The Origin of Humanity: One Gene, Two Days, a Three Times Larger Brain Than Our Cousins

A groundbreaking new study demonstrates that a change to a single gene results in humans having three times bigger brains than our closest cousins, the great apes.  How evolution preserves and repurposes information in limitless ways, creating the incredible variety of life from small, measurable changes.

The human brain is the most complex object in the known universe.  We have peered billions of light years into the sky and found nothing even remotely like it, wherever we may look.  Made up of approximately 100 billion neurons, each essentially a mini-computer of its own, the human mind appears to hold limitless potential.  It is the means by which we can develop a vaccine for a new disease in less than a year, launch spaceships into orbit, and produce timeless works of art.  It is also the primary force by which we have changed the entire face of a planet in merely the blink of an eye of geological time.

Humans, however, are not the only great apes.  Our closest cousins, chimpanzees, have similar brains that measure about a third of our size, around 30 billion neurons.  It has long been a question as to why our brains were able to grow so large, for growing brains is not easy.  Our brains, in fact, consume about 20% of our total energy compared to about 2% of our total body weight, far more than any other single organ.  The question is:  What prompted our ancestors, assumed to be far more like chimpanzees than modern humans, to invest that many precious calories in building brains when the rewards for having them aren’t immediately apparent?

Meaning, we were growing our brains for about 2 million years before we invented modern language, science, arts, and civilization.  What was happening in the interim that benefited us enough to keep going at such huge expense?  Evolutionary biologists have put forward a lot of possibilities, from the rewiring of our brains through a series of proto-languages, to the competition for mates, to hunter and gathering skills, to cooking with fire, to standing upright and working with our hands, even the birth of a proto-politics.

Unfortunately, we may never know for sure as reconstructing the precise conditions of the environment and primitive society of our ancestors a million or even two million years ago is not an easy proposition.  It’s likely that it was some combination of all of these factors and perhaps even others that we are unaware of right now.

At the same time, this shouldn’t imply that there is nothing more we can learn.  On the contrary, modern technology can be used to study and simulate the operations of our genes and how they guide the growth of our bodies, providing amazing insights into our evolutionary development.  We can do these because our genetic code is essentially a map of our history, and by comparing it to our closest cousins, exploring how we evolved and how evolution works overall.

A recent study by the Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge, UK illustrates how deep our knowledge can go.  The study compared the growth of brain development in human, gorilla, and chimpanzee stem cells, mimicking what happens in the earliest stages after conception.  Dr. Madeline Lancaster, the study leader, explained “This provides some of the first insight into what is different about the developing human brain that sets us apart from our closest living relatives, the other great apes. The most striking difference between us and other apes is just how incredibly big our brains are.”

Brains are made of neurons, but neurons don’t start out as the familiar shape from high school biology, the large, rounded top with multiple antennas sticking out and the long stem.  Before they fully develop, neurons begin their life as cylinders, then grow into something resembling an elongated ice cream cone shape, known as neural progenitors.  The simpler shapes in these early stages make it easy for them to multiply before taking their final form.

The more times they replicate during this period the larger the final brain will be.  Mice, for example, pass through the entire process in just a few hours.  The researchers for this study used a simplified version of brain development, a 3D tissue grown from stem cells known as a “brain organoid.”  They found that apes and chimpanzees take around 5 days to complete the process, while humans take around 7.  In addition, human stem cells remain in the cylindrical shape longer and multiple more frequently.  The end result is a lot more brain cells.

Dr. Lancaster explained, “We have found that a delayed change in the shape of cells in the early brain is enough to change the course of development, helping determine the numbers of neurons that are made.  It’s remarkable that a relatively simple evolutionary change in cell shape could have major consequences in brain evolution. I feel like we’ve really learnt something fundamental about the questions I’ve been interested in for as long as I can remember—what makes us human.”

Merely two more days in development and the end result is 3 times bigger brain, and that’s not all the researchers found.  The team also looked at the genes that control the process, trying to determine which sequences turn on and off at the different stages in the organoid development.  They were able to identify a single gene called “ZEB2” that was turned on earlier in chimpanzees and apes.  Then, they went one step further:  Delaying the turning on of the gene in the chimpanzee and ape organoids and also turning on the gene earlier in the human organoids.

The result?  When ZEB2 is delayed in our closest cousins, the brain organoids develop as large as a human.  When it’s shut off early in humans, our brain organoids stop at the size of our largest cousins, meaning that merely one gene that remains inactive for two additional days results in a three fold increase in brain size, a small change has a large effect.

To be sure, organoids are a simplified model and it most certainly takes more than a single gene to make a human brain out of a chimpanzee, but this doesn’t make the study any less groundbreaking or illuminating about how evolution works in general.  The more we learn, the more we discover how small changes like this to a single or a handful of genes result in huge differences in development.

Consider the Hox genes, a set of genes shared by all animals, from fruit flies to humans.  These genes are responsible for laying out the body plan in early development, essentially providing markers for other genes to build out the final structure, whether an appendage or antennae in an insect or a vertebrate in a human. Interestingly, Hox genes are part of a family of homeobox genes, these homeobox genes are present in even single celled organisms, meaning the genes that ultimately determine what shape we will take go back to the earliest complex cells.  In more complex animals, they are normally expressed along the head to tail length of the growing embryo, suggesting that the process to lay out a body plan is shared among all animals and a truly ancient feature of our evolution.

All insects for example have 8 hox genes.  Humans, on the other hand, have 39.  In both species and all other animals, these genes essentially regulate the turning on and off of other genes.  The process is obviously complex, but at a simple level the Hox gene is expressed as a protein, that protein then causes other genes to be expressed in that location.  A single Hox gene can dictate the behavior of huge networks of other genes, turning on the sequence that creates an entire body part.

In this way their function is similar to the ZEB2 gene, and a small change in Hox gene can have a major change on the final form of the body, thus 31 additional Hox genes can result in the difference between a fly and a human.

Of course, I am oversimplifying here, there are a lot more differences between flies and humans than the Hox genes, but that doesn’t alter the underlying point that evolution works because genes are arrayed in complex hierarchies.

There are genes that build the basic molecules of our body, encoding for the carbohydrates, lipids, proteins, and nucleic acids that make up every cell.  As we saw earlier, many of these genes like the homeobox are shared across plants, animals, and microscopic organisms.  There are genes that organize these molecules into different types of cells, skin, hair, muscle, neurons, etc.  These genes are also shared, though not nearly as broadly, in this regard a dog has just about the same genes as a human, but a fly would have some (not all) markedly different ones.   Then there is another level of gene that organizes these cells into organs, and yet another that orchestrates where those organs are positioned in the body.

As many of these genes are also broadly shared, this suggests that the body plan itself evolved first and then the specific body parts came later. This makes perfect sense when you consider the adaptability of the hierarchy:  Since the Hox genes don’t care what they are positioning, they’re infinitely flexible and can more easily accommodate changes to the body parts.  Ultimately, it’s this hierarchy that enabled the wide variety of life to emerge, a small change to the Hox gene separates a stunning variety of insects, a tripling of the Hox genes separates insects from humans, or a small change in ZEB2 separates apes from humans.

In all these cases, the information the genes are acting on is preserved, meaning you don’t need to change the underlying genes at all to alter the shape of a body or the size of a brain.  Imagine if we could design buildings this way, change the size or shape of a floor and the rooms, complete with the furniture, all automatically adjust to the new dimensions.

The information is preserved in another, perhaps even deeper sense as well.  As we saw earlier this year, inside every plant and animal cell is a protein called a cryptochrome.  This protein is sensitive to incoming light and changes in the magnetic field.  Though the protein is billions of years old, it’s used by birds today to navigate their migratory patterns, meaning the incredibly complex behavior of a modern organism is based on a protein that evolved before there were even multi-celled organisms in the first place.  Think about that for a moment:  Billions of years before they were birds or anything resembling birds, the cryptochrome emerged, likely to help a single celled organism respond to changes in the environment, but it helps tell a modern bird where to fly for the winter.

The mysteries of evolution remain deep, but the genes offer a veritable ocean to continue our exploration.  The more we learn the more we are amazed at the infinite flexibility evolution provides with a relative handful of building blocks.

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