Nav: Home

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."
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.

City of Hope

Related Brain Articles:

Unique insight into development of the human brain: Model of the early embryonic brain
Stem cell researchers from the University of Copenhagen have designed a model of an early embryonic brain.
An optical brain-to-brain interface supports information exchange for locomotion control
Chinese researchers established an optical BtBI that supports rapid information transmission for precise locomotion control, thus providing a proof-of-principle demonstration of fast BtBI for real-time behavioral control.
Transplanting human nerve cells into a mouse brain reveals how they wire into brain circuits
A team of researchers led by Pierre Vanderhaeghen and Vincent Bonin (VIB-KU Leuven, Université libre de Bruxelles and NERF) showed how human nerve cells can develop at their own pace, and form highly precise connections with the surrounding mouse brain cells.
Brain scans reveal how the human brain compensates when one hemisphere is removed
Researchers studying six adults who had one of their brain hemispheres removed during childhood to reduce epileptic seizures found that the remaining half of the brain formed unusually strong connections between different functional brain networks, which potentially help the body to function as if the brain were intact.
Alcohol byproduct contributes to brain chemistry changes in specific brain regions
Study of mouse models provides clear implications for new targets to treat alcohol use disorder and fetal alcohol syndrome.
Scientists predict the areas of the brain to stimulate transitions between different brain states
Using a computer model of the brain, Gustavo Deco, director of the Center for Brain and Cognition, and Josephine Cruzat, a member of his team, together with a group of international collaborators, have developed an innovative method published in Proceedings of the National Academy of Sciences on Sept.
BRAIN Initiative tool may transform how scientists study brain structure and function
Researchers have developed a high-tech support system that can keep a large mammalian brain from rapidly decomposing in the hours after death, enabling study of certain molecular and cellular functions.
Wiring diagram of the brain provides a clearer picture of brain scan data
In a study published today in the journal BRAIN, neuroscientists led by Michael D.
Blue Brain Project releases first-ever digital 3D brain cell atlas
The Blue Brain Cell Atlas is like ''going from hand-drawn maps to Google Earth'' -- providing previously unavailable information on major cell types, numbers and positions in all 737 brain regions.
Landmark study reveals no benefit to costly and risky brain cooling after brain injury
A landmark study, led by Monash University researchers, has definitively found that the practice of cooling the body and brain in patients who have recently received a severe traumatic brain injury, has no impact on the patient's long-term outcome.
More Brain News and Brain Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Making Amends
What makes a true apology? What does it mean to make amends for past mistakes? This hour, TED speakers explore how repairing the wrongs of the past is the first step toward healing for the future. Guests include historian and preservationist Brent Leggs, law professor Martha Minow, librarian Dawn Wacek, and playwright V (formerly Eve Ensler).
Now Playing: Science for the People

#566 Is Your Gut Leaking?
This week we're busting the human gut wide open with Dr. Alessio Fasano from the Center for Celiac Research and Treatment at Massachusetts General Hospital. Join host Anika Hazra for our discussion separating fact from fiction on the controversial topic of leaky gut syndrome. We cover everything from what causes a leaky gut to interpreting the results of a gut microbiome test! Related links: Center for Celiac Research and Treatment website and their YouTube channel
Now Playing: Radiolab

The Flag and the Fury
How do you actually make change in the world? For 126 years, Mississippi has had the Confederate battle flag on their state flag, and they were the last state in the nation where that emblem remained "officially" flying.  A few days ago, that flag came down. A few days before that, it coming down would have seemed impossible. We dive into the story behind this de-flagging: a journey involving a clash of histories, designs, families, and even cheerleading. This show is a collaboration with OSM Audio. Kiese Laymon's memoir Heavy is here. And the Hospitality Flag webpage is here.