The best ways to study human evolution don't come from looking at human genes, but from comparing ours to those of nonhuman species that — genetically speaking — are close cousins. The closeness of genes enables scientists to examine in intricate detail the special thing that make us human.
And compared to chimpanzees, what makes us special is apparently our outsized capacity for serious mental illnesses and weird facial shapes, according to two new studies published in the journals Nature, and Nature Genetics, respectively.
Human brains evolved for disease, unlike chimpanzees
Specifically, the researchers found a substantial disparity in the expression of the gene SSTR2, which modifies the activity of neurons in the cerebral cortex — and has shown links in humans to neuropsychiatric diseases (like Alzheimer's dementia and schizophrenia) — in addition to the gene EVC2, which gives our faces their weird, human shape.
"It's important to study human evolution, not only to understand where we came from, but also why humans get so many diseases that aren't seen in other species," said recent Stanford graduate student Rachel Agoglia and lead author of the Nature study.
Agoglia's study examines a new technique that fuses human and chimpanzee skin cells modulated to function like stem cells — which are highly-malleable and may be molded into a wide spectrum of other cell types. Of course, they can't grow into an entire organism.
"These cells serve a very important specific purpose in this type of study by allowing us to precisely compare human and chimpanzee genes and their activities side-by-side," said Associate Professor Hunter Fraser of Stanford's School of Humanities and Sciences, according to a Phys.org report. Fraser is senior author of the Nature Genetics paper and co-senior author of the Nature paper with Sergiu Pașca, who's an associate professor of psychiatry and behavioral sciences in Stanford's School of Medicine.
Coaxing human neurons into 'organoids'
The Fraser lab is especially interested in how the genetics of humans and other primates compare at a level called "cis-regulatory" elements, which determine the expression of other genes in proxy — positioned on the same chromosome, or DNA molecule). The other way — called trans-regulatory factors — can also regulate the expression of genes present on other chromosomes somewhere else in the genome. But trans-regulatory factors (like proteins) are less likely to present different expressions among closely related species than cis-regulatory features.
However, even when scientists have similar cells from chimpanzees and humans at hand, there's still a risk of various interfering factors. For example, subtle differences between species of the timing of development can substantially hinder the study of brain development, explained Pașca in the Phys.org report. Since human and chimpanzee brains mature at very different rates and we lack a precise way of directly comparing them, it's not easy to do a compare-and-contrast investigation. But placing chimpanzee and human DNA inside the same cellular nucleus allows scientists to eliminate most factors disruptive to investigation.
Agoglia coaxed the cells into forming cortical spheroids — also called organoids — which are a bundle of brain cells capable of closely mimicking the growth of a mammalian cerebral cortex.
"The human brain is essentially inaccessible at the molecular and cellular level for most of its development, so we introduced cortical spheroids to help us gain access to these important processes," added Pașca, who is also the Bonnie Uytengsu and Family Director of Stanford Brain Organogenesis.
New technique might help reduce brain diseases
The researchers discovered thousands of genes displaying cis-regulatory differences between the species over a 200-day growth period in fused-cell brain organoids. Then they decided to dive deeper into one of these genes — SSTR2 — which was more emphatically expressed in human neurons, acting as a receptor for a neurotransmitter called somatostatin. Later comparisons between chimpanzee and human cells revealed an elevated protein expression of the SSTR2 gene within human cortical cells. And when the researchers applied a small molecule drug that binds to SSTR2 into both the human and chimpanzee cells, the human neurons reacted much more than the chimpanzee ones.
"Evolution of the primate brain may have involved adding sophisticated neuromodulatory features to neural circuits, which under certain conditions can be perturbed and increase susceptibility to neuropsychiatric disease," explained Pașca.
This is significant because it may be possible to modify human neurons in cortical circuits with neurotransmitters. And most crucially, "neuromodular" activity could also be related to mental illnesses, since SSTR2 is involved in brain diseases. Since these neurological vulnerabilities likely happened when our evolutionary path diverged from other hominids, it may one day be possible to reduce a human brain's susceptibility to mental illness. Provided mental illness is a bug — and not a feature — of human brains.