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The Human Factor

Man, monkey, mouse. They are very different animals, of course, but they have plenty of basic biology in common. Humans and rhesus macaque monkeys are estimated to share about 93% of their DNA. Mice, not to mention monkeys, are similar enough to humans in physiology to make them test subjects for drugs aimed at human diseases. And the brains of all three, though hardly the same size, are all made from the same type of cells.

What is it about our brain that makes us unique? For the answer, researchers at the Kavli Institute for Neuroscience at Yale University are looking at the cerebral cortex.

It's no simple matter to identify the precise physical factors that have set humans apart. Humans, monkeys and mice all have genes that can produce a tail. So why don’t humans have tails? Then there is language. What makes it so vastly more developed in humans, if not entirely unique to them?

The Distinctly Human Brain

Pasko Rakic, M.D.Pasko Rakic, M.D., Sc.D., professor of Neurobiology and Neurology at Yale and director of the Kavli Institute of Neuroscience, is shown with a computer animation of his favorite model for radial unit hypothesis of cortical development and evolution. Credit: Kavli Institute of Neuroscience.

The cerebral cortex is believed to be the primary location of human thought, including the ability to form ideas and feelings into words. In mice, monkeys and humans, its basic building blocks (neurons) are the same, and it has a similar six-layer structure. Though the human cortex is by far the largest of the three --10 times the surface area of the monkey’s; 1,000 times that of the mouse - it’s not yet clear how the human capacity for language develops from the embryo or how it evolved in the history of the species. The physical structures responsible for language are still largely a mystery, as is the genetic code behind them.

But something is at work in our biology to make us, and our brains in particular, unique -- or at least close to it. In his laboratory, Pasko Rakic, M.D., Sc.D., Duberg Professor of Neurobiology and Biology at Yale University and founding director of the Kavli Institute for Neuroscience, always uses mice as experimental models for studying the development of cerebral cortex, “However, you could look at a mouse until your eyes pop out, and you would not find the circuitry that is responsible for language, because mice can’t talk,” he explains. While the basic cellular organization of the cortex in humans and mice looks the same, Rakic states, “the connections are different, the functionality is different.”

Studying that difference is one of the central research initiatives of the Kavli Institute at Yale. As Rakic notes, the knowledge of human, mouse and rhesus macaque genomes means that “we can now compare, for the first time in the history of humankind, all three species.” He and other Institute scientists are looking at the genetic makeup and embryonic development of the cortex in mice, monkeys and humans to see when distinctly human traits appear and which genes produce them. In the process, they are seeking to answer to a question that has occupied linguists, psychologists and philosophers for centuries and has now been taken up by neurobiologists: What makes us human?

Unravelling Our Unique Wiring

Brian of a MouseA microscopic image from the laboratory of Nenad Sestan shows how brains begin to grow in mice, humans and other animals. It shows a mouse at embryonic day 10.5 and the expression of the Fezf2 gene in the developing cortical vesicles (in blue) at the start of brain development. Fezf2 is necessary to guide the growth of neurons and their connections in the formation of the cerebral cortex. Credit: Jie-Guang Chen, Kenneth Kwan and Mladen-Roko Rasin.

Self-understanding is one goal of this research. But the effort also could produce practical benefits in treating mental illness. Institute member Nenad Sestan, M.D., Ph.D., explains: “There is no valid animal model that can entirely replicate some human psychiatric conditions. That is why it is so important to study what is different about human development and function. Understanding this difference is fundamental to understanding human evolution, human behavior and many psychiatric disorders.”

Sestan, an assistant professor of Neurobiology at Yale, is currently leading two projects aimed at defining what, other than sheer size and number of neurons, distinguishes the human cerebral cortex from that of the mouse. In one, he studies “knockout mice,” in which specific genes have been rendered inactive, to identify which genes that are important to cortical development. In the other, he analyzes those genes to learn how they function in the embryonic development of both mice and humans. His object is to learn how shared genes might have changed during millions of years of evolution, coming to express different traits in different species.

In a similar comparison of cortical genes in humans and rhesus macaques, Sestan has identified shared genes linked to a set of neurons found uniquely in the developing cerebral cortex of humans. “What’s interesting is that this gene expression is in the future speech area of the human brain,” he says. The object of all this analysis of macaques, mice and humans is to identify a cell type or genes that have, as he puts it, “a uniquely human expression.”

Sestan says the distinctively human features of the brain will ultimately be found in the brain’s unique wiring – the synaptic connections that are not present in other animals. Scientists can tell from magnetic resonance imaging (MRI) studies that the areas of the brain devoted to speech and language are exceptionally large in humans. But current imaging technology can recognize only large patterns, not the details of the network. It’s not enough to answer what Sestan sees as basic questions about the cerebral cortex: “What is the set of genes, proteins or circumstances that led to these different connections? Then, how are these connections changed by experience?” He hopes his research will provide a clearer view of all the factors, from genes to nurture, that give humans their full capacity for thought and language.