Genes that code for the structure and function of brain regions essential for learning, memory, and decision-making are beginning to be revealed, according to a report published last October in Nature Genetics. Analyzing MRI scans and blood samples from more than 38,000 individuals, as well as gene expression, methylation, and neuropathology of hundreds of postmortem brains, an international team of researchers identified 199 genes that affect the development of the brain, the connections and communication among nerve cells, and susceptibility to neurological disorders.
New tools for studying neural tissue, such as RNA sequencing, have spurred a “very strong revival in studying human postmortem brains,” says Sabina Berretta, director of the Harvard Brain Tissue Resource Center at McLean Hospital in Boston. The Nature Genetics study and others like it have the potential to answer many questions about how the healthy brain functions, but they highlight one of the major challenges neuroscientists face right now—limited access to donated brain tissue, specifically from individuals unaffected by neurological disorders. While the Nature Genetics study included massive amounts of data from scans and blood, the researchers had gene expression data from only 508 postmortem brains.
“We are really fortunate to get donations from people with a very large variety of dementias and other neurological disorders, such as Parkinson’s and Huntington’s disease,” Berretta says. “But we get very few donations from people that suffer from psychiatric disorders, schizophrenia, bipolar disorder, major depression, and anxiety, and [even fewer from] unaffected donors.”
As a result, brain banks are reaching out to religious groups and also scientific communities not tied to any particular neurological condition to increase donations of healthy brains.
What brains end up in banks?
The McLean Hospital’s biobank has collected thousands of brains. While that may seem like a lot, it’s not enough to meet researchers’ demands, Berretta says. “It’s never enough because researchers are asking for more and more tissue for their studies.” Up until a decade ago, studies typically included tissue from a total of maybe 30 individuals, she estimates; now researchers want hundreds, if not thousands, of tissue samples from distinct individuals. That means the demand for brains is far greater than the supply for all individuals, and especially so for unaffected brains.
The reason brain donations from unaffected donors are important . . . is because we need to understand the human brain better.—Sabina Berretta, McLean Hospital
In the Nature Genetics study, the team was able to use brain tissue from unaffected donors, with the samples coming from came from two sources. One was the Religious Orders Study, which has been tracking the health of a group of nuns, priests, and other clergy members since 1993 and will eventually collect more than 1,000 unaffected brains as subjects die and donate their brains to the project. The other was the Rush Memory and Aging Project, started in 1997, to build a cohort of diverse people who agree to yearly health testing and ultimately brain donation. These coordinated efforts are two of many brain banks making an effort to collect more unaffected brains. “These brains are absolutely vital,” says Steve Gentleman, the scientific director of Parkinson’s UK Brain Bank and a neuropathologist at University College London.
Gentleman notes that most of the unaffected donors currently signed up at the Parkinson’s UK Brain Bank are siblings or spouses of donors who have or had Parkinson’s disease. These are good controls for Parkinson’s studies because they are aged matched and live in similar environments to those with neurodegeneration. The drawback is, of course, that with no neurological disease they tend to live longer, sometimes much longer than those with brain disease, he says. By the time researchers are able to examine the unaffected brains, the donors may be in their 80s or 90s, making their brains hard to compare to those of individuals who died in their 50s or 60s.
Age also affects brain banking in another way. There aren’t many samples from children and young adults, says National Institute of Mental Health program officer Abigail Adebisi Soyombo-Shoola. “This is a very sensitive issue,” she says, explaining that the request for a child’s brain can come only hours after death. “At the same time, it is an area of need.” Many questions about brain development from infancy to adulthood in humans remain unanswered, and childhood and adolescence are periods when autism and psychiatric disorders develop. Better understanding the genetics and biochemistry of children’s brains unaffected by those disorders might lead to better treatments, Soyombo-Shoola says.
Donations from young adults, individuals in their 20s and 30s, would also be helpful because these people have not yet experienced significant aging, Berretta notes. Their brains could reveal a lot about what happens as people get older even when they don’t show obvious signs of dementia or other neurological disorders. Ethnic diversity is also in demand, Berretta adds. Most donations today are from individuals of European descent, she says; some come from people of African or Asian descent but very few from Latinx populations.
How are brains donated?
Many brain banks work with medical examiners to acquire donations after a person has died, seeking permission from family members to use the neural tissue for research. But brain banks have been working to acquire donations before a person dies. In 2013, the National Institutes of Health launched the NeuroBioBank, a network of brain banks contracted to make the tissue more accessible to neuroscience investigators. A few years later, a non-profit called The Brain Donor Project was formed to raise awareness of the critical need for brain donation and make it easier to register in advance on their site. McLean also registers potential donors in advance. To further boost numbers, the banks rely on awareness campaigns to let people know that brain donation is an option and that their brains are needed for research; Parkinson’s UK Brain Bank will be launching one soon, Gentleman says. The banks also try to tap into communities that value collection of the tissue, including researchers, to encourage them to sign up as donors, and also to reach other groups, including religious organizations similar to those who donate to the Religious Orders Study.
“We don’t know as much as we think we do about the human brain,” Berretta says. Most of the assumptions made about human neurochemistry and circuitry are based on studies of species other than humans. And the difference between those species and humans are not as minor as researchers originally thought, she explains. “The reason brain donations from unaffected donors are important . . . is because we need to understand the human brain better.”
Correction (February 26): The story was updated to reflect the relationship between the National Institutes of Health and The Brain Donor Project.