New research by a team that included four BBRF grantees has demonstrated the value of studying the causes of complex psychiatric illness by analyzing neurons grown in the laboratory, using stem-cell technology.

In experiments reported in Nature Communications, 2014 BBRF Young Investigator Ian Maze, Ph.D., a Howard Hughes Medical Institute Investigator at the Icahn School of Medicine at Mount Sinai, and 2019 BBRF Young Investigator Lorna A. Farrelly, Ph.D., also at Mount Sinai, and colleagues, used stem cell technology to identify a protein involved in the regulation of gene expression whose inhibition may help to ameliorate abnormalities in neurons that are associated with early pathology in schizophrenia. Adding to the interest of the finding, there is a known drug that can inhibit the protein in question, suggesting a potential future approach to treat or even prevent schizophrenia in some instances.

Developed in the second decade of the 2000s by researchers including BBRF Scientific Council members Ronald McKay, Ph.D., Stewart Anderson, M.D., Fred Gage, Ph.D. and Kristen Brennand, Ph.D., "human induced pluripotent stem cell" (hiPSC) technology involves harmlessly sampling cells (usually skin cells) from an individual and then genetically reprograming these cells to re-develop as other cell types. When reprogrammed as neural cells, these baby cells are grown in culture dishes, and can be brought together with other developing neurons to form "organoids," in which neurons and other cells found in the living brain wire together and form functional networks.

Not only does stem-cell technology enable researchers to generate virtually limitless quantities of live human neurons, overcoming the problem of having to rely on postmortem brain tissue to study brain tissue from psychiatric patients. Just as important, every cell perfectly represents the complex genetics of the patient whose donated skin cells are the basis of the organoid.

This makes hiPSC technology uniquely valuable in the study of illnesses like schizophrenia, in which genetic factors are strongly involved in causation, and pathology in many cases is hypothesized to have its origins in the early development of the brain—a phase that organoids can recapitulate in the lab.

The team, which included BBRF Scientific Council members Dr. Brennand (who is 2018 BBRF Maltz Prize winner, 2016 Independent Investigator and 2012 Young Investigator) and 2011 BBRF Lieber Prize winner and 2010 and 1998 BBRF Distinguished Investigator Carol A. Tamminga, M.D., induced skin cells sampled from individuals with schizophrenia to re-develop as neurons of the type found in the forebrain. Cells in the forebrain process information from the senses and are involved in thinking, perceiving, producing, and understanding language, as well as controlling motor function.

The team made an important observation in reprogrammed neurons derived from patient samples as these cells were maturing: they detected aberrant patterns of epigenetic activity. Epigenetics refers to molecular processes that affect the way specific genes are expressed in a cell. Every human cell contains an individual's entire genome, and gene-regulating factors, including epigenetic factors, determine when and where in the body or in an organ like the brain specific genes will be activated or repressed, depending upon the biological context.

The abnormal epigenetic pattern the team found is called hyperacetylation. Acetyl molecules are among the epigenetic factors that attach to DNA packaging proteins to encourage or repress gene activation. Hyperacetylation means that there are too many acetyl molecules attaching to bundles of DNA called histones. This causes one or more genes to be abnormally regulated.

The team also identified a specific protein, called BRD4, which, when blocked or repressed in its activity of "reading" the epigenetic state of a given histone, can restore or alleviate the severity of aberrant gene expression caused by hyperacetylation. Experiments indicated that a BRD4 inhibitor might specifically alleviate a kind of aberrant gene expression linked with schizophrenia.

This is exciting because a drug called JQ1 has been shown, in other research, to prevent interactions between proteins like BRD4 and bundled DNA. The drug has been tested in anti-cancer applications, but as the team notes, "the potential of using such inhibitors [of BRD4 and related proteins] to alleviate schizophrenia-related gene expression has remained unexplored."

The team proposes that treatments with JQ1 might "partially rescue" irregularities in gene expression associated with schizophrenia. They say their results warrant further experimental investigation of this possibility.

In addition to Drs. Brennand and Maze, Haitao Li, Ph.D. of Tsinghua University, PRC, was also a senior member of the team.