The Dance of Life

INTRODUCTION

CONCEPTION

How many things in life are more intriguing than the story of how you built your body and your mind all by yourself? The origin and development of a new life is one of the greatest mysteries of biology, yet this is something that all of us have done.

We all know how this story starts: one solitary cell—a fertilized egg—divides into a close-knit family of similar-looking cells. But when examined from the viewpoint of the gene and the cell, there are many paths that development can follow, along with the creation of tissues and organs that escalate in form and complexity so rapidly that, paradoxically, while trying to discern the origins of a human life, one can find oneself staring into what seems to be a pathless future.

When this creation story is examined from the viewpoint of a human, who can struggle simply coordinating calendars to meet a few friends on a Saturday night, it is extraordinary how an embryo with no brain, consisting of a single cell, manages to divide and grow to become the most complex sentient being that we know of.

The development of the human embryo appears even stranger when compared to the familiar things we encounter in everyday life, which tend to be made of simple, immutable units, from Lego bricks to microchips and other elements and components. For flexibility, these basic units come in different types, so that wood can be found in planks, dowels, and doors; metal appears in the form of nails, hinges, and screws; and so on. And yet our bodies go one step further than simply having a repertoire of basic bits and pieces. Their basic units are also malleable. They can change their character, they can differentiate from parent cells—known as stem cells—into bone, muscle, brain, and other kinds of cells.

The number of cells it takes to build a human body is around 37.2 trillion—three hundred times the numbers of stars in our galaxy—and it was once thought that there were around two hundred basic types, from nerve cells to skin cells.¹ All possess the same DNA code, but they differ from each other in terms of the parts of the code—genes—that are expressed in them, that is, which range of proteins are manufactured to build and run each cell. Depending on the particular “melody” played on the genome, you end up with a different repertoire of proteins and a different kind of cell.

While brain cells “play” one particular repertoire of the twenty thousand genes, cells in the gut use another range of genes from this master set, and so on and so forth. Thanks to new techniques that are able to read the genetic code of a single cell, we now know that there are in fact many hundreds of different kinds of human cells in the body.² That all this diversity starts from a few cells that appear to be identical to each other is astonishing. To illustrate just how remarkable your origins are, and the extraordinary process of embryo self-organization, let’s imagine building a house in the same way as your body built itself.

First of all, there would be no plans, as such, to construct your body. Nor would there be a blueprint or an architectural drawing or design. There are instructions, but if they work in the same way as the twenty thousand genes used to build your body, there would be no simple relationship between these instructions and how the final house appears, just as there is no simple relationship between a recipe and the appearance of a cake.

There is no project manager or site foreman overseeing this construction project. Nor are there any workers. Nor is there the slightest evidence of a hammer, trowel, or paintbrush. Because this house self-organizes, all of its components share the responsibility for its own construction.

If that vision of components having collective responsibility for their own assembly is not strange enough, to build a house in the same way you built your own body you would have to begin with only one kind of building block—a brick—and as the house constructed itself, this brick would then transform into all sorts of other kinds of building materials, from wood to nails to glass to plaster.

This process of auto-construction has to take place within just nine months, no more, no less. Timing and coordination are everything, yet there is no clock or timepiece in sight. By the end of the first seven days, one kind of building block has morphed into three basic types as molecular structure self-organizes in different ways. After a week, this embryonic dwelling will start to set up its own foundations, burrowing into the ground (in reality, the wall of the uterus), where it will attach itself into the local infrastructure.

At this stage, the embryonic house will look nothing like the finished article. Some kinds of building blocks will destroy themselves, perhaps because they have fulfilled their purpose, while others will morph into many different types. There is complex auto-origami as the elements mold and arrange themselves depending on their individual circumstances. Quite unlike a building, the entire structure remains in working order—in other words, it stays alive—from the beginning to the end of the construction process.

In short, the way the body builds itself is peculiar, strange, and downright alien.

MY SCIENCE

My attempt to understand the nature of our origins is not focused on our evolutionary history but on an individual life, starting with when sperm fertilizes egg and the union starts to divide. For many years, I have dreamed of being able to track the path of each cell in a living embryo from its birthday and throughout the complicated details of its life, until its fate becomes decided or until it dies, as some cells do, as if making space to allow another cell to succeed.

In my laboratory, we focus on the dawn of life. We monitor how the egg is fertilized and how it divides to create a community of cells that change shape, cleave, move to new destinations, and communicate with each other using chemical or mechanical signals. To understand the journey of each cell and how it coordinates with others around it to begin to create a body and make a life, we use special techniques that reveal the invisible world of the embryo.

Before we were able to film development, as we now can do, we devised ways to “paint” cells with specialized dyes or label them with microscopic beads, turning them into sparkling dots of color so we could distinguish one cell from another and their paths as they made an embryo. Today we can also use molecular markers to identify cells and dissect their workings down to the level of genes, proteins, and other molecular components. We try to determine how the embryo constructs itself to the extent that one day we might understand how our body and organs are built and how birth defects arise, and ultimately carry out corrective measures to restore proper functions.

During this first phase of development, this tiny tribe of cells turns from a ball of similar-looking building blocks into a structure with a defined front, back, top, and bottom. Although this is only the start of a life, the processes at work are fundamental. One can already see all the mechanisms at work that will shape the development of the body and mind.

While I have focused my team’s studies on the first chapters of the story of a new life, many other researchers have studied subsequent chapters. For example, the heart takes on its characteristic four-chambered appearance in just under two months.³ After five or so months, the entire group of cells starts to move. During the third trimester, the cerebral cortex of the brain undergoes dramatic surface expansion and folding.⁴ By seven months, the fetus can process perceptual information, such as sound.⁵ By nine, this group of cells has grown so diverse and so big and so intricate that it starts breathing for itself as it enters a world teeming with unfamiliar sounds, bright lights, and bold sensations.

By adulthood, we are talking about tens of trillions of cells, each around a hundredth of a millimeter across.⁶ If each cell were the size of a person, the adult body would measure a couple of hundred miles from head to toe. From the viewpoint of arguably the most important single cell of all, the fertilized egg, the choreography that leads to this vast yet intricately organized group of cells is nothing short of astounding: How do all these brainless cells coordinate their actions to create a sentient being?

A big part of my motivation to study the beginning of this cellular odyssey is pure curiosity, typical of any scientist, a passion to understand how we came to be and the extraordinary way we build ourselves. But I’m also motivated because this knowledge can pave the way for development of new tests and treatments to tackle real problems that affect people’s lives. I don’t believe we should be defined by gender but rather by the imprint we leave on the world. However, as a scientist who’s also a woman and mother, I’ve discovered firsthand why we need a deeper and broader understanding of the details of human development.

EDGES OF CREATION

So far, we have viewed the creation of a new life from a human perspective, in which scientists like me interpret the behavior of cells in a developing embryo as best we can, thereby enabling clinicians to help an infertile couple have a child and doctors to find insights into a multitude of disorders and devise treatments for some of them too.

But there is a much broader context to the dance of life, where we can view the choreography of a living thing in the most basic terms—the space and time it occupies, the blocks of matter from which it is built, the way it responds to information passed down through generations, and the creation and loss of symmetry to establish form.

If we set the dance in the biggest context, we now know that the time and space required to create a body were born in the big bang some 13.8 billion years ago. As the universe cooled, conditions became just right to give rise to the matter required for life, along with the stuff to build us.

You and I and everyone else exist because the moment of creation was lopsided. As the universe cooled, particles and antiparticles annihilated in pairs, but some kind of asymmetry between matter and antimatter meant that a tiny portion of matter—about one particle per billion—managed to persist. Without this violation of symmetry near the moment of creation, the universe would contain nothing but leftover energy.

But to begin a new life, specific kinds of matter are required. Every one of our cells contains 100 trillion atoms, from light elements that emerged after the big bang to heavier ones made within the hearts of stars by colliding neutron stars and other violent cosmic events.⁷ For our bodies to function, the atoms we have inherited from the universe have to present themselves in the right number and right type and have to be arranged in a precise way. In other words, to create a life we also need information to build a body.

Early insights into the instructions of life came from the physicist Erwin Schrödinger, who in 1943 speculated that the body contained a “code-script” to determine the entire pattern of the individual’s future development. This code was not a blueprint, which suggests a static arrangement of atoms, but hereditary information to create a living body that is dynamic and intricate.

Some scientists were critical (“more fiction than science”) of the significance of What Is Life? The Physical Aspect of the Living Cell, the book in which Schrödinger had outlined his ideas.⁸ But his thinking inspired many scientists and among them were Francis Crick and Jim Watson, who uncovered the molecular structure of that code-script in 1953 in their lab at the University of Cambridge, building upon the key x-ray studies of DNA by Rosalind Franklin and Maurice Wilkins in London.⁹ Within the twists and turns of the double helix lie many secrets of our inheritance, notably the genes that control development.

The double helix can unzip down the middle and each side can serve as a template for the other, so that DNA’s information can be passed to the next generation. While the elements required to make DNA can be found in the aftermath of exploding stars, the order of letters in this genetic code is a blend of the instructions passed through the generations, from our ancestors, which we can pass on to our own children.

All living things on Earth are recent links in a chain of information encoded in the replicating molecule DNA, which itself has been multiplying on Earth for some four billion years. Perhaps the first duplications of the first life emerged in deep-sea hydrothermal vents, aided by amino acids from the ocean crust.¹⁰ But there are many theories and, ultimately, this is yet another blurred edge to life’s great story: it remains a mystery how this self-replicating DNA emerged to seed the instructions that evolved into the teeming multitudes of creatures on Earth, first as formless, unicellular life and later the riot of multicellular life around us.

There is yet another dimension to life. The DNA instructions we pass on to our children do not hold a precise plan, like an architect’s blueprint, but a recipe for their ingredients to self-organize in a remarkably coherent way. These instructions kick in during the first few days, beginning a process where a fertilized egg divides and changes to such an extent that these early phases of an embryo’s life are given different names: zygote, morula, blastocyst, and—finally—embryo proper.

Like the cosmos, our lives are shaped by symmetry and its violation, from subtle biases within an individual cell to laying down an axis in a group of cells around which the embryo organizes. Ultimately, symmetry breaking shapes your whole body, from the location of your head and toes to the position of your organs, from the symmetric location of lungs and kidneys to the way the heart is on the left. All this, in turn, derives from asymmetries on the molecular scale.

Symmetry breaking is essential to shape many of the most dramatic phases of our development. Due to symmetry breaking, we change as we develop from a rounded fertilized egg to, after five days, a hollow structure of around two hundred cells, measuring one- or two-tenths of a millimeter across. At that point, the embryo is ready to implant into the wall of the uterus. There, the boundary of one life merges with another. The poet and philosopher Samuel Taylor Coleridge once remarked that the nine months preceding a birth “would, probably, be far more interesting… than all the three score and ten years that follow it.”¹¹ I think the same may well be true when it comes to the first nine days of development.

There are many mysteries that remain in the steps leading to that exquisite pattern of matter that we call a body. Perhaps this should come as no surprise, as the human might well be more complex than the vast structures of light and dark we call the cosmos.¹²

This is the story of my science and my journey to understand how cells in the early embryo arise, how they start to recognize and interact with one another, how they organize step by step to form us with stunning precision, how they direct their own development, how they sense when this process goes wrong, and how we can detect this and determine the reasons why.

There has to be some kind of clock for important events in development to happen on time and in the right sequence, but how does this cellular timepiece work? In other words, what mechanism does an embryo use to mark the passing hours and days? Why, after two and a half days, do all cells develop different ends, so-called outside-inside polarity? Why does a pregnancy take nine months rather than five or a year? Within a developing embryo, that most basic unit of life, the cell, multiplies and changes in a way that is highly choreographed in space and time. Can we understand this most stunning, intricate, and overpowering dance of life?

These are just a few of the questions prompted by research at the current boundaries of scientific understanding, all utterly fascinating. Despite my best efforts and those of many other scientists, there is a limit to what we have managed to answer so far. Even so, we—as a field—have made dramatic progress in recent years.