A person is declared dead when his heart stops beating. This is the case as every organ stops receiving the blood supply. The human brain has high energy needs, estimated to be 10 times that of other tissues of the body. This indicates that the brain must lose its activity soon after death. But recent researches show a gene that comes to life in the brain after death. Thus, these genes were aptly named the “zombie genes”.
Zombie genes are expressed in a single type of cell called glial cells (the inflammatory cells). In the experiment conducted, the cells lengthened like an arm after many hours of death.
“That glial cells enlarge after death isn’t very surprising as they are inflammatory cells whose job is basically to clean things up after brain injuries (like oxygen deprivation or stroke),” said Dr. Jeffrey Loeb, the John S. Garvin Professor and head of neurology and rehabilitation at the UIC College of Medicine and corresponding author of the paper.
Loeb added that the implications of this discovery seem to be more significant since most research studies that use postmortem human brain tissues to find treatments and potential cures for neurological disorders do not account for the activity of the cell.
An experiment on the human brain is really difficult. A fresh human brain helps to study the brain without RNA degradation but for most neuropsychiatric disorders (majorly Alzheimer’s disease, Autism, and Schizophrenia) only post mortem tissues are available.
The brain of alive cannot be used in a study, because sudden removal of brain tissue from a living person in many ways mimics a catastrophic event that occurs with a hypoxic (oxygen-deficient) brain injury or a traumatic death with blood loss.
Most studies on the human brain are performed after death with an average postmortem interval of more than 12 hours. Basically, animal models are used to study the human disease- development and treatment, which may fail to translate back to humans during clinical trials.
An experiment on the human brain especially is really difficult, and quite rare for understanding and developing treatments for neurological and psychiatric disorders, because of the relatively poor translatability from animal models.
“As a means to understand human neuropsychiatric disorders from human samples, we compared the transcription patterns and histological features of postmortem brain to fresh human neocortex isolated immediately following surgical removal”: said the researchers from the University of Illinois Chicago (UIC). The fresh human brain helps to study the brain without RNA degradation unlike postmortem brain.
“We decided to run a simulated death experiment by looking at the expression of all human genes, at time points from 0 to 24 hours, from a large block of recently collected brain tissues, which were allowed to sit at room temperature to replicate the postmortem interval”, said Loeb.
Another group of genes that rapidly degraded in hours after death are present in neurons and shown to be highly involved in human brain activity (such as memory, thinking, and seizure activity). Loeb said that these genes are important to researchers studying disorders like Alzheimer’s disease.
A third group of genes that are the ‘zombie genes’ increased their activity at the same time the neuronal genes were ramping down. The pattern of post-mortem seems to be at peak after approximately 12 hours.
Thus, for the interpretation of research studies on human brain disorder understanding these time-dependent changes in gene expression in post mortem samples of the brain is critical.
“Our findings do not mean that we should throw away human tissue research programs, it just means that researchers need to take into account these genetic and cellular changes, and reduce the post-mortem interval as much as possible to reduce the magnitude of these changes”, added Loeb.
Loeb and his team even noticed that the global pattern of gene expression in fresh human brain tissue didn’t match any of the published reports on postmortem brain gene expression in people with or without neurological disorders.
Loeb is director of the UI NeuroRepository, a bank of human brain tissues. Thus, he collected and stored neural tissues from consented patients with neurological disorders either after they died or during standard care surgery to treat disorders like epilepsy. So, studying the brain tissue was a bit easier in terms of availability to Loeb and colleagues.
For example, during certain surgeries to treat epilepsy, epileptic brain tissue is removed to help eliminate seizures. Not all of the tissue is needed for pathological diagnosis, so some can be used for research. This is the tissue that Loeb and colleagues analyzed in their research.
Loeb said, “our findings will be needed to interpret research on human brain tissues. We just haven’t quantified these changes until now.
“The good news from our findings is that we now know which genes and cell types are stable, which degrade, and which increase over time so that results from postmortem brain studies can be better understood”, he further added.
Fabien Dachet, James B. Brown, Tibor Valyi-Nagy, Kunwar D. Narayan, Anna Serafini, Nathan Boley, Thomas R. Gingeras, Susan E. Celniker, Gayatry Mohapatra, Jeffrey A. Loeb. Selective time-dependent changes in activity and cell-specific gene expression in human postmortem brain. Scientific Reports, 2021; 11 (1) DOI: 10.1038/s41598-021-85801-6Fabien
Dachet, Tibor Valyi-Nagy, Kunwar Narayan, Anna Serafini and Gayatry Mohapatra of UIC; James Brown and Susan Celniker of Lawrence Berkeley National Laboratory; Nathan Boley of the University of California, Berkeley; and Thomas Gingeras of Cold Spring Harbor Laboratory are co-authors on the paper.
This research was funded by grants from the National Institutes of Health (R01NS109515, R56NS083527, and UL1TR002003).