image: This human brain organoid, grown from cultured cells in the Purcell lab at the Fralin Biomedical Research Institute, shows areas of rapid cell division (yellow) and maturing neurons (magenta and green).
Credit: Elizabeth Candelario and Xinyan Eaton/Virginia Tech
The image on Ryan Purcell’s monitor shows what looks like yellow sunbursts among threads of magenta and green. It’s a research image of a microscopic cluster of human neurons reaching for one another across the dark of a petri dish.
Together, this cluster of cells is called a brain organoid, and Purcell, an assistant professor at the Fralin Biomedical Research Institute at VTC, uses them to study a question that brought him to the institute: Why do some people born with a rare genetic deletion develop serious psychiatric disorders, while others with the same variant do not?
With the support of a research grant from the National Institute of Mental Health, Purcell is working to understand why 3q29 deletion syndrome can result in vastly different outcomes between individuals.
He suspects it may have something to do with iron.
A person with a 3q29 deletion carries just one copy instead of two of a series of 21 genes. The deletion is rare — affecting one in roughly 30,000 newborns. But it is among the strongest known genetic risk factors for serious psychiatric conditions such as schizophrenia, so researchers are interested in how it may alter brain development. And its effects are so unevenly distributed that two children with the same deletion can live very different lives.
“Some kids take a bit more time to meet developmental milestones but end up living largely independently,” Purcell said. “Other kids are profoundly disabled and need substantial support for the rest of their lives. We’re trying to get a better understanding of why there’s this wide variation.”
One of the genes lost in the 3q29 deletion encodes the transferrin receptor, a structure on the cell membrane that brings iron into the cell. Every organ uses iron, but the brain uses it in greater proportions, especially during early development.
All neurons rely on mitochondria to generate energy, and mitochondria, in turn, need iron to function. Because of this link, iron deficiency is already considered a risk factor for a range of brain disorders.
Purcell proposes that for children who carry the 3q29 deletion, a level of iron deficiency that would pass unnoticed in a typical child might be exacerbated by a reduced presence of the transferrin receptor typical of neurons affected by the deletion.
Iron deficiency is one of the most common nutrient deficiencies in the world. The World Health Organization estimates that it affects 269 million children under 5 years old. It is also common during pregnancy.
“Probably many pregnant women worldwide are somewhat iron deficient, even if it doesn’t rise to the level of anemia,” Purcell said. “We know that early life iron deficiency is associated with increased risk of psychiatric conditions, but we still understand very little about how iron deficiency may impact developing human neurons.”
In an analysis of the medical records of nearly 100 patients with the 3q29 deletion, Purcell's research collaborator Jennifer Mulle, a professor at Rutgers University, found that roughly one-third had a reported history of anemia. “That's about 10 times what we found in a control group,” Purcell said.
Preclinical studies in Purcell’s lab also support the iron hypothesis. Mice born with the same deletion have less iron in the brain than their wild-type counterparts. Human neurons, when deprived of iron in culture, appear to show mitochondrial dysfunction similar to that observed in donor cells from people with the deletion.
The two-year grant will help Purcell’s team more closely measure the effects of directly manipulating iron in brain organoids, testing whether a level of iron deficiency a healthy brain could tolerate becomes more harmful in a brain already genetically impaired in its ability to take in iron.