Scientist uses 'mini brains' to model how to prevent development of abnormally small heads

March 27, 2020

DUARTE, Calif. -- A City of Hope scientist is one step closer to discovering what weakens a pathogen that appears to cause babies to be born with abnormally small heads.

Interestingly, it takes studying "mini brains" to understand why certain unborn babies infected with cytomegalovirus (CMV) enter the world with shrunken brains, said Yanhong Shi, Ph.D., senior author of the new study, director of the Division of Stem Cell Biology Research and the Herbert Horvitz Professor in Neuroscience at City of Hope.

In the United States, the most common cause of infectious-related birth defects is CMV. About 1 in 5 babies with congenital CMV infection will have birth defects or other long-term health problems. Among those congenital conditions is microcephaly, or abnormally small heads, a concern many soon-to-be mothers had during the 2015 Zika outbreak. However, CMV is a far more common culprit for microcephaly, Shi said.

"We are among the first to model human CMV-induced microcephaly using brain organoids. This is a first step to one day studying more complex neurological complications such as Alzheimer's disease and Parkinson's disease," Shi said, adding that much more developed brain organoids, as the mini brains are more popularly known, are needed for scientists to study complex nervous system diseases that develop later in life.

The study, published in Cell Reports Medicine on March 25, solves a problem that has befuddled scientists for decades - how to create an experimental model that can mimic the complexities of the human brain in order to study neurological disorders. Until recently, scientists were restrained to studying the problem mostly in two dimensional models in a petri dish because they couldn't replicate many key features of neurological disorders in animal models. Notably, animals cannot be used to study human CMV (HCMV)-specific brain disorders because the disease is specific to humans.

Shi and her colleagues, however, found that a strain of HCMV called TB40/E appeared to replicate what HCMV does to an unborn baby's brain in the transition between the first and second trimester. The TB40/E-infected brain organoids were significantly smaller than the control models. Of the 10 genes that were reduced, three were related to calcium signaling, an indication that brain connections were not being made and that the brain's electrical network was not functioning properly. Further testing showed that TB40/E affected critical genes involved in brain development, including ones responsible for the development of the hippocampus, the center of learning and memory.

"A similar organoid strategy can be used to understand how infection by the SARS-CoV-2 virus leads to COVID-19 so that we can test potential therapies for the disease," said Guoqiang Sun, Ph.D., lead author of the study and a staff scientist in the Department of Developmental and Stem Cell Biology at Beckman Research Institute of City of Hope.

To take the study one step further, Shi and her colleagues collaborated across disciplines with Don Diamond, Ph.D., professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope. Diamond has been studying CMV for three decades and is developing vaccines to prevent congenital CMV infection.

The City of Hope scientists tested what could one day prevent or lessen the birth defects created by HCMV-induced microcephaly. They introduced a protective immune system antibody currently in development in the Diamond Lab. When tested in the brain organoid model, it appeared early intervention with these "neutralizing antibodies" may prevent or reduce the most severe consequences of HCMV infection.

"Now that we have a model that replicates how HCMV-induced microcephaly happens, we can use it to test antiviral agents," Shi said. "We can now start looking for real-world solutions."
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Other significant contributors of this study include Xianwei Chen, Ph.D., from the Shi Laboratory at City of Hope, and Flavia Chiuppesi, Ph.D., and Felix Wussow, Ph.D., from the Diamond Laboratory at City of Hope. Scientists at the Salk Institute for Biological Studies and Perelman School of Medicine at University of Pennsylvania also contributed to this study.

The research was supported by the Louise and Herbert Horvitz Charitable Foundation, Sidell-Kagan Scientific & Medical Research Foundation, California Institute for Regenerative Medicine (TRAN1-08525), National Institute of Aging of the National Institutes of Health (R01AG056305, RF1AG061794 and R56AG061171), National Institutes of Health (U19AI131130, R35NS097370 and R37NS047344), Helmsley Charitable Trust (2017-PG-MED001), Grace Foundation, JPB Foundation, Annette C. Merle-Smith Fowler Merle-Smith Family Charitable Lead Trust, Robert and Mary Jane Engman Foundation, Lynn and Edward Streim, Ray and Dagmar Dolby Family Fund, and U.S. Public Health Service (R01 AI103960).About City of Hope

City of Hope is an independent biomedical research and treatment center for cancer, diabetes and other life-threatening diseases. Founded in 1913, City of Hope is a leader in bone marrow transplantation and immunotherapy such as CAR T cell therapy. City of Hope's translational research and personalized treatment protocols advance care throughout the world. Human synthetic insulin and numerous breakthrough cancer drugs are based on technology developed at the institution. A National Cancer Institute-designated comprehensive cancer center and a founding member of the National Comprehensive Cancer Network, City of Hope is the highest ranked cancer hospital in the West, according to U.S. News & World Report's Best Hospitals: Specialty Ranking. Its main campus is located near Los Angeles, with additional locations throughout Southern California. For more information about City of Hope, follow us on Facebook, Twitter, YouTube or Instagram.

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