are set to speak. Along with Cedars-Sinai, institutions with alpha clinics include University of California, San Diego; University of California, Los Angeles; University of Southern California and Children’s Hospital Los Angeles; Stanford University; University of California, Irvine; University of California, Davis; City of Hope; and University of California, San Francisco.

Directors of several Alpha Clinics will moderate panel discussions, and directors of the Alpha Clinics at UC Irvine, UC San Diego, University of Southern California and UC Davis will participate in a discussion of Alpha Clinic operations. Daniela A. Bota, MD, PhD, director of the UC Irvine Alpha Clinic, will talk about chimeric antigen receptor (CAR) therapies, and Mark Walters, MD, UC San Francisco Alpha Clinic director, will discuss current gene therapies, future opportunities and barriers to treatment. 

Lewis expects speakers to highlight the importance of diversity in clinical trials, promote collaboration among researchers and showcase advances in cell and gene therapies.

“The symposium will look to the current status of the field and, more importantly, to the future, as new approaches and therapies are likely to rapidly expand,” said Clive Svendsen, PhD, co-associate project director of Cedars-Sinai's Alpha Clinic and executive director of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai. Svendsen recently co-authored a review paper published in Nature Medicine about stem cell-based therapies for neurological conditions.

The review paper describes stem cell-based treatments for a number of neurological disorders, including amyotrophic lateral sclerosis, also known as ALS. The condition affects nerve cells in the brain and spinal cord that control movement. ALS eventually causes loss of the ability to move, speak, eat and breathe. At this time there is no cure.

The Cedars-Sinai Alpha Clinic is conducting a trial of a therapy, developed by Svendsen and his team, using specially engineered cells to protect damaged motor neurons. To date, six patients have been treated, with no major complications.

Cedars-Sinai’s Alpha Clinic and others throughout California are developing stem-cell based therapies for a variety of conditions: 

• Cedars-Sinai is studying a therapy for retinitis pigmentosa, which breaks down cells in the light-sensitive layer at the back of the eye, the retina, leading to vision loss. The therapeutic cells in the trial release proteins that help protect retinal cells from damage.
• Cedars-Sinai investigators also are testing a treatment for pulmonary arterial hypertension, a rare condition in which elevated blood pressure in lung blood vessels can damage the heart. The initial study was led by Lewis, director of Respiratory Care Services at Cedars-Sinai, and Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute and associate project director of The Alpha Clinic. Investigators concluded that infusions of specialized cell products derived from heart tissue seemed to improve patients’ heart and lung health.
• Alpha Clinics throughout California are studying stem cell-based therapies for several other conditions—including movement disorders such as Parkinson’s disease and Huntington’s disease; Alzheimer’s disease; stroke; epilepsy; spinal cord injury; and multiple sclerosis.

“The Alpha Clinic network is dedicated to accelerating the work of institutions in California, such as Cedars-Sinai, that are developing and testing cell and gene therapies,” Marbán said. “It is a highly collaborative group, and we share resources including our expertise, our infrastructure and our experience with cell delivery to help each other.”

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is creating a resource laboratory to help advance stem cell-based technologies throughout Cedars-Sinai and across California. The institute will serve as a hub for the development of organ-on-a-chip and organoid models that bring precision to patient care and research.  

“We’ve developed extensive expertise in creating induced pluripotent stem cells from patients, then turning those into models of the liver, kidney, heart, lung, brain, spine, pituitary gland, pancreas and other organs,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute and professor of Biomedical Sciences and Medicine at Cedars-Sinai. “We’re now going to provide a core resource so that investigators across Cedars-Sinai and beyond can learn to use these technologies.”

The Cedars-Sinai Shared Resources Laboratory for Advanced Stem Cell Modeling is funded through a $4 million infrastructure grant from the California Institute for Regenerative Medicine (CIRM). The lab will be available to scientists throughout California.

“The Cedars-Sinai Shared Resources Laboratory will be part of a collaborative network of 11 such laboratories across California,” said Uta Grieshammer, CIRM SRL Program lead. “We are looking forward to supporting this network of labs as they share their expertise and provide access to cutting edge technologies, with the goal of accelerating discoveries in regenerative medicine and growing and diversifying the cohort of stem cell researchers in the state.”

Induced pluripotent stem cells, or iPSCs, are cells that can be turned into many different cell types. These cells, in turn, can be grown on specialized chips that allow them to function the way they would in organs in the body. The cells also can be developed into organoids, which are miniaturized, simplified cell groups that mimic some of the key functions of organs.

In recent years, Cedars-Sinai investigators have used organoids and organ-chip technology to study gastrointestinal disease, neurological disorders, Crohn’s disease, musculoskeletal disorders, pituitary tumors, liver diseases, ovarian and breast cancer, lung fibrosis, the cardiotoxicity of cancer therapies, and how cancer develops.

“IPSC-derived organoids hold tremendous promise as a way to further our understanding of cancer development and progression,” said Joshua Breunig, PhD, director of the Cell, Organoid, and Cancer Engineering Special Resource in the Board of Governors Regenerative Medicine Institute. “We can collect a patient’s normal cells, engineer them to become iPSCs and pair the resulting organoids with genetically engineered self-renewing tumors, allowing us to discover and test therapeutics in a more natural tissue-like context.”

In this way, the organoids can truly “personalize” disease models, Breunig said.

“This new resource will give researchers throughout California access to this exciting and powerful new technology,” said Arun Sharma, PhD, research scientist in the Board of Governors Regenerative Medicine Institute and the Smidt Heart Institute at Cedars-Sinai and project director of the new laboratory. “Several of our faculty are highly experienced in this area of research and we will provide outstanding training to others through our educational programs. This includes trainees from underrepresented groups who otherwise might not have access to these systems.”

Cedars-Sinai has received several previous grants from CIRM, including grants for training of graduate and postdoctoral students, grants to develop stem cell-based disease treatments, and grants for biomanufacturing of induced pluripotent stem cells.

“We have developed nearly 1,200 iPSC lines—from healthy patients as well as those with ALS [amyotrophic lateral sclerosis], Parkinson’s disease, Alzheimer’s disease, inflammatory bowel disease, pancreatic cancer and other conditions,” said Dhruv Sareen, PhD, founding executive director of the Cedars-Sinai Biomanufacturing Center and the iPSC Core. “We are putting these into organ-chip models to help us understand disease characteristics and discover new treatments. This new lab will help us—and scientists throughout California—make progress to benefit patients everywhere.”

Read more from Discoveries: Gut Check

“We will be conducting the entire induced pluripotent stem cell reprogramming process in space, and this is the first time this has been done,” said Arun Sharma, PhD, a stem cell biologist and research scientist with the Board of Governors Regenerative Medicine Institute at Cedars-Sinai.

Induced pluripotent stem cells, or iPSCs, are adult cells that are reprogrammed into a state where they can be turned into many other cell types. Large volumes of iPSCs are needed for research and to create stem-cell-based treatments for disease, and investigators believe that the microgravity environment of space could make it easier to manufacture the cells.

During the mission, funded through a NASA In Space Production Applications Award, astronauts aboard the International Space Station will work with cells supplied by the Allen Institute for Cell Science. They will add the elements that will reprogram the cells into stem cells, and periodically transfer the cells to an imaging system that allows investigators on Earth to check on their development.

“Reprogramming the cells is the first step in the iPSC manufacturing process,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute. “The next stage is expansion, which is the growth and replication of the cells so that we can produce billions of them. We want to know how microgravity affects these processes.”

Lessons learned in space will help determine whether large-scale stem cell manufacturing there is feasible, and also will inform biomanufacturing of stem cells on Earth, Svendsen said.

“This space mission will test stem cell manufacturing on a small scale,” said Dhruv Sareen, PhD, founding director of the Cedars-Sinai Biomanufacturing Center and the iPSC Core Facility. “We will use what we learn through these experiments, and lessons from our previous experiments with automated processes in space, to determine how to scale up and create best manufacturing practices for these cells.”

The astronauts will employ the same reprogramming technique developed and used at Cedars-Sinai.

After approximately one month, preserved samples of the cells from the mission will be returned to Earth for quality testing. If all goes well, a mission planned for next year will see the cells turned into brain and heart cells, Sharma said.

“On Earth, we have challenges growing iPSCs, but what if they grow beautifully in microgravity?” Svendsen said. “And what if cell lines created in space have unique characteristics? These are the big questions. And if in 20 years we're making stem cells in space, these experiments will be the origins of it.”

Cedars-Sinai partners in the mission include Axiom Space and BioServe Space Technologies. Project scientist Maedeh Mozneb, PhD, and research associate Madelyn Arzt are key members of the team from the Sharma Lab.

The mission will launch from NASA’s Kennedy Space Center in Florida, on a Northrop Grumman Cygnus spacecraft perched atop a SpaceX Falcon 9 rocket.

The launch is part of a series of NASA-funded missions in which Sharma, Svendsen and Sareen have played key roles. Sharma has also recently been awarded an International Space Station National Laboratory Igniting Innovation grant to conduct further stem cell experiments in space.

“This grant will build on our existing research into biomanufacturing in space with two additional missions,” Sharma said.

The first mission will focus on the creation of cardiac spheroids in space. Cardiac spheroids are tiny clumps of heart muscle cells and heart blood vessel cells, created from stem cells, that function much the way they do in an actual human heart.

“We want to see if the microgravity environment can facilitate the creation of these spheroids,” Sharma said. “It’s possible we’ll be able to achieve better symmetry in space than we can on Earth, where gravity compresses the spheroids against the dish.”

Following that mission, a second mission, connected to the White House Cancer Moonshot, will involve the use of these spheroids to test the potential heart damage (cardiotoxicity) caused by cancer drugs.

“My lab has conducted experiments using stem cell-derived heart cells to explain why and how cancer drugs can damage the heart,” Sharma said. “We’re hoping that these spheroids, created in space, will give us a better way to screen cancer drugs for cardiotoxicity.”

Learn more on the Cedars-Sinai Blog: Stem Cells in Space