Building a Brain: Paola Arlotta on the Choreography of Human Brain Development

Asked by host Lex Fridman to walk through the stages of human brain development, Arlotta begins in the womb. While the embryo builds muscle, heart and blood, it is also building the brain from a simple structure called the neural tube, a tube of cells spanning the length of the embryo from head to tail.

Over many months of gestation, the stem cell-like cells of that tube produce the many other building blocks of the brain. The early stem cells are relatively homogeneous and multipotent, meaning they can make many types of cells. With time the progenitors become more diverse and give rise to progeny that are very different from the parent cells.

She likens embryonic development to making bricks, then putting them together into structures and regions of the brain, and forming connections among the cells, especially neurons that transmit electrical signals.

Fridman recalls that Arlotta has said the order of building matters. She says an engineer might imagine making all the cells and assembling them at the end, but development is much more than that. The cells are made in a specific order that serves the final product, with neurons made first and the supportive glia made later.

The reason is that cells developing next to each other influence one another with signals. A glial cell made alone in a dish therefore differs from one made in a developing embryo surrounded by other cells.

Fridman says that, from an AI perspective, one usually admires the final product, but this makes him realize the development process is the beautiful part. Arlotta agrees, calling it an incredibly choreographed dance that happens the same way each time and builds the organ that lets us do what we are doing today.

On whether we know the code that drives development, Arlotta says it reflects millions of years of evolution fine-tuning gene expression programs so certain cells are made at certain times. But there are also mechanical forces: the embryonic tube does not stay a tube, and the front expands into the primordium of the brain. The pressure and bending a cell feels can tell it to start producing new genes, so physical force shapes cell fate along with chemistry.

Fridman asks how biology compares with machines built by engineers. Arlotta says biological systems are much more prone to taking alternative routes. If you printed a brain from the same cell types, it might not work like a developed brain, because the cells grew in a different environment than the brain's own.

Using development in a dish, you can watch things go wrong or come out different from one run to the next, whereas the embryo almost always gets it right. She notes that what grows in a dish is much simpler than a real brain, and that there are more options for building things differently there. In her view that shows how tightly evolution has constrained how the brain is built in the body.

Fridman asks whether the process is a dictatorship, with some high-level mechanism that kills a cell built wrongly. Arlotta answers that there are many possibilities, pointing to how the brains of a lizard, a chicken and a human differ although they start from stem cells with much the same potential. Evolution builds different brains because that serves each species.

She says nobody knows the entire code of development. Scientists know bits and pieces, such as which genes are involved in making certain cell types and how those cells interact to form the next level of structure. The entirety is so well controlled that she finds it mind-blowing.

Development lasts far longer than the first few months. New cell types continue to be built through birth and after, and myelin, the insulation around axons that lets electricity travel fast, is added after birth. A six-year-old has barely started making the mature oligodendrocytes that wrap axons, and this continues until about 25 or 30 years old, as a process of tweaking and addition that also responds to what we do.