Brain cell tumors, grown in the laboratory for more than a year, reflect changes in a newborn brain Science

By Kelly Servick22 February 2021, 11:00

Put human stem cells in a laboratory dish with the right nutrients, and they will do their best to form a brain. They will fail, but you will get an organoid: a semi-organized cells. Organoids have become a powerful tool for studying brain development and diseases, but researchers assume that these microscopic spots only reflect a brain’s prenatal development – the earliest and simplest stage. A study today shows that with enough time, organoid cells can adopt some of the genetic signatures that brain cells display after birth, potentially increasing the range of disorders and developmental stages they can recreate.

‘Things I would say, before I saw this paper, that you can‘not to do with organoids … actually, maybe you can, “says Madeline Lancaster, a developmental geneticist at the Medical Research Council.‘s Laboratory for Molecular Biology. Lancaster, for example, was not optimistic about the use of organoids to study schizophrenia, which presumably appears in the brain after birth, once neural communication becomes more complex. But she now wonders whether cells from a person with this disorder – which was once ‘reprogrammed’ to a primitive stem cell condition and was encouraged to age in a brain organoid – may reveal important cellular differences underlying the condition.

Stanford University neurobiologist Sergiu Pașca has been making brain organoids for about ten years, and his team has learned that some of these tissue can thrive in a dish for years. In the new study, they collaborated with neurogeneticist Daniel Geschwind and colleagues at the University of California, Los Angeles (UCLA), to analyze how the spots changed during their lifetime.

The researchers exposed human stem cells to a specific set of growth-promoting nutrients to create spherical organoids that contain neurons and other cell types found in the outer layers of the brain. They regularly removed cells to sequence their RNA, indicating which genes are active in producing proteins. Then they compared this gene expression to a database of RNA from cells of human brains of different ages. They noted that when an organoid became 250 to 300 days old – about nine months – its gene expression changed shortly after the birth of the cells of human brains. The cells’ patterns of methylation – chemical labels that can attach to DNA and affect gene activity – are also consistent with increasingly mature human brain cells as the organoids age, the team reported today in Natural Neuroscience.

The researchers documented other signals of maturity in their organoids. Around the time of birth, some brain cells gradually shift to make more of one variant of a protein and of another. A component of a brain cell receptor called NMDA, the key to neuronal communication, is among the proteins that link in shape. And organoid cells, just like their counterparts in the developing brain, made the NMDA switch.

The findings do not mean that the spot itself is comparable to a postnatal brain, warns Pașca. Its electrical activity does not correspond to, for example, an adult brain, and the number of cells does not have important characteristics, including blood vessels, immune cells and sensory inputs. What is striking, however, is that, even in the unnatural circumstances of a laboratory dish, ‘the cells only know how to progress, ”says Pașca.

Organic cells and real brain cells may not mature in a perfect way, says Aparna Bhaduri, a developmental neurobiologist at UCLA, who was not involved in the new work. In a previous study, she and her colleagues found that organoid cells showed important genetic differences from fetal brain cells, along with signs of metabolic stress. She says it is reassuring that the major changes seen during birth appear in the new study in an organoid, just when scientists would expect – about 9 months.

The Pașca team also looked at the expression of genes associated with brain disorders, including autism, schizophrenia, epilepsy and Alzheimer’s disease. The scientists identified clusters of these genes whose activity increased and decreased in step and at the same time reached their peak. The crest can indicate when those genes are most important for brain development – and at what point an organoid may be most helpful in modeling a given disease.

Now that this is clear, an organoid’s cells can run through some of the normal developmental routines of the human brain, Pașca.‘team is exploring ways to “push [the organoids] back and forth in time to get the right period for a disease model, ”he says. This could enable his group and others to study brain diseases in adult organoids without caring for cells for years.