Lab mice endure a lot for science, but there’s often one (temporary) compensation: near-miraculous recovery from diseases that kill people. Unfortunately, experimental drugs that have cured millions of mice with Alzheimer’s disease or schizophrenia or glioblastoma have cured zero people — reflecting the sad fact that, for many brain disorders, mice are pretty lousy models of how humans will respond to a drug.
Scientists have now discovered a key reason for that mouse-human disconnect, they reported on Wednesday: fundamental differences in the kinds of cells in each species’ cerebral cortex and, especially, in the activity of those cells’ key genes.
In the most detailed taxonomy of the human brain to date, a team of researchers as large as a symphony orchestra sorted brain cells not by their shape and location, as scientists have done for decades, but by what genes they used. Among the key findings: Mouse and human neurons that have been considered to be the same based on such standard classification schemes can have large (tenfold or greater) differences in the expression of genes for such key brain components as neurotransmitter receptors.
That makes neurons and circuits connecting brain regions, which were long thought to be essentially identical in mice and people, different in a fundamental way. And it could explain the abysmal record of drug development for neuropsychiatric diseases including schizophrenia, depression, bipolar disorder, and autism.
“All of the drugs people are trying to develop act on receptors or other molecules,” said neurobiologist Ed Lein of the Allen Institute for Brain Science in Seattle, who led the study, published in the journal Nature. “If the neurotransmitter receptor you’re hoping to target isn’t used in the same cells in humans that it is in mice, then your drug will hit the wrong circuit” and not have the same effect in patients as in lab rodents.
Knowing the extensive similarities in the brains of mice and humans, and the differences, should help those developing drugs for brain diseases “make better use of mouse models,” said neuroscientist Dr. Eric Nestler of the Icahn School of Medicine at Mount Sinai, who was not involved in the new study. “This type of very detailed molecular biology is a useful roadmap, and will much better inform the validity of animal models” of brain disorders.
That validity leaves a lot to be desired. Last year, scientists described neuropsychiatric drug development as “in the midst of a crisis” because of all the mouse findings that fail to translate to people. Of every 100 neuropsychiatric drugs tested in clinical trials — usually after they “work” in mice — only nine become approved medications, one of the lowest rates of all disease categories.
Among the many reasons for that are such fundamentals as what “irritability” or “compulsiveness” or even depression looks like in something with whiskers and a tail, Nestler and a colleague wrote in 2010. Knowing how mouse brains and human brains differ genetically won’t solve that problem, but it could help scientists untangle basic differences between the two species’ neurobiology.
“If you want to cure human brain diseases, you have to understand the uniqueness of the human brain,” said study co-author Christof Koch, chief scientist and president of the Allen Institute.
For their study, Lein and his colleagues isolated cells — 15,928 of them — from deceased people’s brains and from tissue removed during surgery for epilepsy. All the cells came from one region (called the middle temporal gyrus) of the human cerebral cortex, the brain’s Mission Control for thought, emotion, memory, and other higher-order functions. The cortex is also where, if things go wrong, the result is neuropsychiatric disease.
The 75 distinct types all had a matching mouse version, as measured by what genes they used. But in many such “homologous” cells, there were dramatic differences in levels of gene expression. In some, 18 percent of the genes showed at least a 10-fold difference in the level of expression between mice and humans.
The differences in brain cells’ genetics parts list “are likely to be functionally relevant, as divergent genes are associated with connectivity and signaling,” the scientists wrote in Nature.
Among the biggest differences: which neurons expressed genes for neurotransmitter receptors (the molecules that neurons use to communicate via those chemicals) and for proteins that knit neurons together into functional circuits.
Serotonin receptors, for instance, allow neurons to react to that neurotransmitter and play a role in appetite, mood, memory, sleep and other core brain functions. Both species have serotonin receptors, but in different kinds of neurons. To a slightly lesser extent, expression of genes for receptors for the neurotransmitter glutamate also differed significantly between homologous mouse and human brain neurons.
“The assumption with model organisms is that neurotransmitters have receptors on the same neurons that humans do,” Lein said. Since that’s apparently not the case, it suggests that “serotonin or glutamate could have very different effects in humans than in mice.” And that, in turn, means that a drug acting on serotonin or glutamate circuitry could affect a mouse very differently than a human.
“I think their findings support what we said nine years ago,” Nestler said. Mice and other lab animals “will be useful models for neuropsychiatric diseases, but you have to take a sober look at them.”