Schizophrenia is an incredibly difficult illness to treat and to live with every day. Patients and their families struggle to manage medication, side effects, and therapy, and it never goes away completely. It’s not a well-understood disorder, but new research into how it begins might be able to change that, thanks to some tiny, lab-created brains.
Michal Stachowiak, Ph.D., Professor, Department of Pathology and Anatomical Sciences at the University of Buffalo Jacobs School of Medicine and Biomedical Sciences was the lead author of the research which is the first of its kind to show the beginnings of mental illness. He explained, “This disease has been mischaracterized for 4,000 years. After centuries of horrendous treatment, including even the jailing of patients, and after it has been characterized as everything from a disease of the spirit or moral values or caused by bad parental influence (a concept that appeared in psychiatric textbooks as recently as 1975) we finally now have evidence that schizophrenia is a disorder that results from a fundamental alteration in the formation and structure of the brain.”
Symptoms of schizophrenia often appear in late adolescence or early adulthood, but the team in Buffalo showed that the roots of the disorder start before birth. It continues some of Stachowiak’s earlier work on the genetics of schizophrenia. While several different genes for the disorder have been identified, the crucial part of the findings is related to a genetic pathway where the genes all come together. It’s called the Integrative Nuclear FGFR 1 Signaling (INFS) pathway and the team wanted to know how it related to schizophrenia. Once this pathway is active, that is where the malformation of the progenitor cells happens that the team believes is the cause of schizophrenia. Their findings show how extremely early in fetal development a brain abnormality can take hold. While symptoms do not show up until years later, the die is cast when those cells form.
Growing “mini-brain” organoids from stem cells is one way to track development from the very beginning of cell division. Using skin cells from patients who had a diagnosis of schizophrenia, as well as healthy controls, they reprogrammed the organoids to try and recreate the process of brain development. They started with cells and nurtured them in vitro. The cells eventually developed embryoid bodies and brain tissue. In the mini-brains that came from schizophrenic patients, there were abnormally developed neural progenitor cells.
These are what turn into neurons that need to connect and function properly. Stachowiak described them saying, “At this stage, we discovered critical malformations in the cortex of the mini-brains formed from the iPSCs of the patients with schizophrenia.” The location of these malformed cells was in a part of the brain that processes memory, attention, cognition, language, and consciousness. The work is vital to understanding how to treat patients with schizophrenia. Knowing that it begins as a malformation of brain tissue in early pregnancy is key to looking for treatments. The video below talks about the work, check it out.