Genetically, humans and chimpanzees are more than 96 percent identical. Similarities, especially in facial expressions and gestures, can hardly be denied. Nevertheless, there are worlds between Homo sapiens and its closest living relative. The reason for this is the brain: the human brain is about three times as large as that of chimpanzees, especially the cerebral cortex, which is responsible for perception, motor skills, learning, and memory formation. However, the major difference in cognitive abilities is not due to the differences in size alone, but also to the activity of the genes – called gene expression – and their networks.

When Proteins Switch Genes On

Katja Nowick, who is based at Freie Universität Berlin, does research on the evolution of the primate brain. A professor of human biology, Nowick particularly wants to understand how evolutionary changes in “gene switches” led to differences in gene regulation. These gene switches include the so-called transcription factors, i.e., proteins that control when, how often, and how strongly a gene (or several at the same time) is switched on. The “language gene” FOXP2, for example, provides the blueprint for such a switch protein that controls the activity of up to 1000 genes in humans. Even tiny changes to such a gene can have far-reaching consequences. Certain mutations in FOXP2, for example, lead to poor speech production in patients and thus to poor intelligibility.

There are about 2000 different gene switches in Homo sapiens. From an evolutionary point of view, many of them are “very young.” They only appeared with the rhesus monkeys 35 million years ago and probably occupy key positions in the brain. Nowick suspects that could have had an effect on how the human brain later evolved.

The more developed primates have more complex switching processes in their brains. In the prefrontal cortex, in particular, the activity patterns of certain gene switches differ considerably between humans and chimpanzees. “Some changes are so specific that they can only be found in the human line,” says Nowick. With the help of bioinformatics, she traces the small, random mutations on the gene switches.

However, simulated evolution can only make predictions and cannot replace experimental studies. In order to understand the complex regulatory networks in the living brain, individual genes can be switched on and off in mice. This is not possible with humans, nor would it be justifiable from an ethical point of view. For functional studies, Nowick and her team rely on cell cultures, among other things.

“From a certain type of pluripotent stem cells, we grow nerve cells from humans and chimpanzees so far that they form small mini-brains,” explains Nowick and continues, “We can then insert human genes into these organoids made from chimpanzee cells and check whether this causes the neurons to behave a bit more like human neurons. And vice versa: we can introduce chimpanzee genes into human cells.”

At first glance, the nerve cells of the two species do not differ. “However, it is becoming clear that during the development of the human brain, many more neuron precursor cells are created,” says Nowick. “And they also divide several times more often than in chimpanzees.” Researchers found out that not just one gene can be responsible for this, but that several must be responsible. They found this out in experiments with people who have microcephaly, i.e., people who have significantly smaller brains, a malformation caused by genetic defects or infections of the mother with the Zika virus or the rubella virus during pregnancy.

Significantly Smaller Brains of Mice near Chernobyl

Scientists still do not yet know all of the genes that affect the size of the brain. Katja Nowick would like to discover more in another project. She says, “Finnish, Swedish, Portuguese, and Ukrainian colleagues have discovered that the brains of mice near Chernobyl, the site of the nuclear disaster in 1986, are significantly smaller than usual. The smallest brains are found where there is the greatest radioactivity.” Are these rodents less intelligent than their conspecifics with normal-sized brains? Behavioral experiments are currently in progress to find out.

The brain is the organ with the greatest energy consumption. “We are also looking at the metabolism of these mice because we think it must be lower,” says Nowick. In the immediate vicinity of the damaged nuclear reactor in present-day Ukraine, the rodents find much less food. Could that be the reason why their brains are smaller? Nowick and her team are also interested in whether the mice’s brains are smaller all over, or just in certain areas of the brain. In a later step, they want to examine the deoxyribonucleic acid (DNA) of the brain tissue, the carrier of the genetic material. They want to find out where the mutations are, and also whether and how gene expression differs in mice from heavily, weakly, and nonradioactively contaminated areas.

Alzheimer’s Disease, Autism, and Schizophrenia

Another research project focuses on gene activity in people with cognitive diseases such as Alzheimer’s disease, autism, or schizophrenia. In this study, the researchers first isolate individual nerve cells from brain samples that patients donated to brain banks. Then they sequence the entire ribonucleic acid (RNA) from these cells. If a gene is activated and read, a copy of the corresponding DNA segment is created – in the form of an RNA. This copy, called transcript, provides the blueprint for a very specific protein. “We then measure how much of each individual transcript is available and analyze whether, for example, the variety of transcripts in Alzheimer’s patients differs from that in healthy people,” explains Nowick. She suspects that a shift in the balance in the transcripts is ultimately responsible for the onset of Alzheimer’s disease.

Katja Nowick finds this project extremely exciting in the context of brain evolution because Alzheimer’s only occurs in humans and not in any other primate. She says, “I think that it is human-specific changes in the genes that lead to higher cognitive performance, but that these changes also make our brains more susceptible to losing balance.” It seems to be mutations in the gene switches that lead to Alzheimer’s in old age. But what is the very first step? Nowick and her team want to find that out by analyzing brain samples from people who were in the very early stages of Alzheimer’s when they died.

A large and strongly networked brain offers enormous advantages: it has made Homo sapiens almost independent of the environment. While almost all other animals are very limited in their habitat, Homo sapiens can live practically anywhere on Earth – except under water. Thanks to their cognitive abilities, knowledge accumulated over many generations, and sophisticated technologies, humans can adapt very quickly to new situations. “If the environment changes dramatically again in the distant future and a new Ice Age comes along, we would not have to wait millions of years for our fur to grow again,” says Nowick swith a smile. “We’d put on appropriate clothes right away.”

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This text originally appeared in German on October 4, 2020, in the Tagesspiegel newspaper supplement published by Freie Universität.