Zero to Birth

How the Human Brain Is Built

William A. Harris

• Publisher: Princeton University Press
• Year: 2022
• ISBN:
  9780691237077
• Topic: Biowissenschaften
• Subtopic: Neurowissenschaft

A revelatory tale of how the human brain develops, from conception to birth and beyond By the time a baby is born, its brain is equipped with billions of intricately crafted neurons wired together through trillions of interconnections to form a compact and breathtakingly efficient supercomputer. Zero to Birth takes you on an extraordinary journey to the very edge of creation, from the moment of an egg's fertilization through each step of a human brain's development in the womb—and even a little beyond.As pioneering experimental neurobiologist W. A. Harris guides you through the process of how the brain is built, he takes up the biggest questions that scientists have asked about the developing brain, describing many of the thrilling discoveries that were foundational to our current understanding. He weaves in a remarkable evolutionary story that begins billions of years ago in the Proterozoic eon, when multicellular animals first emerged from single-cell organisms, and reveals how the growth of a fetal brain over nine months reflects the brain's evolution through the ages. Our brains have much in common with those of other animals, and Harris offers an illuminating look at how comparative animal studies have been crucial to understanding what makes a human brain human.An unforgettable chronicle of one of nature's greatest achievements, Zero to Birth describes how the brain's incredible feat of orchestrated growth ensures that every brain is unique, and how breakthroughs at the frontiers of science are helping us to decode many traits that only reveal themselves later in life.

1

Rise of the Neurons

In which some embryonic cells become neural stem cells, the founders of the nervous system, and in which we get the first glimpses of the evolution of the brain.

Totipotent Stem Cells

The end of the nineteenth century was a time of tremendous progress in embryology. Questions that had been debated for centuries concerning how an organism with all its parts emerges from a single-cell egg were beginning to be answered by experiments rather than debates. One of the most fundamental of these questions was: When a fertilized egg cell divides to make two cells, does each of the two cells have the capability to make a complete being or do the two cells divide this potential in some way? This was a question that just could never be answered by debate. An experiment on real embryos was clearly necessary to resolve the issue.

In 1888, Wilhelm Roux, working at the Institute for Embryology in Wrocław, took up the challenge of answering this question by using frog embryos at the two-cell stage. He inserted a heated needle into one of the two cells and then let the embryo develop from the remaining live cell. Most of the experimental embryos ended up looking like halves of animals, for example, a right or left half of an embryo rather than whole one. Based on these results, Roux argued that the capacity to make a whole animal is indeed divided in two at the very first cell division.¹ As Roux’s was the first scientific experiment ever to be done on any type of embryo, he is credited with being the father of the entire field of experimental embryology, which has been a cornerstone of developmental biology ever since.

Roux’s results were unimpeachable, but his basic interpretation of them drew immediate concern, because it also seemed possible that the dead cell might have affected the development of the single surviving cell next to it. So, a few years later, another embryologist, Hans Driesch, working at a marine biological station in Naples, did a very similar experiment, though he used sea urchin embryos rather than frog embryos. The wonderful thing about the sea urchin embryos is that at the two-cell stage, all it takes is gentle shaking to separate them into single cells. So, in principle, there should be no effects from any neighboring dead cells. The results from Driesch’s experiment were the opposite of Roux’s. Instead of making half animals, each of the two cells gave rise to an entire sea urchin.²

Of course, Driesch’s results strengthened suspicions that the presence of the dead cell in Roux’s experiments might have affected his results. But it was also plausible that the discrepancy pointed to a fundamental difference in the way that sea urchins and frogs develop. Therefore, it became of major interest to know what would happen if the first two cells of a frog embryo could be fully separated and both cells kept alive. But this experiment was (and still is) extremely challenging, because the cells are not yet fully separated at these stages in amphibian embryos. Nevertheless, in 1903, Hans Spemann of the University of Würzburg managed to succeed in doing so by fashioning a tiny noose from a fine hair of his newborn baby’s head. He positioned the noose between the two cells and began, ever so slowly, tightening it, little by little, minute by minute, with amazing steadiness of hand. When the noose was fully tightened, the two cells fell apart from each other, both alive. In many instances, both these cells formed a whole embryo.³ It seems that Roux’s interpretation of divided potency was indeed wrong and was probably an artefact of the effects of the dead cell, though the biological reason for Roux’s results has never really been further investigated.

What about mammals? In 1959, Andrzej Tarakowski at the University of Warsaw separated single cells from a two- or four-cell mouse embryo and then placed each of them into the wombs of foster mothers. These isolated cells often gave rise to healthy baby mice.⁴ Similar experiments have now been done with many other mammals. In humans, identical twins result from a single embryo spontaneously splitting into two, and though it is still not known exactly when or how this splitting occurs, the embryonic cells at the time of such splitting are able to make entire humans. Genetic testing of early human embryos that are fertilized in vitro (IVF embryos) is offered to couples who are at risk of carrying severe genetic abnormalities. In such a procedure, one cell of a human embryo at the four- or the eight-cell stage is removed for testing. If no obvious genetic defects are found, the remaining three- or seven-cell embryo can be reimplanted into the womb, as there is little risk that the removal of just one cell has injured the potential of the remaining cells to make an entire human being. So the results are often happy ones. Thus, the embryonic cells at this stage are said to be “totipotent”: capable of making it all.

Genesis of the Brain

Written in our genes is an eons-long history of the human brain’s evolution. The information there is used to reconstruct an entirely new brain in every single baby. Each of us begins life as a tiny egg, a single cell smaller than a grain of table salt. The cell, like that of its evolutionary ancestors all the way back to the dawn of cellular life 4 billion years ago, is surrounded by a membrane and contains a nucleus. Inside the nucleus of the egg cell are the instructions for making an entire human being. A sperm cell, carrying its own set of complementary instructions, finds the egg and pushes itself inside. With a copy of the genome from each parent, the fertilized egg starts to divide. First, it makes two cells. Two cells become four, then eight, and so on. Soon there is an embryo composed of thousands of cells. Each of these cells contains a nucleus, and each nucleus has access to the full set of instructions.

Some of the instructions for making the brain came from single-cell organisms of the Proterozoic eon.⁵ These protozoans sensed their local environment and responded accordingly. They did not have brains themselves—but they had the makings of brains. Many modern protozoans are excitable and motile; they search for food and mates, they adapt to new situations, they store memories of events, and they make decisions. Modern single-cell creatures, such as paramecia, are relics of this ancient eon that preceded the origin of multicellular animals by at least a billion years. When a paramecium swims into a wall, it reorients and heads off in a new direction. It is the synchronized beating of the thousands of tiny cilia all over its body that propels the paramecium forward. The mechanical stimulus caused by the bump opens calcium channels in the paramecium’s cell membrane. An electrical current carried by calcium ions begins to flow through these channels, and this current changes the voltage across the membrane. Other calcium ion channels in the cell’s membrane are sensitive to this voltage change, and they open in response. The opening of these voltage-sensitive channels allows even more calcium to flow across the membrane, which changes the membrane voltage further and opens yet more channels. This explosive electric feedback is the essence of a neural impulse of the kind used by the neurons in our brains, except that neurons tend to use sodium ions rather than calcium ions to generate an impulse. What this electrical impulse does for the paramecium is to let calcium ions enter instantly all over the membrane, which leads to the simultaneous disruption of the beating of the cilia of the paramecium, causing it to tumble. When the cell recovers, it is heading in a new direction. The paramecium’s channels that are activated by mechanical deformation and those that are activated by voltage are evolutionarily related to the channels found in the neurons of all animals. It seems that many properties that are characteristic of the brain were already encoded in the DNA of our single-cell ancestors. How they got these neural-like properties lies buried even deeper in the early evolution of life on earth.

Protozoans like paramecia have many specialized functions located in distinct compartments of the cell, such as a digestive system, a respiratory system, cilia for motility, a nucleus to carry key information accumulated since the origin of life itself, and an excitable membranous skin capable of making rapid alterations in behavior. Protozoans must do all this, and much more, in a single cell. With the rise of multicellular animals, cells could specialize and divide the labor. A brain is a collection of neurons that communicate with one another using synapses. Nervous systems with real neurons and synapses did not arise, and could not have arisen, until multicellular life began. Jellyfish are members of a phylum of animals called the cnidarians that arose around 600 million years ago. Cnidarians have networks of interconnected neurons that share many characteristics with the neurons of the bilaterally symmetric animals (aka bilaterians) like us. Bilaterians also arose at one of the earliest of branch points on the tree of multicellular animal life. Cnidarians and bilaterians may have evolved neurons and synapses independently, but it is equally likely that these attributes evolved once in a common ancestor to both groups. The first vertebrate animals arose more than 450 million years ago. These early vertebrates are most related to today’s lamprey eels. Lampreys not only have neurons like ours, but they also have a similar layout of the nervous system including a brain with the anatomical and functional beginnings of the cerebral cortex, the region of the brain that is so greatly expanded in humans.⁶

Finding the Neural Stem Cells

When, where, and how do neurons first arise in an animal? About 3.5 billion years ago, single-cell organisms were sometimes joining together to become simple multicellular life forms, which could then afford to divide tasks among themselves. In the multicellular life form known as a human, cells also begin to take on specific tasks. Some will build muscle and bones, some will make skin, some will make the digestive system, and so on. Those that will make the brain and the rest of the nervous system are the neural stem cells.

If you take a trip to a pond in the woods in early spring and collect some freshly laid frog eggs, one of the first things you might notice about these eggs is that they have a darker half and lighter half (figure 1.1). The darker half is known as the “animal” side and lighter half is known is the “vegetal” side. The imaginary line from the animal pole to the vegetal pole forms the animal-to-vegetal axis of the embryo. When a sperm fertilizes a frog egg, it initiates a movement of the dark pigment granules toward the point of sperm entry. This movement leads to a lightening on the opposite side of the egg, where one can see what is known as the “gray crescent” rising like a new moon. The gray crescent is on the side of the frog embryo that will become the dorsal or back side of the future tadpole. We can now draw another imaginary line from dorsal to ventral (back to belly). These dark, light, and gray landmarks remain until the frog embryo reaches a stage of development known as the blastula. The blastula is basically a ball of several hundred cells with a fluid-filled hollow in the middle. Human embryos reach this blastula stage about one week after fertilization.

FIGURE 1.1. A frog egg shortly after fertilization. A remnant of the sperm entry point is seen in the aggregation of pigment granules there (near top of figure). The animal pole is at the top and the vegetal pole is at the bottom. The gray crescent forms opposite the sperm entry point in the animal hemisphere near the equator. The gray crescent marks the dorsal or back side of the developing frog embryo.

Embryologists of the late 1800s wanted to understand how this ball of cells transformed itself into a little tadpole, so they began to follow cells that were consistently positioned at certain coordinates along animal-to-vegetal and dorsal-to-ventral axes. They stained the cells with permanent dyes and noted where the dye ended up. Such experiments are now done in embryology courses at universities throughout the world, and students in these courses discover for themselves the origins of the three great germ layers of the vertebrate embryo: the ectoderm, the mesoderm, and the endoderm (from the Greek words for outer, middle, and inner layers). The light-colored vegetal third of the blastula becomes the endoderm and gives rise to the digestive tract and its organ systems. The equatorial third between animal and vegetal poles, which contains the gray crescent on its dorsal side, becomes the mesoderm, which gives rise to muscles and bones. The dark animal portion of the embryo, known as the animal cap, becomes the ectoderm, giving rise to the epidermis and the nervous system. Students in such embryology courses often go further and find that the primordial nervous system comes from just the dorsal half of the ectoderm, the region that lies directly above the gray crescent.

The Organizer

Knowing which cells of the blastula will become the neural stem cells allowed Hans Spemann, now working in Freiburg, to devise an experiment to test whether these cells are also capable of giving rise to other tissues or whether they have become restricted to making only the nervous system. Spemann thought of testing this by taking groups of cells from a particular position on one embryo and transplanting them to a different position on another embryo. As was his style, Spemann invented a variety of new microtools for these experiments, including incredible fine-glass pipettes with fingertip control that could be used to transfer tiny fragments of embryonic tissue carefully between embryos, and superfine scalpels to cut out such fragments. With such tools and his extreme dexterity, Spemann was able to perform precise cut-and-paste experiments on amphibian embryos. In one series of experiments, he transplanted bits of one blastula to different positions on another. When he transplanted a piece of the dorsal ectoderm from the blastula of a newt embryo (i.e., the piece of the embryo that would have become its nervous system if left in its original positio...